oxyntomodulin and semaglutide

Semaglutide is a glucagon-like peptide-1 receptor agonist that was recently approved by the US Food and Drug Administration for chronic weight management. This paper reviews data on the mechanism of action, weight-loss and cardiometabolic efficacy, and safety of semaglutide 2.4 mg/week for obesity. Semaglutide has demonstrated the largest weight loss of any obesity medication to date with reductions of approximately 15% of initial weight at 68 weeks, accompanied by improvements in cardiovascular risks factors and physical functioning. The approval of this medication provides patients with greater options for weight management.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity; Weight Loss

What is this summary about? This is a plain language summary of the STEP TEENS research study, which was originally published in the

Topics: Adolescent; Body Mass Index; Glucagon-Like Peptides; Humans; Obesity; Randomized Controlled Trials as Topic; Treatment Outcome; Weight Loss

The efficacy of once-weekly (O.W.) semaglutide for the treatment of type 2 diabetes mellitus (T2DM) has been demonstrated in clinical trials. The aim of this systematic literature review was to summarize real-world evidence for O.W. semaglutide.. A comprehensive search of PubMed, Web of Science, Embase, and Scilit databases was performed from January 2017 to June 2022 to identify eligible real-world studies examining O.W. semaglutide in T2DM.. Thirty-one records (18 full-text and 13 abstracts) were identified. The general characteristics of studies and included patients were summarized. Changes in glycated hemoglobin (HbA1c) and body weight were analyzed across studies and according to patient characteristics: baseline HbA1c/weight level, GLP-1 RA-naïve/ GLP-1RA-experienced. The effectiveness of O.W. semaglutide compared with dulaglutide, and the dose of O.W. semaglutide in the real world were also summarized.. This systematic literature review provided complementary evidence to findings from the clinical trials and provided a more comprehensive picture of the use of O.W. semaglutide in routine clinical practice. Results of the review suggested that O.W. semaglutide therapy was associated with improving glycemic control and weight loss in both T2DM patients naïve to GLP-1RA and those previously treated with other GLP-1RA in routine clinical practice.. CRD42022306164.

Topics: Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Treatment Outcome

The history of multiple weight loss medications has been a concerning paradox based on an increased cardiovascular risk despite significant reductions in adipose tissue and weight. A new class of weight loss medications could change this past narrative based on early preliminary results of cardiovascular risk (not events-still need to be determined) and weight reduction in non-diabetics that acutely competes with results achieved with bariatric surgery. The purpose of this review is to provide a comprehensive summary of the advantages and disadvantages of these newer medications, and how they could impact urology.. Weight loss of - 15 to - 20% compared to baseline has become plausible in the short-term and preliminary guidance to reduce acute and chronic adverse events are receiving attention. However, the cost, access, conflicts of interest, supply chain, life-long adherence issues, and the long-term diverse implications on mental and physical health when exposed to this class of medications (GLP-1 agonists) are unknown. The profound caloric reductions should also result in baseline or ongoing nutritional deficiency testing, and general and specific dietary recommendations, which could theoretically mimic some bariatric surgery pre- and post-surgical protocols but has yet to be studied. Regardless, the potential impact of these medicines within a variety of medical specialties needs clinical research. Current and future lifestyle interventions, dietary patterns, and medicines in the weight loss category need to be held to a paradigm whereby cardiovascular health should improve with significant weight loss without a negative impact on mental health. In urology, the ability to impact cancer risk, ED, FSD, incontinence, infertility, nephrolithiasis, and multiple other endpoints are plausible (based on bariatric surgery data) but need preliminary clinical research. Other medicines with a similar or even larger potential impact are in clinical trials, and thus, a concise overview for clinicians and researchers was needed for objective guidance. Currently, comprehensive lifestyle changes utilized with and without these medications continue to garner positive mental, physical, and legacy effects, which suggest that they are as necessary as ever in the treatment of the numerous conditions impacted by unhealthy weight gain.

Topics: Glucagon-Like Peptides; Humans; Obesity; Weight Loss

This systematic review and meta-analysis was conducted to evaluate the efficacy and safety of 24 weeks of semaglutide treatment in patients with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).. PubMed, Embase, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov databases were searched for relevant studies. The primary outcome was the change in the serum alanine transaminase level. The secondary outcomes were changes in liver stiffness, liver function test parameters, metabolic parameters, and safety. Pooled mean differences and relative risks were calculated using random-effects models.. Six hundred studies were screened and eight were included (n = 2413). Semaglutide treatment showed a reduction in serum alanine transaminase [mean difference: 14.07 U/L (95% CI: 19.39 to -8.75); p < 0.001] and aspartate transaminase [mean difference: 6.89 U/L (95% CI: 9.14 to -4.63); p < 0.001] levels. There was a significant improvement in liver fat content [mean difference: 4.97% (95% CI: 6.65 to -3.29); p < 0.001] and liver stiffness [mean difference: 0.96 kPa (95% CI: 1.87 to -0.04); p = 0.04]. There were significant improvements in the glycated hemoglobin level and the lipid profile. However, the risk of serious adverse events [relative risk: 1.54 (95% CI: 1.02 to 2.34); p = 0.04] was high following semaglutide treatment as compared to placebo; the most common ones were gastrointestinal (nausea and vomiting, dyspepsia, decreased appetite, constipation, and diarrhea) and gallbladder-related diseases.. Treatment with 24 weeks of semaglutide could significantly improve liver enzymes, reduce liver stiffness, and improve metabolic parameters in patients with NAFLD/NASH. However, the gastrointestinal adverse effects could be a major concern.

Topics: Alanine Transaminase; Glucagon-Like Peptides; Humans; Liver; Non-alcoholic Fatty Liver Disease

Semaglutide (▼Ozempic solution for injection, ▼Rybelsus tablets-Novo Nordisk) was initially granted market authorisation for the treatment of type 2 diabetes as an adjunct to diet and exercise. In 2021 and 2022, regulatory agencies in the USA and Europe licensed semaglutide (▼Wegovy solution for injection-Novo Nordisk) for the treatment of individuals who are obese, or overweight and who have at least one weight-related comorbidity. Manufacturer-sponsored randomised controlled trials have shown a loss of almost 12% of body weight over a 68-week period, however, once the medication is stopped people regain most of their pretreatment weight. Gastrointestinal adverse events occur commonly with semaglutide, and pancreatitis, diabetic retinopathy and severe allergic reactions have also been reported. Extensive hype in social and general media has resulted in increased demand for semaglutide leading to supply problems across the various licensed products including those used for treatment of diabetes. In the UK, the National Institute for Health and Care Excellence has recommended semaglutide as an option for weight management for a maximum treatment duration of 2 years. Further studies are underway to assess the effect of semaglutide on longer-term health benefits.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity

In the incretin system, Glucagon-like peptide-1 (GLP-1) is a hormone that inhibits the release of glucagon and regulates glucose-dependent insulin secretion. In type 2 diabetes, correcting the impaired incretin system using GLP-1 agonist is a well-defined therapeutic strategy.. This review article aims to discuss the mechanism of action, key regulatory events, clinical trials for glycaemic control, and comparative analysis of semaglutide with the second-line antidiabetic drugs.. Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist with enhanced glycaemic control in diabetes patients. In 2019, USFDA approved the first oral GLP-1 receptor agonist, semaglutide, to be administered as a once-daily tablet. Further, recent studies highlight the ability of semaglutide to improve Glycemic control in obese patients with a reduction in body weight. Still, in clinical practice, in the type 2 DM treatment paradigm, the impact of oral semaglutide remains unidentified. This review article discusses the mechanism of action, pharmacodynamics, key regulatory events, and clinical trials regarding glycaemic control.. The review highlights the comparative analysis of semaglutide with the existing second- line drugs for the management of type 2 diabetes mellitus by stressing its benefits and adverse events.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Incretins

To review the pharmacology, efficacy, and safety of high-dose once-weekly semaglutide for chronic weight management.. PubMed/MEDLINE and ClinicalTrials.gov were searched (inception to September 8, 2021) using keywords "semaglutide" and "obesity," "weight," "high dose," "high-dose," or "2.4.". Clinical trials with published results were included. Publications studying the oral or <2.4 mg formulation of semaglutide were excluded.. Four phase 3, multicenter, randomized, double-blind trials demonstrated efficacy of high-dose once-weekly semaglutide compared with placebo for weight loss. Study populations included patients with overweight or obesity (STEP 1, STEP 3, and STEP 4) or patients with diabetes and with overweight or obesity (STEP 2). Lifestyle interventions for diet and exercise were included for all participants. Weight loss from baseline was significant for all studies, and secondary outcomes demonstrated cardiometabolic improvements including waist circumference, systolic blood pressure, and lipid profiles. Gastrointestinal adverse effects were common, but the medication was otherwise well tolerated.. High-dose semaglutide offers significant weight-lowering potential and favorable effects on cardiometabolic risk factors and glycemic indices. Clinicians and patients should consider the route and frequency of administration, adverse effect profile, and cost when choosing an antiobesity medication. The importance of concomitant lifestyle interventions should be emphasized.. High-dose once-weekly semaglutide can significantly reduce weight, and although gastrointestinal adverse effects were common, it is generally well tolerated.

Topics: Clinical Trials, Phase III as Topic; Double-Blind Method; Glucagon-Like Peptides; Humans; Multicenter Studies as Topic; Obesity Management; Randomized Controlled Trials as Topic

Obesity is a growing epidemic within the USA. Because weight gain is associated with an increased risk of developing life-threatening comorbidities, such as hypertension or type 2 diabetes, there is great interest in developing non-invasive pharmacotherapeutics to help combat obesity. Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of antidiabetic medications that have shown promise in encouraging glycemic control and promoting weight loss in patients with or without type 2 diabetes. This literature review summarizes and discusses the weight loss results from the SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes), PIONEER (Peptide Innovation for Early Diabetes Treatment), and STEP (Semaglutide Treatment Effect in People with Obesity) clinical trial programs. The SUSTAIN and PIONEER clinical trials studied the use of 1.0 mg, once-weekly, subcutaneous and oral semaglutide (a new GLP-1 homolog), respectively, on participants with type 2 diabetes. The STEP trial examined the effects of 2.4 mg, once-weekly, subcutaneous semaglutide on patients with obesity. Trial data and other pertinent articles were obtained via database search through the US National Library of Medicine Clinical Trials and the National Center for Biotechnology Information. All three clinical trials demonstrated that semaglutide (injected or oral) has superior efficacy compared with placebo and other antidiabetic medications in weight reduction, which led to Food and Drug Administration approval of Wegovy (semaglutide) for weight loss.

Topics: Anti-Obesity Agents; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Obesity; Weight Loss

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity; Overweight

Semaglutide is a recently approved glucagon-like peptide-1 receptor agonist used to treat patients with type 2 diabetes mellitus (T2DM). The SUSTAIN 6 trial found a significantly higher rate of retinopathy complications in the semaglutide-treated group compared with the placebo group.. This study aimed to evaluate the association between semaglutide and the risk of retinopathy in patients with T2DM.. Electronic databases were systematically searched up to April 2021 to identify randomized controlled trials that reported diabetic retinopathy (DR) events in semaglutide-treated and control groups. A meta-analysis was conducted using Review Manager 5.4 software to calculate the risk ratio (RR) and 95% confidence intervals (CIs).. A total of 23 randomized trials involving 22,096 patients with T2DM were included. There were 730 incident DR cases-463 in the semaglutide group and 267 in the control group. Overall, semaglutide was not associated with increased DR risk compared with controls when all trials were combined (RR 1.14, 95% CI 0.98-1.33). Subgroup analysis showed that semaglutide was associated with an increased risk of DR compared with placebo (RR 1.24, 95% CI 1.03-1.50). Moreover, patient age ≥ 60 years and diabetes duration ≥ 10 years were also factors for increased risk of DR when using semaglutide (RR 1.27, 95% CI 1.02-1.59; RR 1.28, 95% CI 1.04-1.58, respectively).. Semaglutide was not associated with an increased risk of DR; however, caution regarding DR risk is needed for older patients or those with long diabetes duration when taking semaglutide.

Topics: Diabetes Mellitus, Type 2; Diabetic Retinopathy; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Middle Aged; Randomized Controlled Trials as Topic

Currently, no head-to-head data are available comparing semaglutide 2.0 mg with dulaglutide 3.0 mg or 4.5 mg. We conducted an indirect treatment comparison (ITC) of their effects on glycated hemoglobin (HbA1c) and body weight in patients with type 2 diabetes.. Multilevel network meta-regression was conducted, based on a connected evidence network of published results from the A Study of the Efficacy and Safety of Dulaglutide (LY2189265) in Participants With Type 2 Diabetes 11 trial and individual patient data from the A Research Study to Compare Two Doses of Semaglutide Taken Once Weekly in People With Type 2 Diabetes (SUSTAIN) and SUSTAIN 7 trials.. Semaglutide 2.0 mg significantly reduced HbA1c vs dulaglutide 3.0 mg and 4.5 mg, with estimated treatment differences (ETDs) of -0.44% points (95% credible interval [CrI], -0.68 to -0.19) and -0.28% points (95% CrI, -0.52 to -0.03), respectively. Semaglutide 2.0 mg also significantly reduced body weight vs dulaglutide 3.0 mg and 4.5 mg with ETDs of -3.29 kg (95% CrI, -4.62 to -1.96) and -2.57 kg (95% CrI, -3.90 to -1.24), respectively. Odds of achieving HbA1c < 7.0% were significantly greater for semaglutide 2.0 vs dulaglutide 3.0 mg (odds ratio [OR]: 2.23 [95% CrI, 1.15-3.90]), whereas this did not reach significance for semaglutide 2.0 mg vs dulaglutide 4.5 mg (OR: 1.58 [95% CrI, 0.82-2.78]). Sensitivity analyses supported the main analysis findings.. This ITC demonstrated significantly greater reductions from baseline in HbA1c and body weight with semaglutide 2.0 mg vs dulaglutide 3.0 mg and 4.5 mg. The findings of this study provide important comparative effectiveness information until randomized head-to-head studies become available.

Topics: Body Weight; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins

The purpose of this review paper is to review the efficacy and safety of subcutaneous semaglutide, marketed as Wegovy, a glucagon-like peptide-1 receptor agonist for obesity management.. A MEDLINE search (1970 to June 2021) was conducted to identify Phase 3 trials of subcutaneous semaglutide for obesity management. Published Phase 3 trials from The Semaglutide Treatment Effect in People with obesity (STEP) program were reviewed and summarized.. Based on four Phase 3 trials, subcutaneous semaglutide as 2.4 mg once weekly was compared in efficacy and safety among 5000 randomized participants who were overweight or had obesity. A change in body weight from baseline to end of study was the primary outcome in the STEP program. Participants who received semaglutide had a dose-dependent reduction in body weight from baseline, compared to placebo. Higher percentages of participants had 5%-10% weight reduction from baseline when receiving subcutaneous semaglutide. The patient population was mainly middle-aged female participants with Class II obesity. Additional studies are needed, especially active-comparator trials, to determine the efficacy and safety of semaglutide in a diverse patient population.. Subcutaneous semaglutide is another available option as adjunct therapy to lifestyle modifications for people who are overweight or have obesity based on body weight and body mass index. It resulted in more weight reduction than placebo with gastrointestinal adverse events being the most common safety concerns. Clinical utilization of subcutaneous semaglutide will be determined, as insurance coverage will be a limitation for this new medication.

Topics: Adult; Body Mass Index; Body Weight; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Injections, Subcutaneous; Male; Middle Aged; Obesity; Overweight; Randomized Controlled Trials as Topic; Weight Loss

This meta-analysis aimed to assess the efficacy and safety of once-weekly semaglutide among adults with overweight or obesity.. We searched multiple electronic databases for randomized controlled trials that compared once-weekly semaglutide versus placebo in adults with overweight or obesity. The primary outcomes were the percentage change and absolute change in body weight. Secondary outcomes included achievement of categorical weight loss targets (at least 5, 10, 15, or 20%), cardiometabolic risk profiles, and health-related quality of life.. This meta-analysis included a total of four trials with 3447 patients. Once-weekly semaglutide was superior to placebo in terms of the percentage change and absolute change in body weight. Compared with placebo, once-weekly semaglutide also led to significant increases in the proportions of achievement of categorical weight reduction targets. Moreover, once-weekly semaglutide induced superior reductions in waist circumference and body-mass index compared with placebo. Furthermore, the effect on improving other cardiometabolic risk factors and health-related quality of life was more pronounced for once-weekly semaglutide relative to placebo.. Among adults with overweight or obesity, once-weekly semaglutide could result in clinically meaningful weight loss, which was a promising therapy for treating overweight or obesity.

Topics: Adult; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity; Overweight; Quality of Life

Semaglutide, a glucagon like peptide-1 (GLP-1) receptor agonist, is available as monotherapy in both subcutaneous as well as oral dosage form (first approved oral GLP-1 receptor agonist). It has been approved as a second line treatment option for better glycaemic control in type 2 diabetes and currently under scrutiny for anti-obesity purpose. Semaglutide has been proved to be safe in adults and elderly patients with renal or hepatic disorders demanding no dose modification. Cardiovascular (CV) outcome trials established that it can reduce various CV risk factors in patients with established CV disorders. Semaglutide is well tolerated with no risk of hypoglycaemia in monotherapy but suffers from gastrointestinal adverse effects. A large population affected with COVID-19 infection were diabetic; therefore use of semaglutide in diabetes as well as CV patients would be very much supportive in maintaining health care system during this pandemic situation. Hence, this peptidic drug can be truly considered as a quintessential of GLP-1 agonists for management of type 2 diabetes.

Topics: Aged; COVID-19 Drug Treatment; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Cardiovascular disease is the most common cause of morbidity and mortality worldwide, and the risk is heightened in the presence of obesity. We review semaglutide, a drug recently approved for chronic weight management in adults with obesity or who are overweight.. On 4 June 2021, the US Food and Drug Administration approved semaglutide injection at 2.4 mg once weekly for chronic weight management in adults with obesity or overweight with at least one weight-related condition such as high blood pressure, type 2 diabetes mellitus, or high cholesterol. This subcutaneous injection is the first approved drug for chronic weight management in adults with general obesity or overweight since 2014. The drug is indicated for weight management in patients with a BMI of 27 kg/m2 or greater who have at least one weight-related ailment or in patients with a BMI of 30 kg/m2 or greater.. Semaglutide offers adults with obesity or overweight a new treatment in conjunction with a weight management program consisting of reduced calorie diet and increased physical activity.

Topics: Adult; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity; Overweight; Risk Reduction Behavior; Weight Loss

Obesity is an important risk factor of type 2 diabetes (T2D), which has become an important factor threatening human health. However, no perfect drug choice for obesity exists. Semaglutide is a kind of human glucagon-like peptide-1 (GLP-1) analog that promotes insulin secretion while inhibiting glucagon secretion through a glucose concentration-dependent mechanism. GLP-1 can also delay stomach emptying and suppress appetite to help lose weight. This review summarizes clinical evidence of the semaglutide effect on T2D and obesity and establishes expectations on future clinical trials for obesity treatment.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Motivation; Obesity

Oral semaglutide is the first glucagon-like petide-1 receptor agonist (GLP-1RA) approved for oral use in the treatment of type 2 diabetes mellitus (T2DM). We aim to conduct a comprehensive review of literature to find out the efficacy and safety of oral semaglutide in T2DM, to lay out a clinical consideration for its use in India.. We searched the electronic database of PubMed and Google Scholar from inception until January 31, 2022, using several MeSH keywords and retrieved all available granular details of phase 1, 2 and 3 randomized controlled trials (RCTs) of oral semaglutide. Subsequently, we reviewed the results critically to lay down the clinical recommendation of its use.. Ten phase 3 randomized, placebo- and or active-controlled studies of oral semaglutide (PIONEER programs) are currently published. Seven global trials of oral semaglutide (PIONEER 1-5, 7 and 8) that exclusively studied the efficacy (lowering of HbA1c and body weight, achieving target of HbA1c <7% and other composites of HbA1c and weight) outcomes, found 14 mg oral semaglutide to be superior to placebo or active comparators (empagliflozin, sitagliptin and liraglutide). Efficacy was similar in Asians, although no separate data exists for Indians due to the low number of participants. Expectedly, gastrointestinal intolerance were the most commonly observed side effects with oral semaglutide and the main reason for drug discontinuation.. Oral semaglutide 14 mg is an effective agent in the treatment of T2DM. Real-world studies of semaglutide are clearly needed in India in absence of meaningful data from RCTs in Indians.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide

Cardiovascular outcome trials (CVOTs) are conducted on a background of standard of care including metformin. These analyses sought to determine whether the cardiovascular (CV) effects of semaglutide and other glucagon-like peptide-1 receptor agonists (GLP-1RAs) vary according to baseline metformin use.. A post hoc analysis was conducted using pooled SUSTAIN 6 and PIONEER 6 CVOT data in subjects with and without metformin use at baseline. Additionally, a trial-level meta-analysis was conducted using data from seven CVOTs with GLP-1RAs-SUSTAIN 6, PIONEER 6, HARMONY OUTCOMES, LEADER, REWIND, EXSCEL and AMPLITUDE-O-including adults with type 2 diabetes at high CV risk, and a primary endpoint of time to first major adverse CV event (MACE).. In the post hoc analysis, the no-metformin subgroup was older, with a higher body mass index, lower estimated glomerular filtration rate and higher CV risk at baseline vs the metformin subgroup. Hazard ratios (95% confidence intervals) for the reduction in risk of MACE with semaglutide vs placebo in the metformin and no-metformin subgroups were 0.70 (0.55;0.89) and 0.86 (0.60;1.22), respectively. No significant interaction between the treatment effect on MACE and metformin subgroup was observed. Findings for other CV endpoints were similar. In the meta-analysis, treatment effect (GLP-1RA vs placebo) on CV outcomes was no different with vs without baseline metformin (overall ratio between the hazard ratios for metformin vs no-metformin 1.09 [0.96;1.22]).. These findings indicate that the CV outcomes for semaglutide were similar regardless of baseline metformin use, which may also apply to all GLP-1RAs. Trial registration SUSTAIN 6 (NCT01720446), PIONEER 6 (NCT02692716).

Topics: Adult; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Metformin

Aim To determine the antiobesity effect and safety of glucagon-like peptide-1 receptor agonist (GLP-1RA) including liraglutide, exenatide and semaglutide treatment in overweight/obese patients without diabetes. The random-effect model was used to pool data extracted from included literatures. The weighted mean difference (WMD), odds ratio and 95% confidence interval (CI) were used to present the meta-analysis results (PROSPERO registration number: CRD 42020173199). The sources of intertrial heterogeneity, bias and the robustness of results were evaluated by subgroup analysis, sensitivity analysis and regression analysis, respectively. A total of 24 RCTs were recruited in the present analysis which included 5867 patients. The results showed that the treatment of overweight/obese patients without diabetes with GLP-1RAs including liraglutide, exenatide and semaglutide significantly achieved greater weight loss than placebo [WMD=-5.39, 95% CI (-6.82, -3.96)] and metformin [WMD=-5.46, 95% CI (-5.87, -5.05)]. The subgroup analysis showed that semaglutide displayed the most obvious antiobesity effect in terms of weight loss, the reduction of body mass index (BMI) and waist circumference (WC). However, GLP-1RAs treatments had more gastrointestinal adverse events (such as nausea and vomiting) than placebo and Met. The subgroup analysis also represented that semaglutide displayed the lowest risk of gastrointestinal adverse events among three kinds of GLP-1RAs. Our meta-analysis demonstrated that GLP-1RA had a superior antiobesity effect than placebo/Met in overweight/obese patients without diabetes in terms of body weight, BMI, and WC, especially for semaglutide, which had more obvious antiobesity effect and lower GI adverse events than liraglutide and exenatide.

Topics: Anti-Obesity Agents; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Weight Loss

Topics: Glucagon-Like Peptides; Humans; Obesity; Overweight

To assess the safety and efficacy of semaglutide compared with placebo and other anti-hyperglycaemic agents in type 2 diabetes (T2DM).. We searched PubMed, Scopus, Web of Science, and Cochrane library for relevant randomized controlled trials (RCTs). A network meta-analysis was conducted to compare different doses, durations, and interventions in T2DM. We presented results as mean difference (MD) or relative risk (RR) and 95% confidence interval (CI).. Twenty-six included RCTs studied different doses of subcutaneous (SC) and oral semaglutide, tirzepatide, liraglutide, sitagliptin, canagliflozin, and empagliflozin compared with placebo. Tirzepatide showed the highest efficacy, however, it was comparable to semaglutide. SC semaglutide 1 mg once-weekly showed higher reduction in HbA. Tirzepatide, oral and SC semaglutide has a favourable efficacy in treating T2DM. The adverse events were comparable to placebo; however, gastrointestinal adverse events were highly recorded in tirzepatide, oral and SC semaglutide groups.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Network Meta-Analysis; Sitagliptin Phosphate

Semaglutide, a peptidic GLP-1 receptor agonist, has been clinically approved for treatment of type 2 diabetes mellitus and is available in subcutaneous and oral dosage form. Diabetes, insulin resistance, and obesity are responsible for the pathological manifestations of non-alcoholic steatohepatitis (NASH). Similarly, insulin resistance in brain is also responsible for neurodegeneration and impaired cognitive functions.. Observations from phase-3 clinical trials like SUSTAIN and PIONEER indicated anti-obesity potential of semaglutide, which was established in STEP trials. Various pre-clinical and phase-2 studies have indicated the therapeutic potential of semaglutide in non-alcoholic steatohepatitis and neurodegenerative disorders like Parkinson's and Alzheimer's disease.. Significant weight reduction ability of semaglutide has been demonstrated in various phase-3 clinical trials, for which recently semaglutide became the first long-acting GLP-1 receptor agonist to be approved by the United States Food and Drug Administration for management of obesity. Various pre-clinical and clinical studies have revealed the hepatoprotective effect of semaglutide in NASH and neuroprotective effect in Parkinson's and Alzheimer's disease.. Many GLP-1 receptor agonists have shown hepatoprotective and neuroprotective activity in animal and human trials. As semaglutide is an already clinically approved drug, successful human trials would hasten its inclusion into therapeutic treatment of NASH and neurodegenerative diseases. Semaglutide improves insulin resistance, insulin signalling pathway, and reduce body weight which are responsible for prevention or progression of NASH and neurodegenerative diseases.

Topics: Alzheimer Disease; Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Hypoglycemic Agents; Insulin Resistance; Neurodegenerative Diseases; Non-alcoholic Fatty Liver Disease; Obesity; Parkinson Disease

Despite their established benefits, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) remain underutilized for type 2 diabetes mellitus (T2DM) management, which indicates that subcutaneous injection is an unfavorable mode of delivery from the patient's perspective. This review summarizes existing challenges related to medication adherence and the use of antihyperglycemia injectables, revisits the established safety and efficacy of oral semaglutide, and explores its features and considerations for use among the Indian T2DM population.. We performed a literature search using MEDLINE and the National Institutes of Health Clinical Trials Registry from July 1, 2016, to July 1, 2021, to identify publications on oral semaglutide approval, T2DM treatment guidelines, and clinical evidence for oral drug formulation.. Oral semaglutide is the first oral GLP-1 RA approved for T2DM patients based on phase 3, randomized PIONEER trials. The multitargeted action of this drug offers glycemic control, weight control, and cardiovascular, renal, and additional benefits, including patient convenience and enhanced medication adherence. In addition to achieving glycemic control, the cost of semaglutide is reported to be lower than other GLP-1 RA in the West, thus potentially mitigating the economic burden that appears to be high among the Indian population.. Currently, there is no data available on oral semaglutide in Indian clinical settings. However, significant improvements in glycemic control, cardiac and renal benefits, as well as weight loss across clinical trials should encourage clinicians to prioritize oral semaglutide over other antidiabetic agents.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Obesity is a complex and chronic disease that raises the risk of various complications. Substantial reduction in body weight improves these risk factors. Lifestyle changes, including physical activity, reduced caloric ingestion, and behavioral therapy, have been the principal pillars in the management of obesity. In recent years, pharmacologic interventions have improved remarkably. The Semaglutide Treatment Effect in People with Obesity (STEP) program is a collection of phase-III trials geared toward exploring the utility of once-weekly 2.4 mg semaglutide administered subcutaneously as a pharmacologic agent for patients with obesity. All the STEP studies included diet and exercise interventions but at different intensities. This review paper aims to explore the impact of the behavioral programs on the effect of semaglutide 2.4 mg on weight loss. The results of the STEP trials supported the efficacy of high-dose, once-weekly 2.4 mg semaglutide on body weight reduction among patients with obesity with/without diabetes mellitus. Semaglutide was associated with more gastrointestinal-related side effects compared to placebo but was generally safe and well tolerated. In all the STEP studies, despite the varying intestines of the behavioral programs, weight loss was very similar. For the first time, there may be a suggestion that these behavioral programs might not increase weight reduction beyond the effect of semaglutide. Nevertheless, the importance of nutritional support during substantial weight loss with pharmacotherapy needs to be re-evaluated.

Topics: Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity; Weight Loss

Research on semaglutide's effect on weight loss has been largely focused on Type 2 Diabetics. No meta-analyses of semaglutide's efficacy in non-diabetic individuals have been conducted to date. Expanding the knowledge of semaglutide's outcome in non-diabetics may provide impactful changes at the clinical level.. This systematic review and meta-analysis quantified the efficacy of subcutaneous semaglutide in treating obesity in non-diabetic adult patients compared to placebo.. Academic Search Premier, Cumulative Index to Nursing and Allied Health Literature (CINAHL) complete, MEDLINE with Full Text, Cochrane Central Register of Controlled Trials, medrxiv.org, and clinicaltrials.gov were systematically investigated using a predetermined search strategy from inception to August 21, 2021. Covidence.org was used to screen, select, and extract data by two independent reviewers. Individual study bias was assessed using the Cochrane Risk of Bias 2 tool. Data were exported to RevMan v5.4, where meta-analysis was conducted using a DerSimonian and Laird random-effects model.. The initial search identified 332 relevant articles and ultimately retained four randomized controlled trials encompassing 2,882 participants with a BMI ≥ 27 kg/m. This systematic review and meta-analysis validates the clinical efficacy of semaglutide for the treatment of obesity in the adult, non-diabetic population.

Topics: Adult; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity; Weight Loss

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) were first introduced for the treatment of type 2 diabetes (T2D) in 2005. Despite the high efficacy and other benefits of GLP-1RAs, their uptake was initially limited by the fact that they could only be administered by injection. Semaglutide is a human GLP-1 analog that has been shown to significantly improve glycemic control and reduce body weight, in addition to improving cardiovascular outcomes, in patients with T2D. First approved as a once-weekly subcutaneous injection, semaglutide was considered an ideal peptide candidate for oral delivery with a permeation enhancer on account of its low molecular weight, long half-life, and high potency. An oral formulation of semaglutide was therefore developed by co-formulating semaglutide with sodium N-(8-[2-hydroxybenzoyl]amino)caprylate, a well-characterized transcellular permeation enhancer, to produce the first orally administered GLP-1RA. Pharmacokinetic analysis showed that stable steady-state concentrations could be achieved with once-daily dosing owing to the long half-life of oral semaglutide. Upper gastrointestinal disease and renal and hepatic impairment did not affect the pharmacokinetic profile. In the phase III PIONEER clinical trial program, oral semaglutide was shown to reduce glycated hemoglobin and body weight compared with placebo and active comparators in patients with T2D, with no new safety signals reported. Cardiovascular efficacy and safety are currently being assessed in a dedicated outcomes trial. The development of an oral GLP-1RA represents a significant milestone in the management of T2D, providing an additional efficacious treatment option for patients.

Topics: Body Weight; Caprylates; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Peptides; Sodium

This final article in the supplement aims to summarize a clinical approach for weight management geared toward primary care practitioners, offering practical advice about how to integrate weight management into day-to-day practice. To achieve long-term successful weight loss, a comprehensive multimodal approach is recommended, focusing on both lifestyle modification and appropriate use of therapy. Once-weekly subcutaneous semaglutide 2.4 mg is a novel treatment that can be used as an adjunct to lifestyle modification for the management of overweight and obesity. Key considerations are presented to support its optimal administration in conjunction with lifestyle modification, with a focus on assessing suitability and the importance of dose escalation and monitoring.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity Management; Primary Health Care

Obesity negatively impacts patients' health-related quality of life (QOL) and is associated with a range of complications such as type 2 diabetes (T2D), cardiovascular disease, and sleep apnea, alongside decreased physical function, mobility, and control of eating. The Semaglutide Treatment Effect in People with obesity (STEP) trials compared once-weekly subcutaneous semaglutide 2.4 mg with placebo in adults with overweight or obesity, with or without T2D. This article reviews the effects of semaglutide 2.4 mg on QOL, control of eating, and body composition. Weight-related QOL was assessed using the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT), and health-related QOL was assessed with the 36-item Short Form Health Survey version 2 (SF-36v2®). Control of eating was evaluated using the Control of Eating questionnaire in a subgroup of participants in one trial. Body composition was evaluated via dual-energy x-ray absorptiometry in another trial, in a subgroup of participants with a body mass index of ≤40 kg/m

Topics: Adult; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity; Quality of Life

Obesity is a global health challenge. It is a multifactorial, complex, and progressive disease associated with various health complications and increased mortality. Lifestyle modifications are central to weight management but may be insufficient to maintain clinically meaningful weight loss. Pharmacotherapies are recommended as an adjunct to lifestyle interventions to induce and sustain clinically meaningful weight loss and reduce the risk of comorbidities in appropriate patients. Glucagon-like peptide-1 is an incretin metabolic hormone responsible for a range of physiological effects, including glucose and appetite regulation. Several glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been approved for the treatment of type 2 diabetes since 2005 including exenatide (short- and extended-release), lixisenatide, liraglutide, dulaglutide, albiglutide, and semaglutide. Of these, semaglutide (subcutaneous) and liraglutide are currently US Food and Drug Administration (FDA)-approved for chronic weight management in patients with or without diabetes. The phase 3 Semaglutide Treatment Effect in People with obesity (STEP) program was designed to investigate the effect of semaglutide versus placebo on weight loss, safety, and tolerability in adults with overweight or obesity. Following the submission of the results of the STEP 1-4 trials, the FDA approved once-weekly subcutaneous semaglutide 2.4 mg for chronic weight management in people with overweight or obesity in April 2021. Data from the program demonstrated that semaglutide (2.4 mg once weekly) achieved significant and sustained weight loss, together with improvements in cardiometabolic risk factors compared with placebo, and was generally well tolerated, with a safety profile consistent with other GLP-1RAs. The most common adverse events reported in STEP 1-5 were gastrointestinal events, which were transient, mild-to-moderate in severity, and typically resolved without permanent treatment discontinuation. This article reviews the data from STEP 1-5 and highlights clinically relevant findings for primary care providers.

Topics: Adult; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Obesity; Overweight; Weight Loss

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Injections, Subcutaneous; Nausea; Weight Loss

The gastrointestinal tract secretes gut hormones in response to food consumption, and some of these stimulate insulin secretion. Glucagon-like peptide-1 (GLP-1) is an incretin peptide hormone released from the lower digestive tract that stimulates insulin secretion, suppresses glucagon secretion, and decreases hunger. GLP-1 receptor agonist (GLP-1RA) mimics the action of endogenous GLP-1, consequently reversing hyperglycemia and causing weight reduction, demonstrating its efficacy as an antidiabetic and antiobesity agent. Previously restricted to injection only, the invention of the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino) caprylate resulted in the development of oral semaglutide, the first ingestible GLP-1RA. Oral semaglutide demonstrated its efficacy in glycemic management and body weight loss with a low risk of hypoglycemia as a monotherapy and in combination with other hypoglycemic medications in its clinical trial programs named Peptide Innovation for Early Diabetes Treatment. Consistent with other injectable GLP-1RAs, gastrointestinal side effects were often reported. Additionally, cardiovascular safety was established by demonstrating that oral semaglutide was not inferior to a placebo in terms of cardiovascular outcomes. Thus, oral semaglutide represents a novel treatment option that is particularly well-suited for patients with type 2 diabetes and/or obesity.

Topics: Administration, Oral; Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Treatment Outcome

To estimate the incremental cost-utility ratio of oral semaglutide (14 mg once daily) vs other glucagon-like peptide 1 receptor agonist treatments among adults with type 2 diabetes that was inadequately controlled with 1 to 2 oral antidiabetic drugs from a US payer perspective.. A state-transition model with a competing risk approach was developed for diabetic complications and risk of cardiovascular events based on the UK Prospective Diabetes Study Outcomes Model 1 equations. Baseline population characteristics reflect the PIONEER 4 trial (Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus) of oral semaglutide. Model comparators included subcutaneous semaglutide, dulaglutide, and liraglutide. Treatment effects (change in glycosylated hemoglobin, weight, and systolic blood pressure) were estimated by network meta-analysis. Drug, management, and event costs (in 2019 US dollars), survival after nonfatal events, and utilities were obtained from the literature. Costs and quality-adjusted life-year (QALY) outcomes were discounted at 3% annually over a lifetime horizon. Probabilistic and 1-way sensitivity analyses were performed.. Total estimated costs and QALYs were $144,065 and 12.98 for oral semaglutide, $145,721 and 12.96 for dulaglutide, $145,833 and 12.99 for SC semaglutide, and $149,428 and 12.97 for liraglutide, respectively. Oral semaglutide was less costly and more effective than dulaglutide and liraglutide but less costly than subcutaneous semaglutide with similar effectiveness. Oral semaglutide was favored versus subcutaneous semaglutide in 52.10% of model replications at a willingness-to-pay of $150,000 per QALY.. Oral semaglutide is predicted to offer health benefits similar to subcutaneous semaglutide and ahead of dulaglutide and liraglutide. Oral semaglutide is a cost-effective glucagon-like peptide 1 receptor agonist treatment option.

Topics: Adult; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Prospective Studies; Recombinant Fusion Proteins

Cardiovascular events related to atherosclerosis are responsible for high morbidity and mortality among patients with type 2 diabetes. Improvement in care, especially in early stages, is crucial. Oral semaglutide, a glucagon-like peptide 1 analogue, controls blood glucose and results in significant body weight loss in patients with type 2 diabetes. Beyond these well-known effects, an interesting aspect of this drug is its antiatherogenic activity, which should be further explored in clinical practice. This paper reviews the evidence related to oral semaglutide decreasing cardiovascular risk in patients with type 2 diabetes, focusing on the drug's antiatherosclerotic properties. The glucagon-like peptide 1 analogue restores endothelial dysfunction, induces vasodilatation, and reduces plasma lipids. Oral semaglutide showed cardiovascular safety profile, with significant reduced risk of death from cardiovascular events. Based on current data, clinicians should consider oral semaglutide for type 2 diabetes management.

Topics: Administration, Oral; Animals; Atherosclerosis; Biomarkers; Blood Glucose; Cause of Death; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycemic Control; Humans; Hypoglycemic Agents; Incretins; Risk Assessment; Risk Factors; Treatment Outcome

GLP-1 receptor agonists (GLP-1RAs) are recommended for patients with type 2 diabetes (T2D), particularly those at high cardiovascular risk. Oral semaglutide is the first oral GLP-1RA. In clinical trials, oral semaglutide 14 mg reduced mean HbA

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Primary Health Care

Glucagon-like peptide-1 receptor (GLP-1R) agonists are approved to treat type 2 diabetes and obesity. They elicit robust improvements in glycemic control and weight loss, combined with cardioprotection in individuals at risk of or with pre-existing cardiovascular disease. These attributes make GLP-1 a preferred partner for next-generation therapies exhibiting improved efficacy yet retaining safety to treat diabetes, obesity, non-alcoholic steatohepatitis, and related cardiometabolic disorders. The available clinical data demonstrate that the best GLP-1R agonists are not yet competitive with bariatric surgery, emphasizing the need to further improve the efficacy of current medical therapy.. In this article, we discuss data highlighting the physiological and pharmacological attributes of potential peptide and non-peptide partners, exemplified by amylin, glucose-dependent insulinotropic polypeptide (GIP), and steroid hormones. We review the progress, limitations, and future considerations for translating findings from preclinical experiments to competitive efficacy and safety in humans with type 2 diabetes and obesity.. Multiple co-agonist combinations exhibit promising clinical efficacy, notably tirzepatide and investigational amylin combinations. Simultaneously, increasing doses of GLP-1R agonists such as semaglutide produces substantial weight loss, raising the bar for the development of new unimolecular co-agonists. Collectively, the available data suggest that new co-agonists with robust efficacy should prove superior to GLP-1R agonists alone to treat metabolic disorders.

Topics: Adipose Tissue; Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fatty Liver; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Metabolic Diseases; Obesity; Receptors, Gastrointestinal Hormone; Weight Loss

GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.).. To summarize current knowledge about GLP-1 receptor agonist.

Topics: Animals; Blood Glucose; Body Weight; Cardiovascular System; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemia; Immunoglobulin Fc Fragments; Insulin; Liraglutide; Neurodegenerative Diseases; Peptides; Psoriasis; Recombinant Fusion Proteins

Since the approval of subcutaneous glucagon-like peptide-1 receptor agonists, this therapeutic class has become a preferred choice for the management of type 2 diabetes due to A1C reduction, minimal risk of hypoglycemia, weight loss, and cardiovascular benefit. An oral option, with gastrointestinal absorption, would overcome any potential fear of injection among patients. Oral semaglutide has been studied in randomized controlled trials within the PIONEER program. From a robust pool of literature with a global patient population, oral semaglutide has been an effective option as monotherapy and combination therapy to improve clinical outcomes, such as A1C and body weight from baseline to week 78, depending on the randomized controlled trial. In addition, a noninferiority result was observed with oral semaglutide versus placebo in a cardiovascular outcomes trial in patients with type 2 diabetes with established cardiovascular disease or risk factors. Similar to injectable glucagon-like peptide 1 receptor agonists, transient nausea and vomiting was seen with oral semaglutide. Overall, this new oral option may be a choice for patients with barriers to injectable therapy. This review evaluates and summarizes the pharmacokinetics, pharmacodynamics, and clinical application of oral semaglutide in patients with type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic

Topics: Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Drug Administration Schedule; Economics, Pharmaceutical; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

To evaluate the efficacy and safety of the glucagon-like peptide-1 (GLP-1) receptor agonist (RA) oral semaglutide in the treatment of type 2 diabetes mellitus (T2DM) patients.. Randomized controlled trials comparing oral semaglutide with placebo or other antihyperglycemic agents in T2DM patients were identified by searching PubMed, Embase, Cochrane Library and ClinicalTrials.gov. Risk ratios and mean differences with 95% confidence intervals were used to synthesize the results.. Ten relevant studies involving 8,536 patients were finally included. Compared with placebo, oral semaglutide significantly reduced hemoglobin A1c (HbA1c), body weight, fasting plasma glucose, self-measured plasma glucose (SMPG), serious adverse events and all-cause death and significantly increased the number of participants who achieved HbA1c < 7.0%. Compared with active comparators, oral semaglutide significantly reduced the level of HbA1c, body weight, and SMPG and significantly increased the number of participants who achieved HbA1c < 7.0%. Compared with placebo or active comparators, oral semaglutide did not increase the incidence of adverse events, hypoglycemia (severe or blood glucose-confirmed symptomatic), myocardial infarction, heart failure requiring hospitalization, stroke or acute pancreatitis but did increase the incidence of nausea, diarrhea and vomiting.. Oral semaglutide has favorable efficacy and safety in the treatment of T2DM patients. Oral semaglutide may be superior to liraglutide, dulaglutide, empagliflozin and sitagliptin for T2DM patients who have obesity or poor adherence to injectable GLP-1 RAs.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Middle Aged

Semaglutide is the first peptide to receive European marketing authorization for oral administration in the treatment of type 2 diabetes. The active molecule is the same as the one marketed for weekly subcutaneous administration. It is associated with a new excipient, which protects it from degradation by gastric pepsin and allows its absorption in the stomach. This article presents the pharmacological characteristics of this drug, as well as a critical analysis of the results of the main phase III clinical trials.. Un analogue du glucagon-like peptide 1 (GLP1) administré par voie orale - Une nouveauté dans le traitement du diabète de type 2.. Le sémaglutide est le premier peptide à avoir reçu une autorisation européenne de mise sur le marché, pour une administration quotidienne par voie orale dans le traitement du diabète de type 2. La molécule active est identique à celle qui est déjà commercialisée pour une administration hebdomadaire par voie sous-cutanée. Elle est associée à un nouvel excipent, qui la protège de la dégradation par la pepsine gastrique et permet son absorption dans l’estomac. Cet article présente les caractéristiques pharmacologiques du médicament dans sa nouvelle formulation, ainsi qu’une analyse critique des résultats des principaux essais cliniques de phase III dans lesquels elle a été testée.

Topics: Administration, Oral; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents

There are numerous treatment options currently available for patients with type 2 diabetes mellitus; however, a multitude of patients continue to have inadequately controlled glycemic levels with their current antihyperglycemic regimen. Furthermore, the American Diabetes Association guidelines increasingly highlight the importance of multifactorial management and optimizing medication regimens that include cardiovascular, renal, and/or weight benefits in patients with type 2 diabetes mellitus. Glucagon-like peptide-1 receptor agonists belong to a novel class of type 2 diabetes mellitus agents that are becoming increasingly prevalent owing to their ability to improve glycemic status without the risk of hypoglycemia. Currently, there are three US Food and Drug Administration-approved glucagon-like peptide-1 receptor agonists, subcutaneous semaglutide, dulaglutide, and liraglutide, that also have an indication for reducing major adverse cardiovascular events in patients with type 2 diabetes mellitus and established cardiovascular disease. However, these agents are not often the first options because of their subcutaneous administration. Nevertheless, co-formulation of oral semaglutide with an absorption enhancer has shown to increase its bioavailability and has made its oral absorption possible. In the PIONEER trials, oral semaglutide effectively lowered blood glucose levels, and showed benefits on weight and cardiovascular outcomes; however, there is no Food and Drug Administration indication approved yet as the SOUL trial is still ongoing. Such characteristics of oral semaglutide may improve and increase its use compared to subcutaneous agents and possibly lead to earlier cardiovascular protection in addition to achieving glycemic control.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

To exclude an excess risk of cardiovascular (CV) events, CV outcomes trials (CVOTs) have assessed the effects of new glucose-lowering therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), in patients with type 2 diabetes and established CV disease or CV risk factors. The CV safety of semaglutide vs. placebo, when added to standard care, was evaluated in the SUSTAIN 6 trial for the formulation administered once-weekly subcutaneously and in PIONEER 6 for the new once-daily oral formulation. In SUSTAIN 6 and PIONEER 6, both powered to demonstrate noninferiority (upper 95% confidence interval [CI] of the hazard ratio [HR] <1.8), there were fewer first major adverse CV events with semaglutide vs. placebo, with HRs of 0.74 (95% CI 0.58-0.95) and 0.79 (0.57-1.11), respectively. In SUSTAIN 6, the results were significant for noninferiority and superiority, although the latter was not prespecified. Surprisingly, CV and all-cause mortality were significantly reduced by oral semaglutide in PIONEER 6. The ongoing SOUL CVOT will further inform about CV outcomes with oral semaglutide vs. placebo (NCT03914326). Findings from SUSTAIN 6 and PIONEER 6 fall within the spectrum reported with other GLP-1RA CVOTs: noninferiority vs. placebo for major CV events was seen with lixisenatide and exenatide extended-release, while superiority was demonstrated with liraglutide, albiglutide, and dulaglutide. Beneficial outcomes have been recognized in international guidelines, which recommend subcutaneous liraglutide, semaglutide, and dulaglutide to reduce the risk of CV events in high-risk patients. Both indirect mechanisms

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Kaplan-Meier Estimate; Obesity; Overweight; Patient Safety; Proportional Hazards Models; Prospective Studies; Randomized Controlled Trials as Topic; Risk; Risk Factors

Topics: Animals; Clinical Trials, Phase III as Topic; Energy Metabolism; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity

Topics: Adult; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity; Overweight

Oral semaglutide (Rybelsus

Topics: Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Drug Interactions; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Weight Loss

The PIONEER and SUSTAIN serial trials are designed to assess the efficacy outcomes with semaglutide in patients with type 2 diabetes, but are not powered to assess various safety outcomes. We sought to assess the risk of semaglutide in leading to various serious adverse events (SAEs) in patients with type 2 diabetes. Studies eligible for inclusion were the PIONEER and SUSTAIN trials of semaglutide. We conducted meta-analysis to generate pooled risk ratios (RRs) and 95% confidence intervals (CIs). Meta-analysis was performed using both random-effects and fixed-effects model to evaluate the robustness of pooled results. We implemented subgroup analysis according to drug dosages and routes of administration and type of comparators. Twenty-one trials were included. Semaglutide versus control significantly reduced total SAEs (RR 0.92, 95% CI 0.87-0.97; I

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Topics: Animals; Anti-Obesity Agents; Cardiometabolic Risk Factors; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Weight Loss

Despite the benefits of early and effective glycemic control in the management of type 2 diabetes (T2D), achieving glycated hemoglobin (HbA

Topics: Administration, Oral; Body Weight; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Diet; Exercise Therapy; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Quality of Life; Research Design; Treatment Outcome

Early and effective glycemic control can prevent or delay the complications associated with type 2 diabetes (T2D). The benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming increasingly recognized and they now feature prominently in international T2D treatment recommendations and guidelines across the disease continuum. However, despite providing effective glycemic control, weight loss, and a low risk of hypoglycemia, GLP-1RAs are currently underutilized in clinical practice. The long-acting GLP-1RA, semaglutide, is available for once-weekly injection and in a new once-daily oral formulation. Semaglutide is an advantageous choice for the treatment of T2D since it has greater efficacy in reducing glycated hemoglobin and body weight compared with other GLP-1RAs, has demonstrated benefits in reducing major adverse cardiovascular events, and has a favorable profile in special populations (e.g., patients with hepatic impairment or renal impairment). The oral formulation represents a useful option to help improve acceptance and adherence compared with injectable formulations for patients with a preference for oral therapy, and may lead to earlier and broader use of GLP-1RAs in the T2D treatment trajectory. Oral semaglutide should be taken on an empty stomach, which may influence the choice of formulation. As with most GLP-1RAs, initial dose escalation of semaglutide is required for both formulations to mitigate gastrointestinal adverse events. There are also specific dose instructions to follow with oral semaglutide to ensure sufficient gastric absorption. The evidence base surrounding the clinical use of semaglutide is being further expanded with trials investigating effects on diabetic retinopathy, cardiovascular outcomes, and on the common T2D comorbidities of obesity, chronic kidney disease, and non-alcoholic steatohepatitis. These will provide further information about whether the benefits of semaglutide extend to these other indications.

Topics: Administration, Oral; Body Weight; Cardiovascular Diseases; Comorbidity; Decision Making; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Hemoglobins; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Liver; Metformin; Obesity; Renal Insufficiency, Chronic; Research Design; Risk; Stomach

The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide is the most recently approved agent of this drug class, and the only GLP-1RA currently available as both subcutaneous and oral formulation. While GLP-1RAs effectively improve glycemic control and cause weight loss, potential safety concerns have arisen over the years. For semaglutide, such concerns have been addressed in the extensive phase 3 registration trials including cardiovascular outcome trials for both subcutaneous (SUSTAIN: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and oral (PIONEER: Peptide InnOvatioN for the Early diabEtes tReatment) semaglutide and are being studied in further trials and registries, including real world data studies. In the current review we discuss the occurrence of adverse events associated with semaglutide focusing on hypoglycemia, gastrointestinal side effects, pancreatic safety (pancreatitis and pancreatic cancer), thyroid cancer, gallbladder events, cardiovascular aspects, acute kidney injury, diabetic retinopathy (DRP) complications and injection-site and allergic reactions and where available, we highlight potential underlying mechanisms. Furthermore, we discuss whether effects are specific for semaglutide or a class effect. We conclude that semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease (cholelithiasis). No unexpected safety issues have arisen to date, and the established safety profile for semaglutide is similar to that of other GLP-1RAs where definitive conclusions for pancreatic and thyroid cancer cannot be drawn at this point due to low incidence of these conditions. Due to its potent glucose-lowering effect, patients at risk for deterioration of existing DRP should be carefully monitored if treated with semaglutide, particularly if also treated with insulin. Given the beneficial metabolic and cardiovascular actions of semaglutide, and the low risk for severe adverse events, semaglutide has an overall favorable risk/benefit profile for patient with type 2 diabetes.

Topics: Acute Kidney Injury; Animals; Blood Glucose; Body Weight; Cardiovascular System; Cholelithiasis; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Gallbladder; Gastrointestinal Tract; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin; Nausea; Pancreas; Pancreatic Neoplasms; Pancreatitis; Patient Safety; Peptides; Thyroid Neoplasms; Time Factors

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are highly effective at lowering hemoglobin A1c (HbA1c) and facilitating weight loss. Four agents in the GLP-1 RA class, albiglutide, liraglutide, dulaglutide, and semaglutide, also have cardioprotective effects. However, subcutaneous administration of these agents remains a major reason for their underutilization. A new coformulation of semaglutide with sodium N-[8-(2-hydroxybenzoyl) amino caprylate (SNAC) is the first oral GLP-1 RA reviewed by the U.S. Food and Drug Administration (FDA). The SNAC technology prevents destruction of semaglutide in the stomach and facilitates transcellular absorption through the gastric membrane enabling semaglutide to reach systemic circulation intact. The oral formulation of semaglutide was studied in the PIONEER trials, demonstrating similar efficacy to the presently available GLP-1 RAs with regard to HbA1c lowering and weight loss. Although the PIONEER 6 trial suggests positive effects on cardiovascular mortality with oral semaglutide, these benefits may not fully be appreciated until the completion of the SOUL trial.

Topics: Administration, Oral; Caprylates; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Delivery Systems; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Renal Insufficiency, Chronic

To assess the efficacy and safety of oral semaglutide, a novel glucagon-like peptide-1 receptor agonist, for patients with type 2 diabetes.. We searched Medline, Embase, the Cochrane Library and grey literature sources up to July 1, 2019 for randomized controlled trials (RCTs) comparing oral semaglutide with placebo or other antidiabetic agents. The primary outcome was change from baseline in HbA1c. Secondary outcomes included change from baseline in body weight and blood pressure, cardiovascular endpoints, severe hypoglycaemia, gastrointestinal adverse events and diabetic retinopathy. We synthesized results using weighted mean differences (WMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes, along with 95% confidence intervals (CIs).. We included 11 RCTs with 9890 patients in the systematic review. Compared with placebo, oral semaglutide reduced HbA1c and body weight (WMD -0.89%, 95% CI -1.07 to -0.71 and - 2.99 kg, 95% CI -3.69 to -2.30, respectively). Oral semaglutide was also superior to other active comparators (including liraglutide, empagliflozin and sitaglipitin) in terms of lowering HbA1c (WMD -0.35%, 95% CI -0.43 to -0.26) and reduction of body weight (WMD -1.48 kg, 95% CI -2.28 to -0.67), and had a favourable effect on systolic blood pressure. Compared with placebo, oral semaglutide reduced all-cause mortality (OR 0.58, 95% CI 0.37 to 0.92) and cardiovascular mortality (OR 0.55, 95% CI 0.31 to 0.98), and had a neutral effect on myocardial infarction, stroke, severe hypoglycaemia and diabetic retinopathy. However, treatment with oral semaglutide increased the incidence of nausea, vomiting and diarrhea, while events of acute pancreatitis were rare.. Oral semaglutide can effectively and safely reduce blood glucose, body weight and systolic blood pressure. Nevertheless, it is associated with increased incidence of gastrointestinal adverse events. Further research is needed to clarify its long-term safety and comparative effectiveness against other antidiabetic agents.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide

Topics: Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Obesity

Previously, the only available glucagon-like peptide-1 receptor agonists (GLP-1 RA) were injectable. Approval of oral semaglutide (Rybelsus®) represents the first orally available GLP-1 RA.. To review the literature and describe pharmacologic, pharmacokinetic, and pharmacodynamics properties; clinical safety; and efficacy of oral semaglutide, a newly approved oral GLP-1 RA.. A MEDLINE (1995-October 2019) and ClinicalTrials.gov search was conducted using the terms oral semaglutide, semaglutide, PIONEER, and a combination of those terms. Reference citations from publications identified were also reviewed. All English-language studies, including abstracts, evaluating oral semaglutide use in humans were included in this review.. The approval of oral semaglutide (Rybelsus®) represents a paradigm shift in the management of T2D as this is the first FDA-approved oral GLP-1 RA. Oral semaglutide may be an attractive option for patients with T2D who require improved glycemic control, would like to lose weight, and who are not interested in injectable therapy. However, the lack of positive cardiovascular (CV) and renal data are significant limitations to its use.

Topics: Administration, Oral; Body Weight; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycemic Control; Humans; Hypoglycemic Agents; Treatment Outcome

There is an unmet medical need for an effective anti-fibrotic treatment for NASH with advanced fibrosis.. The authors review the current and novel agents for the treatment of NASH with fibrosis. They also consider the potential future strategies of combination therapies.. Farnesoid X receptor (FXR) agonist (obeticholic acid [OCA]) significantly ameliorated hepatic fibrosis in NASH stage 2/3 fibrosis in an interim analysis of phase 3 trial. Because OCA has several drawbacks such as itching and elevated low-density lipoprotein-cholesterol (LDL-C), non-bile acid FXR agonists are now under development. Selonsertib (apoptosis signaling kinase 1 inhibitor), emricasan (an irreversible pan-caspase inhibitor), and simtsuzumab (a monoclonal antibody against lysyl oxidase-like 2) were discontinued because of no efficacy over placebo. Peroxisome proliferator-activator receptor α/δ agonists, C-C motif chemokine receptor-2/5 antagonists, and thyroid β receptor agonist are ongoing in phase 3 trials. A variety of agents including fibroblast growth factor (FGF)-21 and FGF-19 agonists, as well as acetyl-CoA carboxylase inhibitors, are also expected. Among antidiabetic agents, semaglutide, a novel GLP-1 RA, is ongoing for NASH stage 1-3 fibrosis in a phase 2 trial. Furthermore, the combination of GLP-RA/glucagon receptor agonist and GLP-RA/gastrointestinal peptide agonist are promising future options.

Topics: Chenodeoxycholic Acid; Clinical Trials as Topic; Fibroblast Growth Factors; Glucagon-Like Peptides; Humans; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Peroxisome Proliferator-Activated Receptors; Pioglitazone; Receptors, Cytoplasmic and Nuclear; Treatment Outcome; Vitamin E

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended for glycaemic management in patients with type 2 diabetes (T2D). Oral semaglutide, the first oral GLP-1RA, has recently been approved for clinical use, based on the results of the randomized, Phase 3a Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) clinical trials. The PIONEER programme tested oral semaglutide in patients with T2D of duration ranging from 3.5 to 15 years, from monotherapy through to insulin add-on, in global populations and two trials dedicated to Japanese patients. Outcomes (glycated haemoglobin [HbA1c] and body weight reduction, plus other relevant efficacy and safety endpoints) were tested against both placebo and active standard-of-care medications. A separate trial evaluated the cardiovascular safety of oral semaglutide in patients with T2D at high cardiovascular risk. Over periods of treatment up to 78 weeks, oral semaglutide 7 and 14 mg once daily reduced HbA1c and body weight across the spectrum of T2D, and improved other diabetes-related endpoints, such as fasting plasma glucose. Oral semaglutide provided significantly better efficacy than placebo and commonly used glucose-lowering medications from the dipeptidyl peptidase-4 inhibitor (sitagliptin) and sodium-glucose co-transporter-2 inhibitor (empagliflozin) classes, as well as the subcutaneous GLP-1RAs liraglutide and dulaglutide. Oral semaglutide was well tolerated in line with the known safety profile of GLP-1RAs, with transient gastrointestinal events being the most common side effects reported. Cardiovascular safety was demonstrated for oral semaglutide in patients with cardiovascular disease or high cardiovascular risk. The results of the PIONEER programme suggest that oral semaglutide is efficacious and well tolerated for glycaemic control of T2D. The availability of oral semaglutide may help to broaden treatment choice and facilitate adoption of earlier GLP-1RA treatment in the paradigm of T2D management.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide

Semaglutide is the most recently approved injectable glucagon-like peptide-1 receptor agonist (GLP-1RA) for people with type 2 diabetes (T2DM). It is one of the three currently marketed GLP-1RAs that can be administered once weekly.. This review focusses on the safety of injectable semaglutide. Semaglutide has been assessed in the SUSTAIN phase 3 clinical trial programme, which included patients across the disease spectrum, i.e. treatment-naïve to those receiving insulin. The authors have looked at all published literature on safety considerations of once weekly GLP-1RA with particular reference to semaglutide.. Semaglutide is the most powerful injectable GLP-1RA. The cardiovascular (CV) outcome trial (SUSTAIN 6) showed CV superiority and its adverse event profile is as expected for the GLP-1RA class with predominantly gastrointestinal side-effects. Concerns about the thyroid and pancreatic safety have not been substantiated. There is no indication of renal or liver harm for semaglutide. Data consistent with reno-protection and benefit in liver disease is presented. There is a modest signal for increased gall bladder adverse events. An increase in diabetic retinopathy (DR) events in the SUSTAIN 6 trial is the most concerning safety signal. Caution regarding DR is needed when initiating semaglutide and recommendations are suggested.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Injections

Current estimates suggest that approximately 10% of the global adult population have type 2 diabetes. In recent years there has been a significant increase in the therapeutic options available for its treatment. This article examines the use of injectable semaglutide in the treatment of type 2 diabetes.. We will describe the global problem posed by type 2 diabetes followed by consideration of the glucagon-like peptide 1 receptor agonist class of glucose lowering therapies. The focus is then shifted to semaglutide and a description of the large phase 3 pre-approval trial programme known as SUSTAIN. There is consideration of glucose control, the primary end-point of the phase 3 programme, as well as secondary end-points such as weight and blood pressure. There follows a précis of the cardiovascular outcomes trial for subcutaneous semaglutide (SUSTAIN 6) and the post-approval publications. As well as the SUSTAIN trial programme we used PubMed to identify relevant publications.. This section discusses the position of semaglutide and the risks and benefits versus other once weekly GLP-1RAs and finally the development of an oral version of semaglutide, which has recently been approved in the United States.

Topics: Adult; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Injections

As the cornerstone of type 2 diabetes (T2D) management within the community, primary care providers are now faced with the challenge of not only managing diabetes itself, but also preventing hypoglycemia and weight gain associated with intensive disease management, and reducing cardiovascular risk. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are well established as efficacious treatments for T2D, and the safety/tolerability profile of this drug class is well defined. However, despite their beneficial effects, GLP-1RAs are under-utilized, highlighting the need for novel approaches to increase their use in primary care. Oral semaglutide is the first oral GLP-1RA approved for the treatment of T2D, offering glucose lowering and body weight loss, a low risk of hypoglycemia, and no increase in cardiovascular risk. Oral semaglutide represents an additional treatment option for patients not achieving their glycemic goal despite treatment with metformin, either alone or with other hypoglycemic agents. Oral semaglutide has the potential to increase usage of GLP-1RAs in the primary care setting by addressing clinician and patient concerns about injections, and may facilitate earlier initiation of GLP-1RA therapy in T2D. Due to the formulation of oral semaglutide, clinicians need to be aware of specific considerations in order to ensure optimal use. Such considerations include dosing conditions and use of concomitant medications. This article provides practical guidance on the use of oral semaglutide in the primary care setting, based on evidence from clinical studies, including the phase 3a PIONEER program, and the authors' clinical experience.

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Gonadotropin-Releasing Hormone; Humans; Hypoglycemia; Hypoglycemic Agents; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Weight Loss

Over recent decades, an improved understanding of the pathophysiology of type 2 diabetes mellitus (T2DM) and glucose regulation has led to innovative research and new treatment paradigms. The discovery of the gut peptide glucagon-like peptide-1 (GLP-1) and its role in glucose regulation paved the way for the class of GLP-1 receptor agonist compounds, or GLP-1RAs. The long-acting GLP-1RAs (dulaglutide, exenatide extended-release, liraglutide, semaglutide [injectable and oral]) are classified as such based on a minimum 24-hour duration of clinically relevant effects after administration. In phase 3 clinical trial programs of long-acting GLP-1RAs, A1C typically was reduced in the range of 1% to 1.5%, with reductions close to 2% in some studies. GLP-1RAs when used alone (without sulfonylureas or insulin) have a low risk of hypoglycemia because, like endogenous GLP-1, their insulinotropic effects are glucose-dependent. In addition to local actions in the gastrointestinal (GI) tract, GLP-1RAs stimulate receptors in the central nervous system to increase satiety, resulting in weight loss. All long-acting GLP-1RAs have, at minimum, been shown to be safe and not increase cardiovascular (CV) risk and most (liraglutide, semaglutide injectable, dulaglutide, albiglutide) have been shown in CV outcomes trials (CVOTs) to significantly reduce the risk of major cardiac adverse events. The class has good tolerability overall, with generally transient GI adverse events being most common. The weekly injectable agents offer scheduling convenience and may promote treatment adherence. One long-acting GLP-1RA is available as an oral daily tablet, which may be preferable for some patients and providers.

Topics: Administration, Oral; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Immunoglobulin Fc Fragments; Injections; Liraglutide; Recombinant Fusion Proteins; Satiety Response; Weight Loss

Cardiovascular disease (CVD) is a common and serious comorbidity of type 2 diabetes mellitus (T2DM), and cardiovascular (CV) risk assessment has become an important aspect of evaluating new therapies for T2DM before approval by the FDA. Since 2008, in order to establish safety, new therapies for T2DM have been required to demonstrate that they will not result in an unacceptable increase in CV risk. Studies performed for this purpose are termed CV outcome trials, or CVOTs. This article reviews CVOTs completed to date for the class of long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs; liraglutide, exenatide extended-release, albiglutide, dulaglutide, semaglutide injectable, semaglutide oral) and implications for clinical management of T2DM. All CVOTs have confirmed long-acting GLP-1RAs to be noninferior to (not worse than) placebo with regard to first occurrence of a primary outcome of three-point major adverse cardiovascular events (MACE; composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke). Further, a number of the studies demonstrated a statistically significant reduction in primary outcomes of three-point MACE with GLP-1RA treatment compared with placebo. As a result, the product labeling for liraglutide, semaglutide injectable, and dulaglutide has been updated with an indication for reducing the risk of MACE in adults with T2DM and established CVD (all) or multiple CV risk factors (dulaglutide only). These findings have brought about an exciting paradigm shift from concern about not inflicting CV harm to the exciting prospect of reducing risks of CV outcomes. Major diabetes care guidelines now encourage early consideration of GLP-1RA use in patients with atherosclerotic CVD.

Topics: Administration, Oral; Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Immunoglobulin Fc Fragments; Injections; Liraglutide; Practice Guidelines as Topic; Recombinant Fusion Proteins; Treatment Outcome; United States; United States Food and Drug Administration

Over recent decades, an improved understanding of the pathophysiology of type 2 diabetes mellitus (T2DM) and glucose regulation has led to innovative research and new treatment paradigms. The discovery of the gut peptide glucagon-like peptide-1 (GLP-1) and its role in glucose regulation paved the way for the class of GLP-1 receptor agonist compounds, or GLP-1RAs. The long-acting GLP-1RAs (dulaglutide, exenatide extended-release, liraglutide, semaglutide [injectable and oral]) are classified as such based on a minimum 24-hour duration of clinically relevant effects after administration. In phase 3 clinical trial programs of long-acting GLP-1RAs, A1C typically was reduced in the range of 1% to 1.5%, with reductions close to 2% in some studies. GLP-1RAs when used alone (without sulfonylureas or insulin) have a low risk of hypoglycemia because, like endogenous GLP-1, their insulinotropic effects are glucose-dependent. In addition to local actions in the gastrointestinal (GI) tract, GLP-1RAs stimulate receptors in the central nervous system to increase satiety, resulting in weight loss. All long-acting GLP-1RAs have, at minimum, been shown to be safe and not increase cardiovascular (CV) risk and most (liraglutide, semaglutide injectable, dulaglutide, albiglutide) have been shown in CV outcomes trials (CVOTs) to significantly reduce the risk of major cardiac adverse events. The class has good tolerability overall, with generally transient GI adverse events being most common. The weekly injectable agents offer scheduling convenience and may promote treatment adherence. One long-acting GLP-1RA is available as an oral daily tablet, which may be preferable for some patients and providers.

Topics: Administration, Oral; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glucose; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Recombinant Fusion Proteins; Safety; Treatment Outcome

Cardiovascular disease (CVD) is a common and serious comorbidity of type 2 diabetes mellitus (T2DM), and cardiovascular (CV) risk assessment has become an important aspect of evaluating new therapies for T2DM before approval by the FDA. Since 2008, in order to establish safety, new therapies for T2DM have been required to demonstrate that they will not result in an unacceptable increase in CV risk. Studies performed for this purpose are termed CV outcome trials, or CVOTs. This article reviews CVOTs completed to date for the class of long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs; liraglutide, exenatide extended-release, albiglutide, dulaglutide, semaglutide injectable, semaglutide oral) and implications for clinical management of T2DM. All CVOTs have confirmed long-acting GLP-1RAs to be noninferior to (not worse than) placebo with regard to first occurrence of a primary outcome of three-point major adverse cardiovascular events (MACE; composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke). Further, a number of the studies demonstrated a statistically significant reduction in primary outcomes of three-point MACE with GLP-1RA treatment compared with placebo. As a result, the product labeling for liraglutide, semaglutide injectable, and dulaglutide has been updated with an indication for reducing the risk of MACE in adults with T2DM and established CVD (all) or multiple CV risk factors (dulaglutide only). These findings have brought about an exciting paradigm shift from concern about not inflicting CV harm to the exciting prospect of reducing risks of CV outcomes. Major diabetes care guidelines now encourage early consideration of GLP-1RA use in patients with atherosclerotic CVD.

Topics: Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Immunoglobulin Fc Fragments; Liraglutide; Recombinant Fusion Proteins; United States

Glucagon-like peptide-1 (GLP-1) is an endogenous peptide which is secreted by enteroendocrine L cells, GLP-1 receptor agonists (GLP-1 RAs) can exhibit glucoregulation by stimulating insulin release, promote satiety, delay gastric emptying, and reduce energy intake. Liraglutide is the only GLP-1 RA approved for the treatment of obesity. The phase III clinical study of semaglutide has completed and the result showed significant weight loss effect. GLP-1 RAs have been proven to be safe and effective in clinical trials, they are considered to be promising anti-obesity drugs.. This review provides an overview of recently published patents describing modified GLP-1 RAs, multi-agonists in the treatment or prevention of obesity from January 2015 to April 2020. Moreover, small molecule GLP-1 RAs, recombinant fusion proteins, combination of GLP-1 RAs with other drugs and the preparation of GLP-1 RAs are also covered.. Currently, research on anti-obesity effect of modified GLP-1 RAs has grown significantly, liraglutide accounts for approximately 56% of the global obesity drug market. Long-acting analogues and multifunctional peptides showed good weight loss activity. As more and more clinical trials are carried out, we believe that GLP-1 RAs will occupy an important position in the market of obesity treatment.

Topics: Animals; Anti-Obesity Agents; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Liraglutide; Obesity; Patents as Topic; Peptides

Injectable therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and insulin are high-efficacy options for people with type 2 diabetes (T2D) who require treatment intensification. In addition to high glycemic efficacy, GLP-1RAs offer weight loss benefits, and some agents have been shown to reduce cardiovascular risk. This article summarizes data from two clinical studies with the first oral GLP-1RA, oral semaglutide, in situations where injectable therapy is often considered, and provides guidance on use in primary care. PIONEER 4 compared oral semaglutide 14 mg with an injectable GLP-1RA, liraglutide 1.8 mg, or placebo in patients uncontrolled on oral glucose-lowering therapies. PIONEER 8 compared oral semaglutide with placebo in patients with T2D already on insulin therapy. Treatment with oral semaglutide gave similar reductions in glycated hemoglobin (HbA

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin; Placebos; Randomized Controlled Trials as Topic

Oral semaglutide is a tablet formulation of a glucagon-like peptide-1 receptor agonist (GLP-1RA), recently approved in the USA and other countries. This paper reviews data from clinical trials (PIONEER 1, 2, 3, and 7) comparing oral semaglutide (once-daily doses of 3, 7, or 14 mg) with either once-daily placebo, empagliflozin 25 mg, or sitagliptin 100 mg. After 26 weeks in PIONEER 1, patients randomized to 3, 7, or 14 mg doses of oral semaglutide monotherapy had statistically significant reductions in glycated hemoglobin (HbA

Topics: Administration, Oral; Benzhydryl Compounds; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Primary Health Care; Sitagliptin Phosphate

Patients with type 2 diabetes (T2D) often have comorbidities, such as cardiovascular disease or chronic kidney disease, and a large and growing proportion of the T2D patient population is over 65 years. There are many therapies for the treatment of T2D but not all are suitable for patients with comorbidities. Oral semaglutide is a tablet formulation of a glucagon-like peptide-1 receptor agonist (GLP-1RA) and was recently approved for the treatment of T2D, representing an oral alternative to injectable GLP-1RAs. This article reviews data from: PIONEER 6, a phase 3a cardiovascular outcomes trial in patients at high cardiovascular risk; PIONEER 5, a phase 3a trial in patients with moderate renal impairment; a post-hoc analysis of PIONEER data by age; and pharmacokinetic trials investigating the effects of renal impairment, gastrointestinal disease, and hepatic impairment on the exposure of oral semaglutide. PIONEER 6 demonstrated the cardiovascular safety of oral semaglutide compared with placebo (hazard ratio: 0.79; 95% confidence interval [CI]: 0.57, 1.11; p < 0.001 for noninferiority), ruling out excess cardiovascular risk. In PIONEER 5, oral semaglutide was superior to placebo in decreasing glycated hemoglobin over 26 weeks (estimated treatment difference [ETD]: -0.8%; 95% CI: -1.0, -0.6; p < 0.0001) and body weight (ETD: -2.5 kg; 95% CI: -3.2, -1.8; p < 0.0001), and renal function was unchanged in both treatment groups. There was no effect of age on glycemic efficacy of oral semaglutide and the presence of upper gastrointestinal disease or hepatic impairment did not affect the pharmacokinetics of semaglutide. Across the trials, the safety profile of oral semaglutide was as expected for a GLP-1RA, with gastrointestinal adverse events most commonly reported. As such, oral semaglutide provides an effective oral GLP-1RA treatment option in older patients and/or those with comorbidities, with no requirements for dose adjustment.

Topics: Age Factors; Aged; Cardiovascular Diseases; Comorbidity; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Kidney Failure, Chronic; Randomized Controlled Trials as Topic

Oral semaglutide is the first US Food and Drug Administration-approved oral glucagon-like peptide-1 receptor agonist (GLP-1RA) for the treatment of type 2 diabetes (T2D). Prior articles within this supplement reviewed the PIONEER trial program, which demonstrated that oral semaglutide reduced glycated hemoglobin and body weight when given to patients with uncontrolled T2D on various background therapies, and had a safety profile consistent with subcutaneous GLP-1RAs. This article provides guidance on integrating oral semaglutide into clinical practice in primary care. Patient populations with T2D who may gain benefit from oral semaglutide include those with inadequate glycemic control taking one or more oral glucose-lowering medication (e.g. after metformin), patients for whom weight loss would be beneficial, patients at risk of hypoglycemia, those who would historically have been considered for treatment with a subcutaneous GLP-1RA, and those receiving basal insulin who require treatment intensification. Like other GLP-1RAs, oral semaglutide is contraindicated in those with personal/family history of medullary thyroid carcinoma, and in those with multiple endocrine neoplasia syndrome type 2, as noted in a boxed warning in the prescribing information. Oral semaglutide has not been studied in those with a history of pancreatitis, is not recommended in patients with suspected/confirmed pancreatitis, and is not indicated in type 1 diabetes. When initiating oral semaglutide, gradual dose escalation is recommended to minimize the risk of gastrointestinal adverse events. As food and excess liquid reduce oral semaglutide absorption, patients should swallow the tablet with up to 4 fl oz/120 mL of water on an empty stomach upon waking, and should wait at least 30 minutes before eating, drinking, or taking other oral medications. Those managing patients should be aware of the potential impact of these dosing conditions on concomitant medications. When counseling patients, it is important to discuss these administration instructions, realistic therapeutic expectations, and strategies for mitigation of gastrointestinal events. Oral semaglutide provides a new option for add-on to initial T2D therapy (or later in the treatment paradigm), with the potential to enable more patients to benefit from the improvements in glycemic control, reductions in body weight, and low risk of hypoglycemia afforded by GLP-1RAs.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Primary Health Care

No head-to-head trials have directly compared once-weekly (OW) semaglutide, a human glucagon-like peptide-1 analog, with empagliflozin, a sodium-glucose co-transporter-2 inhibitor, in type 2 diabetes (T2D).. We indirectly compared the efficacy of OW semaglutide 1 mg vs once-daily (OD) empagliflozin 25 mg in patients with T2D inadequately controlled on metformin monotherapy, using individual patient data (IPD) and meta-regression methodology.. IPD for patients with T2D receiving metformin monotherapy and randomized to OW semaglutide 1 mg (SUSTAIN 2, 3, 8 trials), or to OD empagliflozin 25 mg (PIONEER 2 trial) were included. Meta-regression analyses were adjusted for potential prognostic factors and effect modifiers.. The primary efficacy outcomes were change from baseline to end-of-treatment (~1 year) in HbA1c (%-point) and body weight (kg). Responder outcomes and other clinically relevant efficacy measures were analyzed.. Baseline characteristics were similar between OW semaglutide (n = 995) and empagliflozin (n = 410). Our analyses showed that OW semaglutide significantly reduced mean HbA1c and body weight vs empagliflozin (estimated treatment difference: -0.61%-point [95% confidence interval (CI): -0.72; -0.49] and -1.65 kg [95% CI: -2.22; -1.08], respectively; both P < 0.0001). Complementary analyses supported the robustness of these results. A significantly greater proportion of patients on OW semaglutide vs empagliflozin also achieved HbA1c targets and weight-loss responses.. This indirect comparison suggests that OW semaglutide 1 mg provides superior reductions in HbA1c and body weight vs OD empagliflozin 25 mg in patients with T2D when added to metformin monotherapy.

Topics: Benzhydryl Compounds; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptides; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Treatment Outcome

There are roughly 30 million Americans diagnosed with diabetes mellitus (DM), with nearly 95% of these cases being type 2 (T2)-DM. The American Diabetes Association continues to recommend metformin as the first-line initial treatment of T2DM, in combination with lifestyle modifications; yet, many require multiple therapies to achieve adequate glycemic control. In patients with atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, adding a glucagon-like peptide 1 receptor agonist is a preferred treatment option; however, many patients are apprehensive about injecting medications. Semaglutide is the first oral option in this life-saving medication class. The purpose of this article was to review the pharmacology, clinical trials, safety profile, along with recommended dosing and costs, of oral semaglutide used for managing patients with T2DM.. A search through the PubMed, MEDLINE and Cochrane libraries was conducted for literature published from January 2017 through December 2020, using the key word semaglutide. Articles were selected if they were related to the approval of oral semaglutide or provided novel clinical information regarding this drug entity in its oral dosage formulation.. Three Phase II studies of the pharmacokinetic properties and Phase III trials from the PIONEER series were ultimately selected, as these trials were thought to provide pivotal information to the US Food and Drug Administration for the approval of oral semaglutide.. On review of the literature, it appeared that semaglutide is a viable option in treating T2DM. The use of this medication has been associated with glycosylated hemoglobin lowering similar to that with the injectable medication in its same class. Semaglutide was also showed some potential in preventing cardiovascular events as well as increasing weight loss.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Renal Insufficiency, Chronic

According to current guidelines, glucagon-like peptide-1 (GLP-1) receptor agonists are the antidiabetic agent of choice in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease (CVD) and are also the preferable antidiabetic agent in patients with T2DM without CVD but with indicators of high cardiovascular risk. A limitation in the use of GLP-1 receptor agonists is that they are delivered by subcutaneous injections. In this context, the development of an orally administered formulation of semaglutide offers an additional option in the management of patients with T2DM. In the present review, we discuss the findings of the main trials that evaluated the safety and efficacy of oral semaglutide. Oral semaglutide appears to be more effective in reducing HbA

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

In recent years, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) including once-weekly (QW) formulations have been incorporated into type 2 diabetes (T2D) clinical guidelines, making it essential that pharmacists and healthcare professionals (HCPs) have a clear understanding of their safety profiles. Currently, three QW GLP-1 RAs are approved and marketed in the United States for the treatment of T2D: dulaglutide, exenatide extended-release and semaglutide. This review provides pharmacists and HCPs with collated data related to potential safety and tolerability issues when patients use QW GLP-1 RAs, enabling patient education and treatment optimization.. This is a narrative review comparing the safety and tolerability of the three QW GLP-1 RAs, using data from Phase 3 clinical trials. Extracted safety data included gastrointestinal (GI) adverse events (AEs), hypoglycaemia, injection-site reactions, pancreatitis, neoplasms, gallbladder events, and diabetic retinopathy (DR) and/or its complications (DRCs).. A total of 30 trials were identified for inclusion; eight were head-to-head trials involving another GLP-1 RA; of these, six compared GLP-1 RAs with different dosing regimens (QW vs once-daily or twice-daily), and two were direct QW vs QW GLP-1 RA comparisons. The most commonly reported AEs were GI events (notably nausea, vomiting and diarrhoea), but there was variation between the three QW drugs. These were generally mild-to-moderate in severity and transient. Risk of hypoglycaemia, injection-site reactions, pancreatitis, neoplasms and gallbladder events was generally low across the GLP-1 RAs investigated. Overall rates of DR or DRC were low across the trials. Only in one trial (SUSTAIN 6) there were significantly more DRC events reported in patients treated with QW semaglutide (3.0%) compared with placebo (1.8%). This was likely due to the rapid improvement in glucose control in patients with pre-existing DR enrolled within that trial.. This review puts the latest clinical data from the marketed QW GLP-1 RAs into context with results from older Phase 3 trials, to enable pharmacists and HCPs to make informed treatment decisions. Each of the three QW GLP-1 RAs has their own safety profile, which should be considered when choosing the optimal treatment for patients.

Topics: Blood Glucose; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins

As a highly prevalent chronic condition associated with complications and high mortality rates, it is important for pharmacists to have a comprehensive understanding of the impact of type 2 diabetes (T2D) and available treatment options. The use of injectable glucagon-like peptide 1 receptor agonists (GLP-1 RAs) is recommended as an effective and convenient treatment regimen for improving glycaemic control in individuals with T2D, with a good safety profile; however, the wider extent of its potential benefits often are unknown to clinical pharmacists. The objective of this article is to provide an overview of the impact of T2D on individuals and to discuss the multifaceted role of once-weekly (QW) GLP-1 RAs in addressing these challenges.. This is a narrative review of the published literature regarding the use of injectable GLP-1 RAs in managing health complications in people with T2D.. Recent findings reveal additional benefits of GLP-1 RAs in managing T2D complications, including atherosclerotic cardiovascular (CV) disease, retinopathy, neuropathy, and nephropathy. Dulaglutide and semaglutide have been shown to provide additional CV benefit in patients at high risk of CV events compared with standard of care/placebo and may offer renal protection in patients with chronic kidney disease. Cost-effectiveness studies, taking into consideration these different complications, have shown that QW GLP-1 RAs were cost-effective compared with other therapies. GLP-1 RAs may also help to improve overall health-related quality of life, reducing the risk of depression and 'diabetes distress', and limiting the risk of hypoglycaemia.. From the literature, this appears to be the first review of the evidence supporting the multifaceted role of QW GLP-1 RAs in T2D, with particular emphasis on their use in comorbid conditions, as well as associated potential financial and well-being benefits. The results suggest that QW GLP-1 RAs may be an attractive treatment option for improving glycaemic control in T2D, especially in individuals with (or at risk of) additional comorbidities or health complications.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycemic Control; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Quality of Life; Recombinant Fusion Proteins

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may confer a range of benefits for people with type 2 diabetes (T2D), which is reflected through their position within diabetes treatment guidelines. The objective of this narrative review is to explore the efficacy data of once-weekly (QW) GLP-1 RAs in terms of glycaemic control, body weight reduction, cardiovascular (CV) outcomes and potential renal protective effects to assist pharmacists and other healthcare professionals (HCPs) in treatment discussions with patients.. This a narrative review focused on 31 clinical trials involving the Phase 3 clinical programmes of the QW GLP-1 RAs dulaglutide, exenatide extended-release (ER) and semaglutide subcutaneous (s.c.).. The clinical trials were divided by their comparator arms and examined for trends. All QW GLP-1 RAs were superior to placebo for reductions in glycated haemoglobin (HbA. This review collates recently published data and previously published Phase 3 results to allow pharmacists and other HCPs to understand all of the efficacy data available and the corresponding impact on treatment guidelines. QW GLP-1 RAs are emerging as important therapeutic options for people with T2D as they offer a spectrum of benefits extending beyond glycaemic control, but it is important to be aware of their efficacy differences when prescribing and discussing them with patients.

Topics: Blood Glucose; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins

People with type 2 diabetes (T2D) are at increased risk of cardiovascular disease (CVD), which in turn is associated with increased morbidity and mortality. The impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on cardiovascular (CV) outcomes has been investigated in CV outcomes trials (CVOTs). This review aims to help pharmacists and other healthcare professionals (HCPs) gain a better understanding of such CVOTs in T2D with a primary focus on the once-weekly (QW) GLP-1 RAs.. This narrative review mainly focuses on the evaluation of the similarities and differences in the design and results of CVOTs involving currently approved and marketed QW GLP-1 RAs-semaglutide subcutaneous, exenatide extended-release (ER) and dulaglutide. Results from CVOTs of dipeptidyl peptidase-4 inhibitors (DPP4is) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are also included.. Three CVOTs of QW GLP-1 RAs were identified for inclusion in this review: SUSTAIN 6 (semaglutide), EXSCEL (exenatide ER) and REWIND (dulaglutide), all of which varied in terms of trial design, patient demographics and other baseline characteristics. Results from these CVOTs demonstrated the CV safety of QW GLP-1 RAs compared with standard of care. Additionally, CV and renal benefits were demonstrated for semaglutide and dulaglutide, but not for exenatide ER. The CV safety of four DPP4is and three SGLT2is was demonstrated. None of the DPP4is had a CV or renal benefit, whereas all three SGLT2is were associated with CV and renal benefits.. This article provides an overview of the results from QW GLP-1 RA CVOTs, including the recently published results for dulaglutide, and places them within the broader T2D treatment landscape to help HCPs make informed decisions in daily practice. The QW GLP-1 RAs with benefits reaching beyond glycaemic control can provide a comprehensive treatment option for people with T2D at high risk of CVD, with CVD or chronic kidney disease.

Topics: Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins; Research Design

Cardiovascular diseases remain a leading cause for unfavorable outcomes, including death, in patients with type 2 diabetes mellitus (DM2). In the recent decade, novel drugs, including glucagon-like peptide-1 receptor agonists (GPP-1-RA) and sodium-glucose cotransporter-2 inhibitors, have convincingly demonstrated their ability to reduce risk of cardiovascular complications in patients with DM2. This review discusses one of GPP-1-RA, semaglutide, with a special focus on the evidence-based data on its use, cardioprotective properties, and algorithms of administration consistent with current clinical recommendations.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors

Glucagon-like peptide-1 (GLP-1) receptor agonists are effective glucose-lowering drugs, but there is concern that they may increase the risk of malignant neoplasia. The present meta-analysis examined the safety of GLP-1 receptor agonists with regard to malignant neoplasia.. We analyzed data from randomized controlled trials with a minimum duration of 24 weeks that assessed the incidence of neoplasms in type 2 diabetes patients receiving GLP-1 receptor agonists compared with placebo or other hypoglycemic drugs. We searched the MEDLINE, Embase, and Cochrane databases with a language restriction of English through October 1, 2018, and carried out a meta-analysis of the available trial data using a fixed effects model to calculate odds ratios (ORs) for neoplasia.. Thirty-four relevant articles, providing data for 50452 patients, were included in the meta-analysis. Compared with the incidence of malignant neoplasia with placebo or other interventions, no increase in malignant neoplasm formation was observed with the use of GLP-1 receptor agonists (OR 1.04, 95% confidence interval (CI) 0.94-1.15;. GLP-1 receptor agonists can be used without safety concerns related to malignant neoplasia in patients with type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Incidence; Liraglutide; Neoplasms; Risk Factors

GLP-1, a peptide hormone secreted from the gut, stimulating insulin and suppressing glucagon secretion was identified as a parent compound for novel treatments of diabetes, but was degraded (dipeptidyl peptidase-4) and eliminated (mainly by kidneys) too fast (half-life 1-2 min) to be useful as a therapeutic agent. GLP-1 receptor agonist has been used to treat patients with type 2 diabetes since 2007, when exenatide (twice daily) was approved in 2007. Compounds with longer duration of action (once daily, once weekly) and with increasingly better efficacy with respect to glycaemic control and body weight reduction have been developed, and in a recent ADA/EASD consensus statement, were recommended as the first injectable diabetes therapy after failure of oral glucose-lowering medications. Most GLP-1 receptor agonists (lixisenatide q.d., liraglutide q.d., exenatide q.w., dulaglutide q.w., albiglutide q.w., semaglutide q.w., all for s.c. injection, and the first oral preparation, oral semaglutide) have been examined in cardiovascular outcomes studies. Beyond proving their safety in vulnerable patients, most of whom had pre-existing heart disease, liraglutide, semaglutide, albiglutide, and dulaglutide reduced the time to first major adverse cardiovascular events (non-fatal myocardial infarction and stroke, cardiovascular death). Liraglutide, in addition, reduced cardiovascular and all-cause mortality. It is the purpose of the present review to describe clinically important differences, regarding pharmacokinetic behaviour, glucose-lowering potency, effectiveness of reducing body weight and controlling other cardiovascular risk factors, and of the influence of GLP-1 receptor agonist treatment on cardiovascular outcomes in patients either presenting with or without pre-existing cardiovascular disease (atherosclerotic, ischemic or congestive heart failure).

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Peptides; Recombinant Fusion Proteins

Semaglutide is a glucagon-like peptide-1 receptor-agonist (GLP-1 RA), which is injected subcutaneously once a week for treatment of Type 2 diabetes. In this review, the present results of semaglutide treatment are presented. Semaglutide has been evaluated in more than 8,000 patients across the spectrum of Type 2 diabetes. Trials with semaglutide have demonstrated superiority with sustained improved glycaemic control and weight loss compared to oral antidiabetic agents, other GLP-1 RAs and basalinsulin. In addition, semaglutide significantly decreased the occurrence of cardiovascular events compared with standard pharmacological diabetic treatment combined with placebo.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Glucagon-like peptide 1 receptor agonists (GLP1-RA) are prominent agents in the therapeutics of type 2 diabetes mellitus due to their exemplary efficacy in both preprandial and postprandial glycemia, their safety, low risk of hypoglycemia, their multilevel pathophysiological superiority, weight loss and importantly the observed benefits in cardiovascular disease reduction. Their major drawback is the subcutaneous route of administration, constituting a barrier to adoption and reason for treatment discontinuation. Thus, the development of an oral GLP1-RA agent would promote medication adherence and quality of life, further consolidating its beneficial effects in real-life clinical practice. However, this task is hampered by suboptimal gastrointestinal protein absorption. Yet, the introduction of oral semaglutide, a modified form of semaglutide with the addition of a carrier sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, may have provided a safe and effective way to reach systemic circulation while other molecules are in development. Whether this molecule still has the impressive cardiovascular effects demonstrated with the use of its precursor remains to be explored. However, to date, its efficacy and safety have already been showcased in a randomized trial. More research is warranted in order to further consolidate these findings across different type 2 diabetes mellitus (T2DM) subpopulations, and adequately powered studies with a longer follow-up that would allow the exploration of microvascular and macrovascular complications are needed. Finally, studies comparing oral semaglutide and similar molecules with other currently established antidiabetic agents to evaluate the relative efficacy, the cost-effectiveness and further understand its place in T2DM therapeutic algorithm are needed. This review focuses on the development of oral GLP1-RA agents and summarizes the challenges, milestones and expected benefits associated with a successful introduction.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Topics: Adult; Animals; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Pregnancy; Randomized Controlled Trials as Topic

Guidelines increasingly highlight the importance of multifactorial management in type 2 diabetes, in contrast to the more traditional focus on glycemic control. Semaglutide, a recently approved glucagon-like peptide-1 receptor agonist, is indicated in Canada for adults with type 2 diabetes to improve glycemic control as monotherapy with diet and exercise when metformin is inappropriate or as an add-on to either metformin alone or metformin plus a sulfonylurea or basal insulin. The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) clinical trial program for semaglutide comprises 6 pivotal global phase 3a trials (SUSTAIN 1 through 6) and 2 Japanese phase 3a trials. Phase 3b trials include SUSTAIN 7, and SUSTAIN 8 and 9 (both ongoing). Results from the completed trials support the superiority of semaglutide for reduction of glycated hemoglobin levels and weight loss vs. placebo as well as active comparators, including sitagliptin, exenatide extended-release, dulaglutide and insulin glargine. SUSTAIN 6 trial data confirmed cardiovascular safety and demonstrated significant reductions in major cardiovascular events with semaglutide vs. placebo, an outcome that confirmed the noninferiority of semaglutide. The robust and sustained effects of semaglutide on glycated hemoglobin levels and weight loss vs. comparators, as well as its safety and possible cardiovascular benefit, address an unmet need in the treatment of type 2 diabetes. This article overviews data from across the semaglutide clinical trial program, including efficacy and safety results and findings from post hoc analyses. The potential place of semaglutide in clinical practice is discussed.

Topics: Blood Glucose; Body Weight; Canada; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Treatment Outcome

Glucagon-like peptide-1 receptor (GLP-1R) agonists augment insulin secretion and are thus used clinically to improve glycemia in subjects with type 2 diabetes (T2D). As recent data reveal marked improvements in cardiovascular outcomes in T2D subjects treated with the GLP-1R agonists liraglutide and semaglutide in the LEADER and SUSTAIN-6 clinical trials respectively, there is growing interest in delineating the mechanism(s) of action for GLP-1R agonist-induced cardioprotection. Of importance, negligible GLP-1R expression in ventricular cardiac myocytes suggests that cardiac-independent actions of GLP-1R agonists may account for the reduced death rates from cardiovascular causes in T2D subjects enrolled in the LEADER trial. Conversely, vascular smooth muscle cells (VSMCs) appear to express the canonical GLP-1R, and GLP-1/GLP-1R agonists exhibit a number of salutary actions on the vascular endothelium that could potentially contribute to GLP-1R agonists directly improving cardiovascular outcomes in subjects with T2D. We review herein the described actions of GLP-1/GLP-1R agonists on the vascular endothelium, which include antiproliferative actions on VSMCs and endothelial cells, reductions in oxidative stress, and increases in nitric oxide generation. GLP-1 also increases microvascular recruitment and microvascular blood flow. Taken together, such actions may explain the antihypertensive and/or antiatherosclerotic actions attributed to GLP-1/GLP-1R agonists in preclinical and clinical studies. Nonetheless, further mechanistic studies are still necessary to determine the relative importance of such actions in accounting for reductions in macrovascular cardiovascular disease in human subjects with T2D treated with GLP-1R agonists.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Endothelium, Vascular; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Liraglutide

Our aim was to compare once-weekly semaglutide to incretin-based therapies - defined as either dipeptidyl peptidase-4 inhibitors (DPP-4i) or other glucagon-like peptide-1 receptor agonist (GLP-1RA) - in patients with type 2 diabetes.. We searched for randomized trials comparing once-weekly semaglutide to other incretin-based therapies in patients with type 2 diabetes. We pooled trials that compared semaglutide to other GLP-1RA together, and those comparing semaglutide to DPP-4i together. The primary outcome was the change in haemoglobin A. Five trials met our inclusion criteria. There was a significantly greater reduction in haemoglobin A. While both once-weekly semaglutide and other incretin-based therapies can reduce haemoglobin A

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome

Glucagon-like peptide-1 (GLP-1) receptor agonists are highly potent antihyperglycemic drugs that impose low risk of hypoglycemia and also result in body weight reduction. Currently, all approved members of the class require administration by injection. Areas covered: This manuscript reviews oral semaglutide-an experimental GLP-1 receptor agonist in phase-3 clinical development. Available pharmacological and clinical data of the drug are reviewed, and important end-points described. Expert opinion: Oral peptide delivery has become possible with the discovery of absorption enhancers. The clinical development program of once-daily oral semaglutide has shown superiority in reducing glycosylated hemoglobin and body weight in comparison with placebo and active comparators (sitagliptin, liraglutide, and empagliflozin). Safety and tolerability of oral semaglutide is in line with injectable members of the class. Delayed gastric emptying, local increase in pH, and enhanced absorption do not seem to affect the exposure of a number of other oral drugs that have been tested (metformin, digoxin, oral contraceptive ethinylestradiol/levonorgestrel, lisinopril, warfarin, furosemide and rosuvastatin). Clinical questions for further investigation include the effectiveness and safety of oral semaglutide in cardiovascular indications.

Topics: Benzhydryl Compounds; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glucosides; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Sitagliptin Phosphate

Based on reported results of three large cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), we aimed to investigate the overall effect of GLP-1 RAs on major adverse cardiovascular events (MACEs) and to identify subpopulations exhibiting the greatest cardiovascular (CV) benefit.. Three CVOTs reporting effects of long-acting GLP-1 RAs were included: LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide once weekly). In all studies, the primary endpoint was three-point MACE, comprising CV death, non-fatal myocardial infarction, and non-fatal stroke. Overall effect estimates were calculated as hazard ratios and 95% confidence intervals (CIs) using the random-effects model; subgroup analyses reported in the original studies were similarly analyzed.. Overall, statistically significant risk reductions in MACE and CV death were observed. Subgroup analysis indicated a significant racial difference with respect to CV benefit (. Long-acting GLP-1 RAs reduced risks of MACE and CV deaths in high-risk patients with type 2 diabetes mellitus. Our findings of a particularly effective reduction in CV events with GLP-1 RA in Asian populations merits further exploration and dedicated trials in specific populations.

Topics: Aged; Asian People; Black People; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome; White People

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Treatment Outcome

Exenatide once weekly (QW) is a glucagon-like peptide 1 receptor agonist (GLP-1RA) that was approved in 2012 in Europe and the U.S.A. for the treatment of type 2 diabetes (T2D). Areas covered: This review provides an overview of the safety and efficacy of exenatide QW for the treatment of T2D and evaluates the benefit-risk ratio compared to other available long-acting GLP-1RAs. In addition, the authors provide an outline of the novel formulations and delivery methods of exenatide. Expert opinion: Exenatide QW is an efficacious and safe treatment for T2D. However, head-to-head trials have demonstrated exenatide QW to be inferior to liraglutide and semaglutide with respect to effects on fasting plasma glucose, glycated hemoglobin A1c, and bodyweight. In addition, exenatide QW appears inferior to liraglutide and semaglutide in terms of cardiovascular risk reduction. Currently, the overall risk-benefit profiles for the range of GLP-1RAs point to liraglutide and semaglutide as first-choice for the management of T2D, which has been confirmed by a recently published consensus report on the treatment of T2D from the American Diabetes Association and the European Association for the Study of Diabetes. The pricing of exenatide QW will most likely be a key determinant for its place in the future management of T2D.

Topics: Animals; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide

Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with a long elimination half-life, allowing subcutaneous (sc) administration once per week. Both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) recently approved once-weekly sc semaglutide for the treatment of type 2 diabetes mellitus (T2DM). The weight loss efficacy of once-weekly sc semaglutide appears to be superior compared with the other once-weekly GLP-1 RAs in patients with T2DM. Semaglutide was recently evaluated as an antiobesity drug in a phase II dose-finding trial, which demonstrated superior weight loss efficacy of once daily sc semaglutide compared with both placebo and once daily 3.0 mg liraglutide in patients with obesity but without T2DM. The magnitude of semaglutide-induced weight loss in this study exceeded the criteria of both the EMA and FDA for antiobesity drugs, and there were no safety concerns, indicating the eligibility of once daily sc semaglutide as a future antiobesity drug.

Topics: Anti-Obesity Agents; Glucagon-Like Peptides; Humans; Obesity

Type 2 diabetes mellitus (T2DM) has become one of the leading causes of morbidity and mortality in developed countries. Low efficacy, weight gain, and hypoglycemia are the main pitfalls of previous treatments for T2DM. New therapies have been designed with the aim of improving the results in efficacy and quality of life. Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RA) increase glucose-dependent insulin secretion, decrease gastric emptying, and reduce postprandial glucagon secretion. The last GLP-1 RA approved by the US Food and Drug Administration and European Medicines Agency was semaglutide. This review describes its pharmacology, core clinical data coming from the randomized controlled trials included in the development program, proven cardiovascular benefits, safety issues, and precautions for the use of semaglutide in special populations. Additionally, an overview of the positioning of semaglutide in T2DM therapy and practical issues regarding semaglutide initiation are offered.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

The results of large placebo-controlled clinical trials to evaluate cardiovascular risks associated with drugs for type 2 diabetes mellitus indicated different cardiovascular effects among these drugs, but the detailed design of each trial was not completely the same. The aim of this study was to perform time-matched evaluation of cardiovascular risks of drugs for type 2 diabetes.. We used the difference in restricted mean survival time (RMST) as a measure of cardiovascular risks. Regarding drugs for type 2 diabetes used currently, this study included all 10 clinical trials in patients with type 2 diabetes at high cardiovascular risk the results of which have been published as of 30 November 2018. Since the shortest study follow-up time was about 672 days in SUSTAIN-6, we chose 672 days as a common time point to estimate the RMSTs regarding each safety event.. The differences of RMSTs (drugs for type 2 diabetes minus placebo: point estimate and 95% confidence interval) for major adverse cardiovascular events (MACE) were 8 days (1, 15) for semaglutide, 5 days (1, 9) for liraglutide, and 7 days (2, 13) for empagliflozin. Those for death from cardiovascular causes were 5 days (2, 8) for empagliflozin and 2 days (1, 4) for canagliflozin. Those for death from any cause were 4 days (1, 8) for empagliflozin.. Through the evaluation up to 672 days, semaglutide, liraglutide, and empagliflozin decreased the risk of MACE. Concerning the risk of each cardiovascular event, risk reduction was seen with empagliflozin and canagliflozin.

Topics: Benzhydryl Compounds; Canagliflozin; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Follow-Up Studies; Glucagon-Like Peptides; Glucosides; Humans; Hypoglycemic Agents; Liraglutide; Risk Factors; Survival Rate

The prevalence of obesity and related comorbidities is increasing worldwide. Furthermore, clinically meaningful body weight losses has proven difficult to achieve and especially to maintain through sustained lifestyle change in the form of diet and exercise. Pharmacotherapy against obesity is a non-invasive treatment as an adjunct to lifestyle changes, but approved anti-obesity drugs are currently few. This article reviews the major anti-obesity drugs and the benefit-risk profiles of the long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and semaglutide (a modified version of liraglutide with longer half-life and tripled receptor affinity). Generally, GLP-1 RAs are well tolerated and induce significant weight loss and lowering of comorbidities. Studies with liraglutide 3.0 mg/day have shown an average placebo-subtracted weight loss of 5.5 kg (range 4.6-5.9) in 1- to 3-year duration trials. One trial using semaglutide 0.4 mg once daily reported an average weight loss of 11.6% (~ 13.1 kg) after 1 year. Furthermore, semaglutide induced a ~ 6 percentage point larger placebo-subtracted body weight loss in a head-to-head comparison with liraglutide (11.6 vs. 5.5% weight loss, respectively). The safety profiles for both drugs were similar, with transient gastrointestinal disorders being the most commonly reported adverse events. The longest running trial and the most recent trials have not raised any new safety concerns. Long-term trials and post-marketing surveillance is warranted to fully assess both long-term efficacy and safety. Future combinational therapies of mimicked gut hormones involved in regulation of energy homeostasis and/or additional lifestyle change in the form of exercise might further improve efficacy.

Topics: Animals; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Randomized Controlled Trials as Topic; Risk Assessment

Patients with type 2 diabetes (T2D) have an increased risk of cardiovascular disease. Recent cardiovascular outcome trials (CVOTs) with liraglutide, semaglutide, and albiglutide have shown significant reduction in major adverse cardiovascular events. Conversely, the CVOT with exenatide long-acting release (ELAR) confirmed cardiovascular safety of the drug, but did not reached superiority versus placebo. Herein, we systematically evaluated the effect of ELAR versus placebo or active comparators on cardiovascular events and mortality in patients with T2D.. We screened the literature for randomized controlled trials reporting cardiovascular events and deaths in patients receiving ELAR versus those receiving placebo or any other glucose-lowering medications. Event rates were pooled and compared using the random-effects model.. We retrieved 16 trials comparing the occurrence of cardiovascular events and mortality in patients treated with ELAR versus placebo or active comparators. The pooled rate ratio for cardiovascular events was similar in the two groups (0.99; 95% CI 0.92-1.06). The rate ratio for all-cause mortality was significantly lower in exenatide group than in comparators (0.87; 95% CI 0.77-0.97). When results of the EXSCEL trial were omitted, the pooled rate ratio for cardiovascular events and mortality was 0.80 (95% CI 0.40-1.63) and 0.75 (95% CI 0.30-1.84), respectively.. Treatment with ELAR does not increase the risk of cardiovascular events and may reduce all-cause mortality.

Topics: Cardiovascular Diseases; Cardiovascular System; Cause of Death; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Female; Glucagon-Like Peptides; Humans; Incidence; Liraglutide; Male; Middle Aged; Mortality; Randomized Controlled Trials as Topic

Topics: Blood Glucose; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Risk Factors

Regulatory guidelines describe the use of estimands in designing and conducting clinical trials. Estimands ensure alignment of the objectives with the design, conduct and analysis of a trial. An estimand is defined by four inter-related attributes: the population of interest, the variable (endpoint) of interest, the way intercurrent events are handled and the population level summary. A trial may employ multiple estimands to evaluate treatment effects from different perspectives in order to address different scientific questions. As estimands may be an unfamiliar concept for many clinicians treating diabetes, this paper reviews the estimand concept and uses the PIONEER 1 phase 3a clinical trial, which investigated the efficacy and safety of oral semaglutide vs placebo, as an example of the way in which estimands can be implemented and interpreted. In the PIONEER 1 trial, two estimands were employed for each efficacy endpoint and were labelled as: (a) the treatment policy estimand, used to assess the treatment effect regardless of use of rescue medication or discontinuation of trial product, and provides a broad perspective of the treatment effect in the population of patients with type 2 diabetes in clinical practice; and (b) the trial product estimand, used to assess the treatment effect if all patients had continued to use trial product for the planned duration of the trial without rescue medication, thereby providing information on the anticipated treatment effect of the medication. Both approaches are complementary to understanding the effect of the studied treatments.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Models, Statistical; Randomized Controlled Trials as Topic

To determine the comparative efficacy of once-weekly semaglutide relative to sodium-glucose cotransporter 2 inhibitors (SGLT-2is) licensed in Europe and North America among patients with type 2 diabetes (T2D) inadequately controlled with 1-2 oral antidiabetics (OADs), using a network meta-analysis (NMA). Design systematic review and network meta-analysis. Data Sources EMBASE, MEDLINE and CENTRAL were searched from January 1994 to August 2017.. Randomised controlled trials with ≥20 weeks of treatment evaluating once-weekly semaglutide or SGLT-2is. Primary outcomes included change from baseline in: HbA1c, weight, systolic blood pressure, postprandial blood glucose and fasting plasma glucose. Fixed-effect and random-effect Bayesian NMA were used to indirectly compare treatment effects at 26 (±4) weeks. Metaregression and sensitivity analyses were conducted. Model selection was performed using the deviance information criterion and consistency was assessed by comparing indirect (edge-splitting) to direct evidence.. Forty-eight publications representing 21 trials were included. The mean differences (MD) in change from baseline in HbA1c of once-weekly semaglutide 1.0 mg versus SGLT-2is ranged from -0.56% for canagliflozin 300 mg (95% credible interval (CrI): -0.76 to -0.33%), to -0.95% for dapagliflozin 5 mg (95% CrI: -1.20 to -0.69%). The MD in change from baseline in weight of once-weekly semaglutide 1.0 mg versus SGLT-2is ranged from -1.35 kg for canagliflozin 300 mg to -2.48 kg for dapagliflozin 5 mg, while change from baseline in fasting plasma glucose ranged from -0.41 mmol/L for canagliflozin 300 mg to -1.37 mmol/L for dapagliflozin 5 mg. Once-weekly semaglutide was not statistically differentiable than all SGLT-2is in reducing systolic blood pressure. NMA was not feasible for postprandial blood glucose and safety outcomes.. Once-weekly semaglutide demonstrated statistically significant and clinically meaningful reductions in HbA1c and body weight in T2D patients inadequately controlled with 1-2 OADs compared to all SGLT-2is licensed in Europe and North America.

Topics: Benzhydryl Compounds; Canagliflozin; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glucosides; Humans; Hypoglycemic Agents; Metformin; Network Meta-Analysis; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Cardiovascular disease is the leading cause of death in patients with type 2 diabetes.. To assess the impact of glucagon-like peptide-1 receptor agonist (GLP1RA) therapy, compared to placebo, on clinically relevant outcomes including all-cause mortality, cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, and hospitalizations for heart failure, in patients with type 2 diabetes.. EMBASE, MEDLINE, and CENTRAL were searched (inception to September 2016) for randomized, double-blind, placebo-controlled trials of at least one year in duration that compared any GLP1RA to placebo in patients with type 2 diabetes. Both authors independently completed the literature search, data extraction, and risk of bias assessment. For each outcome, a Risk Ratio (RR) and 95% Confidence Interval (CI) were calculated using a Mantel-Haenszel random effects model.. Eight trials (three albiglutide, two lixisenatide, two liraglutide, one semaglutide) consisting of 21,135 patients were included. Most patients had, or were at high risk for, cardiovascular disease. Follow- up ranged from 1-3.8 years. Trials contributing the majority of data were deemed to have a low risk of bias. The risk of all-cause mortality was lowered by 11% in patients receiving a GLP1RA (RR 0.89, 95% CI 0.81-0.99). There was no statistically significant difference between groups with respect to cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalizations for heart failure.. GLP1RA therapy when compared to placebo reduced all-cause mortality in high cardiovascular risk patients with type 2 diabetes. They did not impact cardiovascular mortality, nonfatal MI, nonfatal stroke, or heart failure hospitalizations.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Peptides; Randomized Controlled Trials as Topic

It is known that Cardiovascular (CV) disease is the leading cause of morbidity and mortality in individuals with type 2 diabetes. Over the last years, one of the most discussed topics is the CV safety of anti-diabetic medications. Regarding CV safety of older antidiabetic agents the data are less clear and conclusions about their CV safety are mostly based on randomized controlled trials designed to assess their glucose lowering efficacy. In this review, we summarize the current knowledge about the CV safety of older and newer antidiabetic medications. According to the published literature metformin is the first line agent for the treatment of type 2 diabetes and seems to have cardio-protective effects. The choice of the second line agent when metformin monotherapy fails to achieve HbA1c targets is less clear. In the light of the findings of the EMPA-REG OUTCOME trial and the recently published LEADER and SUSTAIN 6 trials, empagliflozin, liraglutide and semaglutide seem reasonable options as second line agents for patients with CV disease. Sulfonylureas on the other hand, with the exception of gliclazide, should be avoided in those patients, although CV safety trials are still lacking. In individuals without CV disease any of the other classes of anti-diabetic medication can be selected on a patient-centered approach. Saxagliptin, alogliptin, sitagliptin and lixisenatide have been evaluated in CV safety trials and have neutral effects on CV outcomes, while pioglitazone may have some CV benefits. Saxagliptin and alogliptin, however, should be avoided in patients with heart failure, while pioglitazone is contraindicated in this population.

Topics: Benzhydryl Compounds; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptides; Glucosides; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Metformin; Pioglitazone; Sodium-Glucose Transporter 2

Cardiovascular disease (CVD) is the major cause of morbidity and mortality for individuals with type 2 diabetes (T2D). In particular, the risk for stroke is twice that of patients without diabetes, and diabetes may be responsible for >8% of first ischemic strokes. Therefore, the way to prevent stroke in these patients has become an important issue. Traditionally, glucose-lowering drugs had not been shown to protect against stroke. Moreover, several antidiabetic drugs (i.e., sulfonylureas, rosiglitazone) have been reported to be associated with increased risks of CVD and stroke. On the contrary, data on the CV risks and benefits associated with new antidiabetic treatment in patients with T2D are emerging - and look promising. Therefore, it could be of great value to find out if any type of these new antidiabetic agents has protective effect against stroke. We review the available evidence regarding the risk of stroke in individuals taking non-insulin antidiabetic agents. To date, several antidiabetic agents have shown to have a positive effect on stroke prevention. The accumulated evidence suggests that metformin, pioglitazone and semaglutide reduce stroke risk. These agents do not represent only a way of controlling blood glucose and but also offer the opportunity to reduce stroke risk. Surely, new data from ongoing and future studies will provide additional information to select the best treatment for decreasing stroke risk in T2D patients.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Metformin; Pioglitazone; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Thiazolidinediones

Novo Nordisk has developed a subcutaneous formulation of semaglutide (Ozempic

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Approval; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin

The incretin therapies glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-IV (DPP-IV) inhibitors are now well-established as second and third-line therapies and in combination with insulin for the treatment of type 2 diabetes. Over the last decade, there is accumulating evidence of their efficacy and safety from both large multicentre randomized clinical trials (RCT) and observational studies. Cardiovascular outcome trials have confirmed that several of these agents are also non-inferior to placebo with the GLP-1 RA liraglutide and semaglutide recently found to be superior in terms of major adverse cardiovascular events. Observational studies and post-marketing surveillance provide real world evidence of safety and effectiveness of these agents and have provided reassurance that signals for pancreatitis and pancreatic cancer seen in clinical trials are not of major concern in large patient populations. Well-designed real world studies complement RCTs and systematic reviews but appropriate data and methodologies, which are constantly improving, are necessary to answer appropriate clinical questions relating to the use of incretin therapies.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Meta-Analysis as Topic; Observational Studies as Topic; Product Surveillance, Postmarketing; Treatment Outcome

It is critical for individuals with type 2 diabetes mellitus (T2DM) to maintain optimal glycemia while avoiding hypoglycemia, control body weight, and reduce cardiovascular risk. The GLP-1 receptor agonists stimulate glucose-dependent insulin release (low risk of hypoglycemia), inhibit glucagon secretion, slow gastric emptying and suppress appetite (weight loss). The new members of the class are available as once daily or weekly injections. Additionally, some members of the class have demonstrated reduced cardiovascular risk. Areas covered: This manuscript describes semaglutide - a new investigational long acting GLP-1 receptor agonist. The key trials from the clinical development process are reviewed and important end-points highlighted. Expert opinion: Once-weekly semaglutide has shown superiority in reducing glycosylated hemoglobin and body weight in comparison with placebo and active comparators when used as monotherapy or in combination treatment. In addition, semaglutide improved markers of β-cell function and have shown cardiovascular risk reduction similar to once daily liraglutide. Although, overall semaglutide safety was comparable to other GLP-1 receptor agonists (low risk of hypoglycemia and high frequency of gastrointestinal side effects), increase in retinopathy complications requires further investigation.

Topics: Blood Glucose; Body Weight; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous

Glucagon-like peptide-1 (GLP-1) is produced by the gut, and in a glucose-dependent manner stimulates insulin secretion while inhibiting glucagon secretion, reduces appetite and energy intake, and delays gastric emptying. The GLP-1R agonist semaglutide has recently been registered to treat type 2 diabetes. Area covered: This review is of semaglutide in type 2 diabetes, and considers which properties of this GLP-1R agonist, may be responsible for its clinical outcome benefits . Expert opinion: The pharmacokinetics of semaglutide make it ideal for once-weekly dosing. SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) showed that semaglutide 0.5 or 1 mg subcutaneously once-weekly reduced cardiovascular outcomes in subjects with type 2 diabetes and cardiovascular disease or risk, mean age 65 years, baseline HbA1c 8.7% and mean body weight of 92 kg. Although, semaglutide may be a useful drug in this population, it increased retinopathy to a small extent and this needs further investigation. Also, it is not known whether semaglutide will improve cardiovascular outcomes in other populations including those with lower ages, HbA1c values, and body weights similar to those included in the unsuccessful clinical outcome trials with the GLP-1R agonists, lixisenatide and exenatide.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion

The final goal in the management of patients with type 2 diabetes (T2D) is reduction in cardiovascular (CV) complications and total mortality. Various factors including hyperglycemia contribute to these complications and mortality directly and indirectly. In recent years, large-scale CV outcome trials with new antidiabetic medications, such as dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP1) receptor agonists, and sodium glucose cotransporter-2 (SGLT2) inhibitors, have been completed. Most clinical trials with DPP4 inhibitors have shown no inferiority compared with placebo treatments in terms of CV safety. However, they did not show benefits in terms of adverse CV events or mortality. CV outcome trials with GLP1 receptor agonists showed inconsistent results: lixisenatide did not show benefits in preventing major adverse CV events. In contrast, liraglutide and semaglutide (longer acting GLP1 receptor agonists) proved to be superior in terms of alleviating CV morbidity and mortality. Two large-scale CV outcome trials with SGLT2 inhibitors showed significant results: empagliflozin proved to be superior in preventing CV and all-cause mortality, and canagliflozin proved to be superior in preventing CV mortality but not all-cause mortality. So far, controlling cardiometabolic risk factors such as hemodynamic changes and weight loss by SGLT2 inhibitors are suggested to be the main mechanisms for these results. However, the risk-benefit profile for these new drugs will need further elucidation, and more studies are warranted to reveal the possible mechanisms. It will also be important to confirm these results from other ongoing trials with SGLT2 inhibitors.

Topics: Albuminuria; Atherosclerosis; Benzhydryl Compounds; Body Weight; Canagliflozin; Cardiovascular Diseases; Cardiovascular System; Glucagon; Glucagon-Like Peptides; Glucosides; Heart Failure; Hemodynamics; Humans; Hypoglycemic Agents; Ketones; Lipids; Liraglutide; Metabolic Syndrome; Metformin; Non-alcoholic Fatty Liver Disease; Osmosis; Risk Factors; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

It is a great challenge for type 2 diabetes mellitus (T2DM) patients to maintain optimal glycemia, control body weight, blood pressure, and avoiding hypoglycemia. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) can stimulate glucose-dependent insulin while inhibit glucagon secretion, delay gastric emptying, reduce appetite, and energy intake. Recently, a new once-weekly GLP-1 RAs, semaglutide, has been registered to treat patients with T2DM.. We will search Medline, Embase, Cochrane Library, and the ClinicalTrials.gov Website up to February 2018. Studies will be screened by title, abstract, and full text independently in duplicate. Phase III randomized controlled trials (RCTs) reports efficacy and safety data of semaglutide will be eligible for inclusion. Outcome variables will be assessed included glycemic control indexes (glycosylated hemoglobin [HbA1c]%, fasting plasma glucose [FPG], self-monitoring of blood glucose [SMPG], postprandial self-monitoring of blood glucose [PSMPG]), blood pressure indexes (systolic blood pressure [SBP], diastolic blood pressure [DBP], and pulse rate), body weight control indexes (body weight, body mass index [BMI], and waist circumference), and any adverse events (including adverse events [AEs] varying degrees and AEs occurring in ≥5% patients by preferred term or other of clinical interest). Assessment of risk of bias and data synthesis will be performed using STATA software (version 12, Statacorp, College Station, Texas). Outcomes will report by weight mean difference (WMD) and risk ratios (RRs) and their 95% confidence intervals (95% CIs). Heterogeneity among studies will be evaluated using the I statistic.. This review will evaluate glycemic, blood pressure, body weight control, and any adverse events of semaglutide as compared with other therapies.. Our study will provide a comprehensive picture of semaglutide in T2DM.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Middle Aged; Systematic Reviews as Topic

To assess the efficacy and safety of semaglutide, a recently approved glucagon-like peptide 1 receptor agonist (GLP-1 RA) for type 2 diabetes.. We searched major electronic databases and grey literature sources for randomized controlled trials comparing semaglutide with placebo or other antidiabetic agents. Primary outcome was change from baseline in HbA1c. Secondary endpoints included change from baseline in body weight, blood pressure, heart rate and incidence of hypoglycaemia, gastrointestinal adverse effects, pancreatitis and diabetic retinopathy.. A total of 6 placebo-controlled and 7 active-controlled studies with subcutaneous semaglutide were included. We identified only 1 trial with oral semaglutide. Compared with placebo, subcutaneous semaglutide 0.5 and 1 mg reduced HbA1c by 1.01% (95% CI, 0.56-1.47) and 1.38% (1.05-1.70), respectively. Both doses demonstrated superior glycaemic efficacy compared to other antidiabetic agents, including sitagliptin, exenatide, liraglutide, dulaglutide and insulin glargine. Semaglutide also had a beneficial effect on body weight (mean difference vs placebo -4.11 kg, 95% CI -4.85 to -3.37 for semaglutide 1 mg) and systolic blood pressure. We did not observe increased hypoglycaemia rates with semaglutide; nevertheless, we noted an increased incidence of nausea, vomiting and diarrhoea. Cases of pancreatitis were infrequent and the odds ratio for diabetic retinopathy compared with placebo was 1.32 (95% CI, 0.98-1.77).. Semaglutide is a potent once-weekly GLP-1 RA, significantly reducing HbA1c, body weight and systolic blood pressure. However, it is associated with increased incidence of gastrointestinal adverse events. Results for pancreatitis and retinopathy require further assessment in post-approval pharmacovigilance studies.

Topics: Blood Glucose; Body Weight; Controlled Clinical Trials as Topic; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Treatment Outcome

Treatment intensification with additional anti-diabetic agents is recommended in type 2 diabetes (T2D) for patients inadequately controlled on metformin monotherapy. The present network meta-analysis (NMA) evaluated comparative efficacy and safety of once-weekly semaglutide and sodium-glucose co-transporter 2 inhibitors (SGLT-2is) in T2D patients inadequately controlled with metformin.. Randomized controlled trials with ≥20 weeks duration were searched in EMBASE, MEDLINE, and CENTRAL. Primary efficacy outcomes were: change from baseline in HbA. Eight trials were found eligible for this NMA. Statistically significant reductions in HbA1c were observed with both 1.0 mg and 0.5 mg doses of once-weekly semaglutide when compared to SGLT-2is. The mean differences in change from baseline in HbA. Once-weekly semaglutide treatment is significantly better compared to SGLT-2is in achieving adequate glycemic control in T2D patients inadequately controlled with metformin monotherapy.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Metformin; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Type 2 diabetes mellitus (T2DM) is a metabolic condition with an elevated impact on cardiovascular (CV) risk. The innovative therapeutic approaches for T2DM - incretin-based therapies (IBTs), including glucagon-like peptide 1 (GLP-1) receptor agonists, have become popular and more widely used in recent years. The available scientific data from clinical studies and clinical practice highlights their beyond glucose-lowering effects, which is achieved without any increase in hypoglycaemia. The former effects include reduction in body weight, lipids, blood pressure, inflammatory markers, oxidative stress, endothelial dysfunction, and subclinical atherosclerosis, thus reducing and potentially preventing CV events. In fact, the introduction of IBTs is one of the key moments in the history of diabetes research and treatment. Such therapeutic strategies allow customization of antidiabetic treatment to each patient's need and therefore obtain better metabolic control with reduced CV risk. The aim of the present paper is to provide a comprehensive overview of the effects of GLP-1RA on various cardiometabolic markers and overall CV risk, with particular attention on recent CV outcome studies and potential mechanisms. In particular, the effects of liraglutide on formation and progression of atherosclerotic plaque and mechanisms explaining its cardioprotective effects are highlighted.

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Plaque, Atherosclerotic

Type 2 diabetes (T2D) is a debilitating condition and more people are being diagnosed each year. T2D increases patients' risk of developing disabling micro- and macrovascular complications, significantly reduces patients' quality of life, and is a substantial global economic burden. The efficacy and safety of antihyperglycemic therapies have improved over the years and have increased the lifespan for these patients. Consequently, patients are living longer with the condition and the associated comorbidities, but with a lowered quality of life. Therefore, therapies should aim to provide both optimal glycemic control and improve quality of life. Glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy improves glycemic control, reduces body weight, and has a low risk for hypoglycemia. GLP-1 RAs are available as once-daily (OD), twice-daily (BD), or once-weekly (OW) injectable formulations; OW injections may increase patients' satisfaction and improve treatment adherence. In the last decade, concern has been raised about the cardiovascular (CV) safety of antihyperglycemic therapies. Clinical data have been limited on CV outcomes among OW GLP-1 RAs. However, a post hoc analysis of the SUSTAIN-6 trial suggested that semaglutide, the most recently US Food and Drug Administration (FDA)-approved OW GLP-1 RA therapy, may offer cardioprotection, addressing this previously unmet clinical need.

Topics: Cost of Illness; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glucagon-Like Peptides; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Medication Adherence; Quality of Life; Recombinant Fusion Proteins

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are indicated for restoring normoglycemia in patients with type 2 diabetes (T2D). This review analyzed and compared the efficacy results from 30 trials with the once-weekly (OW) GLP-1 RAs albiglutide, dulaglutide, exenatide extended-release (ER) and semaglutide. The 4 OW GLP-1 RAs showed a higher reduction in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG) and body weight, when compared to placebo. Semaglutide significantly reduced the HbA1c level (estimated treatment difference [ETD]: -0.62%; 95% confidence interval [CI], -0.79 to -0.44; P<0.0001), FPG (ETD: -15 mmol/L; 95% CI, -22 to -8.3; P<0.0001) and body weight (ETD: -3.73 kg; 95% CI, -4.53 to -2.93; P<0.0001) compared with exenatide ER. A direct comparison between OW, once-daily (OD), and twice-daily (BD) GLP-1 RAs indicated some trends in efficacy, for example, with OD liraglutide, providing a significant reduction in body weight vs albiglutide (ETD: 1.55 kg; 95% CI, 1.05-2.06; P<0.0001 for albiglutide), dulaglutide (ETD: 0.71 kg; 95% CI, 0.17 -1.26; P=0.011 for dulaglutide), and exenatide ER (ETD: 0.90 kg; 95% CI, 0.39- 1.40; P=0.0005 for exenatide ER). OW GLP-1 RAs also offered improved glycemic control when compared with the dipeptidyl peptidase-4 inhibitor sitagliptin. In conclusion, OW GLP-1 RAs offer a valid therapeutic option for T2D.

Topics: Blood Glucose; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Monitoring; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Treatment Outcome

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been found efficacious in the treatment of type 2 diabetes (T2D), demonstrating the ability to lower HbA1c, and having the potential for inducing weight loss and reducing the risk of hypoglycemia, compared with other antihyperglycemic agents. Currently, 4 once-weekly (OW) GLP-1 RAs are approved: albiglutide, dulaglutide, exenatide ER, and recently, semaglutide. This review compares the relative safety of OW GLP-1 RAs, as well as their safety in comparison to other antihyperglycemic agents, using safety data reported in key sponsor-led phase 3 studies of the 4 OW GLP-1 RAs. The favorable safety profiles of OW GLP-1 RAs, added to their efficacy and the favorable weekly dosing regimen, make these agents appropriate options for patients with T2D. However, there are key differences within this class of drugs in macrovascular, microvascular, gastrointestinal and injection-site reaction adverse events, and these should be considered when healthcare providers are prescribing therapy.

Topics: Blood Glucose; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Monitoring; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Treatment Outcome

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) came to market in the year 2005, as a new therapeutic classification, for clinical use in the management of type 2 diabetes mellitus (T2DM). Since 2005, there have been six approved products on the market, with the newest product being semaglutide (Novo Nordisk). Several studies have been conducted and completed evaluating its pharmacokinetics as a once-weekly subcutaneous injection. As a dose of 0.5 or 1 mg, semaglutide has a half-life of 7 days; therefore, it would reach steady state in 4-5 weeks. There are few drug interactions and dose adjustments are not necessary. However, similar to other GLP-1 RAs, semaglutide can delay gastric emptying and may impact the absorption of oral medications. Based on clinical trials, semaglutide has been compared with placebo, sitagliptin, exenatide extended release, and insulin glargine as monotherapy or add-on therapy. Semaglutide has resulted in a 1.5-1.9% glycosylated hemoglobin A

Topics: Animals; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Half-Life; Humans; Hypoglycemic Agents; Injections, Subcutaneous

To review efficacy and safety of the glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide for type 2 diabetes (T2D).. A literature search of PubMed/MEDLINE and EMBASE using the term semaglutide was completed through April 2018. A search of clinicaltrials.gov was also conducted.. English-language studies assessing the efficacy and/or safety of semaglutide were evaluated.. Semaglutide is a newly approved GLP-1 RA for the treatment of T2D. Administered once weekly at a dose of 0.5 or 1 mg, it has been compared with placebo, sitagliptin, insulin glargine, a combination of oral antidiabetic therapies, and 2 GLP-1 RAs, exenatide ER and dulaglutide, and demonstrated greater efficacy compared with these therapies. Published data from studies ranging from 30 to 104 weeks duration demonstrate efficacy with decreases in hemoglobin A1C (A1C) ranging from 1.1% to 2.2%. Studies show reductions in weight from 1.4 to 6.5 kg. Semaglutide demonstrated a reduction in the composite outcome of cardiovascular (CV) death, nonfatal myocardial infarction, or nonfatal stroke compared with placebo in patients at high risk of CV events (hazard ratio = 0.74; P = 0.02). Common adverse effects include nausea, vomiting, and diarrhea as seen with other GLP-1 RAs. Relevance to Patient Care and Clinical Practice: Semaglutide represents an attractive GLP-1 RA considering its A1C and weight reduction. It provides patient convenience and high patient satisfaction.. Semaglutide is an appealing option for the treatment of T2D as a once-weekly GLP-1 RA with established glycemic, CV, and weight benefits.

Topics: Blood Glucose; Body Weight; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Weight Loss

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are an important asset in the armamentarium for the treatment of type 2 diabetes mellitus (type 2 DM). Incretin failure is a critical etiopathogenetic feature of type 2 DM, which, if reversed, results in improved glycaemic control. GLP-1 RAs are injectable peptides that resemble the structure and function of endogenous incretin GLP-1, but as they are not deactivated by the dipeptidyl peptidase-4 (DPP-4), their half-life is prolonged compared with native GLP-1. Based on their ability to activate GLP-1 receptor, GLP-1 RAs are classified as short-acting (exenatide twice-daily and lixisenatide once-daily), and long-acting (liraglutide once-daily and the once-weekly formulations of exenatide extended-release, dulaglutide, and albiglutide). Semaglutide, another long-acting, once-weekly GLP-1 RA, was recently approved by the FDA and EMA. Although all of these agents potently reduce haemoglobin A1C (HbA1c), there are unique features and fundamental differences among them related to fasting and postprandial hyperglycaemia reduction, weight loss potency, cardiovascular protection efficacy, and adverse events profile. It is imperative that current evidence be integrated and applied in the context of an individualised patient-centred approach. This should include not only glucose management but also targeting as many as possible of the pathophysiologic mechanisms responsible for type 2 DM development and progression.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Recombinant Fusion Proteins

To investigate the safety and efficacy of once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide as monotherapy or add-on to other antihyperglycaemic agents (AHAs) in patients with type 2 diabetes mellitus (T2DM).. PubMed, Embase, Cochrane library and ClinicalTrials.gov were searched from the inception to January 18, 2018. Randomised controlled trials (RCTs) comparing semaglutide with placebo or other AHAs in T2DM patients were included in our meta-analysis. Risk ratio (RR) and mean difference (MD) with 95% confidence intervals (CI) were used to evaluate the outcomes.. A total of 11 studies with 9519 patients were included in our meta-analysis. The results revealed that compared with placebo or other AHAs, semaglutide had further reduced the level of haemoglobin A1c (HbA1c) [MD 1.03%, 95% CI (0.85%, 1.22%), p < 0.00001], self-measured plasma glucose (SMPG) [MD 1.19 mmol/L, 95% CI (0.84 mmol/L, 1.53 mmol/L), p < 0.00001], fasting plasma glucose (FPG) [MD 1.33 mmol/L, 95% CI (0.97 mmol/L, 1.69 mmol/L), p < 0.00001] and weight [MD 3.61 kg, 95% CI (3.05 kg, 4.17 kg), p < 0.00001] and significantly increased participants who achieved HbA1c < 7.0% [RR 2.26, 95% CI (1.89, 2.70), p < 0.00001] in T2DM patients. Semaglutide had a significant increase in the incidence of adverse events (AEs) [RR 1.06, 95% CI (1.02, 1.11), p < 0.0001] and an analogous incidence in serious adverse events (SAEs) [RR 0.94, 95% CI (0.86, 1.02), p = 0.11] and hypoglycaemic events (severe or blood glucose (BG)-confirmed symptomatic) [RR 0.93, 95% CI (0.74, 1.16), p = 0.50] compared with the control group.. This article revealed that semaglutide had a favourable efficacy and safety in treating T2DM patients. It maybe a superior choice for T2DM patients who have obesity or a poor adherence to daily AHAs.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Treatment Outcome

Type 2 diabetes (T2D) carries risks of both cardiovascular (CV) (myocardial infarction, stroke, and peripheral vascular disease) and microvascular (retinopathy/nephropathy/neuropathy) complications. Glucose-lowering is an effective strategy for preventing microvascular complications, but the extent to which it can reduce CV complications is less certain. Glucagon-like peptide-1 (GLP-1) agonists are potent glucose-lowering agents but also have potentially beneficial effects on other traditional (body weight, blood pressure (BP), and LDL cholesterol) and non-traditional risk factors (low grade inflammation and endothelial dysfunction). The results of four large CV outcome trials with GLP-1 agonists are now available. These have compared lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), and long-acting exenatide (EXSCEL) with placebo and standard of care over 2-4 years; four others (including with dulaglutide and albiglutide) are ongoing. LEADER and SUSTAIN-6 have demonstrated reductions in rates of major adverse CV events with active GLP-1 treatment but ELIXA and EXSCEL have not. In this review, we discuss the mechanisms by which GLP-1 receptor agonists act on the CV system and the design and conduct of these trials. Contrary to the assertions that (a) all GLP-1 agonists reduce CV disease in T2D but to different extents or (b) the magnitude of CV protection is predominantly related to glucose-lowering, we argue that CV benefit is specific to agents that provide longer acting agonism at the GLP-1 receptor. The mechanisms involve reduction in body weight and BP, and lowering of LDL-cholesterol and glucose, but pleiotropic effects-including suppression of low grade inflammation, vasodilation, and natriuresis-are also likely relevant.

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Peptides

This article provides an overview of the efficacy and safety of once-weekly glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in the treatment of type 2 diabetes mellitus (T2DM). GLP-1 RAs stimulate pancreatic GLP-1 receptors, which increases insulin secretion, delays gastric emptying, and increases satiety. As a class, GLP-1 RAs lower A1c levels and have been associated with reductions in weight and blood pressure and reduced fluctuations in glucose levels, and they have a low risk of hypoglycemia. Exenatide extended release (ER) and dulaglutide monotherapy have shown similar or superior reductions in A1c and weight compared with various oral antidiabetic drugs (OADs). Semaglutide has been shown to reduce both A1c and body weight compared with placebo and, in head-to-head studies versus both exenatide ER and dulaglutide, showed greater reductions in A1c and body weight. Once-weekly GLP-1 RAs have also been evaluated as add-on therapy in the continuum of care for the treatment of T2DM in combination with a variety of background medications, including 1 or more OADs (metformin, sulfonylureas, and/or thiazolidinediones), basal insulin, and prandial insulin. Gastrointestinal adverse events (e.g., nausea, vomiting, and diarrhea) are the most common side effects with once-weekly GLP-1 RAs. Rates of hypoglycemia, and especially major/severe hypoglycemia, are low with once-weekly GLP-1 RAs but, as expected, are higher when used in combination with sulfonylureas or insulin. These once-weekly GLP-1 RAs provide a safe and effective treatment option for patients with T2DM and may offer improved convenience and possibly greater adherence compared with daily GLP-1 RAs.. This supplement was funded by Novo Nordisk. Handelsman reports research grants from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Grifols, Janssen, Lexicon, Merck, Novo Nordisk, Regeneron, and Sanofi; speaker fees from Amarin, Amgen, AstraZeneca, Boehringer Ingelheim-Lilly, Janssen, Merck, Novo Nordisk, Regeneron, and Sanofi; and has served in advisory capacity to Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eisai, Intarcia, Janssen, Lilly, Merck, Merck-Pfizer, Novo Nordisk, Regeneron, and Sanofi. Cannon reports speaker fees and owns stock in Novo Nordisk. Shannon reports consultant and speaker fees from Novo Nordisk and Boehringer Ingelheim-Lilly Alliance. Schneider reports advisory board fees from Intarcia, Lilly, and Novo Nordisk. Wyne has nothing to disclose.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycemic Index; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins; Treatment Outcome

Technological Innovations in Diabetes Therapy Abstract. In the last few years a whole array of technical innovations has dramatically increased treatment options for patients with diabetes mellitus. Capillary blood glucose measurements are increasingly replaced by continuous glucose monitoring. More and more insulin pump systems are linked up to continuous glucose monitoring, which thereby become ever more self-regulating. Novel ultra-long and ultra-short acting insulins have become available. There will soon be oral alternatives for several anti-diabetic treatments, which hitherto needed to be injected.. Zusammenfassung. Über die vergangenen Jahre hat eine wahre Flut an technologischen Innovationen die Behandlungsmöglichkeiten für Menschen mit Diabetes mellitus drastisch erweitert. Die kapilläre Blutzuckermessung wird nach und nach durch die kontinuierliche Glukosemessung ersetzt. Immer mehr Insulinpumpen-Systeme werden an kontinuierliche Glukosemessung gekoppelt und dadurch zunehmend selbstregulierend. Neue ultra-lang und -kurz wirksame Insuline sind erhältlich. Für mehrere anti-diabetische Wirkstoffgruppen, die bisher injiziert werden mussten, gibt es bald orale Alternativen.

Topics: Administration, Oral; Blood Glucose Self-Monitoring; Clinical Trials, Phase III as Topic; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Insulin Infusion Systems; Inventions; Pancreas, Artificial

Semaglutide once-weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) injection has been approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM). Areas Covered: The safety and efficacy of the semaglutide once-weekly injection are reviewed using results from preliminary pharmacology studies and later-phase randomized control trials (RCTs) and meta-analyses. Semaglutide once-weekly is compared to placebo and active comparators for T2DM in the SUSTAIN clinical trial series, with outcomes of: glycemic control, weight loss, major adverse cardiovascular events, and adverse effects. Risk for diabetic retinopathy complications (DRCs) is reviewed in detail, due to significantly higher risk for DRCs seen in SUSTAIN 6. SUSTAIN 6 is the first instance of a GLP-1 RA demonstrating significantly increased risk for DRCs. Semaglutide's current regulatory approvals, practice considerations, and cost-effectiveness compared to similar therapies are also considered. Expert Commentary: Semaglutide demonstrates high glycemic efficacy and favorable safety profile, and reduces the risk for cardiovascular events. Mild to moderate gastrointestinal events and retinopathy complications were more common with semaglutide compared to placebo, though serious adverse events were similar to controls and infrequent. Improved clinical efficacy should be carefully weighed against the risk for GI and retinopathy complications.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Drug Administration Schedule; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic

Considering the causative or contributory effects of diabetes mellitus on common neurological diseases such as polyneuropathy, stroke and dementia, modern antidiabetic drugs may be expected to reduce incidence or progression of these conditions. Nevertheless, most observed benefits have been small, except in the context of therapy for diabetes mellitus type I and new-onset polyneuropathy. Recently, semaglutide, a GLP-1 analog, has been shown to significantly reduce stroke incidence in a randomized controlled trial. Beneficial effects of antidiabetic drugs on stroke severity or outcome have been controversial, though. The level of risk conferred by diabetes mellitus, the complex pathophysiology of neurological diseases, issues of trial design, side-effects of antidiabetic drugs as well as co-medication might be interacting factors that determine the performance of antidiabetic therapy with respect to neurological outcomes. It might be speculated that early treatment of prediabetes might prevent cerebral arteriosclerosis, cognitive decline or polyneuropathy more effectively, but this remains to be demonstrated.

Topics: Dementia; Diabetes Mellitus; Diabetic Neuropathies; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Stroke

Glucagon-like peptide 1 receptor (GLP-1R) agonists are increasingly being used as treatment for type 2 diabetes. Since the U.S. Food and Drug Administration published recommendations about the cardiovascular safety of new antidiabetes therapies for treating type 2 diabetes in 2008, the results of two outstanding clinical trials using GLP-1R agonists addressing this issue (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results-A Long Term Evaluation [LEADER] and Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes [SUSTAIN-6]) have been published. Both studies found beneficial effects in terms of reducing the rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. However, their results regarding the progression of diabetic retinopathy (DR) were neutral with liraglutide (LEADER) or worse when compared with placebo in the case of semaglutide (SUSTAIN-6). These results are surprising because of the beneficial effects of GLP-1R analogs reported in experimental models of DR. In this Perspective, an overview of the mechanisms by which GLP-1R activation exerts its effects in preventing or arresting experimental DR is given. In addition, we consider the possible reasons for the negative results regarding the progression of DR in the SUSTAIN-6 study, as well as the gaps that still need to be covered to further clarify this important issue in the management of type 2 diabetes.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Disease Models, Animal; Disease Progression; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Molecular Targeted Therapy; Myocardial Infarction; Stroke; Treatment Outcome

The U.S. Food and Drug Administration (FDA) issued a diabetes guidance in 2008 mandating that all new antidiabetes drugs rule out excess cardiovascular (CV) risk, defined as an upper bound of the two-sided 95% CI for major adverse CV events (MACE) of less than 1.80 preapproval and 1.30 postapproval. Over 25 large, prospective, randomized, controlled clinical trials involving nearly 195,000 subjects thus far have been completed or are ongoing in accordance with this guidance. The results of seven trials have been presented so far-three with dipeptidyl peptidase 4 inhibitors, one with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and three with glucagon-like peptide 1 receptor agonists (GLP-1 RA). While all seven trials showed noninferiority in the rate of MACE with the use of these agents compared with placebo, three of them revealed CV benefits. Treatment with empagliflozin (an SGLT2 inhibitor) and treatment with liraglutide (a GLP-1 RA) both significantly reduced the risk of MACE, mortality from CV causes, and mortality from any cause when compared with placebo. Treatment with semaglutide, another GLP-1 RA, showed a significantly lower rate of MACE but not mortality from CV or any cause compared with placebo. In all of the trials, the effects of treatment on outcomes were out of proportion to the small differences in glycemic control levels, suggesting that the effects observed were likely unrelated to differences in the glucose-lowering efficacy. Overall, the results of these trials yield a favorable benefit-risk balance for these therapies in mitigating CV risk in patients with type 2 diabetes. More research is needed to elucidate the underlying mechanisms and confirm whether the CV benefits are a class effect or whether the benefits persist in patients without established CV disease or are evident even in patients without diabetes.

Topics: Animals; Benzhydryl Compounds; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptides; Glucosides; Humans; Hypoglycemic Agents; Liraglutide; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome

Type 2 diabetes is a chronic metabolic disease characterized by persistent hyperglycemia resulting from progressive deficient of insulin in patients with a background of insulin resistance. Current treatment algorithms recommended by American Diabetes Association/The European Association for the Study of Diabetes promote a patient-centered approach that takes into account a comprehensive consideration of pharmacological properties of drugs, including glucose-lowering action, effects on body weight, correction on multiple pathophysiologic defects, tolerability, and long-term safety. Glucagon-likepeptide1 (GLP-1) receptor analogues are appealing due to the improved glycemic control in a glucose-dependent manner, modest weight loss and low risk of hypoglycemia. Areas covered: Semaglutide (Novo Nordisk), a once-weekly GLP-1 analogue, is currently in the phase III clinical trial for the treatment of type 2 diabetes. This article aims to review the pharmacological and clinical profiles of semaglutide based on the available clinical data. Expert opinion: Semaglutide achieved greater reduction from baseline in HbA

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance

Glucagon-like peptide-1 receptor agonist (GLP-1RAs) labels warn about acute pancreatitis (AP) and impose upon doctors the obligation to inform patients about symptoms of AP. Here we systematically reviewed the risk of AP in randomized placebo-controlled trials (RCTs) investigating the effect of GLP-1RAs in type 2 diabetes. We performed a systematic review with meta-analysis of long-term (minimum 24 months), placebo-controlled GLP-1RA RCTs in which AP was a predefined adverse event and adjudicated by blinded and independent adjudicating committees. Three high-quality RCTs included a total of 9347 GLP-1RA-treated and 9353 placebo-treated patients with type 2 diabetes. Compared to placebo, treatment with GLP1-RA was not associated with increased risk of AP (Peto odds ratio 0.745 [95% CI, 0.47-1.17]). Trial Sequential Analysis suggested that additional evidence is needed. In conclusion, this review found no evidence that treatment with GLP-1RA increases the risk of AP in patients with type 2 diabetes.

Topics: Acute Disease; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Odds Ratio; Pancreatitis; Peptides; Randomized Controlled Trials as Topic; Risk Factors

Recently, cardiovascular outcome trials with glucose-lowering drugs used in type 2 diabetes mellitus, namely glucagon-like peptide-1 receptor agonists (GLP-1RA), liraglutide and semaglutide, showed a reduction in cardiovascular events, which had not been observed in trials with other incretin-based drugs, such as lixisenatide or with dipeptidyl peptidase-4 inhibitors (DPP4i). Mechanisms underlying the observed cardiovascular differences between DPP4i and GLP1-RA, and across individual GLP1-RA are poorly understood. This review is aimed at collecting and summarizing available evidence from experimental and mechanistic studies on the action of GLP1-RA and DPP4i on the cardiovascular system, both deriving from clinical and pre-clinical sources. The results of cardiovascular outcome trials are interpreted on the basis of the experimental preclinical data available, paying particular attention to the heart failure results, and suggesting some novel intriguing hypotheses to explain some of the unexpected findings of cardioprotection of incretin-based drugs. In particular, we discuss the possible contribution to the incretin cardiovascular effects of a direct cardiac action of GLP-1 metabolites through GLP-1 receptor-independent pathways, and of DPP4 substrates other than GLP-1.

Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Incretins; Liraglutide; Treatment Outcome

Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce the risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We report the design and baseline data for FLOW (NCT03819153), a trial investigating the effects of semaglutide, a once-weekly (OW) GLP-1RA, on kidney outcomes in participants with CKD and T2D.. FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial. Participants with T2D, estimated glomerular filtration rate (eGFR) ≥50‒≤75 ml/min/1.73 m2 and urine albumin:creatinine ratio (UACR) >300‒<5000 mg/g or eGFR ≥25‒<50 ml/min/1.73 m2 and UACR >100‒<5000 mg/g were randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with renin-angiotensin-aldosterone system blockade (unless not tolerated/contraindicated). The composite primary endpoint is time to first kidney failure (persistent eGFR <15 ml/min/1.73 m2 or initiation of chronic kidney replacement therapy), persistent ≥50% reduction in eGFR or death from kidney or CV causes.. Enrolled participants (N = 3534) had a baseline mean age of 66.6 years [standard deviation (SD) 9.0], haemoglobin A1c of 7.8% (SD 1.3), diabetes duration of 17.4 years (SD 9.3), eGFR of 47.0 ml/min/1.73 m2 (SD 15.2) and median UACR of 568 mg/g (range 2‒11 852). According to Kidney Disease: Improving Global Outcomes guidelines categorisation, 68.2% were at very high risk for CKD progression.. FLOW will evaluate the effect of semaglutide on kidney outcomes in participants with CKD and T2D, and is expected to be completed in late 2024.

Topics: Aged; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Kidney; Renal Insufficiency, Chronic

To investigate the effects of switching from liraglutide or dulaglutide to once-weekly semaglutide on glycaemic control and treatment satisfaction in patients with type 2 diabetes.. In this multicentre, open-labelled, prospective, randomized, parallel-group comparison study, patients treated with liraglutide 0.9-1.8 mg/day (plan A) or dulaglutide 0.75 mg/week (plan B) were either switched to semaglutide or continued current therapy. The primary endpoint was the mean change in glycated haemoglobin over 24 weeks. The secondary endpoints included the changes of Diabetes Treatment Satisfaction Questionnaire scores, body weight and metabolic indices.. In total, 110 patients were enrolled, and 10 were excluded; therefore, 37 patients in plan A and 63 patients in plan B completed the study. Glycated haemoglobin levels were significantly reduced in the semaglutide group in both plans [plan A, 7.8% ± 1.0% to 7.8% ± 0.7% (liraglutide) vs. 7.9% ± 0.7% to 7.3% ± 0.7% (semaglutide), p < .01; plan B, 7.8% ± 1.0% to 7.9% ± 1.2% (dulaglutide) vs. 7.8% ± 0.8% to 7.1% ± 0.6% (semaglutide), p < .01]. Semaglutide also improved Diabetes Treatment Satisfaction Questionnaire scores in both groups (plan A, +0.1 vs. +8.3, p < .01; plan B, -1.2 vs. +3.5, p < .01). Switching from dulaglutide yielded greater reductions in body weight and improved metabolic parameters.. Once-weekly semaglutide administration improved glycaemic control and treatment satisfaction after switching from liraglutide or dulaglutide. These results highlighted a useful treatment option for patients with metabolic abnormalities despite glucagon-like receptor-1 receptor agonist treatment.

Topics: Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Patient Satisfaction; Personal Satisfaction; Prospective Studies; Recombinant Fusion Proteins

Prescribing information instructs taking oral semaglutide (a glucagon-like peptide-1 analogue) in the fasting state, followed by a post-dose fasting period of ≥ 30 min. This trial compared the recommended dosing schedule with alternative schedules.. This was a randomised, single-centre, multiple-dose, open-label, five-armed, parallel-group trial in healthy subjects who received once-daily oral semaglutide (3 mg for 5 days followed by 7 mg for 5 days). Subjects (n = 156) were randomised to five dosing schedules: 2-, 4-, or 6-h pre-dose fast followed by a 30-min post-dose fast (treatment arms: 2 h-30 min, 4-30 min, 6 h-30 min); 2-h pre-dose fast followed by an overnight post-dose fast (treatment arm: 2 h-night); or overnight pre-dose fast followed by a 30-min post-dose fast (reference arm: night-30 min). Semaglutide plasma concentration was measured regularly until 24 h after the 10th dose. Endpoints included area under the semaglutide plasma concentration-time curve during a 24-h interval after the 10th dose (AUC. Compared with an overnight pre-dose fast (reference arm: night-30 min), shorter pre-dose fasting times in the 2 h-night, 2 h-30 min, 4 h-30 min, and 6 h-30 min treatment arms resulted in significantly lower semaglutide AUC. This trial supports dosing oral semaglutide in accordance with prescribing information, which requires dosing in the fasting state.. ClinicalTrials.gov (NCT04513704); registered August 14, 2020.. Oral semaglutide is a human glucagon-like peptide-1 analogue that has been approved for the treatment of type 2 diabetes. It has been established that taking oral semaglutide with food or large volumes of water decreases absorption of the drug in the body. Current prescribing information instructs taking oral semaglutide on an empty stomach (known as the fasting state), with 120 mL/4 oz of water, then waiting for at least 30 min before consuming any food, water, or taking other oral medications. This study investigates whether different dosing schedules for oral semaglutide could potentially offer more flexibility to patients in the timing of their oral semaglutide dosing. The trial, conducted in healthy volunteers, compares the dosing schedule described in the prescribing information with different fasting times before (pre-dose) and after (post-dose) taking oral semaglutide during the day or evening, to see if there were any effects on the concentration of drug in the body. Compared to the recommended overnight fasting period, shorter pre-dose fasting periods of 2–6 h with a 30-min post-dose fast considerably reduced semaglutide exposure in the body. Similarly, semaglutide exposure was also reduced with a 2-h pre-dose fast combined with post-dose overnight fasting. These findings further support the current prescribing information, which states that patients should take their oral semaglutide dose after an overnight fast.

Topics: Administration, Oral; Area Under Curve; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Healthy Volunteers; Humans; Hypoglycemic Agents

To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants.. In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m. SOUL will provide evidence regarding the CV effects of oral semaglutide in individuals with type 2 diabetes and established ASCVD and/or CKD.

Topics: Aged; Atherosclerosis; Cardiovascular Diseases; Coronary Artery Disease; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulins; Male; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

Prior to this study, it is known that type 2 diabetes is linked to obesity and a sedentary lifestyle, leading to inadequate β-cell function and insulin resistance. Limited research has explored the metabolic effects of combining exercise training with antidiabetic medications, particularly focusing on insulin secretion in patients with type 2 diabetes and moderately preserved β-cell function.. The effect of the interaction of semaglutide and physical training on pancreatic β-cell secretory function is unknown in patients with type 2 diabetes.. Thirty-one patients with type 2 diabetes underwent 12 weeks of aerobic training alone or concurrent to treatment with semaglutide. Patients randomly allocated to concurrent semaglutide and training were treated with semaglutide for 20 weeks before the training and evaluated at inclusion and again before and after the training intervention. Patients randomized to training were evaluated before and after training. The primary outcome was a change in insulin secretory capacity with training, evaluated by a 2-stepped hyperglycemic (20 and 30 mM) clamp.. Training increased the incremental area under the curve for insulin from 21 to 27 nM × 2 hours (ratio 1.28, 95% CI 1.02-1.60) during clamp step 1 and from 40 to 64 nM × 2 hours (ratio 1.61, 95% CI 1.25-2.07) during step 2. Semaglutide treatment increased insulin secretion from 16 to 111 nM × 2 hours (ratio 7.10, 95% CI 3.68-13.71), and from 35 to 447 nM × 2 hours (ratio 12.74, 95% CI 5.65-28.71), correspondingly. Semaglutide and training increased insulin secretion from 130 to 171 nM × 2 hours (ratio 1.31, 95% CI 1.06-1.63), and from 525 to 697 nM × 2 hours (ratio 1.33, 95% CI 1.02-1.72), correspondingly. The median increase in total insulin secretion with the combination was 134 nM × 2 hours greater (95% CI 108-232) than with training.. The combination of aerobic training and semaglutide treatment synergistically improved β-cell secretory function. (ClinicalTrials.gov number, ID NCT04383197).

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin

Combining the GLP-1 receptor agonist semaglutide with the long-acting amylin analogue cagrilintide has weight-loss benefits; the impact on glycated haemoglobin (HbA. This 32-week, multicentre, double-blind, phase 2 trial was conducted across 17 sites in the USA. Adults with type 2 diabetes and a BMI of 27 kg/m. In people with type 2 diabetes, treatment with CagriSema resulted in clinically relevant improvements in glycaemic control (including CGM parameters). The mean change in HbA. Novo Nordisk.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Heart failure with preserved ejection fraction is increasing in prevalence and is associated with a high symptom burden and functional impairment, especially in persons with obesity. No therapies have been approved to target obesity-related heart failure with preserved ejection fraction.. We randomly assigned 529 patients who had heart failure with preserved ejection fraction and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or higher to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The dual primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in the 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level.. The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo (estimated difference, 7.8 points; 95% confidence interval [CI], 4.8 to 10.9; P<0.001), and the mean percentage change in body weight was -13.3% with semaglutide and -2.6% with placebo (estimated difference, -10.7 percentage points; 95% CI, -11.9 to -9.4; P<0.001). The mean change in the 6-minute walk distance was 21.5 m with semaglutide and 1.2 m with placebo (estimated difference, 20.3 m; 95% CI, 8.6 to 32.1; P<0.001). In the analysis of the hierarchical composite end point, semaglutide produced more wins than placebo (win ratio, 1.72; 95% CI, 1.37 to 2.15; P<0.001). The mean percentage change in the CRP level was -43.5% with semaglutide and -7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). Serious adverse events were reported in 35 participants (13.3%) in the semaglutide group and 71 (26.7%) in the placebo group.. In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo. (Funded by Novo Nordisk; STEP-HFpEF ClinicalTrials.gov number, NCT04788511.).

Topics: Glucagon-Like Peptides; Heart Failure; Humans; Obesity; Stroke Volume

To compare the clinical usefulness of once-weekly glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide at the doses approved for use in Japanese patients with type 2 diabetes.. In total, 120 patients with glycated haemoglobin (HbA1c) ≥7% were randomly assigned to dulaglutide (n = 59) or semaglutide group (n = 61), and 107 participants (dulaglutide/semaglutide = 53/54) completed the 24-week trial. The primary endpoint was the difference of HbA1c level between the two groups at 24 weeks.. HbA1c level at 24 weeks was significantly lower in the semaglutide group (7.9 ± 0.5%-6.7 ± 0.5%) compared with the dulaglutide group (8.1 ± 0.6%-7.4 ± 0.8%) (p < .0001). Reduction in body mass index and visceral fat area were also more significant in the semaglutide group (p < .05, respectively). The achievement rate of HbA1c <7% was higher in the semaglutide group (p < .0001). The parameters such as low-density lipoprotein cholesterol, alanine aminotransferase and γ-glutamyl transpeptidase were decreased in the semaglutide group. Surprisingly, only semaglutide group significantly improved the apolipoprotein B/A1 ratio, which is considered a useful myocardial infarction risk index. Using computed tomography, the liver to spleen ratio was significantly elevated only in the semaglutide group. In contrast, gastrointestinal symptoms were observed in 13.2% of dulaglutide and 46.3% of semaglutide group (p < .01). The Diabetes Treatment-Related Quality of Life scores related to pain and gastrointestinal symptoms were also superior in the dulaglutide group.. This prospective trial showed that semaglutide has more pronounced glucose- and body mass index-lowering effects and reduces liver fat percentage and visceral fat area and that dulaglutide has less gastrointestinal symptoms and superior Diabetes Treatment-Related Quality of Life scores related to pain and gastrointestinal symptoms.

Topics: Diabetes Mellitus, Type 2; East Asian People; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Pain; Prospective Studies; Quality of Life; Recombinant Fusion Proteins; Treatment Outcome

We evaluated gastrointestinal (GI) adverse events (AEs) with once-weekly semaglutide 2.4 mg in adults with overweight or obesity and their contribution to weight loss (WL).. AE analyses pooled data from the Semaglutide Treatment Effect in People With Obesity (STEP) 1-3 trials for participants randomized to 68 weeks of semaglutide 2.4 mg (n = 2117) or placebo (n = 1262). WL was analysed by presence/absence of GI AEs. Mediation analysis estimated WL effects mediated by and unrelated to GI AEs. GI tolerability with semaglutide 2.4 mg maintenance and cessation after dose escalation was evaluated using STEP 4 data among 803 participants tolerating 20 weeks of semaglutide run-in.. GI AEs were more common with semaglutide 2.4 mg than placebo, with most frequently nausea (43.9% vs. 16.1% of participants), diarrhoea (29.7% vs. 15.9%), vomiting (24.5% vs. 6.3%) and constipation (24.2% vs. 11.1%). Most GI AEs with semaglutide were non-serious (99.5% of AEs), mild-to-moderate (98.1%), transient and occurred most frequently during/shortly after dose escalation. Few semaglutide-treated participants (4.3%) permanently discontinued treatment for GI AEs. In STEP 1-3, mean WL with semaglutide 2.4 mg was similar in participants without (9.6%-17.1%) versus with GI AEs (11.4%-17.7%). Consistent with this observation, mediation analysis found that GI AEs contributed little to semaglutide-induced WL: of the additional 7.6%-14.4% WL with semaglutide versus placebo, <1 percentage point was mediated by GI AEs. In STEP 4, semaglutide 2.4 mg maintenance was well tolerated.. GI AEs were more common with semaglutide 2.4 mg than placebo, but typically mild-to-moderate and transient. Semaglutide-induced WL was largely independent of GI AEs.

Topics: Adult; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Obesity; Overweight; Weight Loss

A post-hoc exploratory analysis of the PIONEER 9 and 10 trials evaluated the effect of baseline age (<65 and ≥65 years) on the efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes. In PIONEER 9 and 10, patients were randomized to once-daily oral semaglutide (3, 7 or 14 mg) or a comparator (placebo or once-daily subcutaneous liraglutide 0.9 mg [PIONEER 9]; once-weekly subcutaneous dulaglutide 0.75 mg [PIONEER 10]) for 52 weeks, with 5 weeks' follow-up. In total, 701 patients were included (PIONEER 9: N = 243; PIONEER 10: N = 458). Glycaemic efficacy of oral semaglutide was similar in Japanese patients aged <65 years compared with those ≥65 years, and there did not appear to be a clear pattern between age subgroup and body weight changes. Across treatment arms, adverse events generally occurred in greater proportions of patients aged ≥65 versus <65 years. There was generally a higher rate of premature trial product discontinuation because of adverse events in the older age group. These results indicate that oral semaglutide is efficacious in Japanese patients irrespective of age.

Topics: Administration, Oral; Aged; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Japan

To investigate whether upper gastrointestinal (GI) disease has any effect on the exposure of oral semaglutide, an important consideration given that its absorption occurs primarily in the stomach.. In an open-label, parallel-group trial (NCT02877355), subjects aged 18-80 years with type 2 diabetes with mild-to-moderate upper GI disease (N = 36; chronic gastritis [n = 5], gastroesophageal reflux disease [n = 8], and both [n = 23]) or without upper GI disease (N = 19) received oral semaglutide 3 mg once daily for 5 days, followed by 7 mg for 5 days. The primary and key supportive endpoints were the area under the semaglutide plasma concentration-time curve (AUC) from 0 to 24 hours after last trial product administration on day 10 (AUC. Semaglutide exposure was not statistically significantly different between subjects with and without upper GI disease. Estimated group ratios (subjects with/without upper GI disease) were 1.18 (95% confidence interval [CI], 0.80, 1.75) for AUC. There was no significant difference in exposure to oral semaglutide in subjects with or without upper GI disease, hence no dose adjustment is required.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Gastrointestinal Diseases; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Middle Aged; Young Adult

Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management.. To compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity.. Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338).. Participants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85).. The primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points.. Of 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001); weight change with pooled placebo was -1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide.. Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks.. ClinicalTrials.gov Identifier: NCT04074161.

Topics: Body Weight; Diabetes Mellitus; Diet Therapy; Drug Administration Schedule; Exercise; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Liraglutide; Male; Middle Aged; Obesity; Odds Ratio; Overweight; Patient Dropouts; Placebos; Treatment Outcome; United States; Weight Loss

Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups.. Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m. In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups. Reductions from baseline in glycosylated hemoglobin ranged from -1.7 to -2.1 with semaglutide 0.5 mg, -1.8 to -2.4 with semaglutide 1.0 mg and -0.6 to -1.0 with comparators. Corresponding ranges for bodyweight (kg) were -1.0 to -2.5, -2.4 to -4.3 and 1.0 to -1.0 kg, respectively. The safety profile of semaglutide was broadly similar across BMI and age subgroups.. In this post-hoc analysis with modest subgroup numbers, once-weekly semaglutide appeared consistently more efficacious versus comparators across age and BMI subgroups in Japanese patients, with a similar safety profile.

Topics: Aged; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Japan

Our objective was to evaluate the long-term cost-effectiveness of once-weekly semaglutide 1 mg versus once-daily canagliflozin 300 mg in patients with type 2 diabetes mellitus (T2DM) uncontrolled with metformin from the healthcare payer and societal perspectives in Canada.. Head-to-head data from the SUSTAIN 8 randomised trial (NCT03136484) were extrapolated over 40 years using economic simulation modelling. The cost-effectiveness of once-weekly semaglutide 1 mg versus canagliflozin 300 mg for treating T2DM was estimated using the Swedish Institute for Health Economics-Diabetes Cohort Model (IHE-DCM) and the Economic and Health Outcomes Model of T2DM (ECHO-T2DM). Unit costs and disutility weights capturing treatments and key macro- and microvascular complications were sourced from the literature to best match the Canadian setting. A probabilistic base-case simulation and sensitivity analyses were conducted.. Once-weekly semaglutide 1 mg was associated with reductions in macro- and microvascular complications, yielding incremental cost-effectiveness ratios (ICERs) of (Canadian dollars [CAD]) CAD16,392 and 18,098 per incremental quality-adjusted life-year (QALY) gained versus canagliflozin 300 mg for IHE-DCM and ECHO-T2DM, respectively, from a healthcare payer perspective. Accounting for productivity loss as well, ICERs were CAD14,127 and 13,188 per QALY gained for IHE-DCM and ECHO-T2DM, respectively, from a societal perspective. Sensitivity analyses confirmed that the base-case results were robust to changes in input parameters and assumptions used.. At a willingness-to-pay threshold of CAD50,000 per QALY gained, once-weekly semaglutide 1 mg was cost-effective over 40 years versus once-daily canagliflozin 300 mg for the treatment of T2DM in patients failing to maintain glycemic control with metformin alone.

Topics: Canada; Canagliflozin; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Metformin; Quality-Adjusted Life Years

Non-alcoholic steatohepatitis (NASH) is associated with increased risk of liver-related and cardiovascular morbidity and mortality. Given the complex pathophysiology of NASH, combining therapies with complementary mechanisms may be beneficial. This trial evaluated the safety and efficacy of semaglutide, a glucagon-like peptide-1 receptor agonist, alone and in combination with the farnesoid X receptor agonist cilofexor and/or the acetyl-coenzyme A carboxylase inhibitor firsocostat in patients with NASH.. This was a phase II, open-label, proof-of-concept trial in which patients with NASH (F2-F3 on biopsy, or MRI-proton density fat fraction [MRI-PDFF] ≥10% and liver stiffness by transient elastography ≥7 kPa) were randomised to 24 weeks' treatment with semaglutide 2.4 mg once weekly as monotherapy or combined with once-daily cilofexor (30 or 100 mg) and/or once-daily firsocostat 20 mg. The primary endpoint was safety. All efficacy endpoints were exploratory.. A total of 108 patients were randomised to semaglutide (n = 21), semaglutide plus cilofexor 30 mg (n = 22), semaglutide plus cilofexor 100 mg (n = 22), semaglutide plus firsocostat (n = 22) or semaglutide, cilofexor 30 mg and firsocostat (n = 21). Treatments were well tolerated - the incidence of adverse events was similar across groups (73-90%) and most events were gastrointestinal in nature. Despite similar weight loss (7-10%), compared with semaglutide monotherapy, combinations resulted in greater improvements in liver steatosis measured by MRI-PDFF (least-squares mean of absolute changes: -9.8 to -11.0% vs. -8.0%), liver biochemistry, and non-invasive tests of fibrosis.. In patients with mild-to-moderate fibrosis due to NASH, semaglutide with firsocostat and/or cilofexor was generally well tolerated. In exploratory efficacy analyses, treatment resulted in additional improvements in liver steatosis and biochemistry vs. semaglutide alone. Given this was a small-scale open-label trial, double-blind placebo-controlled trials with adequate patient numbers are warranted to assess the efficacy and safety of these combinations in NASH.. NCT03987074.. Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis (NASH), are serious liver conditions that worsen over time if untreated. The reasons people develop NASH are complex and combining therapies that target different aspects of the disease may be more helpful than using single treatments. This trial showed that the use of 3 different types of drugs, namely semaglutide, cilofexor and firsocostat, in combination was safe and may offer additional benefits over treatment with semaglutide alone.

Topics: Azetidines; Double-Blind Method; Fibrosis; Glucagon-Like Peptides; Humans; Isobutyrates; Isonicotinic Acids; Non-alcoholic Fatty Liver Disease; Oxazoles; Pyrimidines; Treatment Outcome

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, shows a remarkable ability to lower blood glucose, enabling many patients with long-standing type 2 diabetes to achieve normoglycaemia. We aimed to understand the physiological mechanisms underlying the action of tirzepatide in type 2 diabetes.. This multicentre, randomised, double-blind, parallel-arm, phase 1 study was done at two centres in Germany. Eligible patients were aged 20-74 years, had type 2 diabetes for at least 6 months, and were being treated with lifestyle advice and stable doses of metformin, with or without one additional stable dose of another oral antihyperglycaemic medicine, 3 months before study entry. Via a randomisation table, patients were randomly assigned (3:3:2) to subcutaneously receive either tirzepatide 15 mg, semaglutide 1 mg, or placebo once per week. Endpoint measurements were done at baseline and the last week of therapy (week 28). The primary endpoint was the effect of tirzepatide versus placebo on the change in clamp disposition index (combining measures of insulin secretion and sensitivity) from baseline to week 28 of treatment and was analysed in the pharmacodynamic analysis set, which comprised all randomly assigned participants who received at least one dose of a study drug and had evaluable pharmacodynamic data. Safety was analysed in the safety population, which comprised all randomly assigned participants who received at least one dose of a study drug. Secondary endpoints included the effect of tirzepatide versus semaglutide on the change in clamp disposition index from baseline to week 28 of treatment, glucose control, total insulin secretion rate, M value (insulin sensitivity), and fasting and postprandial glucagon concentrations. Exploratory endpoints included the change in fasting and postprandial insulin concentrations. This study is registered with ClinicalTrials.gov, NCT03951753, and is complete.. Between June 28, 2019, and April 8, 2021, we screened 184 individuals and enrolled 117 participants, all of whom were included in the safety population (45 in the tirzepatide 15 mg group, 44 in the semaglutide 1 mg group, and 28 in the placebo group). Because of discontinuations and exclusions due to missing or unevaluable data, 39 patients in each treatment group and 24 patients in the placebo group comprised the pharmacodynamic analysis set. With tirzepatide, the clamp disposition index increased from a least squares mean of 0·3 pmol m. The glycaemic efficacy of GIP/GLP-1 receptor agonist tirzepatide in type 2 diabetes results from concurrent improvements in key components of diabetes pathophysiology, namely β-cell function, insulin sensitivity, and glucagon secretion. These effects were large and help to explain the remarkable glucose-lowering ability of tirzepatide seen in phase 3 studies.. Eli Lilly.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Insulins; Islets of Langerhans; Treatment Outcome

Rubino DM, Greenway FL, Khalid U, et al.

Topics: Adult; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Liraglutide; Obesity; Overweight; Weight Gain; Weight Loss

To compare the efficacy and safety of once-weekly (OW) semaglutide versus thrice-daily (TID) insulin aspart (IAsp) in participants with inadequately controlled type 2 diabetes (T2D) treated with insulin glargine (IGlar) and metformin.. SUSTAIN 11 (NCT03689374) was a randomized (1:1), parallel, open-label, multinational, phase 3b trial. After a 12-week run-in to optimize once-daily IGlar U100, 1748 adults with T2D (HbA1c >7.5% to ≤10.0%) were randomized to OW semaglutide or TID IAsp as add-on to optimized IGlar and metformin for 52 weeks. The primary outcome was change in HbA1c from randomization to week 52. Confirmatory secondary endpoints included the occurrence of severe hypoglycaemic episodes and change in body weight (BW). Safety was assessed.. HbA1c (randomization: 8.6% [70.0 mmol/mol]) decreased by 1.5% points (16.6 mmol/mol) and 1.2% points (13.4 mmol/mol) with semaglutide (n = 874) and IAsp (n = 874), respectively (estimated treatment difference [ETD] -0.29% points [95% confidence interval {CI} -0.38; -0.20]; P < .0001 for non-inferiority). Few severe hypoglycaemic episodes were recorded in either group, with no statistically significant difference between the groups. Change in BW from randomization (87.9 kg) to week 52 was in favour of semaglutide (-4.1 kg) versus IAsp (+2.8 kg) (ETD -6.99 kg [95% CI -7.41; -6.57]). A higher proportion of participants experienced adverse events with semaglutide (58.5%) versus IAsp (52.1%); most were mild to moderate.. In this basal insulin-treated population, OW semaglutide improved glycaemic control to a greater extent than TID IAsp and provided numerically greater weight loss.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Aspart; Insulin Glargine; Metformin; Treatment Outcome

Incretin-based therapies exert antihyperglycaemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent fashion. The first-in-class oral glucagon-like peptide-1 receptor agonist semaglutide has potent effects on glycaemic and weight control, but little evidence has been published for the superiority of semaglutide for glycaemic control in patients after switching from a dipeptidyl peptidase-4 (DPP-4) inhibitor. Therefore, we aim to verify the efficacy of oral semaglutide in patients with T2D being treated with a DPP-4 inhibitor.. This study is a multicentre, prospective, randomised, open-label, parallel-group trial. In total, 172 participants with T2D who have been treated with a DPP-4 inhibitor for more than 12 weeks and who have a glycated haemoglobin (HbA1c) level of 7.0%-9.9% will be randomised to continue using their existing DPP-4 inhibitor or switch to oral semaglutide for 24 weeks. Biochemical analyses and physical assessment will be performed, and adverse events will be recorded at baseline and at the end of the study. The primary endpoint will be the effect of oral semaglutide on the change in HbA1c. The secondary endpoints will be the mean changes in body weight, abdominal circumference, systolic and diastolic blood pressure (BP), pulse rate, the relationship between improvement of metabolic parameters including HbA1c and patient background characteristics, side effects and other laboratory parameters.. This will be the first study to compare the effects of switching from a DPP-4 inhibitor to oral semaglutide on glycaemic control in patients with T2D. The results will be disseminated in peer-reviewed journals and at scientific conferences. Hokkaido University Certified Review Board (CRB no.1180001) has approved the protocol (no. 020-013).. UMIN000045270 in the University Hospital Medical Information Network; jRCT1011210032 in the Japan Registry of Clinical Trials.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Multicenter Studies as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity; Overweight

No retrospective cohort study has assessed the effectiveness of semaglutide at doses used in randomized clinical trials to treat obesity (ie, 1.7 and 2.4 mg).. To study weight loss outcomes associated with semaglutide treatment at doses used in randomized clinical trials for patients with overweight or obesity.. This cohort study, conducted at a referral center for weight management, retrospectively collected data on the use of semaglutide for adults with overweight or obesity between January 1, 2021, and March 15, 2022, with a follow-up of up to 6 months. A total of 408 patients with a body mass index (BMI) of 27 or more were prescribed weekly semaglutide subcutaneous injections for 3 months or more. Patients with a history of bariatric procedures, taking other antiobesity medications, and with an active malignant neoplasm were excluded.. Weekly 1.7-mg or 2.4-mg semaglutide subcutaneous injections for 3 to 6 months.. The primary end point was the percentage of weight loss. Secondary end points were the proportion of patients achieving weight loss of 5% or more, 10% or more, 15% or more, and 20% or more after 3 and 6 months and the percentage of weight loss for patients with or without type 2 diabetes after 3 and 6 months.. The study included 175 patients (132 women [75.4%]; mean [SD] age, 49.3 [12.5] years; mean [SD] BMI, 41.3 [9.1]) in the analysis at 3 months and 102 patients at 6 months. The mean (SD) weight loss after 3 months was 6.7 (4.4) kg, equivalent to a mean (SD) weight loss of 5.9% (3.7%) (P < .001), and the mean (SD) weight loss after 6 months was 12.3 (6.6) kg, equivalent to a mean (SD) weight loss of 10.9% (5.8%) (P < .001 from baseline). Of the 102 patients who were followed up at 6 months, 89 (87.3%) achieved weight loss of 5% or more, 56 (54.9%) achieved weight loss of 10% or more, 24 (23.5%) achieved weight loss of 15% or more, and 8 (7.8%) achieved weight loss of 20% or more. Patients with type 2 diabetes had a lower mean (SD) percentage weight loss at 3 and 6 months compared with those without type 2 diabetes: 3.9% (3.1%) vs 6.3% (3.7%) at 3 months (P = .001) and 7.2% (6.3%) vs 11.8% (5.3%) at 6 months (P = .005).. The results of this cohort study suggest that weekly 1.7-mg and 2.4-mg doses of semaglutide were associated with weight loss similar to that seen in randomized clinical trials. Studies with longer periods of follow-up are needed to evaluate prolonged weight loss outcomes.

Topics: Adult; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Middle Aged; Obesity; Overweight; Retrospective Studies; Weight Loss

The STEP 5 trial assessed the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg versus placebo (both plus behavioral intervention) for long-term treatment of adults with obesity, or overweight with at least one weight-related comorbidity, without diabetes. The co-primary endpoints were the percentage change in body weight and achievement of weight loss of ≥5% at week 104. Efficacy was assessed among all randomized participants regardless of treatment discontinuation or rescue intervention. From 5 October 2018 to 1 February 2019, 304 participants were randomly assigned to semaglutide 2.4 mg (n = 152) or placebo (n = 152), 92.8% of whom completed the trial (attended the end-of-trial safety visit). Most participants were female (236 (77.6%)) and white (283 (93.1%)), with a mean (s.d.) age of 47.3 (11.0) years, body mass index of 38.5 (6.9) kg m

Topics: Adult; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Male; Middle Aged; Obesity; Overweight; Treatment Outcome; Weight Loss

People with overweight or obesity often suffer from associated cardiometabolic diseases and comorbidities. Current therapies for obesity include lifestyle intervention, bariatric surgery, and pharmacotherapy. The magnitude of weight loss achieved with these therapies can determine the level of improvement in various comorbidities. Once-weekly subcutaneous semaglutide 2.4 mg is a glucagon-like peptide-1 receptor agonist recently approved by the US Food and Drug Administration for the treatment of obesity. This article reviews data from the global phase 3 Semaglutide Treatment Effect in People with obesity (STEP) program, comparing the efficacy of once-weekly subcutaneous semaglutide 2.4 mg versus placebo for weight loss and improvements in cardiometabolic parameters across the STEP 1 to 5 trials. In STEP 1 to 3 and STEP 5, semaglutide led to greater reductions from baseline versus placebo in body weight, waist circumference, body mass index, systolic blood pressure (SBP), and diastolic blood pressure, as well as positive changes in glycated hemoglobin (HbA

Topics: Cardiometabolic Risk Factors; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Lipids; Obesity; Overweight; Weight Loss

To evaluate, through exploratory post hoc subgroup analyses, the efficacy and safety of oral semaglutide versus comparators in Japanese patients enrolled in the global PIONEER 1, 3, 4 and 8 clinical trials.. Patients were randomized to once-daily oral semaglutide 3, 7 or 14 mg or comparator (placebo, sitagliptin 100 mg or liraglutide 1.8 mg). Change from baseline in glycated haemoglobin (HbA1c) and body weight, and proportions of patients attaining HbA1c <7.0% (53 mmol/mol) and body weight loss ≥5%, were analysed at week 26 for all Japanese patients in each trial separately using the treatment policy estimand (regardless of treatment discontinuation or rescue medication use). Adverse events (AEs) were analysed descriptively.. Reductions in HbA1c from baseline in Japanese patients were 1.0% to 1.2% (11.3 mmol/mol to 13.3 mmol/mol) and 1.4% to 1.7% (15.7 mmol/mol to 18.3 mmol/mol) for oral semaglutide 7 mg and 14 mg, respectively. HbA1c reductions were similar or greater than with comparators. Body weight reductions were 1.0% to 2.7% and 3.7% to 4.7% for oral semaglutide 7 mg and 14 mg, respectively, and were generally greater with oral semaglutide than comparators. As expected, the main class of AEs was gastrointestinal, and these AEs comprised most commonly mild-to-moderate constipation, nausea and diarrhoea.. Oral semaglutide appears efficacious and well tolerated in Japanese patients across the type 2 diabetes spectrum.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Japan; Treatment Outcome

Glucagon-like peptide-1 receptor agonists may be a treatment option in patients with non-alcoholic fatty liver disease (NAFLD).. To investigate the effects of semaglutide on liver stiffness and liver fat in subjects with NAFLD using non-invasive magnetic resonance imaging (MRI) methods.. This randomised, double-blind, placebo-controlled trial enrolled subjects with liver stiffness 2.50-4.63 kPa by magnetic resonance elastography (MRE) and liver steatosis ≥10% by MRI proton density fat fraction (MRI-PDFF). The primary endpoint was change from baseline to week 48 in liver stiffness assessed by MRE.. Sixty-seven subjects were randomised to once-daily subcutaneous semaglutide 0.4 mg (n = 34) or placebo (n = 33). Change from baseline in liver stiffness was not significantly different between semaglutide and placebo at week 48 (estimated treatment ratio 0.96 (95% CI 0.89, 1.03; P = 0.2798); significant differences in liver stiffness were not observed at weeks 24 or 72. Reductions in liver steatosis were significantly greater with semaglutide (estimated treatment ratios: 0.70 [0.59, 0.84], P = 0.0002; 0.47 [0.36, 0.60], P < 0.0001; and 0.50 [0.39, 0.66], P < 0.0001) and more subjects achieved a ≥ 30% reduction in liver fat content with semaglutide at weeks 24, 48 and 72, (all P < 0.001). Decreases in liver enzymes, body weight and HbA. The change in liver stiffness in subjects with NAFLD was not significantly different between semaglutide and placebo. However, semaglutide significantly reduced liver steatosis compared with placebo which, together with improvements in liver enzymes and metabolic parameters, suggests a positive impact on disease activity and metabolic profile. ClinicalTrials.gov identifier: NCT03357380.

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Elasticity Imaging Techniques; Glucagon-Like Peptides; Humans; Magnetic Resonance Imaging; Non-alcoholic Fatty Liver Disease

Glucagon-like peptide-1 receptor agonists (GLP-1RA) are used for the treatment of type 2 diabetes. Whether clinically important responses and adverse events (AEs) are dependent on the route of administration has not been determined. We demonstrate that nearly identical exposure-response pharmacodynamic relationships are determined by plasma semaglutide levels achieved through oral versus injectable administration for changes in HbA

Topics: Administration, Oral; Blood Pressure; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Injections; Injections, Subcutaneous; Male; Middle Aged; Triglycerides

Oral semaglutide (Rybelsus®) is a co-formulation of semaglutide, a glucagon-like peptide-1 (GLP-1 RA) receptor agonist, with an absorption enhancer, sodium N- (8- [2- hydroxybenzoyl] amino) caprylate (SNAC), which facilitates the absorption of semaglutide across the gastric epithelium in a concentration dependent manner. The safety and efficacy of oral semaglutide were assessed in the PIONEER clinical trial programme, which included 9543 patients with type 2 diabetes (T2DM). Across a range of different T2DM patients receiving different background medications, oral semaglutide provides more effective glycaemic control than common oral glucose-lowering therapies, associated with a clinically relevant reduction in body weight, including in patients with more advanced T2DM on insulin treatment. The tolerability profile for oral semaglutide was consistent with the other GLP-1 RAs. Cardiovascular (CV) safety of oral semaglutide was noninferior to placebo in CV high-risk patients. Available in three doses (3, 7 and 14 mg) to be gradually increased, Rybelsus® is currently reimbursed in Belgium after failure of antidiabetic treatment (including metformin; HbA1C superior to 7.5 % or 58 mmol/mol) in T2DM patients with a body mass index ? 30 kg/m².. Le sémaglutide oral (Rybelsus®) est une co-formulation du sémaglutide, agoniste des récepteurs du glucagon-like peptide-1 (AR GLP-1), couplé à un rehausseur d’absorption, le sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), ce qui facilite le passage du sémaglutide au travers de l’épithélium gastrique de manière dose-dépendante. La sécurité et l’efficacité du sémaglutide oral (SO) ont été évaluées dans le programme d’études cliniques PIONEER, qui a inclus 9.543 patients diabétiques de type 2 (DT2). Dans une large gamme de patients DT2 ayant bénéficié de différents médicaments hypoglycémiants préalables, le SO permet d’obtenir un contrôle glycémique plus efficace qu’avec les traitements hypoglycémiants oraux courants, ainsi qu’une perte de poids intéressante, y compris chez les patients atteints de DT2 plus avancé traités par insuline. Le profil de tolérance du SO est comparable aux autres AR GLP-1 et la sécurité cardiovasculaire établie chez des patients à haut risque par rapport au placebo (non-infériorité). Disponible en trois posologies (3, 7 et 14 mg) à accroître progressivement, Rybelsus® est remboursé en Belgique après échec d’un traitement antidiabétique (dont la metformine; HbA1C sup�rieur a 7,5 % ou 58 mmol/mol) chez des patients DT2 avec un indice de masse corporelle ? 30 kg/m².

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

To evaluate the effect of oral semaglutide on energy intake and appetite in subjects with type 2 diabetes (T2D).. In this randomized, double-blind, placebo-controlled, two-period cross-over trial, 15 subjects with T2D received 12 weeks of treatment with once-daily oral semaglutide (4-week dose escalation from 3 to 7 to 14 mg) followed by placebo, or vice versa. Energy intake was measured during an ad libitum lunch, evening meal and snack box after a standard breakfast. Appetite ratings were measured using a visual analogue scale after standard and fat-rich breakfasts. Other assessments included eating and craving control (using the Control of Eating Questionnaire), and changes in body weight and composition.. Following a standard breakfast, total daily ad libitum energy intake was significantly lower (38.9%) with oral semaglutide versus placebo in 13 evaluable subjects (estimated treatment difference, -5096.0 kJ; 95% CI -7000.0, -3192.1; P = .0001). After a fat-rich breakfast, there were significant differences in favour of oral semaglutide versus placebo for measures of satiety, hunger and for overall appetite score, with no significant differences following a standard breakfast. Fewer food cravings and better eating control were seen with oral semaglutide versus placebo. Overall, mean body weight decreased by 2.7 kg with oral semaglutide and 0.1 kg with placebo, mostly attributable to body fat mass loss.. After 12 weeks of treatment, ad libitum energy intake was lower with oral semaglutide versus placebo, resulting in reduced body fat mass, and was associated with increased satiety and fullness after a fat-rich breakfast, and improved eating control.. NCT02773381.

Topics: Appetite; Body Weight; Breakfast; Cross-Over Studies; Diabetes Mellitus, Type 2; Eating; Energy Intake; Food Preferences; Glucagon-Like Peptides; Humans

Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known.. We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients.. In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed.. This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.).

Topics: Adolescent; Adult; Aged; Amylases; Biopsy; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glucagon-Like Peptides; Humans; Injections, Subcutaneous; Lipase; Liver; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Young Adult

To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity.. A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch.. In adults with obesity, once-weekly s.c. semaglutide 2.4 mg suppressed appetite, improved control of eating, and reduced food cravings, ad libitum energy intake and body weight versus placebo. There was no evidence of delayed gastric emptying at week 20, assessed indirectly via paracetamol absorption.

Topics: Adult; Appetite; Double-Blind Method; Energy Intake; Gastric Emptying; Glucagon-Like Peptides; Humans; Obesity; Prospective Studies

Coronary artery disease (CAD) is leading cause of morbidity and mortality among type 2 diabetics (T2DM).. 140 T2DM will be enrolled in randomized, double blind, placebo controlled Semaglutide Treatment On Coronary Plaque Progression (STOP) trial to determine effect of weekly subcutaneous semaglutide on coronary plaque progression. All participants will undergo Coronary Artery Calcium (CAC) Scoring and Coronary Computed Tomography Angiography (CCTA) at our center. A Fisher test, ANOVA and Kruskal Wallis were used.. As of May 2020, 87 patients (81%) randomized (mean age 56.4 ± 8.4 yrs. and 62% male) with documented CAD by CCTA. Approximately 20% of screened study population were screen failed due to normal coronaries (n= 14) or HbA1C<7 (n=7). Of interest, 14 persons with diabetes with normal coronaries (no calcification) were significantly more likely to be females (21% vs 62%), have higher glomerular filtration rate (106.5 ± 19.4 vs 89.9 ± 22.6 mL/min/1.73m. Among T2DM, there is a significant portion who have normal coronary arteries and may have a better prognosis. Excluding these participants from cardiovascular studies may improve power and decrease sample size.

Topics: Computed Tomography Angiography; Coronary Angiography; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Humans; Male; Middle Aged; Plaque, Atherosclerotic; Predictive Value of Tests; Prevalence

Topics: Double-Blind Method; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Non-alcoholic Fatty Liver Disease; Placebos

Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.. In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.. The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).. In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

Topics: Adult; Anti-Obesity Agents; Body Composition; Body Mass Index; Cholelithiasis; Diarrhea; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Healthy Lifestyle; Humans; Injections, Subcutaneous; Lipids; Male; Middle Aged; Nausea; Obesity; Prediabetic State; Weight Loss

This double-blind, randomized, single-site, crossover trial compared the injection-site experience with the starting doses of semaglutide and dulaglutide. Healthy subjects (aged 18-75 years; body mass index ≥ 25 kg/m

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptides; Healthy Volunteers; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins

Weight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight loss approaches.. To compare the effects of once-weekly subcutaneous semaglutide, 2.4 mg vs placebo for weight management as an adjunct to intensive behavioral therapy with initial low-calorie diet in adults with overweight or obesity.. Randomized, double-blind, parallel-group, 68-week, phase 3a study (STEP 3) conducted at 41 sites in the US from August 2018 to April 2020 in adults without diabetes (N = 611) and with either overweight (body mass index ≥27) plus at least 1 comorbidity or obesity (body mass index ≥30).. Participants were randomized (2:1) to semaglutide, 2.4 mg (n = 407) or placebo (n = 204), both combined with a low-calorie diet for the first 8 weeks and intensive behavioral therapy (ie, 30 counseling visits) during 68 weeks.. The co-primary end points were percentage change in body weight and the loss of 5% or more of baseline weight by week 68. Confirmatory secondary end points included losses of at least 10% or 15% of baseline weight.. Of 611 randomized participants (495 women [81.0%], mean age 46 years [SD, 13], body weight 105.8 kg [SD, 22.9], and body mass index 38.0 [SD, 6.7]), 567 (92.8%) completed the trial, and 505 (82.7%) were receiving treatment at trial end. At week 68, the estimated mean body weight change from baseline was -16.0% for semaglutide vs -5.7% for placebo (difference, -10.3 percentage points [95% CI, -12.0 to -8.6]; P < .001). More participants treated with semaglutide vs placebo lost at least 5% of baseline body weight (86.6% vs 47.6%, respectively; P < .001). A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of at least 10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P < .001). Gastrointestinal adverse events were more frequent with semaglutide (82.8%) vs placebo (63.2%). Treatment was discontinued owing to these events in 3.4% of semaglutide participants vs 0% of placebo participants.. Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings.. ClinicalTrials.gov Identifier: NCT03611582.

Topics: Adult; Anti-Obesity Agents; Cognitive Behavioral Therapy; Combined Modality Therapy; Diet, Reducing; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Injections, Subcutaneous; Male; Middle Aged; Obesity; Overweight; Weight Loss

This trial assessed the efficacy and safety of the GLP-1 analogue once a week subcutaneous semaglutide 2·4 mg versus semaglutide 1·0 mg (the dose approved for diabetes treatment) and placebo for weight management in adults with overweight or obesity, and type 2 diabetes.. From June 4 to Nov 14, 2018, 1595 patients were screened, of whom 1210 were randomly assigned to semaglutide 2·4 mg (n=404), semaglutide 1·0 mg (n=403), or placebo (n=403) and included in the intention-to-treat analysis. Estimated change in mean bodyweight from baseline to week 68 was -9·6% (SE 0·4) with semaglutide 2·4 mg vs -3·4% (0·4) with placebo. Estimated treatment difference for semaglutide 2·4 mg versus placebo was -6·2 percentage points (95% CI -7·3 to -5·2; p<0·0001). At week 68, more patients on semaglutide 2·4 mg than on placebo achieved weight reductions of at least 5% (267 [68·8%] of 388 vs 107 [28·5%] of 376; odds ratio 4·88, 95% CI 3·58 to 6·64; p<0·0001). Adverse events were more frequent with semaglutide 2·4 mg (in 353 [87·6%] of 403 patients) and 1·0 mg (329 [81·8%] of 402) than with placebo (309 [76·9%] of 402). Gastrointestinal adverse events, which were mostly mild to moderate, were reported in 256 (63·5%) of 403 patients with semaglutide 2·4 mg, 231 (57·5%) of 402 with semaglutide 1·0 mg, and 138 (34·3%) of 402 with placebo.. In adults with overweight or obesity, and type 2 diabetes, semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in bodyweight compared with placebo.. Novo Nordisk.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Male; Middle Aged; Obesity; Overweight; Treatment Outcome; Weight Loss

To assess the effects of oral semaglutide on postprandial glucose and lipid metabolism, and gastric emptying, in subjects with type 2 diabetes (T2D).. In this randomized, double-blind, single-centre, crossover trial, subjects with T2D received once-daily oral semaglutide (escalated to 14 mg) followed by placebo, or vice versa, over two consecutive 12-week periods. Glucose and lipid metabolism, and gastric emptying (paracetamol absorption) were assessed before and after two types of standardized meals (standard and/or fat-rich) at the end of each treatment period. The primary endpoint was area under the glucose 0-5-h curve (AUC. Fifteen subjects were enrolled (mean age 58.2 years, HbA1c 6.9%, body weight 93.9 kg, diabetes duration 3.1 years; 13 [86.7%] males). Fasting concentrations of glucose were significantly lower, and C-peptide significantly greater, with oral semaglutide versus placebo. Postprandial glucose (AUC. Oral semaglutide significantly improved fasting and postprandial glucose and lipid metabolism, and delayed gastric emptying.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Gastric Emptying; Glucagon-Like Peptides; Glucose; Humans; Hypoglycemic Agents; Lipid Metabolism; Male; Middle Aged; Postprandial Period

Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been coformulated in a tablet with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). We investigated tablet erosion and the pharmacokinetics of oral semaglutide administered with 2 different water volumes and evaluated the relationships between these parameters. In a randomized, single-center (Quotient Sciences, UK), open-label, 2-period crossover trial, 26 healthy men received single doses of 10 mg oral semaglutide with 50 or 240 mL water while fasting. Tablet erosion and gastrointestinal transit were assessed by gamma scintigraphy. Semaglutide and SNAC plasma concentrations were measured until 24 and 6 hours, respectively, after administration. Complete tablet erosion (CTE) occurred in the stomach irrespective of water volume administered with the tablet (primary end point). Mean time to CTE was 85 versus 57 minutes with 50 versus 240 mL water (ratio 50/240 mL, 1.51; 95% confidence interval, 0.96-2.37; P = .072). Area under the semaglutide concentration-time curve from 0 to 24 hours (AUC

Topics: Administration, Oral; Adult; Area Under Curve; Caprylates; Cross-Over Studies; Fasting; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Male; Middle Aged; Radionuclide Imaging; Tablets; Water

The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown.. To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly.. Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes.. A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups.. The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]).. Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%).. Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks.. ClinicalTrials.gov Identifier: NCT03548987.

Topics: Adult; Anti-Obesity Agents; Blood Pressure; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Injections, Subcutaneous; Male; Middle Aged; Obesity; Overweight; Waist Circumference; Weight Loss

The first oral glucagon-like peptide-1 receptor agonist (GLP-1RA) comprises semaglutide co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Oral semaglutide may alter the pharmacokinetics of co-administered drugs via effects of semaglutide or SNAC. Two separate one-sequence crossover trials investigated the effects of oral semaglutide and SNAC on the pharmacokinetics of ethinylestradiol, levonorgestrel, furosemide and rosuvastatin.. The AUC values of ethinylestradiol and levonorgestrel were not affected by oral semaglutide co-administration (estimated ratios [90% CI] 1.06 [1.01-1.10] and 1.06 [0.97-1.17], respectively); C. Co-administration with oral semaglutide did not affect the pharmacokinetics of ethinylestradiol or levonorgestrel. There was a small increase in exposure of furosemide and rosuvastatin; however, these increases are not expected to be of clinical relevance.. NCT02845219 and NCT03010475.

Topics: Ethinyl Estradiol; Female; Furosemide; Glucagon-Like Peptides; Healthy Volunteers; Humans; Hypoglycemic Agents; Levonorgestrel; Male; Postmenopause; Rosuvastatin Calcium

Topics: Anti-Obesity Agents; Biopsy; Body Mass Index; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Monitoring; Female; Gastrointestinal Agents; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liver; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Treatment Outcome

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 diabetes. The efficacy and safety of once-weekly tirzepatide as compared with semaglutide, a selective GLP-1 receptor agonist, are unknown.. In an open-label, 40-week, phase 3 trial, we randomly assigned 1879 patients, in a 1:1:1:1 ratio, to receive tirzepatide at a dose of 5 mg, 10 mg, or 15 mg or semaglutide at a dose of 1 mg. At baseline, the mean glycated hemoglobin level was 8.28%, the mean age 56.6 years, and the mean weight 93.7 kg. The primary end point was the change in the glycated hemoglobin level from baseline to 40 weeks.. The estimated mean change from baseline in the glycated hemoglobin level was -2.01 percentage points, -2.24 percentage points, and -2.30 percentage points with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and -1.86 percentage points with semaglutide; the estimated differences between the 5-mg, 10-mg, and 15-mg tirzepatide groups and the semaglutide group were -0.15 percentage points (95% confidence interval [CI], -0.28 to -0.03; P = 0.02), -0.39 percentage points (95% CI, -0.51 to -0.26; P<0.001), and -0.45 percentage points (95% CI, -0.57 to -0.32; P<0.001), respectively. Tirzepatide at all doses was noninferior and superior to semaglutide. Reductions in body weight were greater with tirzepatide than with semaglutide (least-squares mean estimated treatment difference, -1.9 kg, -3.6 kg, and -5.5 kg, respectively; P<0.001 for all comparisons). The most common adverse events were gastrointestinal and were primarily mild to moderate in severity in the tirzepatide and semaglutide groups (nausea, 17 to 22% and 18%; diarrhea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively). Of the patients who received tirzepatide, hypoglycemia (blood glucose level, <54 mg per deciliter) was reported in 0.6% (5-mg group), 0.2% (10-mg group), and 1.7% (15-mg group); hypoglycemia was reported in 0.4% of those who received semaglutide. Serious adverse events were reported in 5 to 7% of the patients who received tirzepatide and in 3% of those who received semaglutide.. In patients with type 2 diabetes, tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks. (Funded by Eli Lilly; SURPASS-2 ClinicalTrials.gov number, NCT03987919.).

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Male; Metformin; Middle Aged; Nausea; Weight Loss

We evaluated the effect of the latest GLP-1 RA semaglutide on tongue fat storage in obese women.. We conducted a randomized single-blind, pilot study.. Twenty-five obese women with polycystic ovary syndrome (PCOS) (33.7 ± 5.3 years, body mass index (BMI) 36.1 ± 3.9 kg/m2, mean ± SD) were randomized to semaglutide 1.0 mg or placebo for 16 weeks. We quantified tongue volume and its fat tissue and fat proportion by magnetic resonance imaging.. Tongue fat tissue and fat proportion significantly reduced after semaglutide vs placebo (-1.94 ± 5.51 vs. + 3.12 ± 4.87 cm. This is the first study confirming the beneficial effect of semaglutide on tongue structure in obese women with PCOS. Further studies are needed to assess the clinical importance of such findings.

Topics: Adiposity; Adult; Double-Blind Method; Female; Glucagon-Like Peptides; Humans; Obesity; Pilot Projects; Single-Blind Method; Tongue

Preclinical studies demonstrated that glucagon-like peptide 1 (GLP-1) is locally synthesized in taste bud cells and that GLP-1 receptor exists on the gustatory nerves in close proximity to GLP-1-containing taste bud cells. This local paracrine GLP-1 signalling seems to be specifically involved in the perception of sweets. However, the role of GLP-1 in taste perception remains largely unaddressed in clinical studies. Whether any weight-reducing effects of GLP-1 receptor agonists are mediated through the modulation of taste perception is currently unknown.. This is an investigator-initiated, randomized single-blind, placebo-controlled clinical trial. We will enrol 30 women with obesity and polycystic ovary syndrome (PCOS). Participants will be randomized in a 1:1 ratio to either semaglutide 1.0 mg or placebo for 16 weeks. The primary endpoints are alteration of transcriptomic profile of tongue tissue as changes in expression level from baseline to follow-up after 16 weeks of treatment, measured by RNA sequencing, and change in taste sensitivity as detected by chemical gustometry. Secondary endpoints include change in neural response to visual food cues and to sweet-tasting substances as assessed by functional MRI, change in body weight, change in fat mass and change in eating behaviour and food intake.. This is the first study to investigate the role of semaglutide on taste perception, along with a neural response to visual food cues in reward processing regions. The study may identify the tongue and the taste perception as a novel target for GLP-1 receptor agonists.. The study has been approved by the Slovene National Medical Ethics Committee and will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Results will be submitted for publication in an international peer-reviewed scientific journal.. ClinicalTrials.gov NCT04263415 . Retrospectively registered on 10 February 2020.

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity; Perception; Randomized Controlled Trials as Topic; Single-Blind Method; Taste

SUSTAIN 10 compared the efficacy and safety of the anticipated most frequent semaglutide dose (1.0mg) with the current most frequently prescribed liraglutide dose in Europe (1.2mg), reflecting clinical practice.. In this phase 3b, open-label trial, 577 adults with type 2 diabetes (HbA. Mean HbA. Semaglutide was superior to liraglutide in reducing HbA

Topics: Administration, Oral; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Liraglutide; Male; Metformin; Middle Aged; Treatment Outcome

When selecting treatments for type 2 diabetes (T2D), it is important to consider not only efficacy and safety, but also other treatment attributes that have an impact on patient preference. The objective of this study was to examine preference between injection devices used for two weekly GLP-1 receptor agonists.. The PREFER study was an open-label, multicentre, randomized, crossover study assessing patient preference for dulaglutide and semaglutide injection devices among injection-naïve patients receiving oral medication for type 2 diabetes. After being trained to use each device, participants performed all steps of injection preparation and administered mock injections into an injection pad. Time-to-train (TTT) for each device was assessed in a subset.. There were 310 evaluable participants (48.4% female; mean age, 60.0 years; 78 participants in the TTT subgroup). More participants preferred the dulaglutide device than the semaglutide device (84.2% vs. 12.3%; P < 0.0001). More participants perceived the dulaglutide device to have greater ease of use (86.8% vs. 6.8%; P < 0.0001). After preparing and using the devices, more participants were willing to use the dulaglutide device (93.5%) than the semaglutide device (45.8%). Training participants to use the dulaglutide device required less time than the semaglutide device (3.38 vs. 8.14 minutes; P < 0.0001).. Participants with type 2 diabetes preferred the dulaglutide injection device to the semaglutide injection device. If patients prefer a device, they may be more willing to use the medication, which could result in better health outcomes. Furthermore, a shorter training time for injection devices may be helpful in busy clinical practice settings.

Topics: Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Patient Preference; Recombinant Fusion Proteins

Variations in the prevalence and etiology of type 2 diabetes (T2D) across race and ethnicity may affect treatment responses. Semaglutide is a glucagon-like peptide-1 analog approved for once-weekly, subcutaneous treatment of T2D.. To compare semaglutide efficacy and safety in race and ethnicity subgroups across the SUSTAIN trials.. Post hoc analysis of data from phase 3 randomized SUSTAIN 1-5 and 7 (pooled), and SUSTAIN 6 trials.. 3074 subjects (SUSTAIN 1-5 and 7) and 1648 subjects (SUSTAIN 6).. Semaglutide 0.5 or 1.0 mg, placebo, or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg, insulin glargine 100IU/ml and dulaglutide 0.75 or 1.5 mg).. Change in hemoglobin A1C (HbA1c) and body weight from baseline to weeks 30, 40 and 104, and other efficacy and safety endpoints.. HbA1c was reduced from baseline by 1.0 to 1.5 percentage points and 1.3 to 2.0 percentage points, and body weight was reduced by 2.3 to 4.7 kg and 3.6 to 6.1 kg with semaglutide 0.5 and 1.0 mg, respectively, across race and ethnicity subgroups. Minor changes in blood pressure and lipid profiles were observed. Adverse events (AEs) were reported in similar proportions of subjects across trials. More Asian versus other race subgroups discontinued treatment prematurely due to AEs. The most commonly reported AEs were gastrointestinal disorders.. In this SUSTAIN trials post hoc analysis, semaglutide was associated with consistent and clinically relevant reductions in HbA1c and body weight in subjects with T2D, with minor variations in efficacy and safety outcomes associated with race or ethnicity.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Ethnicity; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin Glargine; Male; Middle Aged; Racial Groups; Recombinant Fusion Proteins; Treatment Outcome

Topics: Administration, Oral; Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Male; Middle Aged; Placebo Effect; Treatment Outcome

To assess what drives change in health-related quality of life (HRQoL) in type 2 diabetes in the SUSTAIN 6 trial and identify potential mediators of the treatment effect of semaglutide on HRQoL scores.. The Short Form (SF)-36v2® questionnaire [comprising physical component summary (PCS) and mental component summary (MCS)] was used to assess changes in HRQoL from baseline to week 104, by treatment, in a prespecified analysis. This post-hoc analysis assessed change in PCS and MCS using the following factors as parameter/covariate, using descriptive statistics and linear regressions: major adverse cardiac events, hypoglycaemia, gastrointestinal adverse events, at least one episode of nausea, vomiting or diarrhoea, and change in glycated haemoglobin (HbA1c), body weight, blood pressure, heart rate and estimated glomerular filtration rate.. Mean change in overall PCS score was +1.0 with semaglutide versus +0.4 with placebo, and +0.5 versus -0.2 for MCS. The treatment effect of semaglutide versus placebo (unadjusted estimate) was 0.7 [(95% confidence interval 0.1, 1.2); P = 0.018] on PCS and this was reduced when adjusted for change in HbA1c [0.4 (-0.2, 1.0), P = .167] and body weight [0.3 (-0.3, 0.9), P = .314]. The unadjusted treatment effect on MCS [0.7 (-0.0, 1.5), P = .054] was only reduced when adjusted for change in HbA1c [0.3 (-0.4, 1.1), P = .397]. When adjusting for all other parameters separately, the estimated effect of semaglutide on PCS and MCS qualitatively did not change.. Semaglutide improved HRQoL versus placebo; greater improvements with semaglutide versus placebo were possibly mediated, in part, by change in HbA1c and body weight. Clinicaltrials.gov: NCT01720446 (SUSTAIN 6).

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Quality of Life; Risk Factors; Standard of Care; Treatment Outcome

Cardiovascular morbidity and mortality are a major burden in patients with type 2 diabetic mellitus. In a landmark study, semaglutide (an injectable glucagon like peptide-1 receptor agonist) has been shown to significantly reduce cardiovascular events, however, the mechanism of benefit is still unknown. The primary hypothesis of our current study is to assess the effect of semaglutide to reduce progression of noncalcified coronary atherosclerotic plaque volume as measured by serial coronary CTA as compared to placebo in persons with diabetes over 1 year.. One hundred forty patients will be enrolled after signing informed consent and followed up for 12 months and with a phone call 30 days after medical discontinuation. All the participants will undergo coronary artery calcium scoring and coronary computed tomography angiography at our center at baseline and 12 months. Eligible participants will be randomly assigned to semaglutide 2 mg/1.5 ml (1.34 mg/ml) prefilled pen for subcutaneous (SC) injection or placebo 1.5 ml, pen-injector for SC injection in a 1:1 fashion as add-on to their standard of care.. As of July 2019, the study was approximately 30% enrolled with an estimated enrollment completion by first quarter of 2020 and end of study by first quarter 2021. Thirty patients were enrolled as of 23 July 2019. Preliminary data of demographics and clinical characteristics were summarized.. Our current study will provide important imaging-derived data that may add relevance to the clinically derived outcomes from liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results and semaglutide and cardiovascular outcomes in patients with type 2 diabetic mellitus 6 trials.

Topics: Computed Tomography Angiography; Coronary Angiography; Coronary Artery Disease; Diabetes Mellitus, Type 2; Disease Progression; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Incretins; Plaque, Atherosclerotic; Randomized Controlled Trials as Topic; Treatment Outcome; Vascular Calcification

Given the unique phenotype of type 2 diabetes in Japanese patients, novel therapies such as oral semaglutide require evaluation in this population. PIONEER 9 aimed to assess the dose-response of oral semaglutide and to compare the efficacy and safety of oral semaglutide with placebo and a subcutaneous GLP-1 receptor agonist in a Japanese population.. PIONEER 9 was a 52-week, phase 2/3a, randomised, controlled trial done at 16 sites (clinics and university hospitals) in Japan. Japanese patients aged 20 years or older with uncontrolled type 2 diabetes managed by diet or exercise or with oral glucose-lowering drug monotherapy (washed out) were randomly assigned (1:1:1:1:1) to receive double-blind once-daily oral semaglutide (3 mg, 7 mg, or 14 mg) or placebo, or open-label subcutaneous once-daily liraglutide 0·9 mg. The primary endpoint was change in HbA. Between Jan 10, and July 11, 2017, 243 patients were randomly assigned to oral semaglutide 3 mg (n=49), 7 mg (n=49), or 14 mg (n=48), or placebo (n=49), or to liraglutide 0·9 mg (n=48). Changes in HbA. This study showed that oral semaglutide provides significant reductions in HbA. Novo Nordisk.

Topics: Administration, Oral; Adult; Aged; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged

New glucose-lowering medications need to be investigated in east Asian populations, as the clinical characteristics of type 2 diabetes differ between western and east Asian patients. The PIONEER 10 study aimed to evaluate the safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes.. PIONEER 10 was an open-label, randomised, active-controlled, phase 3a trial done at 36 sites (clinics and university hospitals) in Japan. Patients aged 20 years and older with uncontrolled type 2 diabetes were randomly assigned (2:2:2:1) to receive once-daily oral semaglutide 3 mg, 7 mg, or 14 mg, or once-weekly subcutaneous dulaglutide 0·75 mg for 52 weeks, as an add-on to their background medication. The primary endpoint was the number of treatment-emergent adverse events over 57 weeks. Supportive secondary endpoints (not controlled for multiplicity) included mean change from baseline in HbA. Between Jan 10, and May 30, 2017, 492 patients were screened and 458 were randomly assigned to oral semaglutide 3 mg (n=131), 7 mg (n=132), or 14 mg (n=130), or dulaglutide 0·75 mg (n=65). 448 (98%) patients completed the trial. Adverse events occurred in 101 (77%) of 131 patients with oral semaglutide 3 mg, 106 (80%) of 132 with oral semaglutide 7 mg, 111 (85%) of 130 with oral semaglutide 14 mg, and 53 (82%) of 65 with dulaglutide. The most common adverse events were infections and gastrointestinal events. Gastrointestinal adverse events (mostly mild and transient constipation and nausea) occurred in a dose-dependent manner with oral semaglutide. Adverse events led to premature treatment discontinuation in four (3%) of 131 patients receiving oral semaglutide 3 mg, eight (6%) of 132 receiving oral semaglutide 7 mg, eight (6%) of 130 receiving oral semaglutide 14 mg, and two (3%) of 65 receiving dulaglutide. No deaths or severe hypoglycaemic events were reported. Based on the treatment policy estimand (ie, regardless of study drug discontinuation or rescue medication use), estimated mean reductions in HbA. Oral semaglutide was well tolerated in Japanese patients with type 2 diabetes. Once-daily oral semaglutide significantly reduced HbA. Novo Nordisk.

Topics: Administration, Oral; Adult; Aged; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Recombinant Fusion Proteins

It is unknown if the cardioprotective and renal effects of glucagon-like peptide-1 receptor agonists are consistent across blood pressure (BP) categories in patients with type 2 diabetes and at high risk of cardiovascular events. Using data from the LEADER (9340 patients) and SUSTAIN 6 (3297 patients) trials, we evaluated post hoc the cardiorenal effect of liraglutide and semaglutide on major adverse cardiovascular events (MACE) and nephropathy by baseline BP categories using a Cox proportional hazards model (treatment and subgroup as factors; adjusted for cardiorenal risk factors). Data from the two trials were analysed separately. In the LEADER and SUSTAIN 6 trials, the prevalence of stage 1 hypertension was 30% and 31%, respectively, and of stage 2 hypertension 41% and 43%, respectively. There was no statistical heterogeneity across the BP categories for the effects of liraglutide (P = .06 for MACE; P = .14 for nephropathy) or semaglutide (P = .40 for MACE; P = .27 for nephropathy) versus placebo. This implies that liraglutide and semaglutide may be beneficial for patients with type 2 diabetes, irrespective of their baseline BP.

Topics: Blood Pressure; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide

The obesity epidemic is a public health concern, warranting further research into pharmacological treatments for weight management (WM) as an adjunct to lifestyle interventions. The Semaglutide Treatment Effect in People with obesity (STEP) program aims to investigate the effect of semaglutide versus placebo on weight loss, safety, and tolerability in adults with obesity or overweight.. Across five phase 3 trials (NCT03548935, WM; NCT03552757, WM in type 2 diabetes; NCT03611582, WM with intensive behavioral therapy; NCT03548987, sustained WM; and NCT03693430, long-term WM), ~5,000 participants are being randomly assigned to receive semaglutide 2.4 mg once weekly subcutaneously versus placebo. Results will be available in 2020/2021. For all trials, the primary end point is change from baseline to end of treatment in body weight.. Participants have a mean age of 46.2 to 55.3 years, are mostly female (mean: 74.1%-81.0%), and have a mean BMI of 35.7 to 38.5 kg/m. The STEP program evaluates the efficacy and safety of semaglutide 2.4 mg subcutaneously once weekly in a broad population. The trials will provide insights on WM in people with obesity with and without type 2 diabetes and on long-term follow-up.

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Male; Middle Aged; Obesity; Treatment Outcome

According to current guidelines, glucagon-like peptide-1 (GLP-1) receptor agonists are the antidiabetic agent of choice in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease (CVD) and are also the preferable antidiabetic agent in patients with T2DM without CVD but with indicators of high cardiovascular risk. A limitation in the use of GLP-1 receptor agonists is that they are delivered by subcutaneous injections. In this context, the development of an orally administered formulation of semaglutide offers an additional option in the management of patients with T2DM. In the present review, we discuss the findings of the main trials that evaluated the safety and efficacy of oral semaglutide. Oral semaglutide appears to be more effective in reducing HbA

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Cardiovascular disease (CVD) is a major cause of morbidity and mortality. Although it has been widely appreciated that obesity is a major risk factor for CVD, treatments that produce effective, durable weight loss and the impact of weight reduction in reducing cardiovascular risk have been elusive. Instead, progress in CVD risk reduction has been achieved through medications indicated for controlling lipids, hyperglycemia, blood pressure, heart failure, inflammation, and/or thrombosis. Obesity has been implicated as promoting all these issues, suggesting that sustained, effective weight loss may have independent cardiovascular benefit. GLP-1 receptor agonists (RAs) reduce weight, improve glycemia, decrease cardiovascular events in those with diabetes, and may have additional cardioprotective effects. The GLP-1 RA semaglutide is in phase 3 studies as a medication for obesity treatment at a dose of 2.4 mg subcutaneously (s.c.) once weekly. Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) is a randomized, double-blind, parallel-group trial testing if semaglutide 2.4 mg subcutaneously once weekly is superior to placebo when added to standard of care for preventing major adverse cardiovascular events in patients with established CVD and overweight or obesity but without diabetes. SELECT is the first cardiovascular outcomes trial to evaluate superiority in major adverse cardiovascular events reduction for an antiobesity medication in such a population. As such, SELECT has the potential for advancing new approaches to CVD risk reduction while targeting obesity.

Topics: Cardiotonic Agents; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Male; Middle Aged; Obesity; Outcome Assessment, Health Care; Overweight; Randomized Controlled Trials as Topic; Weight Loss

The first tablet formulation of a glucagon-like peptide-1 receptor agonist(GLP-1RA), oral semaglutide, was approved in September 2019 for the treatment of adults with type 2 diabetes (T2D). This article reviews data from the PIONEER phase 3a clinical trial program, which assessed the efficacy and safety of oral semaglutide in more than 9500 patients at different stages on the disease trajectory (mean diabetes duration,3.5-15 years) and on a range of background treatment regimens(monotherapy, added to 1 or 2 oral glucose-lowering agents, or added to insulin). The studies compared oral semaglutide (doses of 3 mg, 7 mg, or14 mg) with placebo, and selected commonly used glucose-lowering agents (empagliflozin 25 mg, sitagliptin 100 mg, or liraglutide 1.8mg). Across the studies, oral semaglutide provided greater glycated hemoglobin (A1C) reductions than placebo, empagliflozin, or sitagliptinat 26 weeks, and similar A1C reductions as liraglutide. The proportion of patients achieving the A1C level recommended by the American Diabetes Association of less than 7.0% (53 mmol/mol) was greater with oral semaglutide (7 mg, 42%-69%; 14 mg, 55%-77%) than placebo (7%-31%)and active comparators (25%-62%), with durable target achievement. Oral semaglutide was associated with similar reductions in body weight as empagliflozin and greater reductions than placebo, sitagliptin, or liraglutide. Oral semaglutide was also efficacious in patients with T2D and moderate renal impairment. These findings indicate that oral semaglutide presents a valuable option for treating patients with T2D in a managed care setting, with the potential to expand the number of patients benefiting from GLP‑1RAs.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Managed Care Programs

To investigate the efficacy, safety, and tolerability of oral semaglutide added to insulin with or without metformin.. Patients with type 2 diabetes uncontrolled on insulin with or without metformin were randomized to oral semaglutide 3 mg (. Oral semaglutide was superior to placebo in reducing HbA

Topics: Adult; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Nausea; Treatment Outcome; Weight Loss

Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue approved for the treatment of type 2 diabetes. The impact of switching treatment from another GLP-1 receptor agonist (GLP-1RA) to semaglutide was investigated by analyses of exposure-response models.. HbA1c and body weight time-course models were developed, using up to 30 weeks of observations from four trials in the semaglutide phase 3 programme. Given the recommended dosing for each GLP-1RA, pharmacokinetic profiles were simulated based on published population pharmacokinetic models and exposure was adjusted by the relative potencies to ensure that model predictions matched the effects observed in clinical trials. After 26 weeks of simulated treatment with liraglutide, dulaglutide or exenatide extended-release, simulated semaglutide treatment was initiated 1 day after the last once-daily dose of liraglutide and 1 week after the last once-weekly doses of dulaglutide or exenatide extended-release.. The potency-adjusted total effective GLP-1RA concentration increased after switching from another GLP-1RA to semaglutide and was associated with reductions ranging from ~0.3% to ~0.8%-points for HbA1c and from ~2% to ~4% for body weight with semaglutide 1.0 mg. Temporary slight deteriorations in HbA1c were observed after switching to semaglutide 0.25 mg from liraglutide 1.2/1.8 mg or dulaglutide 1.5 mg.. Exposure-response modelling suggests that switching to semaglutide from liraglutide, dulaglutide or exenatide extended-release results in further reductions in HbA1c and body weight. Initial slight deterioration in outcome values when switching to semaglutide 0.25 mg could be avoided by initiating semaglutide treatment at a higher dose.

Topics: Adult; Aged; Body Weight; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Models, Statistical

To assess the cardiovascular (CV) safety of oral semaglutide, the first tablet formulation of a glucagon-like peptide-1 receptor agonist.. PIONEER 6 is a multinational, randomized, placebo-controlled, double-blind trial in patients with type 2 diabetes at high risk of CV events (defined as being aged ≥50 years and having established CV disease [CVD] or moderate [stage 3] chronic kidney disease [CKD], or being aged ≥60 years with ≥1 other CV risk factor). Patients were randomized to once-daily oral semaglutide (up to 14 mg) or placebo added to standard of care. The primary composite endpoint is time to first occurrence of CV death or non-fatal myocardial infarction or non-fatal stroke. The primary hypothesis was to exclude an excess in CV risk with oral semaglutide by assessing non-inferiority versus placebo for the primary endpoint (non-inferiority margin of 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio). PIONEER 6 is event-driven, with follow-up continuing until accrual of at least 122 primary outcome events. There is no pre-defined minimal duration.. Overall, 3183 patients have been enrolled (mean age 66.1 years, 31.6% females) in 214 sites across 21 countries. At baseline, the mean duration of diabetes was 14.9 years, mean glycated haemoglobin concentration was 66 mmol/mol (8.2%), and 84.6% of patients had established CVD/moderate CKD.. PIONEER 6 will provide evidence regarding the CV safety of oral semaglutide in patients with type 2 diabetes and high CV risk.

Topics: Administration, Oral; Aged; Aged, 80 and over; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Placebos; Renal Insufficiency, Chronic

Oral semaglutide is a novel tablet containing the human glucagon-like peptide-1 (GLP‑1) analogue semaglutide, co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The safety and pharmacokinetics of oral semaglutide were investigated in two randomised, double-blind, placebo-controlled trials.. In a single-dose, first-in-human trial, 135 healthy males received oral semaglutide (2-20 mg semaglutide co-formulated with 150-600 mg SNAC) or placebo with SNAC. In a 10-week, once-daily, multiple-dose trial, 84 healthy males received 20 or 40 mg oral semaglutide (with 300 mg SNAC), placebo, or placebo with SNAC, and 23 males with type 2 diabetes (T2D) received 40 mg oral semaglutide (with 300 mg SNAC), placebo, or placebo with SNAC.. Oral semaglutide was safe and well-tolerated in both trials. The majority of adverse events (AEs) were mild, with the most common AEs being gastrointestinal disorders. In the single-dose trial, semaglutide exposure was highest when co-formulated with 300 mg SNAC. In the multiple-dose trial, semaglutide exposure was approximately twofold higher with 40 versus 20 mg oral semaglutide in healthy males, in accordance with dose proportionality, and was similar between healthy males and males with T2D. The half-life of semaglutide was approximately 1 week in all groups.. The safety profile of oral semaglutide was as expected for the GLP-1 receptor agonist drug class. Oral semaglutide co-formulated with 300 mg SNAC was chosen for further clinical development. The pharmacokinetic results supported that oral semaglutide is suitable for once-daily dosing. CLINICALTRIALS.. NCT01037582, NCT01686945.

Topics: Administration, Oral; Adolescent; Adult; Area Under Curve; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Healthy Volunteers; Humans; Hypoglycemic Agents; Male; Metabolic Clearance Rate; Middle Aged; Young Adult

Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy.. To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes.. Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized.. Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved.. The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight.. Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, -0.3% [95% CI, -0.4% to -0.1%] and -0.5% [95% CI, -0.6% to -0.4%], respectively; P < .001 for both) and body weight (differences, -1.6 kg [95% CI, -2.0 to -1.1 kg] and -2.5 kg [95% CI, -3.0 to -2.0 kg], respectively; P < .001 for both) from baseline to week 26. Noninferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically significantly greater with semaglutide, 14 mg/d, vs sitagliptin.. Among adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting.. ClinicalTrials.gov Identifier: NCT02607865.

Topics: Administration, Oral; Adult; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Sitagliptin Phosphate; Sulfonylurea Compounds

Oral semaglutide is a tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analog semaglutide with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by semaglutide, or other mechanisms. Two one-sequence crossover trials investigated the effect of oral semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin.. In trial 1, 52 healthy subjects received lisinopril (20 mg single dose) or warfarin (25 mg single dose) with subsequent coadministration with SNAC alone (300 mg single dose), followed by oral semaglutide 20 mg once daily (steady state). In trial 2, 32 healthy subjects received digoxin (500 μg single dose) or metformin (850 mg twice daily for 4 days), with subsequent coadministration with SNAC alone followed by oral semaglutide, as in trial 1.. There were no apparent effects of oral semaglutide on area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C. Oral semaglutide or SNAC alone did not appear to affect the exposure of lisinopril, warfarin, or digoxin, and, based on its wide therapeutic index, the higher metformin exposure with oral semaglutide was not considered clinically relevant.

Topics: Administration, Oral; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Caprylates; Cardiotonic Agents; Case-Control Studies; Cross-Over Studies; Digoxin; Drug Interactions; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Healthy Volunteers; Humans; Hypoglycemic Agents; Lisinopril; Male; Metformin; Middle Aged; Warfarin

The Impact of Weight on Quality of Life-Lite (IWQOL-Lite) is widely used in evaluations of weight-loss interventions, including pharmaceutical trials. Because this measure was developed using input from individuals undergoing intensive residential treatment, the IWQOL-Lite may include concepts not relevant to clinical trial populations and may be missing concepts that are relevant to these populations. An alternative version, the IWQOL-Lite Clinical Trials Version (IWQOL-Lite-CT), was developed and validated according to the US Food and Drug Administration's (FDA's) guidance on patient-reported outcomes. Psychometric analyses were conducted to validate the IWQOL-Lite-CT using data from two randomized trials (NCT02453711 and NCT02906930) that included individuals with overweight/obesity, with and without type 2 diabetes. Additional measures included the SF-36, global items, weight and body mass index. The IWQOL-Lite-CT is a 20-item measure with two primary domains (Physical [seven items] and Psychosocial [13 items]). A five-item Physical Function composite and Total score were also supported. Cronbach's alpha and intraclass correlation coefficients exceeded 0.77 at each time point; patterns of construct validity correlations were consistent with hypotheses; and scores demonstrated treatment benefit. The IWQOL-Lite-CT is appropriate for assessing weight-related physical and psychosocial functioning in populations commonly targeted for obesity clinical trials. Qualification from the FDA is being sought for use of the IWQOL-Lite-CT in clinical trials to support product approval and labelling claims.

Topics: Adult; Aged; Body Mass Index; Body Weight; Female; Glucagon-Like Peptides; Humans; Male; Middle Aged; Obesity; Psychometrics; Quality of Life; Surveys and Questionnaires; Weight Loss

Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide.. We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome).. A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57). Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide.. In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo. (Funded by Novo Nordisk; PIONEER 6 ClinicalTrials.gov number, NCT02692716.).

Topics: Administration, Oral; Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Risk

To investigate treatment satisfaction with semaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, versus placebo/active comparators in the SUSTAIN clinical trial programme.. In SUSTAIN 2-5 and 7, the Diabetes Treatment Satisfaction Questionnaire was used to evaluate patient-perceived treatment satisfaction, hyperglycaemia and hypoglycaemia. Post hoc subgroup analyses were conducted to explore the effects of gastrointestinal adverse events (GI AEs), weight loss (≥5%) or achieving glycaemic (HbA1c < 7%) targets on treatment satisfaction.. Overall treatment satisfaction increased from baseline to end of treatment with all treatments across trials. Improvements were significantly greater with semaglutide versus comparators/placebo in SUSTAIN 2-5 (all P < 0.05), and generally greater in patients who achieved versus did not achieve weight loss and glycaemic targets, often with greater improvements with semaglutide 1.0 mg versus comparator/placebo in both weight loss groups. In SUSTAIN 7, improvements in overall treatment satisfaction were generally similar between semaglutide and dulaglutide, irrespective of weight loss or glycaemic control. In SUSTAIN 7, changes in overall treatment satisfaction score were generally lower in patients with versus without GI AEs at week 16 (except dulaglutide 0.75 mg), but similar by week 40. Perceived hyperglycaemia was significantly reduced from baseline to end of treatment with semaglutide versus all comparators/placebo (all P < 0.05). No differences between treatments were observed for perceived hypoglycaemia.. Semaglutide was associated with significantly greater (SUSTAIN 2-5) or similar (SUSTAIN 7) improvements in overall treatment satisfaction versus comparators/placebo. Improvements in overall treatment satisfaction were generally greater in patients achieving versus not achieving treatment targets. Clinicaltrials.gov: NCT01930188 (SUSTAIN 2), NCT01885208 (SUSTAIN 3), NCT02128932 (SUSTAIN 4), NCT02305381 (SUSTAIN 5) and NCT02648204 (SUSTAIN 7). EudraCT: 2012-004827-19 (SUSTAIN 2), 2012-004826-92 (SUSTAIN 3), 2013-004392-12 (SUSTAIN 4), 2013-004502-26 (SUSTAIN 5) and 2014-005375-91 (SUSTAIN 7).

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Patient Satisfaction; Surveys and Questionnaires; Weight Loss

To assess the safety and efficacy of monotherapy with once-weekly subcutaneous (s.c.) semaglutide vs sitagliptin in Japanese people with type 2 diabetes (T2D).. In this phase IIIa randomized, open-label, parallel-group, active-controlled, multicentre trial, Japanese adults with T2D treated with diet and exercise only or oral antidiabetic drug monotherapy (washed out during the run-in period) received once-weekly s.c. semaglutide (0.5 or 1.0 mg) or once-daily oral sitagliptin 100 mg. The primary endpoint was number of treatment-emergent adverse events (TEAEs) after 30 weeks.. Overall, 308 participants were randomized and exposed to treatment, with similar baseline characteristics across the groups. In total, 2.9% of participants in both the semaglutide 0.5 mg and the sitagliptin group prematurely discontinued treatment, compared with 14.7% in the semaglutide 1.0 mg group. The majority of discontinuations in the semaglutide 0.5 and 1.0 mg groups were attributable to adverse events (AEs). More TEAEs were reported in semaglutide- vs sitagliptin-treated participants (74.8%, 71.6% and 66.0% in the semaglutide 0.5 mg, semaglutide 1.0 mg and sitagliptin groups, respectively). AEs were mainly mild to moderate. Gastrointestinal AEs, most frequently reported with semaglutide, diminished in frequency over time. The mean glycated haemoglobin (HbA1c [baseline 8.1%]) decreased by 1.9% and 2.2% with semaglutide 0.5 and 1.0 mg, respectively, vs 0.7% with sitagliptin (estimated treatment difference [ETD] vs sitagliptin -1.13%, 95% confidence interval [CI] -1.32; -0.94, and -1.44%, 95% CI -1.63; -1.24; both P < .0001). Body weight (baseline 69.3 kg) was reduced by 2.2 and 3.9 kg with semaglutide 0.5 and 1.0 mg, respectively (ETD -2.22 kg, 95% CI -3.02; -1.42 and -3.88 kg, 95% CI -4.70; -3.07; both P < .0001).. In Japanese people with T2D, more TEAEs were reported with semaglutide than with sitagliptin; however, the semaglutide safety profile was similar to that of other glucagon-like peptide-1 receptor agonists. Semaglutide significantly reduced HbA1c and body weight compared with sitagliptin.

Topics: Administration, Oral; Constipation; Diabetes Mellitus, Type 2; Diarrhea; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Incretins; Injections, Subcutaneous; Japan; Nausea; Patient Dropouts; Severity of Illness Index; Sitagliptin Phosphate; Weight Loss

To evaluate diabetic retinopathy (DR) data from across the SUSTAIN clinical trial programme.. The SUSTAIN clinical trial programme evaluated the efficacy and safety of semaglutide, a glucagon-like peptide-1 analogue, for the treatment of type 2 diabetes (T2D). In SUSTAIN 6, a 2-year, pre-approval cardiovascular outcomes trial, semaglutide was associated with a significant increase in the risk of DR complications (DRC) vs placebo. DR data from across the SUSTAIN trials were evaluated, and post hoc analyses of the SUSTAIN 6 data were conducted. These included subgroup analyses to identify at-risk patients and a mediation analysis with initial change in glycated haemoglobin (HbA1c; percentage-points at week 16) as a covariate, to examine the role of the magnitude of reduction in HbA1c as an intermediate factor affecting risk of DRC.. There was no imbalance in DR adverse events across the SUSTAIN 1 to 5 and Japanese trials. The majority of the effect with semaglutide vs placebo in SUSTAIN 6 may be attributed to the magnitude and rapidity of HbA1c reduction during the first 16 weeks of treatment in patients who had pre-existing DR and poor glycaemic control at baseline, and who were treated with insulin.. Early worsening of DR is a known phenomenon associated with the rapidity and magnitude of improvement in glycaemic control with insulin; the DRC findings in SUSTAIN 6 are consistent with this. Guidance regarding the early worsening of DR is recommended with insulin. Similar recommendations may be appropriate for semaglutide.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Japan; Male; Middle Aged; Risk Factors

To evaluate the safety and efficacy of once-weekly subcutaneous semaglutide as monotherapy or combined with an oral antidiabetic drug (OAD) vs an additional OAD added to background therapy in Japanese people with type 2 diabetes (T2D) inadequately controlled on diet/exercise or OAD monotherapy.. In this phase III, open-label trial, adults with T2D were randomized 2:2:1 to semaglutide 0.5 mg or 1.0 mg, or one additional OAD (a dipeptidyl peptidase-4 inhibitor, biguanide, sulphonylurea, glinide, α-glucosidase inhibitor or thiazolidinedione) with a different mode of action from that of background therapy. The primary endpoint was number of adverse events (AEs) after 56 weeks.. Baseline characteristics were balanced between treatment arms (601 randomized). More AEs were reported in the semaglutide 0.5 mg (86.2%) and 1.0 mg (88.0%) groups than in the additional OAD group (71.7%). These were typically mild/moderate. Gastrointestinal AEs were most frequent with semaglutide, which diminished over time. The mean glycated haemoglobin (HbA1c) concentration (baseline 8.1%) was significantly reduced with semaglutide 0.5 mg and 1.0 mg vs additional OAD (1.7% and 2.0% vs 0.7%, respectively; estimated treatment difference [ETD] vs additional OAD -1.08% and -1.37%, both P < .0001). Body weight (baseline 71.5 kg) was reduced by 1.4 kg and 3.2 kg with semaglutide 0.5 mg and 1.0 mg, vs a 0.4-kg increase with additional OAD (ETD -1.84 kg and -3.59 kg; both P < .0001). For semaglutide-treated participants, >80% achieved an HbA1c concentration <7.0% (Japanese Diabetes Society target).. Semaglutide was well tolerated, with no new safety issues identified. Semaglutide treatment significantly reduced HbA1c and body weight vs additional OAD treatment in Japanese people with T2D.

Topics: Administration, Oral; Aged; Combined Modality Therapy; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Drug Resistance; Drug Therapy, Combination; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Japan; Male; Middle Aged; Weight Loss

Randomized clinical trials with the aim of evaluating the cardiovascular risks associated with glucagon-like peptide 1 (GLP-1) receptor agonists, lixisenatide, liraglutide, semaglutide, and exenatide, have been conducted. They showed different results among the agents, but the reason has not been explained.. To evaluate the cardiovascular risks associated with GLP-1 receptor agonists by using an alternative measure to the hazard ratio.. We used the difference in restricted mean survival time (RMST) as a measure of cardiovascular risks. Four randomized clinical trials with cardiovascular events as a primary endpoint, ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide), were reevaluated by estimating the RMSTs for each of the agents and placebo based on the reconstructed individual patient data for each time-to-event outcome from publicly available information.. The differences of RMSTs (GLP-1 receptor agonist minus placebo: point estimate and 95% CI) for primary composite endpoint of cardiovascular events were 0 days [-14, 14] in ELIXA (1080 days follow-up), 20 days [6, 34] in LEADER (1620 days follow-up), 8 days [1, 15] in SUSTAIN-6 (672 days follow-up), and 11 days [-3, 26] in EXSCEL (1825 days follow-up). As for the risk of other cardiovascular outcomes, there were no substantial differences between GLP-1 receptor agonists and placebo.. Liraglutide and semaglutide decrease the risk of major adverse cardiovascular events compared with placebo when using the difference in RMST. The previously reported result that GLP-1 receptor agonists do not increase the risk of cardiovascular outcomes compared with placebo is also confirmed.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Peptides; Proportional Hazards Models; Risk Factors

Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) as a tablet for oral administration. This trial (NCT02014259) investigated the pharmacokinetics, safety and tolerability of oral semaglutide in subjects with and without renal impairment.. Subjects were categorised as having normal renal function (n = 24), mild (n = 12), moderate (n = 12) or severe (n = 12) renal impairment, or end-stage renal disease (ESRD) requiring haemodialysis (n = 11) and received once-daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days) in the fasting state, followed by 30 min fasting after dosing. Semaglutide plasma concentrations were measured during dosing and for up to 21 days after the last dose.. Semaglutide exposure (area under the plasma concentration-time curve from time zero to 24 h after the tenth dose and maximum concentration after the tenth dose) did not vary in a consistent pattern across the renal function groups. Similarly, there was no apparent effect of renal impairment on the semaglutide half-life (geometric mean range 152-165 h). Except for one subject in the ESRD group, semaglutide was not detected in urine. Haemodialysis did not affect the pharmacokinetics of semaglutide. Adverse events were in line with those observed for other GLP-1 receptor agonists and no safety concerns were identified.. There was no apparent effect of renal impairment or haemodialysis on the pharmacokinetics of oral semaglutide. Based on this trial, renal impairment should not affect dose recommendations for oral semaglutide.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Half-Life; Humans; Hypoglycemic Agents; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Renal Insufficiency

The efficacy and safety of semaglutide vs comparators in non-elderly (<65 years) and elderly (≥65 years) patients with type 2 diabetes (T2D) across the SUSTAIN 1-5 trials were evaluated. Patients were randomized to once-weekly subcutaneous semaglutide (0.5 or 1.0 mg) vs placebo, sitagliptin, exenatide or insulin. The primary objective was change in HbA1c and secondary objectives were changes in body weight and safety. Mean HbA1c decreased from baseline by 1.2%-1.5% and 1.5%-1.9% vs 0%-0.9% (non-elderly, n = 3045) and by 1.3%-1.5% and 1.2%-1.8% vs 0.2%-1.0% (elderly, n = 854) with semaglutide 0.5 and 1.0 mg vs comparators. Similar reductions from baseline in mean body weight with semaglutide occurred in both age groups. Similar proportions of patients experienced adverse events; premature treatment discontinuations were higher in elderly vs non-elderly patients. No increased risk of severe or blood glucose-confirmed hypoglycaemia was seen with semaglutide vs comparators between age groups. Semaglutide had a comparable efficacy and safety profile in non-elderly and elderly patients across the SUSTAIN 1-5 trials, making it an effective treatment option for elderly patients with T2D.

Topics: Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Sitagliptin Phosphate; Treatment Outcome

Combination therapy with insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is important for treating type 2 diabetes (T2D). This trial assesses the efficacy and safety of semaglutide, a GLP-1RA, as an add-on to basal insulin.. To demonstrate the superiority of semaglutide vs placebo on glycemic control as an add-on to basal insulin in patients with T2D.. Phase 3a, double-blind, placebo-controlled, 30-week trial.. This study included 90 sites in five countries.. We studied 397 patients with uncontrolled T2D receiving stable therapy with basal insulin with or without metformin.. Subcutaneous semaglutide 0.5 or 1.0 mg once weekly or volume-matched placebo.. Primary endpoint was change in glycated Hb (HbA1c) from baseline to week 30. Confirmatory secondary endpoint was change in body weight from baseline to week 30.. At week 30, mean HbA1c reductions [mean baseline value, 8.4% (67.9 mmol/mol)] with semaglutide 0.5 and 1.0 mg were 1.4% (15.8 mmol/mol) and 1.8% (20.2 mmol/mol) vs 0.1% (1.0 mmol/mol) with placebo [estimated treatment difference (ETD) vs placebo, -1.35 (14.8 mmol/mol); 95% CI, -1.61 to -1.10 and ETD, -1.75% (19.2 mmol/mol); 95% CI, -2.01 to -1.50; both P < 0.0001]. Severe or blood glucose-confirmed hypoglycemic episodes were reported in 11 patients (17 events) and 14 patients (25 events) with semaglutide 0.5 and 1.0 mg, respectively, vs seven patients (13 events) with placebo (estimated rate ratio vs placebo, 2.08; 95% CI, 0.67 to 6.51 and estimated rate ratio vs placebo, 2.41; 95% CI, 0.84 to 6.96 for 0.5 and 1.0 mg; both P = nonsignificant). Mean body weight decreased with semaglutide 0.5 and 1.0 mg vs placebo from baseline to end of treatment: 3.7, 6.4, and 1.4 kg (ETD, -2.31; 95% CI, -3.33 to -1.29 and ETD, -5.06; 95% CI, -6.08 to -4.04 kg; both P < 0.0001). Premature treatment discontinuation due to adverse events was higher for semaglutide 0.5 and 1.0 mg vs placebo (4.5%, 6.1%, and 0.8%), mainly due to gastrointestinal disorders.. Semaglutide, added to basal insulin, significantly reduced HbA1c and body weight in patients with uncontrolled T2D vs placebo.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Treatment Outcome; Young Adult

Semaglutide is a human glucagon-like peptide-1 analog that has been co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, for oral administration. This trial (NCT02016911) investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of oral semaglutide. Subjects were classified into groups: normal hepatic function (n = 24), and mild (n = 12), moderate (n = 12), or severe (n = 8) hepatic impairment according to Child-Pugh criteria, and received once-daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days). Semaglutide plasma concentrations were measured during dosing and for up to 21 days post-last dose. Area under the semaglutide plasma concentration-time curve from 0-24 hours after the 10th dose (primary end point) and maximum semaglutide concentration after the 10th dose appeared similar across hepatic function groups. Similarly, there was no apparent effect of hepatic impairment on time to maximum semaglutide concentration (median range 1.0-1.5 hours) or half-life (geometric mean range 142-156 hours). No safety concerns were identified in subjects with hepatic impairment receiving semaglutide. Reported adverse events were in line with those observed for other glucagon-like peptide-1 receptor agonists. There was no apparent effect of hepatic impairment on the pharmacokinetics, safety, and tolerability of oral semaglutide. The results of this trial suggest that dose adjustment of oral semaglutide is not warranted in subjects with hepatic impairment.

Topics: Administration, Oral; Adult; Area Under Curve; Blood Glucose; Female; Glucagon-Like Peptides; Half-Life; Humans; Hypoglycemic Agents; Liver Diseases; Male; Middle Aged

To assess the effect of baseline body mass index (BMI) and the occurrence of nausea and/or vomiting on weight loss induced by semalgutide, a once-weekly glucagon-like peptide 1 analogue for the treatment of type 2 diabetes. Semaglutide demonstrated superior reductions in HbA1c and superior weight loss (by 2.3-6.3 kg) versus different comparators across the SUSTAIN 1 to 5 trials; the contributing factors to weight loss are not established.. Subjects with inadequately controlled type 2 diabetes (drug-naïve or on background treatment) were randomized to subcutaneous semaglutide 0.5 mg (excluding SUSTAIN 3), 1.0 mg (all trials), or comparator (placebo, sitagliptin, exenatide extended release or insulin glargine). Subjects were subdivided by baseline BMI and reporting (yes/no) of any nausea and/or vomiting. Change from baseline in body weight was assessed within each trial and subgroup. A mediation analysis separated weight loss into direct or indirect (mediated by nausea or vomiting) effects.. Clinically relevant weight-loss differences were observed across all BMI subgroups, with a trend towards higher absolute weight loss with higher baseline BMI. Overall, 15.2% to 24.0% and 21.5% to 27.2% of subjects experienced nausea or vomiting with semaglutide 0.5 and 1.0 mg, respectively, versus 6.0% to 14.1% with comparators. Only 0.07 to 0.5 kg of the treatment difference between semaglutide and comparators was mediated by nausea or vomiting (indirect effects).. In SUSTAIN 1 to 5, semaglutide-induced weight loss was consistently greater versus comparators, regardless of baseline BMI. The contribution of nausea or vomiting to this weight loss was minor.

Topics: Adult; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin Glargine; Male; Middle Aged; Nausea; Sitagliptin Phosphate; Treatment Outcome; Vomiting; Weight Loss

To investigate the effects of semaglutide vs placebo on glucagon and other counterregulatory hormones during hypoglycaemia in type 2 diabetes (T2D).. In this double-blind, placebo-controlled, single-centre trial, we randomized 38 men and women (treated only with metformin) 1:1 to 2 12-week crossover periods of once-weekly subcutaneous semaglutide or placebo, each followed by a hypoglycaemic clamp procedure. The primary endpoint was change in glucagon concentration from target plasma glucose (PG) level 5.5 mmol/L to nadir (target 2.5 mmol/L).. Semaglutide treatment did not compromise the counterregulatory glucagon response during experimental hypoglycaemia in people with T2D.

Topics: Adult; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Female; Glucagon-Like Peptides; Humans; Hypoglycemia; Male; Middle Aged; Placebos

Since the first oral glucagon-like peptide-1 analog comprises semaglutide co-formulated with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which induces a transient, localized increase in gastric pH, we have investigated whether a proton pump inhibitor affects the pharmacokinetics of oral semaglutide.. A single-center, randomized, open-label, parallel-group trial investigated pharmacokinetic interactions of oral semaglutide with omeprazole (40 mg once-daily) in 54 healthy subjects. Primary endpoints were area under the plasma concentration-time curve over 24 h for semaglutide (AUC. Exposure of semaglutide appeared to be slightly increased, although not statistically significantly, with oral semaglutide plus omeprazole versus oral semaglutide alone (AUC. There was a slight non-statistically significant increase in semaglutide exposure when oral semaglutide was administered with omeprazole, but this is not considered clinically relevant and no dose adjustment is likely to be required.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Drug Interactions; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Male; Middle Aged; Omeprazole; Proton Pump Inhibitors

Obesity is a major public health issue, and new pharmaceuticals for weight management are needed. Therefore, we evaluated the efficacy and safety of the glucagon-like peptide-1 (GLP-1) analogue semaglutide in comparison with liraglutide and a placebo in promoting weight loss.. We did a randomised, double-blind, placebo and active controlled, multicentre, dose-ranging, phase 2 trial. The study was done in eight countries involving 71 clinical sites. Eligible participants were adults (≥18 years) without diabetes and with a body-mass index (BMI) of 30 kg/m. Between Oct 1, 2015, and Feb 11, 2016, 957 individuals were randomly assigned (102-103 participants per active treatment group and 136 in the pooled placebo group). Mean baseline characteristics included age 47 years, bodyweight 111·5 kg, and BMI 39·3 kg/m. In combination with dietary and physical activity counselling, semaglutide was well tolerated over 52 weeks and showed clinically relevant weight loss compared with placebo at all doses.. Novo Nordisk A/S.

Topics: Adult; Blood Glucose; Body Mass Index; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Liraglutide; Male; Middle Aged; Obesity; Placebos; Treatment Outcome; Weight Loss

Oral administration of therapeutic peptides is hindered by poor absorption across the gastrointestinal barrier and extensive degradation by proteolytic enzymes. Here, we investigated the absorption of orally delivered semaglutide, a glucagon-like peptide-1 analog, coformulated with the absorption enhancer sodium

Topics: Administration, Oral; Adolescent; Adult; Aged; Animals; Cell Membrane; Dogs; Epithelial Cells; Gastric Mucosa; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; Male; Middle Aged; Rats; Stomach; Time Factors; Young Adult

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Drug Administration Schedule; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Treatment Outcome

Several pharmacological treatment options are available for type 2 diabetes; however, many patients do not achieve optimum glycaemic control and therefore new therapies are necessary. We assessed the efficacy and safety of semaglutide, a glucagon-like peptide-1 (GLP-1) analogue in clinical development, compared with insulin glargine in patients with type 2 diabetes who were inadequately controlled with metformin (with or without sulfonylureas).. We did a randomised, open-label, non-inferiority, parallel-group, multicentre, multinational, phase 3a trial (SUSTAIN 4) at 196 sites in 14 countries. Eligible participants were insulin-naive patients with type 2 diabetes, aged 18 years and older, who had insufficient glycaemic control with metformin either alone or in combination with a sulfonylurea. We randomly assigned participants (1:1:1) to either subcutaneous once-weekly 0·5 mg or 1·0 mg semaglutide (doses reached after following a fixed dose-escalation regimen) or once-daily insulin glargine (starting dose 10 IU per day, then titrated weekly to a pre-breakfast self-measured plasma glucose target of 4·0-5·5 mmol/L [72-99 mg/dL]) for 30 weeks. In all treatment groups, previous background metformin and sulfonylurea treatment was continued throughout the trial. We did the randomisation using an interactive voice or web response system. The primary endpoint was change in mean HbA. Between Aug 4, 2014, and Sept 3, 2015, we randomly assigned 1089 participants to treatment; the mITT population consisted of 362 participants assigned to 0·5 mg semaglutide, 360 to 1·0 mg semaglutide, and 360 to insulin glargine. 49 (14%) participants assigned to 0·5 mg semaglutide discontinued treatment prematurely, compared with 55 (15%) assigned to 1·0 mg semaglutide, and 26 (7%) assigned to insulin glargine. Most discontinuations were due to adverse events-mostly gastrointestinal with semaglutide, and others such as skin and subcutaneous tissue disorders (eg, rash, pruritus, and urticaria) with insulin glargine. From a mean baseline HbA. Compared with insulin glargine, semaglutide resulted in greater reductions in HbA. Novo Nordisk A/S.

Topics: Aged; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin Glargine; Male; Metformin; Middle Aged

The pharmacokinetics and tolerability of semaglutide, a once-weekly human glucagon-like peptide-1 analog in development for the treatment of type 2 diabetes mellitus, were investigated in subjects with/without renal impairment (RI).. Fifty-six subjects, categorized into renal function groups [normal, mild, moderate, severe, and end-stage renal disease (ESRD)], received a single subcutaneous dose of semaglutide 0.5 mg. Semaglutide plasma concentrations were assessed ≤480 h post-dose; the primary endpoint was the area under the plasma concentration-time curve from time zero to infinity.. Semaglutide exposure in subjects with mild/moderate RI and ESRD was similar to that in subjects with normal renal function. In subjects with severe RI, the mean exposure of semaglutide was 22% higher than in subjects with normal renal function, and the 95% confidence interval (1.02-1.47) for the ratio exceeded the pre-specified limits (0.70-1.43). When adjusted for differences in sex, age, and body weight between the groups, all comparisons were within the pre-specified clinically relevant limits. Across RI groups there was no relationship between creatinine clearance (CL. When adjusted for differences in sex, age, and body weight, semaglutide exposure was similar between subjects with RI and subjects with normal renal function. Semaglutide (0.5 mg) was well-tolerated. Dose adjustment may not be warranted for subjects with RI. CLINICALTRIALS.. NCT00833716.

Topics: Adolescent; Adult; Aged; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Male; Middle Aged; Renal Insufficiency; Young Adult

Semaglutide is a glucagon-like peptide-1 analogue in development for the once-weekly treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (metformin, warfarin, atorvastatin and digoxin) was evaluated in healthy subjects.. Subjects received metformin (500 mg twice daily for 3.5 days), warfarin (25 mg, single dose), atorvastatin (40 mg, single dose) or digoxin (0.5 mg, single dose) before and with subcutaneous semaglutide treatment at steady state (1.0 mg). Lack of drug-drug interaction was concluded if the 90% confidence intervals for the area under the plasma concentration-time curve ratio before and with semaglutide were within a pre-specified interval (0.80-1.25).. Overall, metformin, warfarin, atorvastatin and digoxin pharmacokinetics were not affected to a clinically relevant degree with semaglutide co-administration. Estimated area under the plasma concentration-time curve ratios for all concomitant medications before and with semaglutide treatment were within the pre-specified interval. In addition, semaglutide did not affect maximum plasma concentration of concomitant medications to a relevant degree. Furthermore, no clinically relevant change in international normalised ratio response to warfarin was observed with semaglutide co-administration. Most adverse events with semaglutide treatment were mild or moderate. Adverse events with semaglutide and co-administered medication were comparable to those reported during treatment with semaglutide alone, and were mostly gastrointestinal related.. No clinically significant pharmacokinetic or pharmacodynamic interactions were identified and no new safety issues observed with combined treatment with semaglutide. This suggests that no dose adjustments should be required when semaglutide is administered concomitantly with these medications.

Topics: Adolescent; Adult; Atorvastatin; Cross-Over Studies; Digoxin; Drug Interactions; Drug Therapy, Combination; Female; Glucagon-Like Peptides; Healthy Volunteers; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Warfarin; Young Adult

Glucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection.. To compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes.. Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers) in 14 countries conducted between December 2013 and December 2014. Of 1106 participants assessed, 632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized. Randomization was stratified by metformin use.. Once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks.. The primary end point was change in hemoglobin A1c (HbA1c) from baseline to week 26. Secondary end points included change from baseline in body weight and adverse events.. Baseline characteristics were comparable across treatment groups. Of the 632 randomized patients (mean age, 57.1 years [SD, 10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI, 31.7 [SD, 4.3]), 583 (92%) completed the trial. Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, -0.7% to -1.9%) and subcutaneous semaglutide (-1.9%) and placebo (-0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, -0.4% to -1.6%; P = .01 for 2.5 mg, <.001 for all other dosages). Reductions in body weight were greater with oral semaglutide (dosage-dependent range, -2.1 kg to -6.9 kg) and subcutaneous semaglutide (-6.4 kg) vs placebo (-1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, -0.9 to -5.7 kg; P < .001). Adverse events were reported by 63% to 86% (371 of 490 patients) in the oral semaglutide groups, 81% (56 of 69 patients) in the subcutaneous semaglutide group, and 68% (48 of 71 patients) in the placebo group; mild to moderate gastrointestinal events were most common.. Among patients with type 2 diabetes, oral semaglutide resulted in better glycemic control than placebo over 26 weeks. These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety.. clinicaltrials.gov Identifier: NCT01923181.

Topics: Administration, Oral; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Male; Middle Aged; Nausea

The aim of this trial was to investigate the mechanism of action for body weight loss with semaglutide.. This randomised, double-blind, placebo-controlled, two-period crossover trial investigated the effects of 12 weeks of treatment with once-weekly subcutaneous semaglutide, dose-escalated to 1.0 mg, in 30 subjects with obesity. Ad libitum energy intake, ratings of appetite, thirst, nausea and well-being, control of eating, food preference, resting metabolic rate, body weight and body composition were assessed.. After a standardised breakfast, semaglutide, compared with placebo, led to a lower ad libitum energy intake during lunch (-1255 kJ; P  < .0001) and during the subsequent evening meal ( P  = .0401) and snacks ( P  = .0034), resulting in a 24% reduction in total energy intake across all ad libitum meals throughout the day (-3036 kJ; P  < .0001). Fasting overall appetite suppression scores were improved with semaglutide vs placebo, while nausea ratings were similar. Semaglutide was associated with less hunger and food cravings, better control of eating and a lower preference for high-fat foods. Resting metabolic rate, adjusted for lean body mass, did not differ between treatments. Semaglutide led to a reduction from baseline in mean body weight of 5.0 kg, predominantly from body fat mass.. After 12 weeks of treatment, ad libitum energy intake was substantially lower with semaglutide vs placebo with a corresponding loss of body weight observed with semaglutide. In addition to reduced energy intake, likely mechanisms for semaglutide-induced weight loss included less appetite and food cravings, better control of eating and lower relative preference for fatty, energy-dense foods.

Topics: Adiposity; Adult; Appetite Depressants; Appetite Regulation; Basal Metabolism; Body Mass Index; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Energy Intake; Feeding Behavior; Female; Food Preferences; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Injections, Subcutaneous; Male; Middle Aged; Obesity; Self Report; Weight Loss

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Glucagon-Like Peptides; Humans; Hyperglycemia; Insulin Aspart

To investigate the dose-response relationship of semaglutide versus placebo and open-label liraglutide in terms of glycemic control in patients with type 2 diabetes.. This was a 12-week, randomized, double-blind phase 2 trial. Patients (n = 415) were randomized to receive a subcutaneous injection of semaglutide once weekly without dose escalation (0.1-0.8 mg) or with dose escalation (E) (0.4 mg steps to 0.8 or 1.6 mg E over 1-2 weeks), open-label liraglutide once daily (1.2 or 1.8 mg), or placebo. The primary end point was change in HbA1c level from baseline. Secondary end points included change in body weight, safety, and tolerability.. Semaglutide dose-dependently reduced the level of HbA1c from baseline (8.1 ± 0.8%) to week 12 by up to -1.7%, and body weight by up to -4.8 kg (1.6 mg E, P < 0.001 vs. placebo). Up to 81% of patients achieved an HbA1c level of <7%. HbA1c level and weight reductions with semaglutide 1.6 mg E were greater than those with liraglutide 1.2 and 1.8 mg (based on unadjusted CIs), but adverse events (AEs) and withdrawals occurred more frequently. The incidence of nausea, vomiting, and withdrawal due to gastrointestinal AEs increased with the semaglutide dose; most events were mild to moderate, transient, and ameliorated by dose escalation. There were no major episodes of hypoglycemia and few cases of injection site reactions.. After 12 weeks, semaglutide dose-dependently reduced HbA1c level and weight in patients with type 2 diabetes. No unexpected safety or tolerability concerns were identified; gastrointestinal AEs typical of glucagon-like peptide 1 receptor agonists were mitigated by dose escalation. On this basis, weekly semaglutide doses of 0.5 and 1.0 mg with a 4-week dose escalation were selected for phase 3.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Liraglutide; Male; Middle Aged; Nausea; Treatment Outcome; Vomiting

Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown.. We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio.. At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.. In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Kaplan-Meier Estimate; Male; Middle Aged

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Weight Loss

Escalating doses of insulin required with progression of type 2 diabetes may lead to weight gain. Weight loss associated with semaglutide may be beneficial. However, data on the use of semaglutide in patients requiring high daily doses of insulin are currently lacking.. The purpose of this project was to evaluate the impact of semaglutide on total daily dose (TDD) of insulin when initiated in patients with type 2 diabetes mellitus (T2DM) on high daily doses of insulin. Secondary objectives assessed included changes in weight, body mass index (BMI), blood pressure, heart rate, and diabetes and blood pressure medications.. This IRB exempt retrospective medical record review included patients with T2DM prescribed semaglutide and at least 100 units TDD of insulin between January 1, 2019, and December 31, 2019.. Of the 72 patients included, the TDD of insulin decreased from baseline to 6 months (183 ± 98 units and 143 ± 99 units,. Improvement in glycemic control occurred despite reductions in TDD of insulin. Improvements in A1c and body weight were clinically significant. This analysis adds to existing literature supporting the use of GLP-1 RAs in patients on high daily doses of insulin.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Retrospective Studies; Weight Loss

Higher doses of the glucagon-like peptide-1 agonist semaglutide and, more recently, tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 agonist showed a significant reduction in body weight in patients with type 2 diabetes mellitus. However, their comparative value for money for this indication is unclear. Therefore, we aimed to establish which provides better value for money.. We calculated the cost needed to treat to achieve a 1% reduction in body weight using high-dose tirzepatide (15 mg) versus semaglutide (2.4 mg). The body weight reductions were extracted from published results of SURMOUNT-1 and STEP 1 trials, respectively. In addition, we performed a scenario analysis to mitigate the primary differences between the two study populations. Drug costs were based on US GoodRx prices as of October 2022.. Using tirzepatide resulted in a weight loss of 17.8% (95% CI: 16.3%-19.3%) compared with 12.4% (95% CI: 11.5%-13.4%) for semaglutide. The total cost of 72 weeks of tirzepatide was estimated at $17 527 compared with $22 878 for 68 weeks of semaglutide. Accordingly, the cost needed to treat per 1% of body weight reduction with tirzepatide is estimated at $985 (95% CI: $908-$1075) compared with $1845 (95% CI: $1707-$1989) with semaglutide. Scenario analysis confirmed these findings.. Tirzepatide provides better value for money than semaglutide for weight reduction.

Topics: Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Weight Loss

Topics: Cardiovascular Diseases; Coronary Artery Disease; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

SURE Netherlands (NCT03929679) evaluated the use of once-weekly (OW) semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1RA), in routine clinical care for individuals with type 2 diabetes (T2D).. Adults (age ≥ 18 years) with T2D were enrolled into the single-arm study. The primary endpoint was change from baseline to end of study (EOS;  approx. 30 weeks) in glycated haemoglobin (HbA. In total, 211 participants (mean age 60.5 years; diabetes duration 13.3 years) initiated semaglutide; most were receiving metformin (82.9%) and/or basal insulin (59.2%) at baseline, and 6.2% switched from another GLP-1RA. Mean baseline HbA. Individuals with T2D treated with OW semaglutide experienced significant and clinically relevant improvements in glycaemic control and BW from baseline. These results from a diverse real-world population in the Netherlands support the use of OW semaglutide in treating adults with T2D in routine clinical practice.

Topics: Adolescent; Adult; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin; Middle Aged; Netherlands; Quality of Life

Topics: Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Weight Loss

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity

Glucagon-like peptide-1 receptor agonists improve glycaemic control: some are now available as oral and subcutaneous formulations, and some have indications for reducing cardiovascular risk. The expanded scope for these therapies warrants comprehensive safety evaluations. We report the safety/tolerability of subcutaneous and oral semaglutide from the SUSTAIN and PIONEER clinical trial programmes, respectively.. Adverse events (AEs) from 16 randomized placebo- or active-controlled phase IIIa trials in patients with type 2 diabetes (n = 11 159) including once-weekly subcutaneous semaglutide (n = 3150; SUSTAIN trials) or once-daily oral semaglutide (n = 4116; PIONEER trials) were analysed. Data pools were analysed for each programme, with separate analyses of cardiovascular outcomes trials (CVOTs; n = 6480).. In the phase IIIa pools, gastrointestinal disorders were reported in 41.9%/39.1% of patients with subcutaneous/oral semaglutide, respectively (most prevalent during initiation/escalation) versus 22.0%/24.8% with comparators. Rates of kidney disorders, acute pancreatitis, malignant neoplasms, hypoglycaemia, diabetic retinopathy, heart failure and other cardiovascular events were similar for semaglutide versus comparators. Cholelithiasis incidence was higher with subcutaneous and oral semaglutide versus placebo. Diabetic retinopathy incidence was higher with subcutaneous semaglutide versus placebo in SUSTAIN 6. Small pulse rate increases occurred with both formulations; there was no increased rate of arrhythmias. Fatal AE incidence was similar between semaglutide and comparators. Versus placebo, CVOTs showed a reduced risk of major adverse cardiovascular events with subcutaneous semaglutide and non-inferiority criteria were met with oral semaglutide.. The most common AEs with semaglutide were gastrointestinal disorders, which decreased with continued therapy. These comprehensive safety/tolerability data may better inform patient selection and guidance in care.

Topics: Acute Disease; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Gastrointestinal Diseases; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Pancreatitis

Topics: Anti-Obesity Agents; Child; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Obesity; Phentermine; Weight Loss

SURE Italy, a multicentre, prospective, open-label, observational, real-world study, investigated once-weekly semaglutide in patients with type 2 diabetes (T2D) in routine clinical practice.. Adults with T2D and ≥1 documented glycated haemoglobin (HbA1c) level within 12 weeks of semaglutide initiation were enrolled. The primary endpoint was change in HbA1c from baseline to end of study (EOS; ~30 weeks). Other endpoints included changes in body weight, waist circumference and patient-reported outcomes, and the proportion of patients achieving HbA1c <7.0% or <6.5%, weight loss ≥5% and a post-hoc composite endpoint (HbA1c reduction of ≥1%-point and weight loss ≥5%). These endpoints were reported for patients on semaglutide at EOS [effectiveness analysis set (EAS)]. Safety data were reported in the full analysis set.. Of 579 patients who initiated semaglutide (full analysis set), 491 completed the study on treatment (EAS). Mean baseline HbA1c was 8.0%, and 20.7% (120 of 579) of patients had HbA1c <7.0%. Mean semaglutide dose at EOS was 0.66 ± 0.28 mg. In the EAS, mean HbA1c and body weight decreased by 1.1%-point (95% confidence interval 1.20, 1.05; P < .0001) and 4.2 kg (95% confidence interval 4.63, 3.67; P < .0001), respectively. At EOS, 61.7% and 40.8% of patients achieved HbA1c <7.0% and <6.5%, respectively, 40.5% achieved weight loss ≥5% and 25.3% achieved the post-hoc composite endpoint. Patient-reported outcomes improved from baseline to EOS. No new safety concerns were identified.. In routine clinical practice in Italy, patients with T2D treated with once-weekly semaglutide for 30 weeks achieved clinically significant improvements in HbA1c, body weight and other outcomes.

Topics: Adult; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Prospective Studies; Weight Loss

The extracellular matrix (ECM) is fundamental for the normal endocrine functions of pancreatic islet cells and plays key roles in the pathophysiology of type 2 diabetes. Here we investigated the turnover of islet ECM components, including islet amyloid polypeptide (IAPP), in an obese mouse model treated with semaglutide, a glucagon-like peptide type 1 receptor agonist.. Male one-month-old C57BL/6 mice were fed a control diet (C) or a high-fat diet (HF) for 16 weeks, then treated with semaglutide (subcutaneous 40 μg/kg every three days) for an additional four weeks (HFS). The islets were immunostained and gene expressions were assessed.. Comparisons refer to HFS vs HF. Thus, IAPP immunolabeling and beta-cell-enriched beta-amyloid precursor protein cleaving enzyme (Bace2, -40 %) and heparanase immunolabeling and gene (Hpse, -40 %) were mitigated by semaglutide. In contrast, perlecan (Hspg2, +900 %) and vascular endothelial growth factor A (Vegfa, +420 %) were enhanced by semaglutide. Also, semaglutide lessened syndecan 4 (Sdc4, -65 %) and hyaluronan synthases (Has1, -45 %; Has2, -65 %) as well as chondroitin sulfate immunolabeling, and collagen type 1 (Col1a1, -60 %) and type 6 (Col6a3, -15 %), lysyl oxidase (Lox, -30 %) and metalloproteinases (Mmp2, -45 %; Mmp9, -60 %).. Semaglutide improved the turnover of islet heparan sulfate proteoglycans, hyaluronan, chondroitin sulfate proteoglycans, and collagens in the islet ECM. Such changes should contribute to restoring a healthy islet functional milieu and should reduce the formation of cell-damaging amyloid deposits. Our findings also provide additional evidence for the involvement of islet proteoglycans in the pathophysiology of type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Diet; Extracellular Matrix; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Islet Amyloid Polypeptide; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Vascular Endothelial Growth Factor A

Topics: Female; Glucagon-Like Peptides; Humans; Insulin Resistance; Polycystic Ovary Syndrome; Social Media

To investigate the impact of treatment with once-weekly subcutaneous semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), for up to 2 years in people with type 2 diabetes (T2D) managed in routine clinical practice.. The study was based on data from national registries. People who redeemed at least one prescription of semaglutide and had 2 years of follow-up were included. Data were collected at baseline and after 180, 360, 540 and 720 days of treatment (all timepoints ± 90 days).. In total, 9284 people redeemed at least one semaglutide prescription (intention-to-treat) and 4132 people redeemed semaglutide continuously (on-treatment). For the on-treatment cohort, the median (interquartile range) age was 62.0 (16.0) years, diabetes duration was 10.8 (8.7) years, and glycated haemoglobin (HbA1c) level was 62.0 (18.0) mmol/mol at baseline. A subset of the on-treatment cohort, comprising 2676 people, had HbA1c measurements at baseline and at least once during 720 days. The mean (95% confidence interval) changes in HbA1c after 720 days were -12.6 (-13.6; -11.6) mmol/mol (P < 0.001) for GLP-1RA-naïve people, and -5.6 (-6.2; -5.0) mmol/mol (P < 0.001) for GLP-1RA-experienced people. Similarly, 55% of GLP-1RA-naïve people and 43% of GLP-1RA-experienced people reached a HbA1c target of ≤53 mmol/mol after 2 years.. People treated with semaglutide in routine clinical practice experienced clinically relevant and sustained improvements in glycaemic control after 180, 360, 540 and 720 days, irrespective of former GLP-1RA exposure, effects which were comparable with those observed in clinical studies. These results support the use of semaglutide in routine clinical practice for the long-term management of T2D.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Middle Aged

Real-world data are required to support glucagon-like peptide-1 receptor agonist use in type 2 diabetes (T2D). SURE France assessed once-weekly semaglutide in adults with T2D in real-world clinical practice.. This multicentre, prospective, open-label, single-arm study included adults with T2D and ≥1 documented glycated haemoglobin (HbA1c) value ≤12 weeks before semaglutide initiation. The primary endpoint was HbA1c change from baseline to end of study (EOS; ~30 weeks). Secondary endpoints included change from baseline to EOS in body weight (BW) and waist circumference (WC); and proportion achieving HbA1c targets. Baseline characteristics and safety were reported for the full analysis set (patients initiating semaglutide). Analysis of other endpoints was based on the effectiveness analysis set (study completers receiving semaglutide at EOS).. Of 497 patients initiating semaglutide (41.6% female, mean age 58.3 years), 348 completed the study on treatment. Baseline HbA1c, diabetes duration, BW and WC, were 8.3%, 10.0 years, 98.2 kg and 114.2 cm, respectively. The most common reasons for initiating semaglutide were to improve glycaemic control (79.7%), reduce BW (69.8%) and address cardiovascular risk (24.1%). At EOS, mean changes were: HbA1c, -1.2% points [95% confidence interval (CI) -1.32; -1.10]; BW, -4.7 kg (95% CI -5.38; -4.07); and WC, -4.9 cm (95% CI -5.94; -3.88). At EOS, 81.7%, 67.7% and 51.6% of patients achieved an HbA1c target of <8.0%, <7.5% and <7.0%, respectively. No new safety concerns were identified.. These results support the benefits of semaglutide in a real-world setting in adults with T2D in France showing a significant reduction in HbA1c and body weight.

Topics: Adult; Body Weight; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Prospective Studies

Topics: Appetite Depressants; England; Glucagon-Like Peptides; Humans; Obesity

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Feeding Behavior; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Risk Factors

Metabolic functions of GLP-1 and its analogues have been extensively investigated. In addition to acting as an incretin and reducing body weight, we and others have suggested the existence of GLP-1/fibroblast growth factor 21 (FGF21) axis in which liver mediates certain functions of GLP-1 receptor agonists. In a more recent study, we found with surprise that four-week treatment with liraglutide but not semaglutide stimulated hepatic FGF21 expression in HFD-challenged mice. We wondered whether semaglutide can also improve FGF21 sensitivity or responsiveness and hence triggers the feedback loop in attenuating its stimulation on hepatic FGF21 expression after a long-term treatment. Here, we assessed effect of daily semaglutide treatment in HFD-fed mice for 7 days. HFD challenge attenuated effect of FGF21 treatment on its downstream events in mouse primary hepatocytes, which can be restored by 7-day semaglutide treatment. In mouse liver, 7-day semaglutide treatment stimulated FGF21 as well as genes that encode its receptor (FGFR1) and the obligatory co-receptor (KLB), and a battery of genes that are involved in lipid homeostasis. In epididymal fat tissue, expressions of a battery genes including Klb affected by HFD challenge were reversed by 7-day semaglutide treatment. We suggest that semaglutide treatment improves FGF21 sensitivity which is attenuated by HFD challenge.

Topics: Animals; Diet, High-Fat; Fibroblast Growth Factors; Glucagon-Like Peptides; Hepatocytes; Liver; Mice; Mice, Inbred C57BL; Transcription Factors

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Topics: Fibrosis; Glucagon-Like Peptides; Humans; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease

Topics: Adolescent; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Pediatric Obesity

Topics: Adolescent; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Pediatric Obesity

Topics: Adolescent; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Pediatric Obesity

We report a case in which the use of semaglutide for weight loss was associated with delayed gastric emptying and intraoperative pulmonary aspiration of gastric contents.. A 42-yr-old patient with Barrett's esophagus underwent repeat upper gastrointestinal endoscopy and ablation of dysplastic mucosa. Two months earlier, the patient had started weekly injections of semaglutide for weight loss. Despite having fasted for 18 hr, and differing from the findings of prior procedures, endoscopy revealed substantial gastric content, which was suctioned before endotracheal intubation. Food remains were removed from the trachea and bronchi using bronchoscopy. The patient was extubated four hours later and remained asymptomatic.. Patients using semaglutide and other glucagon-like peptide 1 agonists for weight management may require specific precautions during induction of anesthesia to prevent pulmonary aspiration of gastric contents.. RéSUMé: OBJECTIF: Nous rapportons un cas dans lequel l’utilisation de sémaglutide à des fins de perte de poids a été associée à un retard de vidange gastrique et à une aspiration pulmonaire peropératoire du contenu gastrique. CARACTéRISTIQUES CLINIQUES: Un patient de 42 ans souffrant d’un œsophage de Barrett a subi une cinquième endoscopie gastro-intestinale supérieure avec ablation de la muqueuse dysplasique. Deux mois plus tôt, le patient avait commencé à recevoir des injections hebdomadaires de sémaglutide pour perdre du poids. Bien qu’à jeun depuis 18 heures et à la différence des évaluations lors des interventions antérieures, l’endoscopie a révélé un contenu gastrique important, qui a été aspiré avant l’intubation endotrachéale. Les restes de nourriture ont été retirés de la trachée et des bronches par bronchoscopie. Le patient a été extubé quatre heures plus tard et est demeuré asymptomatique. CONCLUSION: Les patients utilisant du sémaglutide et d’autres agonistes du peptide analog au glucagon-1 pour la gestion du poids pourraient nécessiter des précautions spécifiques lors de l’induction de l’anesthésie pour empêcher l’aspiration pulmonaire du contenu gastrique.

Topics: Diabetes Mellitus, Type 2; Endoscopy, Gastrointestinal; Gastroparesis; Glucagon-Like Peptides; Humans; Weight Loss

Low-grade inflammation is associated with complications of type 2 diabetes. Glucagon-like peptide-1 receptor agonists and sodium-glucose transporter-2 inhibitors have shown cardioprotective effects that are independent of their glucose-lowering effects. Cardio-protection could be mediated by the anti-inflammatory effects of these medications, but there is currently limited evidence to support this hypothesis. We conducted a prospective clinical study in patients with type 2 diabetes requiring treatment intensification. Ten patients were assigned to receive empagliflozin 10 mg and 10 patients to receive s/c semaglutide (titrated to 1 mg once a week) in a non-randomised manner. All parameters were measured at baseline and after 3 months. Fasting plasma glucose and glycated haemoglobin improved significantly in both treatment groups, with no between-group differences. Body weight and body mass index reduced significantly more in the semaglutide group, whereas waist circumference decreased only in the empagliflozin group. There was a trend for high-sensitivity CRP reduction in both treatment groups that did not reach statistical significance. Interleukin-6 and the neutrophil-to-lymphocyte ratio did not change in either group. Ferritin and uric acid decreased significantly only in the empagliflozin group, and ceruloplasmin decreased significantly only in the semaglutide group. Though there were clinically meaningful improvements in diabetes control in both treatment arms, we could detect only minor changes in some inflammatory markers.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Prospective Studies; Treatment Outcome

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Retrospective Studies; Treatment Outcome

The aim of this study was to compare the effectiveness of semaglutide versus liraglutide for treating post-metabolic and bariatric surgery (MBS) weight recurrence.. A retrospective analysis of 207 adults with post-MBS weight recurrence treated with semaglutide 1.0 mg weekly (n = 115) or liraglutide 3.0 mg daily (n = 92) at an academic center from January 1, 2015, through April 1, 2021, was conducted. The primary end point was percentage body weight change at 12 months of treatment with regimens containing semaglutide or liraglutide.. The mean sample age was 55.2 years; mean BMI was 40.4 kg/m. These results show that treatment regimens including semaglutide 1.0 mg weekly lead to superior weight loss compared with liraglutide 3.0 mg daily for treating post-MBS weight recurrence, regardless of procedure type or the magnitude of weight recurrence.

Topics: Adult; Bariatric Surgery; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Obesity, Morbid; Postoperative Period; Retrospective Studies; Treatment Outcome; Weight Gain; Weight Loss

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Triglycerides

This Medical News article discusses chronic weight management with semaglutide, sold under the brand names Ozempic and Wegovy.

Topics: Glucagon-Like Peptides; Humans; Popular Culture; Weight Loss

Topics: Glucagon-Like Peptides; Humans; Plastic Surgery Procedures; Surgeons; Surgery, Plastic

The weight loss drug semaglutide (Wegovy) is now approved for pediatric patients ages 12 and older whose body mass index categorizes them as obese.

Topics: Anti-Obesity Agents; Child; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Weight Loss

As new glucagon-like peptide 1 receptor agonist (GLP-1 RA) formulations are available, the aim of this study was to understand dulaglutide and subcutaneous (s.c.) semaglutide dosing patterns in people with type 2 diabetes mellitus (T2DM) in the UK and Germany as well as oral semaglutide in the UK.. Adults with evidence of T2DM and a prescription of dulaglutide or semaglutide between August 2020 and December 2021 were identified using the IQVIA Longitudinal Prescription Data (LRx). Patients were divided into cohort 1 (incident users) and cohort 2 (prevalent users) based on previous exposure to GLP-1 RAs and were followed up to 12 months post-index.. During the patient selection window in Germany and the UK, 368,320 and 123,548 patients respectively received at least one prescription of a study GLP-1 RA. Among dulaglutide users in Germany at 12 months post-index, the 1.5-mg dosage formulation was the most common for both cohort 1 (65.6%) and 2 (71.2%). Among s.c. semaglutide users at 12 months post-index, 39.2% and 58.4% of cohort 1 received 0.5 mg and 1.0 mg, respectively. In the UK, at 12 months post-index, the most common dulaglutide dosage formulation was 1.5 mg (71.7% cohort 1 and 80.9% cohort 2). Among s.c. semaglutide users at 12 months post-index, 0.5- and 1.0-mg formulations were the most common for both cohort 1 (38.9% and 56.0%, respectively) and cohort 2 (29.5% and 67.1%, respectively). Prescribing of the more recently introduced 3.0- and 4.5-mg formulations for dulaglutide and oral semaglutide was also reported in the study.. Dosing patterns of GLP-1 RAs, although similar between the UK and Germany, were heterogeneous over time. Given that the higher dulaglutide doses and oral semaglutide were recently introduced to the market, additional real-world evidence studies which include clinical outcomes is required.

Topics: Adult; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Retrospective Studies; United Kingdom

Topics: Glucagon-Like Peptides; Humans; Obesity; United Kingdom

To compare the efficacy of tirzepatide 10 and 15 mg with semaglutide 2.4 mg using an indirect treatment comparison.. Using SURMOUNT-1 and STEP 1 trial data, mean percentage change in body weight from baseline and odds ratio (OR) of achieving 5% or greater weight loss were compared between tirzepatide 10 and 15 mg at week 72 and semaglutide 2.4 mg at week 68 using matching-adjusted indirect comparison of the efficacy estimand. Sensitivity analyses were completed using different methods, including the Bucher method, also using different estimands and/or time points.. Greater reductions in percentage change in body weight were observed with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg (tirzepatide 10 mg mean difference: -4.67% [95% CI -5.91%, -3.43%]; tirzepatide 15 mg mean difference: -5.92% [95% CI -7.16%, -4.68%]; both P < .001). Similarly, more participants achieved 5% or greater weight loss with tirzepatide 10 mg (OR 2.61 [95% CI 1.48, 4.57]; P < .001) and 15 mg (OR 2.75 [95% CI 1.57, 4.81]; P < .001) compared with semaglutide 2.4 mg. All sensitivity analyses were consistent, except for an OR of achieving 5% or greater weight loss with tirzepatide 10 mg using the Bucher method to analyse the treatment regimen estimand (P = .074).. Currently there are no direct comparisons of tirzepatide and semaglutide for weight management. Using the matching-adjusted indirect treatment comparison method to compare the efficacy of tirzepatide and semaglutide for chronic weight management, this analysis showed greater weight loss with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg.

Topics: Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity; Weight Loss

Topics: Drug Costs; Drug Development; Glucagon-Like Peptides; Humans; Obesity

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

To determine the relationship between exposure and weight-loss trajectories for the glucagon-like peptide-1 analogue semaglutide for weight management.. Data from one 52-week, phase 2, dose-ranging trial (once-daily subcutaneous semaglutide 0.05-0.4 mg) and two 68-week phase 3 trials (once-weekly subcutaneous semaglutide 2.4 mg) for weight management in people with overweight or obesity with or without type 2 diabetes were used to develop a population pharmacokinetic (PK) model describing semaglutide exposure. An exposure-response model describing weight change was then developed using baseline demographics, glycated haemoglobin and PK data during treatment. The ability of the exposure-response model to predict 1-year weight loss based on weight data collected at baseline and after up to 28 weeks of treatment, was assessed using three independent phase 3 trials.. Based on population PK, exposure levels over time consistently explained the weight-loss trajectories across trials and dosing regimens. The exposure-response model had high precision and limited bias for predicting body weight loss at 1 year in independent datasets, with increased precision when data from later time points were included in the prediction.. An exposure-response model has been established that quantitatively describes the relationship between systemic semaglutide exposure and weight loss and predicts weight-loss trajectories for people with overweight or obesity who are receiving semaglutide doses up to 2.4 mg once weekly.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity; Overweight; Weight Loss

Topics: Adolescent; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Weight Loss

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Topics: Fibrosis; Glucagon-Like Peptides; Humans; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease

Topics: Glucagon-Like Peptides; Humans; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease

Approved by the Food and Drug Administration (FDA) in 2017 for diabetes and in 2021 for weight loss, semaglutide has seen widespread use among individuals who aim to lose weight. The aim of this study was to evaluate weight loss and the influence of clinical factors on semaglutide patients in real-world clinical practice.. Using data from 10 health systems within the Greater Plains Collaborative (a PCORnet Clinical Research Network), nearly 4000 clinical factors encompassing demographic, diagnosis, and prescription information were extracted for semaglutide patients. A gradient-boosting, machine-learning classifier was developed for weight-loss prediction and identification of the most impactful factors via SHapley Additive exPlanations (SHAP) value extrapolation.. A total of 3555 eligible patients (539 of whom were observed 52 weeks following exposure) from March 2017 to April 2022 were studied. On average, individuals lost 4.44% (male individuals, 3.66%; female individuals, 5.08%) of their initial weight. History of diabetes mellitus diagnosis was associated with less weight loss, whereas prediabetes and linaclotide use were associated with more pronounced weight loss.. Weight loss in patients prescribed semaglutide from real-world evidence was strong but attenuated compared with previous clinical trials. Machine-learning analysis of electronic health record data identified factors that warrant further research and consideration when tailoring weight-loss therapy.

Topics: Female; Glucagon-Like Peptides; Humans; Male; Prediabetic State; United States; United States Food and Drug Administration; Weight Loss

Topics: Glucagon-Like Peptides; Humans; Injections

Topics: Glucagon-Like Peptides; Humans; Patients

Topics: Cardiovascular Diseases; Glucagon-Like Peptides; Heart Failure; Humans

Topics: Diabetes Mellitus, Type 1; Glucagon-Like Peptides; Humans

The first oral form of the glucagon-like peptide-1 receptor agonist, oral semaglutide, has recently been launched and potently controls glycemia and body weight in subjects with type 2 diabetes. This drug carries the absorption enhancer and requires specific protocols of administration. The mechanism of action of oral semaglutide is not fully understood, for which an appropriate experimental model is required. This study explores the metabolic effects of oral semaglutide in mice under human protocols and doses. Oral semaglutide was bolus and once daily injected into high-fat diet-induced obese (DIO) mice under human protocols, followed by monitoring blood glucose, food intake, and body weight. Oral semaglutide 0.23 mg/kg, a comparable human dose (14 mg) in a small volume of water under human protocols rapidly decreased blood glucose and food intake and continuously reduced food intake and weight gain for 3 days in DIO mice. At 0.7 mg/kg (42 mg), this drug was somewhat more potent. Oral semaglutide with human protocols and doses rapidly reduces blood glucose and food intake and continuously suppresses feeding and weight in DIO mice. This study establishes mice as a model suitable for analyzing the mechanism of anti-obesity/diabetes actions of oral semaglutide.

Topics: Animals; Blood Glucose; Diet, High-Fat; Eating; Glucagon-Like Peptides; Mice, Obese

Topics: Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Overweight; Pregnancy; Pregnancy Outcome

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin; Insulin, Regular, Human

Given the lack of real-world data on oral semaglutide use outside clinical trials, the purpose of this study was to describe dose, prescriber specialty, and change in hemoglobin A1c (HbA1c) after 6 months of oral semaglutide treatment for patients with type 2 diabetes mellitus (T2DM).. This was a retrospective study among adult patients with T2DM with ≥ 1 claim for oral semaglutide between November 1, 2019`1-June 30, 2020. Patients had continuous health plan enrollment ≥ 12 months prior to (pre-index) and ≥ 6 months following (post-index) the date of the first oral semaglutide claim (index). Dose at initiation and specialty of the prescribing provider were captured. Change in HbA1c between the last post- and pre-index HbA1c measurement was calculated. Patients were stratified by pre-index HbA1c ≥ 9% (poorly controlled) and HbA1c < 9%.. A total of 744 HbA1c < 9% and 268 poorly controlled patients were included in the study. Most patients had an initial oral semaglutide dose of 7 mg (49.3%) or 3 mg (42.9%), prescribed most frequently by a primary care provider (27.8%). Mean HbA1c reduction was 0.8% (p < 0.001). Patients with poorly controlled T2DM had greater HbA1c reductions than patients with HbA1c < 9% (2.0% versus 0.4%, p < 0.001). Patients persistent with oral semaglutide (≥ 90 days continuous treatment) had a mean HbA1c reduction of 0.9% (p < 0.001); persistent patients with poorly controlled T2DM had a mean reduction of 2.5%.. Patients with T2DM in this study experienced significant reductions in HbA1c within 6 months following initiation of oral semaglutide. Patients with a higher starting HbA1c experienced greater HbA1c reductions. The initial dose of oral semaglutide was higher than prescribing instructions indicated for more than half of the study patients.

Topics: Adult; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Retrospective Studies

Topics: Glucagon-Like Peptides; Heart Failure; Humans; Stroke Volume

Topics: Deception; Glucagon-Like Peptides; Humans; United Kingdom

The weight loss following Semaglutide treatment, a GLP-1 receptor agonist, might be responsible for some effects observed on the nonalcoholic fatty liver disease of obese mice.. Two groups of C57BL/6 male mice (n = 30/group) were fed the diets Control (C) or high-fat (HF) for 16 weeks. Then, separated into six new groups for an additional four weeks (n = 10/group) and treated with Semaglutide (S, 40 µg/kg) or paired feeding (PF) with S groups (C; C-S; C-PF; HF; HF-S; HF-PF).. Semaglutide reduced energy consumption leading to weight loss. Simultaneously it improved glucose intolerance, glycated hemoglobin, insulin resistance/sensitivity, plasma lipids, and gastric inhibitory polypeptide. Semaglutide and paired feeding mitigated liver steatosis and adipose differentiation-related protein (Plin2) expression. Semaglutide also improved hormones and adipokines, reduced lipogenesis and inflammation, and increased beta-oxidation. Semaglutide lessened liver glucose uptake and endoplasmic reticulum (ER) stress. Among the 14 genes analyzed, 13 were modified by Semaglutide (93 %, six genes were changed exclusively by Semaglutide, and seven other genes were affected by the combination of Semaglutide and paired feeding). In seven genes, the paired diet showed no effect (50% of the genes tested). No marker was affected exclusively by paired feeding.. Semaglutide and the consequent weight loss reduced obese mice liver inflammation, insulin resistance, and ER stress. However, weight loss alone did show few or no action on some significant study findings, like liver steatosis, leptin, insulin, resistin, and amylin. Furthermore, hepatic inflammation mediated by MCP-1 and partially by TNF-alpha and IL6 were also not reduced by weight loss. Furthermore, weight loss alone did not lessen hepatic lipogenesis as determined by the findings of SREBP-1c, CHREBP, PPAR-alpha, and SIRT1. Semaglutide was implicated in improving glucose uptake and lessening ER stress by reducing GADD45, independent of weight loss.

Topics: Animals; Disease Models, Animal; Endoplasmic Reticulum; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Nutritional Support; Obesity; Weight Loss

To evaluate HbA1c and body weight changes when semaglutide 0.5- or 1.0-mg once-weekly (QW) is switched to dulaglutide 3.0- or 4.5-mg QW via exposure-response modelling.. HbA1c and body weight time-course models were developed and validated with data from the SUSTAIN 1 to 10 trials for semaglutide and the AWARD-11 trial for dulaglutide. Simulations were conducted for HbA1c and body weight over 52 weeks. In the initial 26 weeks, semaglutide was initiated at 0.25-mg and titrated to 0.5- or 1.0-mg QW via 4-weekly stepwise titration, followed by 26 weeks of dulaglutide initiated at 0.75- or 1.5-mg QW and escalated to 3.0- or 4.5-mg QW via 4-weekly stepwise titration.. At 26 weeks, model-predicted mean changes from baseline in HbA1c and weight for semaglutide 0.5 mg were up to -1.55% and -3.44 kg, respectively. After switching to dulaglutide 3.0 mg, further reductions were 0.19% and 1.40 kg, respectively, at 52 weeks. Predicted mean HbA1c and weight changes for semaglutide 1.0 mg at 26 weeks were -1.84% and -4.96 kg, respectively; after switching to dulaglutide 4.5 mg, HbA1c was maintained with additional weight reduction of up to 0.57 kg at 52 weeks. Glycaemic control was preserved when switching from semaglutide 1.0 mg to dulaglutide 3.0 mg.. Switching from semaglutide 0.5 mg to dulaglutide 3.0 or 4.5 mg with dose escalation potentially yields additional HbA1c and weight reductions; switching from semaglutide 1.0 mg to dulaglutide 4.5 mg may enhance weight loss.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins; Weight Loss

There are significant injuries of pancreatic islets due to obesity and insulin resistance. Therefore, GLP-1 receptor agonists like Semaglutide might benefit the islet structural remodeling and its endocrine function in diet-induced obese mice. One-month-old male C57BL/6 mice were allotted into two dietary groups (n = 60/group) and fed for 16 weeks a control diet (C) or a high‒fat diet (HF). Then, for an additional four weeks, the main groups were resampled to include treatment (Semaglutide, S, 40 μg/kg), or paired feed with the treated group (PF), totaling six groups (n = 20/group): C, CS, CPF, HF, HFS, HFPF. Biochemistry, stereology, immunohistochemistry/immunofluorescence, confocal microscopy, and RT-qPCR were used in the study. The mouse model reproduced metabolism and bodily changes due to diet-induced obesity. Pancreatic islet hypertrophy was observed with alpha- and beta-cell remodeling, cell disarray, and apoptosis. Semaglutide increased islet cell proliferation and recovered islet size and alpha- and beta-cell masses. The changes include recovery of glucose and hormone levels, reduction of pro-inflammatory markers, improvement of pancreatic duodenal homeobox 1 (PDX-1), glucose transporter 2 (GLUT-2), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAF-A), and peroxisome proliferator-activated receptors (PPAR) -gamma. In conclusion, damage to the pancreatic islet caused by insulin resistance and the attempt to adapt the islet of obese mice involved different pathways, especially the pro-inflammatory pathway, PDX1, and PPAR-alpha and gamma. Semaglutide showed beneficial effects on these pathways, reducing the lesion on the islet. However, the weight loss influence of Semaglutide was of little relevance in the pancreatic islet.

Topics: Animals; Apoptosis; Cell Proliferation; Disease Models, Animal; Glucagon-Like Peptides; Glucagon-Secreting Cells; Insulin-Secreting Cells; Male; Mice; Obesity

Topics: Benzhydryl Compounds; Cost-Benefit Analysis; Denmark; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glucosides; Humans; Hypoglycemic Agents

Testicular torsion is a serious emergency and a well-known cause of male infertility. It represents 10 %-15 % of scrotal diseases in children. Kisspeptin (KISS1) is a hormone secreted from the hypothalamic nuclei and testis, but its role in testis is not fully understood. Semaglutide is a novel antidiabetic glucagon-like peptide 1 (GLP-1) analog. Hence, we designed the current study to elucidate the possible ameliorative effect of semaglutide on ischemia/reperfusion-induced testicular dysfunction in rats and highlight the role of the testicular GLP-1/PCG-1α-PPAR-α-KISS1 signaling pathway. We randomly divided 50 male Sprague Dawley into five equal groups (10 rats each): SHAM, exendin 9-39 -treated (EX), testicular torsion/detorsion (T/D), testicular torsion/detorsion and semaglutide-treated (SEM + T/D), and testicular torsion/detorsion, exendin, and semaglutide-treated (EX + SEM + T/D). We quantified serum follicle-stimulating hormone, luteinizing hormone, total testosterone, testicular oxidative stress markers, testicular gene expression of GLP-1/KISS1 pathway-related genes (KISS1, KISS1R, GLP-1, GLP-1R, PGC-1α, PPAR-α), steroidogenesis pathway-related genes (STAR, CYP11A1, CYP17A1, HSD17B3, CYP19A1), HO-1, Nrf-2, and testicular protein expression of HIF-1α, TNF-α, NF-κβ, Caspase-3, FAS, proliferating cell nuclear antigen, and KISS1 through testicular histopathology and immunohistochemistry assays. Testicular torsion/detorsion markedly elevated proapoptotic, proinflammatory, and oxidative stress marker levels, noticeably downregulating the expression of GLP-1/KISS1 and steroidogenesis pathway-related proteins. Semaglutide administration significantly ameliorated all these deleterious effects. Nevertheless, injecting exendin, a GLP1-R antagonist, before semaglutide abolished all the documented improvements. We concluded that semaglutide ameliorated ischemia/reperfusion-induced testicular dysfunction by modulating the GLP-1/PGC-1α-PPAR-α/KISS1/steroidogenesis signaling pathway, improving testicular oxidative state, and suppressing testicular inflammation and apoptosis.

Topics: Animals; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Ischemia; Kisspeptins; Male; Oxidative Stress; PPAR alpha; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Signal Transduction; Testis

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity

The method of therapy administration and injection device characteristics have been documented to influence perceptions and preference of treatment among patients with type 2 diabetes (T2D). We aimed to assess the metabolic effectiveness and patient-reported satisfaction of once-weekly semaglutide compared to liraglutide in suboptimally controlled patients with T2D.. We conducted this single-center cohort study at diabetes center clinics at a tertiary care hospital between February 2021 and August 2021. We included suboptimally controlled patients with T2D who had been treated with liraglutide for at least 3 months at baseline, then shifted to once-weekly semaglutide and followed up for the same period. Ambulatory glucose profile (AGP) metrics [i.e., mean glucose level, glycemic variability (GV), time above range (TAR), and time in range (TIR)] for baseline and follow-up were compared. To assess the satisfaction with shifting, we used the valid Arabic version of the Diabetes Treatment Satisfaction Questionnaire status (DTSQs) and change (DTSQc) while the injection device preference was assessed using the Diabetes Injection Device Preference Questionnaire (DID-PQ).. We included 52 patients (25 male and 27 female), with a mean age of 48 (± 6) years and a mean diabetes mellitus duration of 7.27 (± 3.79) years. We observed a significantly decreased mean HbA1c level following semaglutide treatment (7.79% at study end vs. 8.07% at baseline, p < 0.001) and body weight (84.64 ± 7.68 vs. 87.15 ± 8.011, p < 0.001). Compared to the glucometrics data at baseline, we observed a significantly improved mean average glucose, GV, TAR, and TIR (p < 0.001). Data from the DTSQs and DTSQc questionnaires showed a high level of patient-reported satisfaction after shifting to semaglutide treatment. All patients preferred/strongly preferred once-weekly semaglutide over liraglutide in most DID-PQ questionnaire domains.. Switching from once-daily liraglutide to once-weekly semaglutide led to improvements in both clinical measures of glycemic control and patient-reported satisfaction.

Topics: Blood Glucose; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Patient Reported Outcome Measures; Patient Satisfaction; Personal Satisfaction; Treatment Outcome

To evaluate whether the potent hypophagic and weight-suppressive effects of growth differentiation factor-15 (GDF15) and semaglutide combined would be a more efficacious antiobesity treatment than either treatment alone by examining whether the neural and behavioural mechanisms contributing to their anorectic effects were common or disparate.. Three mechanisms were investigated to determine how GDF15 and semaglutide induce anorexia: the potentiation of the intake suppression by gastrointestinal satiation signals; the reduction in motivation to feed; and the induction of visceral malaise. We then compared the effects of short-term, combined GDF15 and semaglutide treatment on weight loss to the individual treatments. Rat pharmaco-behavioural experiments assessed whether GDF15 or semaglutide added to the satiating effects of orally gavaged food and exogenous cholecystokinin (CCK). A progressive ratio operant paradigm was used to examine whether GDF15 or semaglutide reduced feeding motivation. Pica behaviour (ie, kaolin intake) and conditioned affective food aversion testing were used to evaluate visceral malaise. Additionally, fibre photometry studies were conducted in agouti-related protein (AgRP)-Cre mice to examine whether GDF15 or semaglutide, alone or in combination with CCK, modulate calcium signalling in hypothalamic AgRP neurons.. Semaglutide reduced food intake by amplifying the feeding-inhibitory effect of CCK or ingested food, inhibited the activity of AgRP neurons when combined with CCK, reduced feeding motivation and induced malaise. GDF15 induced visceral malaise but, strikingly, did not affect feeding motivation, the satiating effect of ingested food or CCK signal processing. Combined GDF15 and semaglutide treatment produced greater food intake and body weight suppression than did either treatment alone, without enhancing malaise.. GDF15 and semaglutide reduce food intake and body weight through largely distinct processes that produce greater weight loss and feeding suppression when combined.

Topics: Agouti-Related Protein; Animals; Anorexia; Body Weight; Cholecystokinin; Eating; Glucagon-Like Peptides; Growth Differentiation Factor 15; Mice; Rats; Weight Loss

Non-alcoholic steatohepatitis (NASH) has emerged as a major challenge for public health because of high global prevalence and lack of evidence-based therapies. Most animal models of NASH lack sufficient validation regarding disease progression and pharmacological treatment. The Gubra-Amylin NASH (GAN) diet-induced obese (DIO) mouse demonstrate clinical translatability with respect to disease etiology and hallmarks of NASH. This study aimed to evaluate disease progression and responsiveness to clinically effective interventions in GAN DIO-NASH mice. Disease phenotyping was performed in male C57BL/6J mice fed the GAN diet high in fat, fructose, and cholesterol for 28-88 weeks. GAN DIO-NASH mice with biopsy-confirmed NASH and fibrosis received low-caloric dietary intervention, semaglutide (30 nmol/kg/day, s.c.) or lanifibranor (30 mg/kg/day, p.o.) for 8 and 12 weeks, respectively. Within-subject change in nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) and fibrosis stage was evaluated using automated deep learning-based image analysis. GAN DIO-NASH mice showed clear and reproducible progression in NASH, fibrosis stage, and tumor burden with high incidence of hepatocellular carcinoma. Consistent with clinical trial outcomes, semaglutide and lanifibranor improved NAS, whereas only lanifibranor induced regression in the fibrosis stage. Dietary intervention also demonstrated substantial benefits on metabolic outcomes and liver histology. Differential therapeutic efficacy of semaglutide, lanifibranor, and dietary intervention was supported by quantitative histology, RNA sequencing, and blood/liver biochemistry. In conclusion, the GAN DIO-NASH mouse model recapitulates various histological stages of NASH and faithfully reproduces histological efficacy profiles of compounds in advanced clinical development for NASH. Collectively, these features highlight the utility of GAN DIO-NASH mice in preclinical drug development.

Topics: Animals; Benzothiazoles; Biopsy; Diet; Disease Models, Animal; Disease Progression; Glucagon-Like Peptides; Humans; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Sulfonamides

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptides; Humans

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptides; Humans

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptides; Humans

Empagliflozin and oral semaglutide reduce the incidence of cardiovascular mortality (CVM) in patients with type 2 diabetes mellitus. However, these therapies impose a significant financial burden on healthcare systems. Therefore, we compared the value for money of empagliflozin versus oral semaglutide to prevent CVM. We calculated the cost needed to treat to prevent 1 case of CVM using either drug by multiplying the annualized number needed to treat to prevent 1 event by the annual cost of the therapy. Efficacy estimates were extracted from published randomized controlled trials data. We performed a scenario analysis to mitigate the primary differences between the populations of randomized controlled trials. Drug costs were calculated as 75% of the United States National Average Drug Acquisition Cost listing. The annualized number needed to treat for empagliflozin in EMPA-REG-OUTCOME was 141 (95% confidence interval [CI] 104 to 230) and 141 (95% CI 96 to 879) for oral semaglutide in PIONEER 6. The annual treatment costs are $4,797 for empagliflozin versus $7,133 for oral semaglutide. Therefore, the corresponding costs needed to treat are $676,385 ($498,894-$1,101,039) and $1,005,855 (95% CI $684,837-$6,270,544) respectively. In conclusion, our findings suggest that empagliflozin provides better value for money than oral semaglutide to prevent CVM in patients with type 2 diabetes mellitus at the current United States prices of the interventions.

Topics: Benzhydryl Compounds; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glucosides; Humans; Hypoglycemic Agents; United States

GLP-1 (glucagon-like peptide-1) is one of the incretin hormone secreted from L cells in the small intestine and it is known to promote insulin secretion in a glucose concentration-dependent manner and have a hypoglycemic effect. However, since endogenous GLP-1 is rapidly degraded by ubiquitously expressing DPP-4, a GLP-1 receptor agonist with a longer half-life has been required. Semaglutide is a GLP-1 analog that has 94% homology with human GLP-1 and it binds to the GLP-1 receptor in pancreatic β-cells to induce the insulin secretion in a glucose concentration-dependent manner. Semaglutide has a high affinity for the fatty acid binding site of albumin and has an extended half-life by being protected from degradation by DPP-4, due to specific modification of its amino acid sequence. A once weekly semaglutide (Ozempic

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Tablets

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Life Style; Weight Loss

Semaglutide, a glucagon-like peptide 1 receptor agonist, reduced major adverse cardiovascular events (MACE) in people with type 2 diabetes (T2D) at high risk of cardiovascular disease (CVD) in a post hoc analysis of pooled data from Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN) 6 and Peptide Innovation for Early Diabetes Treatment (PIONEER) 6. We estimated the benefit of adding semaglutide to standard of care (SoC) on life-years free of new/recurrent CVD events in people with T2D at high risk of CVD.. The Diabetes Lifetime-perspective prediction (DIAL) competing risk-adjusted lifetime CVD risk model for people with T2D was developed previously. Baseline characteristics of the pooled cohort from SUSTAIN 6 and PIONEER 6 (POOLED cohort) (N = 6,480) were used to estimate individual life expectancy free of CVD for patients in the POOLED cohort. The hazard ratio of MACE from adding semaglutide to SoC was derived from the POOLED cohort (hazard ratio [HR] 0.76 [95% CI 0.62-0.92]) and combined with an individual's risk to estimate their CVD benefit.. Adding semaglutide to SoC was associated with a wide distribution in life-years free of CVD gained, with a mean increase of 1.7 (95% CI 0.5-2.9) life-years. Estimated life-years free of CVD gained with semaglutide was dependent on baseline risk (life-years free of CVD gained in individuals with established CVD vs. those with cardiovascular risk factors only: 2.0 vs. 0.2) and age at treatment initiation.. Adding semaglutide to SoC was associated with a gain in life-years free of CVD events that was dependent on baseline CVD risk and age at treatment initiation. This study helps contextualize the results of semaglutide clinical trials.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Risk Factors; Standard of Care

Greater medication adherence and persistence have been associated with improved glycemic control in patients with type 2 diabetes mellitus. This study compared adherence, persistence, and treatment patterns among patients naïve to glucagon-like peptide 1 receptor agonists initiating once-weekly injectable treatment with dulaglutide versus semaglutide over 6-month (6M) and 12-month (12M) follow-up periods.. This retrospective, observational cohort study used administrative claims data from three IBM MarketScan research databases. Data from adult patients with type 2 diabetes newly initiating treatment with dulaglutide or semaglutide between January 2018 and January 2020 (index date was defined as the earliest fill date), without evidence of glucagon-like peptide 1 receptor agonist use in the 6M baseline period, and with continuous enrollment in the 6M baseline and 6M or 12M follow-up period were included. Dulaglutide initiators were propensity score-matched, in a 1:1 ratio, to semaglutide initiators in each 6M and 12M follow-up cohort (26,284 and 13,837 pairs, respectively).. In the matched cohorts, baseline characteristics were balanced; the mean age was 53 years, and 50% of patients were women. Compared to semaglutide initiators, dulaglutide initiators were more adherent (6M, 63.4% vs 47.8%; 12M, 54.4% vs 43.3%; both, P < 0.0001), more persistent on therapy (6M, 72% vs 62%, 12M, 55.5% vs 45.3%, both, P < 0.001), and had more mean days of persistence (6M, 145 vs 132, 12M, 254.3 vs 220.7; both, P < 0.001).. At both 6M and 12M follow-up, dulaglutide initiators had significantly greater adherence and greater persistence compared with matched semaglutide initiators.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Recombinant Fusion Proteins; Retrospective Studies

The ABCD semaglutide audit was designed to capture the routine clinical outcomes of people commenced on semaglutide in the UK. Previous work showed differential reductions in HbA1c and weight dependent on previous glucagon-like peptide-1 receptor agonist (GLP-1RA) exposure. The analysis, in this research letter, shows that decreases in HbA1c and weight associated with semaglutide occur irrespective of previous GLP-1RA use. However, HbA1c reductions were less if switched from dulaglutide or liraglutide and weight changes were attenuated if switched from dulaglutide or exenatide, potentially suggesting differing potencies between GLP-1RAs. Dedicated studies with head-to-head comparisons are needed to confirm these findings.

Topics: Diabetes Mellitus, Type 2; Drug Substitution; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Weight Loss

To evaluate the cardiovascular (CV) efficacy of liraglutide and semaglutide in patients with type 2 diabetes (T2D) and peripheral artery disease (PAD).. LEADER and SUSTAIN 6 trials investigated subcutaneous liraglutide (≤1.8 mg/day) and semaglutide (0.5 or 1.0 mg/week), respectively, versus placebo in patients with T2D and high CV risk (median follow-up: 3.8 and 2.1 years, respectively). The primary outcome was a composite of CV death, non-fatal myocardial infarction or non-fatal stroke (major adverse CV event [MACE]) according to the presence of PAD at baseline.. Overall, 1184/9340 (12.7%) patients in LEADER and 460/3297 (14.0%) in SUSTAIN 6 had PAD at baseline. Patients with PAD were at an ~35% increased risk of MACE versus those without (LEADER: hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.17-1.58; SUSTAIN 6: HR 1.33, 95% CI 0.94-1.83). The effects of both therapies on MACE were consistently beneficial in patients with PAD (liraglutide: HR 0.77, 95% CI 0.58-1.01; semaglutide: 0.61, 0.33-1.13) and without (liraglutide: HR 0.89, 95% CI 0.79-1.00; semaglutide: HR 0.77, 95% CI 0.58-1.01; P. Both liraglutide and semaglutide reduce MACE with consistent CV efficacy regardless of PAD status.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Peripheral Arterial Disease

To evaluate the efficacy and safety of oral semaglutide versus comparators by patient characteristic subgroups in patients with type 2 diabetes.. Change from baseline in glycated haemoglobin (HbA1c) and body weight, and achievement of HbA1c <7.0% with oral semaglutide 7 mg, oral semaglutide 14 mg, flexibly dosed oral semaglutide (flex) and comparators were assessed across baseline subgroups (age, race, ethnicity, diabetes duration, body mass index and HbA1c) from the PIONEER programme. Treatment differences were analysed using a mixed model for repeated measurements for continuous variables and a logistic regression model for the binary endpoint. Pooled safety data were analysed descriptively.. Changes from baseline in HbA1c and body weight, and the odds of achieving HbA1c <7.0%, were greater with oral semaglutide 14 mg/flex (n = 1934) and higher or similar with oral semaglutide 7 mg (n = 823) versus comparators (n = 2077) across most subgroups. Changes in HbA1c with oral semaglutide 14 mg/flex were greater for patients with higher baseline HbA1c (HbA1c >9.0%: -1.7% to -2.6%; HbA1c <8.0%: -0.7% to -1.2%). In some trials, Asian patients experienced greater HbA1c reductions with oral semaglutide 14 mg/flex (-1.5% to -1.8%) than other racial groups (-0.6% to -1.6%). The overall incidence of adverse events (AEs) with oral semaglutide was similar to that with comparators and was consistent across subgroups. More gastrointestinal AEs were observed with oral semaglutide, versus comparators, across subgroups.. Oral semaglutide demonstrated consistently greater HbA1c and body weight reductions across a range of patient characteristics, with greater HbA1c reductions seen at higher baseline HbA1c levels.

Topics: Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents

The objective of this study was to investigate the effects of semaglutide, a long acting glucagon-like peptide-1 receptor agonist, on atherosclerotic inflammation and calcification using a multimodality positron emission tomography and computed tomography (PET/CT) approach.. Atherosclerotic New Zealand White rabbits were randomized to an intervention- (n = 12) or placebo group (n = 11) receiving either semaglutide or saline-placebo. PET/CT imaging was done before and after 16-weeks of intervention. Three different radiotracers were used: [. Semaglutide decreased vascular uptake of tracers imaging activated macrophages and cellular metabolism but not micro-calcifications compared to a saline placebo. This supports the hypothesis that semaglutide reduces atherosclerotic inflammation by means of decreased activated macrophage activity.

Topics: Animals; Atherosclerosis; Calcinosis; Fluorodeoxyglucose F18; Glucagon-Like Peptides; Inflammation; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Rabbits; Radionuclide Imaging; Radiopharmaceuticals

Registered trials and real-world evidence (RWE) studies provided evidence on the efficacy of once-weekly (OW) semaglutide on hyperglycaemia and cardiovascular risk factors as add-on or de-novo treatment in type 2 diabetes (T2D).. In a retrospective analysis of electronic data files from 258 T2D patients, this RWE study aimed to explore the impact of OW semaglutide on biochemical and anthropometric outcomes after 6 and 12 months in patients receiving at least one prescription of OW semaglutide between September 2019 and May 2021.. During the study period, 154 and 56 consecutive patients completed the 6 and 12 months of OW semaglutide treatment. HbA1c levels decreased by -1.02±0.1% after 6 months and -1.1±0.1% after 12 months of OW semaglutide (p<0.0001 for both). At these time-points, HbA1c values were <7% in 61% and 57% of cases. HbA1c reduction was greater in patients with higher baseline HbA1c levels and it occurred irrespective of gender, age, insulin therapy and complications. The residual number of cases with HbA1c ≥9% by the study end was low (5.3% vs 18.9% at baseline). Weight loss occurred in 73.5% and 78.1% of cases and, compared to baseline, it was ≥5% in 21.2- 25.4% and ≥10% in 6.8-18.2% after 6 and 12 months, respectively. Significant predictors of HbA1c reduction after 6 months of OW semaglutide treatment were baseline HbA1c (p<0.0001), bodyweight reduction (p<0.0001) and disease duration (p<0.001), while baseline HbA1c was the only predictor of HbA1c response after 12 months (p<0.0001). Reported adverse events were consistent with the known safety profile of semaglutide.. Real-world evaluation of weekly subcutaneous treatment with semaglutide in a cohort of Italian diabetic patients.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Retrospective Studies

Topics: Glucagon-Like Peptides; Humans; Injections, Subcutaneous

The recent approval in the USA (Food and Drug Administration), Canada (Health Canada), UK (Medicines and Healthcare products Regulatory Agency), and EU (European Medicines Agency) of once-weekly injectable semaglutide 2.4 mg, as an adjunct to a calorie-controlled diet and increased physical activity, for chronic weight management provides health-care practitioners with an additional option when prescribing weight-loss medication.. We describe the chemistry, mechanism of action, and pharmacological properties of semaglutide (a glucagon-like peptide 1 receptor agonist [GLP-1 RA]) and discuss clinical data and considerations for using once-weekly subcutaneous semaglutide 2.4 mg as treatment for overweight and obesity among patients with and without type 2 diabetes (T2D).. Once-weekly subcutaneous semaglutide 2.4 mg is the most efficacious medication approved for chronic weight management among patients with overweight and obesity, with and without T2D, and is the first drug to induce sustained double-digit reductions in percentage body weight over 1- to 2-year treatment periods. It demonstrates a similar safety and tolerability profile to other GLP-1 RAs. Semaglutide 2.4 mg treatment could dramatically improve clinical approaches to weight management, but the relatively high cost might prevent patients accessing treatment. Further research exploring the cost-effectiveness of subcutaneous semaglutide 2.4 mg is required.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity; Overweight; Pharmaceutical Preparations

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents

Type A insulin resistance (IR) syndrome is a very uncommon genetic disorder affecting the insulin receptor (INSR) gene, characterized by severe IR without the presence of obesity. Patients with this condition will eventually develop diabetes, presenting a variable response to insulin-sensitizers, such as metformin and thiazolidinediones, and high doses of insulin. We report for the first time the results of the use of combination therapy with a glucagon-like peptide-1 receptor agonist and a sodium-glucose cotransporter 2 inhibitor for the treatment of diabetes in the context of type A IR syndrome.

Topics: Benzhydryl Compounds; Diabetes Mellitus; Glucagon-Like Peptides; Glucosides; Humans; Insulin; Insulin Resistance

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents

Prader-Willi syndrome is the most frequent genetic cause of obesity and is often complicated by glucose metabolism alterations. Conventional therapies prescribed for type 2 diabetes frequently failed to achieve adequate glycemic control in patients with Prader-Willi syndrome. Beneficial effects of glucagon like peptide-1 receptor agonists exenatide and liraglutide have been reported for the management of type 2 diabetes in Prader-Willi syndrome, but no data are currently available in this population on the use of semaglutide.. We report for the first time the use of semaglutide 1 mg per week in a 33-yearold man with Prader-Will syndrome complicated by poorly controlled diabetes and severe obesity. After 12 months of semaglutide treatment, we observed an important reduction in glycated hemoglobin levels (11.1% to 7.2%) and body weight (99.5 kg to 94.3 kg), with a notable decrease in fat mass and insulin requirements. Interestingly, our patient had already tried liraglutide therapy in adjunction to metformin and insulin therapy, reporting no substantial efficacy.. The beneficial effects of semaglutide on glycemic control and weight reduction provide a promising treatment for diabetes and obesity in Prader-Willi syndrome, even where other glucagons like peptide-1 receptor agonists have failed. Further studies are required to confirm the efficacy and safety of semaglutide in patients with Prader-Willi syndrome.

Topics: Adult; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycemic Control; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Male; Obesity; Prader-Willi Syndrome; Weight Loss

Novel glucagon-like peptide-1 (GLP-1) receptor agonist oral semaglutide has demonstrated greater improvements in glycated hemoglobin (HbA1c) and body weight versus oral medications empagliflozin and sitagliptin, and injectable GLP-1 analog liraglutide, in the PIONEER clinical trial program. Based on these data, the present analysis aimed to evaluate the long-term cost-effectiveness of oral semaglutide versus empagliflozin, sitagliptin and liraglutide in Spain.. Outcomes were projected over patients' lifetimes using the IQVIA CORE Diabetes Model (v9.0), discounted at 3.0% annually. Cohort characteristics and treatment effects were sourced from PIONEER 2 and 4 for the comparisons of oral semaglutide 14 mg versus empagliflozin 25 mg and liraglutide 1.8 mg, respectively, and PIONEER 3 for oral semaglutide 7 and 14 mg versus sitagliptin 100 mg. Costs were accounted from a healthcare payer perspective in 2020 euros (EUR). Patients were assumed to receive initial therapies until HbA1c exceeded 7.5% and then treatment-intensified to basal insulin.. Oral semaglutide 14 mg was associated with improvements in quality-adjusted life expectancy of 0.13, 0.19 and 0.06 quality-adjusted life years (QALYs) versus empagliflozin 25 mg, sitagliptin 100 mg and liraglutide 1.8 mg, respectively, with direct costs EUR 168 higher versus empagliflozin and EUR 236 and 1415 lower versus sitagliptin and liraglutide, respectively. Oral semaglutide 14 mg was associated with an incremental cost-effectiveness ratio (ICER) of EUR 1339 per QALY gained versus empagliflozin and was considered dominant (clinically superior and cost saving) versus sitagliptin and liraglutide. Additional analyses demonstrated that oral semaglutide 7 mg was associated with improvements of 0.11 QALYs and increased costs of EUR 226 versus sitagliptin and was therefore associated with an ICER of EUR 2011 per QALY gained.. Oral semaglutide 14 mg was dominant versus sitagliptin and liraglutide, and cost-effective versus empagliflozin, for the treatment of type 2 diabetes in Spain.

Topics: Administration, Oral; Benzhydryl Compounds; Clinical Trials as Topic; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Sitagliptin Phosphate; Spain

Semaglutide and liraglutide are glucagon-like peptide-1 (GLP-1)-based diabetes drugs. Semaglutide possesses a longer half-life. Utilizing relatively lower doses, we compared the beneficial metabolic effects of these 2 drugs in mice fed a high-fat diet (HFD), aiming to deepen our mechanistic understanding on their energy homeostatic functions.. Male C57BL/6J mice were fed an HFD for 10 weeks, followed by daily phosphate-buffered saline (PBS, as control); liraglutide (150 μg/kg body weight); or semaglutide (12 μg/kg body weight, low dose [LD]; or 60 μg/kg body weight, high dose [HD]) injection for 4 weeks. Metabolic tolerance and other tests were conducted within the 4-week period. Expression of metabolism-related genes, including Fgf21 in the liver and adipose tissues, was assessed after mice were euthanized.. HFD-induced body weight gain, increasing inguinal fat tissue mass, glucose defects and insulin intolerance were effectively and comparably attenuated in the 3 experimental groups. HD semaglutide showed an even better effect on attenuating hyperleptinemia. Liraglutide but not semaglutide treatment enhanced hepatic fibroblast growth factor 21 (FGF21) protein level. All 3 experimental groups showed elevated expression of genes that encode pyruvate dehydrogenase kinase 4 and enoyl-CoA hydratase and 3-hydroxyacyl-coenzyme A dehydrogenase, associated with reduced plasma triglyceride levels. Finally, the plasma "GLP-1" level in HD semaglutide-treated mice was 14-fold higher than in HFD-fed control mice.. Liraglutide, but not semaglutide, increased hepatic FGF21 protein level, whereas semaglutide had a greater effect on attenuating hyperleptinemia. Thus, these 2 GLP-1-based diabetes drugs may target metabolic organs, including liver and adipose tissue, with differing levels of efficacy.

Topics: Animals; Body Weight; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Male; Mice; Mice, Inbred C57BL

To conduct an adjusted indirect treatment comparison (aITC) of the efficacy of tirzepatide 5/10/15 mg versus semaglutide 2 mg in patients with type 2 diabetes.. The primary analysis was a Bucher aITC of the change from baseline at week 40 in HbA1c (%) and body weight (kg). Aggregate data from the SURPASS-2 study that met the HbA1c inclusion criterion of the SUSTAIN FORTE study and from SUSTAIN FORTE metformin-only treated patients were used for primary analysis.. The SURPASS-2 refined population comprised 238/245/240 and 240 participants for tirzepatide 5/10/15 mg and semaglutide 1 mg, respectively. The SUSTAIN FORTE metformin-only population comprised 222 and 227 participants for semaglutide 1 and 2 mg, respectively. In this aITC, tirzepatide 10 and 15 mg significantly reduced HbA1c versus semaglutide 2 mg with an estimated treatment difference (ETD) of -0.36% (95% confidence interval [CI] -0.63, -0.09) and -0.4% (95% CI -0.67, -0.13), respectively. Tirzepatide 10 and 15 mg significantly reduced body weight versus semaglutide 2 mg with an ETD of -3.15 kg (95% CI -4.84, -1.46) and -5.15 kg (95% CI -6.85, -3.45), respectively. There were no significant differences between tirzepatide 5 mg and semaglutide 2 mg on change from baseline in HbA1c and body weight.. In this aITC, HbA1c and weight reductions were significantly greater for tirzepatide 10 and 15 mg versus semaglutide 2 mg and were similar for tirzepatide 5 mg versus semaglutide 2 mg. These findings provide comparative effectiveness insights in the absence of a head-to-head clinical trial.

Topics: Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Gastric Inhibitory Polypeptide; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Treatment Outcome

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Insulins; Liver Transplantation; Male; Middle Aged

Topics: Azetidines; Dancing; Glucagon-Like Peptides; Humans; Isobutyrates; Isonicotinic Acids; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Oxazoles; Pyrimidines

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP1a), reduces the risk of major adverse cardiovascular events (MACE) in patients with Type 2 diabetes mellitus (T2DM). An oral version of semaglutide is now available, and patients may prefer it over the subcutaneous form. Our objective was to compare the value for money of the two modalities by assessing the cost needed to treat (CNT) to prevent MACE.. The CNT to prevent MACE was figured by multiplying the one-year number needed to treat (NNT) with either oral or subcutaneous semaglutide by the annual cost of therapy. Efficacy estimates and the resulting NNT figures were extracted from the published results of the SUSTAIN-6 and the PIONEER-6 trials for the injectable and oral versions of semaglutide, respectively. Drug costs were estimated as 75% of the United States national average drug acquisition cost listing in June 2021. We performed a scenario analysis to mitigate the primary differences between the populations in the two trials. Sensitivity analysis was performed to evaluate the effect of price changes of the interventions.. The CNT to prevent one MACE with subcutaneous semaglutide in SUSTAIN-6 was $966,693 ($594,888-$5,035,302) compared to $948,689 ($463,465-∞) with oral semaglutide in PIONEER-6. The scenario analysis demonstrated a 17% lower CNT for oral semaglutide. The difference between CNTs was sensitive to price fluctuations of the two interventions.. Oral and subcutaneous semaglutide prescribed to prevent MACE in patients with T2DM provide similar value for money. The choice between both therapies should be guided mainly by patient preferences.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

This analysis of 3,375 adults with overweight/obesity across the Semaglutide Treatment Effect in People with obesity (STEP) 1, 3, and 4 trials evaluated whether more participants with prediabetes had normoglycemia after 68 weeks' treatment with once-weekly semaglutide 2.4 mg plus lifestyle intervention versus placebo and assessed changes in glucose metabolism in participants with prediabetes.. STEP 1, 3, and 4 were phase 3, 68-week, randomized, placebo-controlled, multinational trials; STEP 4 had a 20-week semaglutide run-in and 48-week randomized period. Analyses included changes (week 0-68; before the washout period) in glycemic status (prespecified: STEP 1 and 3; post hoc: STEP 4), and in HbA1c, fasting plasma glucose (FPG), and HOMA insulin resistance (HOMA-IR) among participants with prediabetes (post hoc).. Significantly more participants with baseline (week 0) prediabetes (n = 1,536) had normoglycemia at week 68 with semaglutide versus placebo (STEP 1, 84.1% vs. 47.8%; STEP 3, 89.5% vs. 55.0%; STEP 4, 89.8% vs. 70.4%; all P < 0.0001). Fewer participants with baseline normoglycemia had prediabetes at week 68 with semaglutide versus placebo (STEP 1, 2.9% vs. 10.9%; STEP 3, 3.2% vs. 5.8%; STEP 4, 1.1% vs. 5.0%). Semaglutide resulted in greater improvements in HbA1c, FPG, and HOMA-IR than placebo among participants with baseline prediabetes (all P < 0.01).. STEP 1, 3, and 4 collectively provide a robust assessment of the effects of semaglutide on glucose metabolism and prediabetes in a large cohort of adults with overweight/obesity while on treatment. Among participants with baseline prediabetes, 68 weeks' treatment with semaglutide versus placebo led to significant improvements in glucose metabolism and a higher likelihood of normoglycemia.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Obesity; Overweight; Prediabetic State

Topics: Adult; Cost-Benefit Analysis; Glucagon-Like Peptides; Humans; Obesity; Overweight; Quality-Adjusted Life Years; United States

Body weight (BW) loss is an essential therapeutic goal in type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists are effective in reducing BW, but their effect on body composition has not yet been fully explored. The study aim was to assess the impact of Semaglutide on body composition in patients with T2D.. Forty patients with T2D were treated with subcutaneous Semaglutide and evaluated at the baseline (T0) and after three (T3) and six (T6) months. Body composition was assessed by a phase-sensitive bioimpedance analyzer. Visceral adipose tissue (VAT) thickness was also measured with an ultrasonographic method (US-VAT). Anthropometric variables, muscular strength, and laboratory tests were analyzed and compared.. A significant decrease in VAT, the fat mass index (FMI), and BW loss was observed at all observation times. US-VAT, the skeletal mass index (SMI), the fat-free mass index (FFMI), waist circumferences, and glycated hemoglobin had lessened after three months and remained stable at T6. No variations in muscle strength, the muscle quality index, and body water were found.. In a real-life setting, Semaglutide provided significant weight loss mainly due to a reduction in the FMI and VAT, with non-clinically relevant changes in the SMI, the FFMI, and muscle strength. Most importantly, the results were obtained after three months of treatment and persisted thereafter.

Topics: Body Composition; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Prospective Studies

Topics: Glucagon-Like Peptides; Humans; Liraglutide; Weight Loss

Semaglutide is a glucagon-like-peptide-1 (GLP-1) analogue marketed for once-weekly subcutaneous administration for type 2 diabetes mellitus. Like other long-acting GLP-1 analogues, semaglutide reduces gastric emptying and, potentially, alters the rate of absorption of orally co-administered drugs. The objective of the current analysis was to evaluate the effects on the gastric emptying rate caused by semaglutide on pharmacokinetic model parameters of paracetamol and atorvastatin in healthy subjects. Non-linear mixed effect modeling was used to estimate population pharmacokinetic model parameters of paracetamol and atorvastatin after single doses with or without semaglutide. The absorption rate (ka) of paracetamol decreased by 53% when co-administered with semaglutide. For atorvastatin, ka and transit compartment rate (ktr) decreased by 72% and 91%, respectively. Thus, gastric emptying, measured as T50, i.e., drug disappearance from the absorption compartments, showed an additional 5-min delay for paracetamol and a 67-min delay for atorvastatin when co-administered with semaglutide. Semaglutide affected pharmacokinetic model parameters of paracetamol and atorvastatin, and minor quantitative differences in gastric emptying between placebo vs. semaglutide administration were observed. However, these effects of semaglutide were considered not to be of clinical relevance.

Topics: Acetaminophen; Atorvastatin; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

The impact of glucagon-like peptide-1 receptor agonists on patients with heart failure has not been fully described. Our main objective was to evaluate the safety and clinical and glycemic efficacy of once-weekly semaglutide in obese patients with type 2 diabetes and heart failure.. In this observational, retrospective, real-world study, we enrolled outpatients with type 2 diabetes, obesity, and heart failure who started semaglutide and were followed-up on at 3, 6, and 12 months.. A total of 136 patients were included. From baseline to 12 months, there was a significant improvement on the Kansas City Cardiomyopathy Questionnaire total symptom score (59.0 ± 24.1 vs 79.9 ± 28.4 points, p<0.01), a reduction in the proportion of patients with New York Heart Association functional class III (40.4% to 16.2%, p<0.01), and a reduction in N-terminal pro-brain natriuretic peptide levels (969.5 ± 653.5 vs 577.4 ± 322.1 pg/mL, p<0.01). Emergency department visits due to heart failure, hospitalizations due to heart failure, and all-cause hospitalizations also declined. Additionally, significant reductions in glycated hemoglobin (-1.4%) and body weight (-12.7 kilograms) were observed as well as a de-intensification of antidiabetic therapy. Moreover, semaglutide was safe and well-tolerated.. In obese patients with type 2 diabetes and heart failure, the use of once-weekly semaglutide was safe and clinically efficacious, improving health and functional status. Nevertheless, more strong evidence on glucagon-like peptide-1 receptor agonists in heart failure is required.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Heart Failure; Humans; Obesity; Retrospective Studies

Aim of the present study was to evaluate the impact of once-weekly semaglutide on different end-points indicative of metabolic control, cardiovascular risk, dietary behavior, and treatment satisfaction in T2DM.. This was a retrospective observational study conducted in a diabetes clinic. Changes in HbA1c, fasting blood glucose (FBG), weight, blood pressure, lipid profile, and number of antihypertensive drugs at 32 weeks (T1) after the first prescription of semaglutide (T0) were analyzed. Furthermore, at T1 patients were asked to fill-in the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the Control of Eating Questionnaire (COEQ).. Overall, 104 patients were identified (mean age 63.6 ± 10.4 years, 58.7% men, diabetes duration 12.7 ± 8.7 years). After 32 weeks of treatment with semaglutide, HbA1c levels were reduced by 1.38%, FBG by - 56.53 mg/dl, weight by 6.03 kg. Systolic and diastolic blood pressure, total, HDL-, LDL-, and non -HDL cholesterol, and triglycerides significantly improved. The number of glucose-lowering and antihypertensive drugs also decreased. At T1, DTSQ score was 32.23 ± 1.44, whereas COEQ indicated low levels of hunger and good control of eating.. The study documented benefits of semaglutide on metabolic control and multiple CV risk factors, simplification of therapeutic schemes and high satisfaction with diabetes treatment, and eating behaviors indicative of healthy diet and reduced food intake.

Topics: Aged; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Feeding Behavior; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Male; Middle Aged; Risk Factors

Non-cardiomyocytes (nonCMs) play an important part in cardiac fibrosis pathophysiology, but the underlying molecular pathways are unknown. Semaglutide has cardioprotective properties, but it is still unclear whether it helps with cardiac fibrosis and what the processes are. The goal of this study is to use single cell transcriptomics approaches to investigate the molecular mechanism of semaglutide's cardioprotective action in obese mice. We found 15 non-CMs, with fibroblasts making up the majority of them. We found eight DEGs that altered significantly following semaglutide treatment by screening for differentially expressed genes (DEGs). DEGs were shown to have biological activities primarily related to extracellular matrix and collagen synthesis and distribution, with Serpinh1 and Pcolce expression being the most dramatically altered. Serpinh1 and Pcolce were mostly found in fibroblasts, which play a key role in the fibrosis of the heart. Furthermore, we discovered that semaglutide lowered cardiac collagen content and alleviated obesity-induced ventricular wall hypertrophy. As a result, our findings show that Serpinh1 and Pcolce, which are expressed by fibroblasts, may play a role in the development of obese cardiac fibrosis. By reducing Serpinh1 and Pcolce expression and delaying cardiac fibrosis, semaglutide may have a cardioprotective effect.

Topics: Animals; Cardiomegaly; Collagen; Fibroblasts; Fibrosis; Glucagon-Like Peptides; Mice; Mice, Obese; Myocytes, Cardiac; Transcriptome

About 20-25% of patients experience weight regain (WR) or insufficient weight loss (IWL) after bariatric metabolic surgery (BS). Therefore, we aimed to retrospectively assess the effectiveness of adjunct treatment with the GLP-1 receptor agonist semaglutide in non-diabetic patients with WR or IWL after BS.. Post-bariatric patients without type 2 diabetes (T2D) with WR or IWL (n = 44) were included in the analysis. The primary endpoint was weight loss 3 and 6 months after initiation of adjunct treatment. Secondary endpoints included change in BMI, HbA1c, lipid profile, hs-CRP, and liver enzymes.. Patients started semaglutide 64.7 ± 47.6 months (mean ± SD) after BS. At initiation of semaglutide, WR after post-bariatric weight nadir was 12.3 ± 14.4% (mean ± SD). Total weight loss during semaglutide treatment was - 6.0 ± 4.3% (mean ± SD, p < 0.001) after 3 months (3.2 months, IQR 3.0-3.5, n = 38) and - 10.3 ± 5.5% (mean ± SD, p < 0.001) after 6 months (5.8 months, IQR 5.8-6.4, n = 20). At 3 months, categorical weight loss was > 5% in 61% of patients, > 10% in 16% of patients, and > 15% in 2% of patients. Triglycerides (OR = 0.99; p < 0.05), ALT (OR = 0.87; p = 0.05), and AST (OR = 0.89; p < 0.05) at baseline were negatively associated with weight loss of at least 5% at 3 months' follow-up (p < 0.05).. Treatment options to manage post-bariatric excess weight (regain) are scarce. Our results imply a clear benefit of adjunct treatment with semaglutide in post-bariatric patients. However, these results need to be confirmed in a prospective randomized controlled trial to close the gap between lifestyle intervention and revision surgery in patients with IWL or WR after BS.

Topics: Bariatric Surgery; C-Reactive Protein; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Lipids; Obesity, Morbid; Prospective Studies; Retrospective Studies; Triglycerides; Weight Gain; Weight Loss

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity; Overweight

Exploratory analysis to determine the effect of semaglutide versus comparators on high-sensitivity C-reactive protein (hsCRP) in subjects with type 2 diabetes.. Geometric mean baseline hsCRP was similar across trials (range 2.7-3.0 mg/L). Semaglutide reduced hsCRP levels by clinical cutoffs and tertiles from baseline to end-of-treatment in all trials versus comparators (estimated treatment ratios [ETRs] versus comparators: 0.70-0.76; p < 0.01) except versus placebo in PIONEER 5 (ETR [95% CI]: 0.83 [0.67-1.03]; p > 0.05). The effect of semaglutide on hsCRP was partially mediated (20.6-61.8%) by change in HbA. Semaglutide reduced hsCRP ratios-to-baseline versus comparators in subjects with type 2 diabetes (not significant with CKD). This effect was partially mediated via reductions in HbA. ClinicalTrials.gov identifiers: NCT01885208 (first registered June 2013), NCT02906930 (first registered September 2016), NCT02863328 (first registered August 2016), NCT02827708 (first registered July 2016).

Topics: Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Treatment Outcome

Background Semaglutide holds the promise for weight loss and risk reduction. Less is known about racial and ethnic disparities in financial barriers among the semaglutide-eligible population. Methods and Results We conducted a cross-sectional analysis of adults aged 18 years or older using data from the National Health and Nutrition Examination Survey 2015 to 2020. We analyzed adults eligible for semaglutide based on Food and Drug Administration labeling and assessed financial barriers and social determinants of health among the eligible population overall and by race and ethnicity. A total of 13 711 adults were included in the final analysis. In 2015 to 2020, 51.1% (48.3%-53.2%) of US adults (≈43.3 million) met the Food and Drug Administration eligibility criteria for semaglutide. The percentage of adults eligible for semaglutide was highest among Black adults (56.6% [54.2%-59.1%]), followed by Hispanic adults (55.0% [52.8%-57.3%]). Among adults eligible for semaglutide, 11.9% (10.1%-13.6%) were uninsured, 13.3% (12.1%-14.5%) lacked a usual source of care, 33.6% (30.2%-36.9%) had low family income, and 38.9% (36.5%-41.3%) lacked higher education. Compared with White individuals, significantly larger proportions of Black and Hispanic individuals were uninsured, lacked a usual source of care, had low family income, or lacked higher education (

Topics: Adult; Black or African American; Cross-Sectional Studies; Ethnicity; Glucagon-Like Peptides; Humans; Nutrition Surveys; Obesity; Overweight; United States

To investigate the use of once-weekly semaglutide in a real population of people with type 2 diabetes mellitus (T2DM) in three Spanish hospitals.. An observational, retrospective and multicenter clinical study was designed that included 166 participants with T2DM, distinguishing between a group naïve to GLP-1RA (n=72) and another switching from another GLP-1RA (n=94), all managed in the outpatient clinical setting. The primary endpoint was the change in HbA1c from baseline to the end of the study. The secondary endpoints included changes in body weight and the proportion of people with T2DM, achieving HbA1c <7.0% and body weight loss >5%.. After 24 months of follow-up, the reductions in HbA1c were -0.91 ± 0.7% (p<0.001) in the total cohort, -1.13 ± 1.38% (p<0.019) for GLP-1RA-naïve participants, and -0.74 ± 0.9% (p<0.023) for GLP-1RA-experienced participants. Body weight reductions were -12.42 ± 9.1% in GLP-1RA-naïve participants vs. -7.65 ± 9.7% in GLP-1RA-experienced participants (p<0.001). In the total cohort, 77.1% reached the objective of an HbA1c level <7%, and 12.7% reached between 7.1% and 7.5%. Additionally, 66.9% achieved a weight reduction ≥5%. Of all cohort, 90% received 1 mg of semaglutide once a week. The reported adverse events were consistent with the known safety profile of semaglutide.. In routine clinical practice in Spain, the use of semaglutide once a week was associated with statistically significant and clinically relevant improvements in HbA1c and body weight in a wide range of adults with T2DM, without notable adverse effects, which supports real-world use.

Topics: Adult; Ambulatory Care Facilities; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Retrospective Studies; Spain

Glucagon like peptide-1 receptor agonists (GLP-1 RA) are potent antidiabetic drugs associated with significant weight loss and minimal risk of hypoglycemia. Semaglutide is a GLP-1 RA with a proven cardiovascular benefit. It is currently also available in oral form, which is especially suitable for the treatment of the initial phase of type 2 diabetes. However, it is also effective at later initiation of therapy, in different diabetic populations. The PIONEER 6 trial demonstrated cardiovascular safety of oral semaglutide, its administration was accompanied by a significant reduction in cardiovascular and overall mortality.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents

The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program.. This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg).. Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants. With once-weekly semaglutide, relative bodyweight was reduced from baseline to end of study by 4.0-7.3% in the overall populations, and 2.7-10.4% in Japanese participants. In the Japanese subpopulation, no new safety concerns were identified with once-weekly semaglutide, and there were no adverse events leading to death or severe hypoglycemic episodes.. In this post-hoc analysis, participants with type 2 diabetes initiating once-weekly semaglutide experienced improvements in glycated hemoglobin and bodyweight in both the overall and Japanese population, and no new safety concerns were identified among Japanese participants, supporting the efficacy of once-weekly semaglutide in this population.

Topics: Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Japan; Treatment Outcome

Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) has been extensively studied, the role of its underlying pathogenesis remains unclear, and there is currently no approved therapeutic strategy for NAFLD. The purpose of this study was to observe the beneficial effects of Semaglutide on NAFLD in vivo and in vitro, as well as its potential molecular mechanisms.. Semaglutide was used to treat type 2 diabetes mellitus (T2DM) combined with NAFLD mice for 12 weeks. Hepatic function and structure were evaluated by liver function, blood lipids, liver lipids, H&E staining, oil red staining and Sirius staining. The expression of α/β hydrolase domain-6 (ABHD6) was measured by qPCR and Western blotting in vivo and in vitro. Then, dual-luciferase reporter assay was performed to verify the regulation of the upstream miR-5120 on ABHD6.. Our data revealed that Semaglutide administration significantly improved liver function and hepatic steatosis in T2DM combined with NAFLD mice. Furthermore, compared with controls, up-regulation of ABHD6 and down-regulation of miR-5120 were found in the liver of T2DM+NAFLD mice and HG+FFA-stimulated Hepa 1-6 hepatocytes. Interestingly, after Semaglutide intervention, ABHD6 expression was significantly decreased in the liver of T2DM+NAFLD mice and in HG+FFA-stimulated Hepa 1-6 hepatocytes, while miR-5120 expression was increased. We also found that miR-5120 could regulate the expression of ABHD6 in hepatocytes, while Semaglutide could modulate the expression of ABHD6 through miR-5120. In addition, GLP-1R was widely expressed in mouse liver tissues and Hepa 1-6 cells. Semaglutide could regulate miR-5120/ABHD6 expression through GLP-1R.. Our data revealed the underlying mechanism by which Semaglutide improves hepatic steatosis in T2DM+NAFLD, and might shed new light on the pathological role of miR-5120/ABHD6 in the pathogenesis of T2DM+NAFLD.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Liver; Mice; Mice, Inbred C57BL; MicroRNAs; Monoacylglycerol Lipases; Non-alcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is commonly observed in patients with type 2 diabetes (T2D). Semaglutide, a glucagon-like peptide 1 receptor agonist, may have a therapeutic role by targeting common mechanisms involved in the pathophysiology of T2D and NAFLD. The study aimed to assess the effectiveness of Semaglutide on NAFLD in patients with T2D.. Forty-eight patients were treated with subcutaneous Semaglutide in add-on to metformin for 52 weeks. After the baseline visit (T0), follow-up was scheduled quarterly (T3, and T6) and then at 12 months of therapy (T12). During each visit, body composition was analyzed by phase-sensitive bio-impedance, and NAFLD was diagnosed and staged by Ultrasound (US) imaging. Surrogate biomarkers of NAFLD were also calculated and followed over time.. A significant decrease in anthropometric and glucometabolic parameters, insulin resistance, liver enzymes, and laboratory indices of hepatic steatosis was observed during treatment. Similarly, fat mass and visceral adipose tissue (VAT) decreased over time more than skeletal muscle and free-fat mass. US-assessed VAT thickness and the 12-point steatosis score also declined at T3 up to T12. Liver steatosis improved in most patients (70%), showing a reduction by at least one class in the semiquantitative US staging.. Besides glucose control and body composition improvements, Semaglutide was effective in ameliorating the clinical appearance and severity of NAFLD in T2D patients.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Non-alcoholic Fatty Liver Disease; Prospective Studies

Anti-obesity medications used with lifestyle intervention produce greater and more sustained weight loss than does lifestyle intervention alone. However, until 2021, FDA-approved medications for the long-term treatment of obesity in the general adult population had not demonstrated the sustained loss of 15% body weight needed to meet or exceed all guideline-recommended targets for weight-related complications. To meet this need, investigators launched the Semaglutide Treatment Effect in People with obesity (STEP) program of phase 3 clinical trials to assess the safety and efficacy of a weekly 2.4-mg subcutaneous injection of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA). Following the results of STEPs 1 to 4, the FDA approved semaglutide therapy in patients with obesity. This article examines the design, efficacy, and safety of semaglutide therapy as revealed by the results of STEPs 1 to 4. These trials included adults with obesity who reported at least 1 unsuccessful attempt to reduce body weight by means of diet. STEP 2 studied effects on patients who also had type 2 diabetes (T2D); STEPs 1, 3, and 4 excluded patients with this condition. STEP 3 examined the effect of this pharmacotherapy plus intensive behavioral therapy and a 2-step, intensively restricted dietary plan. STEP 4 assessed the effects of continuing semaglutide 2.4 mg vs switching to placebo after an initial treatment period. In the trials comparing the effects of semaglutide 2.4‑mg treatment with those of placebo across 68 weeks and in patients with no T2D (ie, STEPs 1 and 3), patients treated with semaglutide achieved a mean -14.9% to -16.0% weight change. This far exceeds the 4.0% to 10.9% weight loss seen with other approved antiobesity medications. In STEPs 2 and 4, the estimated treatment differences between the semaglutide 2.4-mg and placebo arms were -6.2% and -14.8%, respectively. Safety and tolerability of this treatment in STEPs 1 to 4 was consistent with those of other GLP-1RA-based therapies. Ultimately, the results of the first 4 STEP trials demonstrated that semaglutide 2.4 mg is a safe, well-tolerated, and highly effective treatment to promote weight loss, avoid weight regain, and mitigate the effects of the prevalent, chronic disease of obesity. In November 2022, based upon the results of STEPs 1 to 3 and other trials, the American Gastroenterological Association recommended that semaglutide 2.4 mg "be prioritized over other approved [anti-obesity medic

Topics: Adult; Anti-Obesity Agents; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Weight Loss

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Obesity; Primary Health Care

Topics: Diabetes Mellitus, Type 2; Gastric Dilatation; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Topics: Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide Receptors; Glucagon-Like Peptides; Humans; Japan; Kidney Failure, Chronic; Male; Middle Aged; Obesity; Renal Dialysis; Treatment Outcome

Achieving efficacious systemic levels of orally administered peptides is incredibly challenging due to the significant barriers to their bioavailability-their stability in the gastrointestinal tract and challenge of transepithelial transit, and variable pharmacokinetics. Even so, as the generally preferred route of administration, significant research effort in academic and industrial settings has focused on enabling the systemic absorption of orally delivered peptides. Despite several decades of research, few have ever reached the market. The recent approval of Rybelsus® (oral semaglutide) by the FDA [1], the EMA [2], and the Pmda [3] represents a significant landmark in the delivery of therapeutic peptides and is the culmination of more than 30 years research and development of the drug delivery technology enabling the product-Emisphere's Eligen™ technology-and an outstanding commitment to scientific, technical, and clinical innovation by Novo Nordisk. Following years of fundamental and applied research, an innovative clinical strategy led to the aptly named PIONEER clinical programme. This included ten Phase 3 clinical trials that demonstrated the tablet formulation to be as effective as the already approved injectable form of the drug, and more effective than competitor products in terms of its blood glucose lowering effects and weight loss. Not only is this a potentially life changing medicine for diabetic patients, it holds tremendous commercial potential for Novo Nordisk, with some analysts predicting the product to reach $5 billion in peak revenues [3]. In this "Inspirational Note," we summarize some of the public domain work that led to the achievement of this significant milestone and provide commentary on its potential future impact.

Topics: Administration, Oral; Blood Glucose; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Peptides

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Weight Loss

Topics: Diabetes Mellitus, Type 2; Diabetic Retinopathy; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Topics: Adult; Behavior Therapy; Glucagon-Like Peptides; Humans; Obesity; Overweight

Topics: Adult; Behavior Therapy; Glucagon-Like Peptides; Humans; Obesity; Overweight

Long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs), like liraglutide and semaglutide, are viable treatments for diabetes and obesity. Liraglutide directly activates hypothalamic proopiomelanocortin (POMC) neurons while indirectly inhibiting Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons ex vivo. While temporal control of GLP-1R agonist concentration as well as accessibility to tissues/cells can be achieved with relative ease ex vivo, in vivo this is dependent upon the pharmacokinetics of these agonists and relative penetration into structures of interest. Thus, whether liraglutide or semaglutide modifies the activity of POMC and NPY/AgRP neurons in vivo as well as mechanisms required for any changes in cellular activity remains undefined.. In order to resolve this issue, we utilized neuron-specific transgenic mouse models to examine changes in the activity of POMC and NPY/AgRP neurons after injection of either liraglutide or semaglutide (intraperitoneal - I.P. and subcutaneous - S·C.). POMC and NPY/AgRP neurons were targeted for patch-clamp electrophysiology as well as in vivo fiber photometry.. We found that liraglutide and semaglutide directly activate and increase excitatory tone to POMC neurons in a time-dependent manner. This increased activity of POMC neurons required GLP-1Rs in POMC neurons as well as a downstream mixed cation channel comprised of TRPC5 subunits. We also observed an indirect upregulation of excitatory input to POMC neurons originating from glutamatergic cells that also required TRPC5 subunits. Conversely, GLP-1Ra's decreased excitatory input to and indirectly inhibited NPY/AgRP neurons through activation of K-ATP and TRPC5 channels in GABAergic neurons. Notably, the temporal activation of POMC and inhibition of NPY/AgRP neuronal activity after liraglutide or semaglutide was injected [either intraperitoneal (I.P.) or subcutaneous (S·C.)] was dependent upon the nutritional state of the animals (fed vs food-deprived).. Our results support a mechanism of liraglutide and semaglutide in vivo to activate POMC while inhibiting NPY/AgRP neurons, which depends upon metabolic state and mirrors the pharmacokinetic profile of these compounds in vivo.

Topics: Agouti-Related Protein; Animals; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Injections, Intraperitoneal; Injections, Subcutaneous; Liraglutide; Male; Mice; Mice, Knockout; Mice, Transgenic; Neurons; Neuropeptide Y; Pro-Opiomelanocortin; Time Factors

Topics: Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Hypoglycemic Agents

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used to treat diabetes and obesity and reduce rates of major cardiovascular events, such as stroke and myocardial infarction. Nevertheless, the identity of GLP-1R-expressing cell types mediating the cardiovascular benefits of GLP-1RA remains incompletely characterized. Herein, we investigated the importance of murine Glp1r expression within endothelial and hematopoietic cells. Mice with targeted inactivation of Glp1r in Tie2+ cells exhibited reduced levels of Glp1r mRNA transcripts in aorta, liver, spleen, blood, and gut. Glp1r expression in bone marrow cells was very low and not further reduced in Glp1rTie2-/- mice. The GLP-1RA semaglutide reduced the development of atherosclerosis induced by viral PCSK9 expression in both Glp1rTie2+/+ and Glp1rTie2-/- mice. Hepatic Glp1r mRNA transcripts were reduced in Glp1rTie2-/- mice, and liver Glp1r expression was localized to γδ T cells. Moreover, semaglutide reduced hepatic Tnf, Abcg1, Tgfb1, Cd3g, Ccl2, and Il2 expression; triglyceride content; and collagen accumulation in high-fat, high-cholesterol diet-fed Glp1rTie2+/+ mice but not Glp1rTie2-/- mice. Collectively, these findings demonstrate that Tie2+ endothelial or hematopoietic cell GLP-1Rs are dispensable for the antiatherogenic actions of GLP-1RA, whereas Tie2-targeted GLP-1R+ cells are required for a subset of the antiinflammatory actions of semaglutide in the liver.

Topics: Animals; Atherosclerosis; Endothelial Cells; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Hematopoietic Stem Cells; Humans; Liver; Male; Metabolic Syndrome; Mice

Topics: Animals; Apoptosis; Cell Line; Cognitive Dysfunction; Cytokines; Disease Models, Animal; Epilepsy; Glucagon-Like Peptides; Hippocampus; Inflammasomes; Inflammation; Male; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; NLR Family, Pyrin Domain-Containing 3 Protein; Pentylenetetrazole; Seizures

Frias JP, Davies MJ, Rosenstock J, et al.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Weight Loss

Topics: Body Mass Index; Clinical Trials as Topic; Glucagon-Like Peptides; Humans; Obesity; Patient Compliance; Placebos

To compare 6-month adherence, persistence and treatment patterns among patients initiating once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs), dulaglutide versus semaglutide, and dulaglutide versus exenatide BCise, using claims from the HealthCore Integrated Research Database.. Patients aged ≥18 years, with type 2 diabetes, ≥1 claim for dulaglutide, semaglutide or exenatide BCise during the index period February 2018 to December 2018 (index date = earliest GLP-1RA fill date), no claim for GLP-1RAs in the 6-month pre-index period, and continuous enrolment 6 months pre- and post-index were included. Dulaglutide users were propensity-matched 1:1 to semaglutide users (3852 pairs) or exenatide BCise users (1879 pairs). The proportions of adherent (proportion of days covered ≥80%) patients were compared using chi-squared tests. Persistence, measured as days to discontinuation, was analysed using a Cox regression model.. Matched cohorts (dulaglutide:semaglutide and dulagutide:exenatide BCise) were balanced in baseline characteristics and the mean age was 54 and 55 years, respectively, with approximately 51% and 49% women, respectively. At 6 months, significantly more dulaglutide users were adherent than semaglutide (59.7% vs. 42.7%; P <0.0001) or exenatide BCise users (58.1% vs. 40.3%; P <0.0001). Cox regression showed that dulaglutide users were less likely to discontinue therapy than semaglutide (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.66, 0.76) or exenatide BCise users (HR 0.59, 95% CI 0.53, 0.65; P <0.0001, both).. At 6-month follow-up, a higher proportion of patients initiating dulaglutide were adherent to and persistent with their treatment, compared to matched patients initiating either semaglutide or exenatide BCise.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Recombinant Fusion Proteins

A single-dose, shield-activated pen-injector for each of the three approved dose variants (0.25, 0.5 and 1 mg) of once-weekly subcutaneous semaglutide has been developed to improve usability. This analysis presents findings from the summative usability testing process for the single-dose semaglutide pen-injectors, including the pen-injector four-pack cartons and instructions for use.. A total of 60 adults representing four user groups were included: patients with/without pen-injector experience, non-pharmacist healthcare professionals and pharmacists (each n = 15). Participants carried out four tasks: (i) pen-injector carton retrieval; (ii) first simulated injection; (iii) pen-injector retrieval; and (iv) second simulated injection. All participants carried out task 1, and patients and non-pharmacist healthcare professionals took part in tasks 2-4 (n = 45). The number and types of use errors, close calls and operational difficulties were evaluated, and participants subjectively rated the ease of each task on a scale of 1 (difficult) to 7 (easy).. No potentially serious use errors and only one non-serious use error were reported. Eight participants committed use errors with no potential for harm, one participant committed an unclassified use error, one participant encountered a close call with no potential for harm and one participant experienced an operational difficulty. Mean ease-of-use ratings were 6.7 (task 1), 5.9 (task 2), 6.6 (task 3) and 6.9 (task 4).. All three dose variants of the semaglutide single-dose pen-injector were considered easy to use (subjective feedback scores near 7) and not associated with any serious use errors, even when participants received no training before study participation.

Topics: Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Humans; Injections, Subcutaneous; Male; Middle Aged; Patient Acceptance of Health Care; Syringes; User-Centered Design

Oral semaglutide was approved in 2019 for blood glucose control in patients with type 2 diabetes mellitus (T2DM) and was the first oral glucagon-like peptide 1 receptor agonist (GLP-1 RA). T2DM is associated with substantial healthcare expenditures in the US, so the cost of a new intervention should be weighed against clinical benefits.. This study evaluated the budget impact of a treatment pathway with oral semaglutide 14 mg daily versus oral sitagliptin 100 mg daily among patients not achieving target glycated hemoglobin (HbA1c) level despite treatment with metformin.. This study used the validated IQVIA™ CORE Diabetes Model to simulate the treatment impact of oral semaglutide 14 mg and sitagliptin 100 mg over a 5-year time horizon from a US healthcare sector (payer) perspective. Trial data (PIONEER 3) informed cohort characteristics and treatment effects, and literature sources informed event costs. Population and market share data were from the literature and data on file. The analysis evaluated the estimated budget impact of oral semaglutide 14 mg use for patients currently using sitagliptin 100 mg considering both direct medical and treatment costs to understand the impact on total cost of care, given underlying treatment performance and impact on avoidable events.. In a hypothetical plan of 1 million lives, an estimated 1993 patients were treated with sitagliptin 100 mg in the target population. Following these patients over 5 years, the incremental direct medical and treatment costs of a patient using oral semaglutide 14 mg versus sitagliptin 100 mg was $US16,562, a 70.7% increase (year 2019 values). A hypothetical payer would spend an additional $US3,300,143 (7.1%) over 5 years for every 10% of market share that oral semaglutide 14 mg takes away from sitagliptin 100 mg. Univariate and scenario analyses with alternate inputs and assumptions demonstrated consistent results.. Use of oral semaglutide 14 mg in patients currently receiving sitagliptin 100 mg substantially increases the budget impact for patients with T2DM whose blood glucose level is not controlled with metformin over a 5-year time horizon for US healthcare payers.. Budget impact of oral semaglutide intensification versus sitagliptin among US patients with type 2 diabetes mellitus uncontrolled with metformin.. Patients with type 2 diabetes mellitus (T2DM) have many treatment options. Choices depend on factors such as cost, preference, and patient characteristics. Oral semaglutide was recently approved for the treatment of T2DM as the first oral therapy of its class. This study estimated the cost for patients treated with sitagliptin 100 mg, a commonly used T2DM treatment, versus oral semaglutide 14 mg for patients whose disease is not well controlled with metformin. Costs and effects were estimated over 5 years for each treatment strategy using predictive model equations and clinical trial data for the two treatments. These costs were considered for both a hypothetical healthcare plan of 1 million lives and the full US population. A patient treated with oral semaglutide 14 mg would expect to see 70.7% higher costs than a patient treated with sitagliptin 100 mg over 5 years. For every 10% of patients who would switch from sitagliptin 100 mg to oral semaglutide 14 mg, costs would increase by 7.1%. Changing the cost of oral semaglutide 14 mg had the greatest impact on model results. The findings from the analysis were consistent across a range of alternate model inputs. Oral semaglutide 14 mg is more costly than sitagliptin 100 mg over 5 years.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Sitagliptin Phosphate

Topics: Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Non-alcoholic Fatty Liver Disease

To provide pharmacists with information on counseling patients with type 2 diabetes (T2D) receiving oral semaglutide.. Oral semaglutide, the first oral glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1RA), was approved for the treatment of adults with T2D by the US Food and Drug Administration in September 2019. Semaglutide has been coformulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate to improve bioavailability of semaglutide following oral administration. Oral semaglutide has been shown to have efficacy and safety profiles similar to those of other GLP-1RAs. Many patients with T2D have a complex oral medication regimen to manage their T2D and concomitant chronic comorbid conditions. Therefore, it is important that patients follow the dose administration instructions closely: oral semaglutide should be taken on an empty stomach upon waking with a sip (≤120 mL) of plain water and at least 30 minutes before the first food, beverage, or other oral medications of the day. The most common adverse effects of oral semaglutide are gastrointestinal (typically nausea, diarrhea, and vomiting). It is important for pharmacists to counsel patients prescribed oral semaglutide about optimal oral dosing, why correct dosing conditions are necessary, expected therapeutic response, and effective strategies to mitigate potential gastrointestinal adverse events.. Information and practical strategies provided by pharmacists may facilitate initiation and maintenance of oral semaglutide therapy and ensure that each patient achieves an optimal therapeutic response.

Topics: Administration, Oral; Adult; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Pharmacists

To investigate the protective efficacies and potent mechanisms of combination therapy with semaglutide and rosiglitazone (RSG) on the high-glucose incubated human ARPE-19 cells and diabetic retinopathy (DR) model rats.. The CCK-8 methods were used to evaluate the protective effects of semaglutide and RSG alone or combination on the cell viability of high-glucose treated ARPE-19 cells. After the DR rat model was established, the effects of combined treatment on general indexes, retinal morphological changes, retinal Müller cells as well as PI3K/Akt/MTOR related factors of DR model rats were investigated.. The CCK-8 assay showed obviously enhanced protective efficacies of combination therapy with semaglutide and RSG on the ARPE-19 with oxidative stress induced by high-glucose with combination index all below 1.5 demonstrating obvious synergistic effects. Combined incubation could also effectively decrease the expression of inflammatory factors, including TNF-α, IL-1β, IL-6, and the increase of ROS content in ARPE cell culture supernatant induced by high-glucose. Combined use of the antioxidant, PI3K/Akt and mTOR inhibitors, we further demonstrated that combined incubation of semaglutide and RSG could effectively by reduce high glucose-induced inflammatory injury inhibiting ROS/PI3K/Akt/mTOR signaling. Furthermore, chronic combination treatment effectively improved the histopathological characteristics and down-regulated the GFAP expression in Müller cells as well as PI3K/Akt/MTOR signaling pathway-related factors in retina which was better than any monomer treatment group.. Combined semaglutide with RSG exhibited synergistically protective efficacies on retinal cells by decreasing the GFAP expression, inhibiting oxidative stress and PI3K/Akt/MTOR signaling-transduction in DR model rats.

Topics: Animals; Antioxidants; Cell Line; Cell Survival; Diabetic Retinopathy; Disease Models, Animal; Drug Therapy, Combination; Ependymoglial Cells; Glial Fibrillary Acidic Protein; Glucagon-Like Peptides; Humans; Inflammation; Male; Phosphatidylinositol 3-Kinases; Protective Agents; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Rosiglitazone; Signal Transduction; TOR Serine-Threonine Kinases

Topics: Adverse Drug Reaction Reporting Systems; Diabetic Retinopathy; Drug-Related Side Effects and Adverse Reactions; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; United States; United States Food and Drug Administration

Topics: Adult; Glucagon-Like Peptides; Humans; Obesity; Overweight

The anorexigenic peptide glucagon-like peptide-1 (GLP-1) is secreted from gut enteroendocrine cells and brain preproglucagon (PPG) neurons, which, respectively, define the peripheral and central GLP-1 systems. PPG neurons in the nucleus tractus solitarii (NTS) are widely assumed to link the peripheral and central GLP-1 systems in a unified gut-brain satiation circuit. However, direct evidence for this hypothesis is lacking, and the necessary circuitry remains to be demonstrated. Here we show that PPG

Topics: Animals; Central Nervous System; Eating; Female; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Male; Mice; Mice, Inbred C57BL; Neurons; Peripheral Nervous System; Proglucagon; Receptors, Oxytocin; Satiety Response; Vagus Nerve

In the REWIND trial, dulaglutide reduced cardiovascular (CV) risk versus placebo in patients with type 2 diabetes in both the "established CV disease" (CVD) and "CV risk factor" subgroups. The SUSTAIN 6 and PIONEER 6 trials of semaglutide used different criteria for established CVD from those used in REWIND. The present post hoc analysis assessed the effect of semaglutide on major adverse CV events (MACE) in a pooled population of SUSTAIN 6 and PIONEER 6 patients, re-categorized into CV risk subgroups using the REWIND CVD criteria. In the pooled analysis (n = 6480), a lower percentage of patients were in the established CVD subgroup, when using the REWIND CVD criteria, compared with the original trial CVD criteria (66.5% vs. 83.8%, respectively). After re-categorization, the risk of MACE was significantly lower with semaglutide versus placebo in the established CVD subgroup (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.59, 0.92) and nonsignificantly lower in the CV risk factor subgroup (HR 0.84, 95% CI 0.55, 1.28) (P-interaction = 0.60). These results suggest that the CV effects of semaglutide may extend to patients with type 2 diabetes across the CV risk continuum.

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Topics: Adult; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptides; Humans; Obesity; Overweight

To assess the long-term cost-effectiveness of novel glucagon-like peptide-1 (GLP-1) analog oral semaglutide versus sodium-glucose cotransporter-2 inhibitor empagliflozin, dipeptidyl peptidase-4 inhibitor sitagliptin and injectable GLP-1 analog liraglutide in the Netherlands, based on the results of the PIONEER clinical trials.. Outcomes were projected over patient lifetimes using the IQVIA CORE Diabetes Model. Clinical data were derived from PIONEER 2, 3 and 4. Patients were assumed to receive initial treatments until glycated hemoglobin exceeded 7.5%, then treatment-intensified to basal insulin therapy. Costs were accounted from a societal perspective in 2019 euros (EUR).. Oral semaglutide 14 mg was associated with improvements in quality-adjusted life expectancy of 0.15, 0.22 and 0.09quality-adjusted life years (QALYs) versus empagliflozin 25 mg, sitagliptin 100 mg and liraglutide 1.8 mg, respectively, with combined costs EUR1,032 higher, EUR115 higher and EUR1,267 lower. Oral semaglutide was therefore associated with incremental cost-effectiveness ratios of EUR7,061 and EUR516 per QALY gained versus empagliflozin and sitagliptin, respectively.. Based on long-term projections, oral semaglutide 14 mg was considered cost-effective versus empagliflozin 25 mg and sitagliptin 100 mg and dominant versus liraglutide 1.8 mg for the treatment of type 2 diabetes in the Netherlands.

Topics: Administration, Oral; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Male; Middle Aged; Netherlands; Randomized Controlled Trials as Topic

Topics: Adult; Cardiovascular Diseases; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Obesity; Risk Factors

Topics: Anti-Obesity Agents; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Incretins; Obesity; Treatment Outcome; Weight Loss

Topics: Body Weight; Comorbidity; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Life Style; Obesity; Overweight

Topics: Adult; Glucagon-Like Peptides; Humans; Obesity; Overweight; Weight Loss

Topics: Glucagon-Like Peptides; Humans; Islet Amyloid Polypeptide; Obesity Management

Topics: Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Pharmaceutical Preparations; Weight Loss

The absorption, distribution and elimination of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist for treating type 2 diabetes, was investigated using a population pharmacokinetic model based on data from clinical pharmacology trials.. A previously developed, two-compartment pharmacokinetic model, based on subcutaneous and intravenous semaglutide, was extended to include data from six oral semaglutide trials conducted in either healthy volunteers or subjects with renal or hepatic impairment. Five trials employed multiple doses of oral semaglutide (5-10 mg) and one was a single-dose (10 mg) trial. In a separate analysis, the model was re-estimated using data from a trial in subjects with type 2 diabetes.. The model accurately described concentration profiles across trials. Post-dose fasting time, co-ingestion of a large water volume, and body weight were the most important covariates affecting semaglutide exposure. Bioavailability was 0.8% when oral semaglutide was dosed using the recommended dosing conditions (30 min post-dose fasting time, administered with ≤ 120 mL of water), increasing with a longer post-dose fasting time and decreasing with higher water volume. Within-subject variability in bioavailability was 137%, which with once-daily dosing and a long half-life translates into 33% within-subject variability in steady-state exposure. There was no significant difference in oral bioavailability of semaglutide in healthy subjects and subjects with type 2 diabetes.. The updated model provided a general characterisation of semaglutide pharmacokinetics following oral, subcutaneous and intravenous administration in healthy subjects and subjects with type 2 diabetes. Within-individual variation of oral bioavailability was relatively high, but reduced considerably at steady state. CLINICALTRIALS.. NCT01572753, NCT01619345, NCT02014259, NCT02016911, NCT02249871, NCT02172313, NCT02877355.

Topics: Administration, Oral; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Pharmacology, Clinical

Oral semaglutide is the first oral glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes, and showed significant benefits in glycaemic control and weight reduction versus active comparators in the PIONEER phase 3a randomized controlled trial programme. In this retrospective study, we present early data on the use of oral semaglutide in clinical practice, from the US IBM Explorys electronic health record database. In 782 patients prescribed oral semaglutide, 54.5% were women, and the mean age (SD) was 57.8 years (11.3); 66.0% of patients received their prescription from a primary care practitioner. Although prescribing information recommends increasing the dose to 7 mg after 30 days, 37.0% of patients received a prescription only for the initial 3 mg dose. Mean body mass index was 36.2 kg/m

Topics: Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Middle Aged; Retrospective Studies

Topics: Adult; Glucagon-Like Peptides; Humans; Obesity; Overweight

To investigate once-weekly (OW) semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), in patients with type 2 diabetes (T2D) in routine clinical practice.. The SURE Canada study was a multicenter, prospective, observational study. Adults with T2D and one or more documented HbA1c values 12 weeks or less before semaglutide initiation were enrolled. The primary endpoint was change in HbA1c from baseline to end of study (EOS; ~30 weeks). Secondary endpoints included change in body weight (BW), waist circumference and patient-reported outcomes (PROs) and the proportion of patients achieving HbA1c of less than 7.0%, weight loss (WL) of 5% or higher, and a composite of HbA1c reduction of 1% or higher and WL of 3% or higher at EOS. Data were analysed and presented for patients on semaglutide at EOS overall and for the following baseline medication subgroups: oral antihyperglycaemic drugs (OADs) only; GLP-1RA experienced; insulin ± OADs without GLP-1RA.. In total, 452 patients initiated semaglutide and 356 completed the study on treatment. For the 452 patients, mean baseline HbA1c was 8.1%; 86 (19.0%) patients had HbA1c of less than 7.0%. Mean dose of semaglutide at EOS was 0.76 ± 0.31 mg. Mean HbA1c was reduced by 0.9%-point (95% confidence interval [CI]: 0.97; 0.78). Mean BW was reduced by 4.3 kg (95% CI: 4.79; 3.76). At EOS, 46.9% of patients achieved HbA1c of less than 7.0%, 40.9% achieved WL of 5% or higher and 24.1% achieved the composite endpoint. PROs improved from baseline to EOS. No new safety concerns were reported.. In SURE Canada, patients treated with OW semaglutide in routine clinical practice experienced clinically significant improvements in HbA1c, BW and other outcomes, supporting semaglutide use in routine clinical practice.

Topics: Adult; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Prospective Studies

The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric G

Topics: Animals; Binding Sites; Cell Line; CHO Cells; Cricetulus; Cryoelectron Microscopy; Diabetes Mellitus, Type 2; Enzyme Activation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; HEK293 Cells; Humans; Molecular Dynamics Simulation; Protein Conformation; Sf9 Cells; Spodoptera

Topics: Adult; Anti-Obesity Agents; Clinical Trials, Phase III as Topic; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Obesity

Topics: Anti-Obesity Agents; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Obesity

Topics: Diabetes Mellitus, Type 2; Gastric Emptying; Glucagon-Like Peptides; Glucose; Humans; Lipid Metabolism; Postprandial Period

Topics: Administration, Oral; Benzhydryl Compounds; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Drug Costs; Glucagon-Like Peptides; Glucosides; Humans; Hypoglycemic Agents; Liraglutide; Sitagliptin Phosphate; United States

Topics: Adult; Glucagon-Like Peptides; Humans; Obesity; Overweight

Topics: Adult; Glucagon-Like Peptides; Humans; Obesity; Overweight

Topics: Adult; Glucagon-Like Peptides; Humans; Obesity; Overweight

Topics: Adult; Glucagon-Like Peptides; Humans; Obesity; Overweight

Topics: Adult; Glucagon-Like Peptides; Humans; Obesity; Overweight

Topics: Adult; Glucagon-Like Peptides; Humans; Obesity; Overweight

Topics: Diabetes Mellitus, Type 2; Gastric Emptying; Glucagon-Like Peptides; Glucose; Humans; Lipid Metabolism; Postprandial Period

Wilding JPH, Batterham RL, Calanna S, et al.

Topics: Adult; Diabetes Mellitus; Glucagon-Like Peptides; Humans; Obesity; Overweight; Weight Loss

Topics: Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Non-alcoholic Fatty Liver Disease

Topics: Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Non-alcoholic Fatty Liver Disease

The glucagon-like peptide-1 receptor (GLP-1R) regulates insulin secretion, carbohydrate metabolism, and appetite and is an important target for treatment of type 2 diabetes and obesity. Multiple GLP-1R agonists have entered into clinical trials, with some, such as semaglutide, progressing to approval. Others, including taspoglutide, failed due to the high incidence of side effects or insufficient efficacy. GLP-1R agonists have a broad spectrum of signaling profiles, but molecular understanding is limited by a lack of structural information on how different agonists engage with the GLP-1R. Here, we report cryoelectron microscopy (cryo-EM) structures and cryo-EM 3D variability analysis of semaglutide- and taspoglutide-bound GLP-1R-Gs protein complexes. These reveal similar peptide interactions to GLP-1 but different motions within the receptor and bound peptides, providing insights into the molecular determinants of GLP-1R peptide engagement.

Topics: Cell Line; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; GTP-Binding Proteins; Humans; Models, Molecular; Multiprotein Complexes; Peptides; Protein Binding; Protein Domains; Structure-Activity Relationship

Topics: Adult; Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Overweight; Weight Loss

Cardiovascular (CV) effects of once-weekly subcutaneous (s.c.) semaglutide 0.5 and 1 mg and dulaglutide 1.5 mg are reported in their respective placebo-controlled cardiovascular outcome trials (CVOTs), SUSTAIN 6 and REWIND. There is no head-to-head CVOT comparing these treatments and heterogeneity between their CVOTs renders conventional indirect comparison inappropriate. Therefore, a matching-adjusted indirect comparison (MAIC) was performed to compare the effects of s.c. semaglutide and dulaglutide on major adverse cardiovascular events (MACE) in patients with and without established cardiovascular disease (CVD).. Individual patient data from SUSTAIN 6 were matched with aggregate data from REWIND, using a propensity score method to balance baseline effect-modifying patient characteristics. Hazard ratios (HRs) for three-point (3P) MACE (CV death, non-fatal myocardial infarction, non-fatal stroke), anchored via placebo, were then indirectly compared between balanced populations. Sensitivity analyses were performed to test the robustness of the main analysis.. After matching, included effect modifiers were balanced. In the main analysis, s.c. semaglutide was associated with a statistically significant 35% reduction in 3P MACE versus placebo (HR, 0.65 [95% confidence interval [CI]; 0.48, 0.87]) and nonsignificantly greater reduction (26%) versus dulaglutide (HR, 0.74 [95% CI; 0.54, 1.01]). Results were supported by all sensitivity analyses.. This study demonstrated a statistically significant lower risk of 3P MACE for s.c. semaglutide versus placebo, in a population with lower prevalence of pre-existing CVD than that in the pre-specified primary analysis in SUSTAIN 6. Reduction in 3P MACE with s.c. semaglutide was greater than with dulaglutide, although not statistically significant.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins

To compare the effects of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg on HbA1c and body weight in patients with type 2 diabetes.. A Bucher indirect comparison was conducted to compare efficacy outcomes of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg using published results from the SUSTAIN 7 and AWARD-11 trials. Sensitivity analyses using individual patient data from SUSTAIN 7 and aggregate data from AWARD-11 were conducted to explore the impact of adjustment for cross-trial imbalances in baseline characteristics.. Semaglutide 1.0 mg significantly reduced HbA1c versus dulaglutide 3.0 mg, with an estimated treatment difference (ETD) of -0.24%-points (95% confidence interval [CI] -0.43, -0.05), with comparable reductions in HbA1c versus dulaglutide 4.5 mg with an ETD of -0.07%-points (95% CI -0.26, 0.12). Semaglutide 1.0 mg significantly reduced body weight versus dulaglutide 3.0 and 4.5 mg with an ETD of -2.65 kg (95% CI -3.57, -1.73) and -1.95 kg (95% CI -2.87, -1.03), respectively. Sensitivity analyses supported the primary analysis findings.. This indirect comparison showed significantly greater reductions in HbA1c with semaglutide 1.0 mg versus dulaglutide 3.0 mg and comparable HbA1c reductions versus dulaglutide 4.5 mg. Semaglutide 1.0 mg significantly reduced body weight versus both dulaglutide 3.0 and 4.5 mg. With several glucagon-like peptide-1 receptor agonists available, information regarding their comparative efficacy can be valuable to clinicians.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins

The once-weekly administered glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1RA) semaglutide, has, in clinical trials, demonstrated significant reductions in glycated haemoglobin A. We observed effects of semaglutide once weekly on HbA

Topics: Aged; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Injections, Subcutaneous; Male; Middle Aged; Outpatients; Retrospective Studies; Treatment Outcome

Topics: Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Topics: Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Rubino D, Abrahamsson N, Davies M, et al.

Topics: Adult; Double-Blind Method; Glucagon-Like Peptides; Humans; Injections, Subcutaneous; Obesity; Overweight; Weight Loss

Topics: Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Obesity

Topics: Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Models, Statistical; Randomized Controlled Trials as Topic; Sitagliptin Phosphate

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Metformin; Network Meta-Analysis; Sodium-Glucose Transporter 2 Inhibitors

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide

To evaluate the impact of relevant patient-level characteristics on the efficacy and safety of subcutaneous, once-weekly semaglutide in subjects with type 2 diabetes.. Exploratory post hoc analyses of pooled SUSTAIN 1-5 (phase 3a) randomized, controlled trials examined the change from baseline in HbA1c and body weight (BW), and the proportions of subjects achieving the composite endpoint (HbA1c < 7.0% [53 mmol/mol]), without weight gain or severe/blood glucose-confirmed symptomatic hypoglycaemia at week 30 with semaglutide (0.5/1.0 mg) across clinically relevant patient subgroups: baseline HbA1c (≤7.5%, >7.5%-8.0%, >8.0%-8.5%, >8.5%-9.0% and > 9.0%), background medications, diabetes duration and pancreatic beta-cell function.. Mean HbA1c (% point) reductions increased from lowest to highest HbA1c subgroups (-0.9%, -1.2%,-1.5%, -1.7% and -2.3% [effect of subgroup within treatment: P = 0.247] for semaglutide 0.5 mg, and -1.1%, -1.4%, -1.9%, -2.1% and -2.7% [P = 0.045] for semaglutide 1.0 mg), with mean HbA1c ranges at week 30 of 6.3%-7.3% and 6.1%-6.9%, respectively. The corresponding BW reductions generally decreased with increasing baseline HbA1c (-4.4, -3.9, -3.9, -3.3 and -2.9 kg [P = 0.004], and -6.4, -5.9, -5.2, -4.5 and -4.8 kg [P < 0.001], respectively). HbA1c and BW reductions were consistently greater for semaglutide 1.0 mg versus 0.5 mg across background medication, diabetes duration and pancreatic beta-cell function subgroups. Adverse events with semaglutide were consistent with the glucagon-like peptide-1 receptor agonist class, with gastrointestinal events the most common.. Semaglutide was consistently efficacious across the continuum of diabetes care in a broad spectrum of patient subgroups with a range of clinical characteristics.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents

Topics: Benzhydryl Compounds; Blood Pressure; Body Weight; Cost-Benefit Analysis; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Administration Routes; Drug Administration Schedule; Glucagon-Like Peptides; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Models, Econometric; Models, Statistical; Network Meta-Analysis; Quality-Adjusted Life Years; Sodium-Glucose Transporter 2 Inhibitors; Spain

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Drug Approval; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Male; Middle Aged; United States

To investigate the effects of semaglutide versus comparators on major adverse cardiovascular events (MACE: cardiovascular [CV] death, nonfatal myocardial infarction [MI] and nonfatal stroke) and hospitalization for heart failure (HF) in the SUSTAIN (subcutaneous semaglutide) and PIONEER (oral semaglutide) trials across subgroups of varying CV risk.. Post hoc analyses of individual patient-level data combined from SUSTAIN 6 and PIONEER 6 were performed to assess MACE and HF. MACE were analysed in subjects with and without: established CV disease and/or chronic kidney disease; prior MI or stroke; and prior HF. MACE in the SUSTAIN and PIONEER glycaemic efficacy trials were also assessed.. In SUSTAIN 6 and PIONEER 6 combined, the hazard ratio (HR) for effect of semaglutide versus placebo on overall MACE was 0.76 (95% CI 0.62, 0.92), which was mainly driven by the effect on nonfatal stroke (HR 0.65 [95% CI 0.43, 0.97]). The HR for hospitalization for HF was 1.03 (95% CI 0.75, 1.40). The HRs for MACE were <1.0 in all subgroups, except for those with prior HF (HR 1.06 [95% CI 0.72, 1.57]); P-values for interaction of subgroup on treatment effect were >0.05, except for HF (0.046). In the combined glycaemic efficacy trials, the HR for effect of semaglutide versus comparators on MACE was 0.85 (95% CI 0.55, 1.33).. In SUSTAIN and PIONEER combined, glucagon-like peptide-1 analogue semaglutide showed consistent effects on MACE versus comparators across varying CV risk. No effect of semaglutide on MACE was observed in subjects with prior HF.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Risk Factors

Topics: Administration, Oral; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Injections, Subcutaneous; Liraglutide; Peptides; Recombinant Fusion Proteins

Once-weekly semaglutide 1 mg is a novel glucagon-like peptide 1 receptor agonist (GLP-1 RA) that, in the SUSTAIN clinical trials, has demonstrated greater reductions in glycated haemoglobin (HbA1c) and body weight than the other GLP-1 RAs exenatide extended-release (ER) 2 mg, dulaglutide 1.5 mg and liraglutide 1.2 mg. The aim of this analysis was to evaluate the relative cost of control of achieving treatment goals in people with type 2 diabetes (T2D) treated with once-weekly semaglutide versus exenatide ER, dulaglutide and liraglutide from a UK perspective.. Proportions of patients reaching HbA1c targets (< 7.0% and < 7.5%), weight loss targets (≥ 5% reduction in body weight) and composite endpoints (HbA1c < 7.0% without weight gain or hypoglycaemia; reduction in HbA1c of ≥ 1% and weight loss of ≥ 5%) were obtained from the SUSTAIN clinical trials. Annual per patient treatment costs were based on wholesale acquisition costs from July 2019 in the UK. Cost of control was calculated by plotting relative treatment costs against relative efficacy.. The annual per patient cost was similar for all GLP-1 RAs. Once-weekly semaglutide was superior to exenatide ER, dulaglutide and liraglutide in bringing patients to HbA1c and weight loss targets, and to composite endpoints. When looking at the composite endpoint of HbA1c < 7.0% without weight gain or hypoglycaemia, exenatide ER, dulaglutide and liraglutide were 50.0%, 21.6% and 51.3% less efficacious in achieving this, respectively, than once-weekly semaglutide. Consequently, the efficacy-to-cost ratios for once-weekly semaglutide were superior to all comparators in bringing patients to all endpoints.. The present study showed that once-weekly semaglutide offers superior cost of control versus exenatide ER, dulaglutide and liraglutide in terms of achieving clinically relevant, single and composite endpoints. Once-weekly semaglutide 1 mg would therefore represent good value for money in the UK setting.

Topics: Body Weight; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Male; Middle Aged; Recombinant Fusion Proteins; United Kingdom; Weight Gain

To investigate the protective effects and mechanism of semaglutide on exercise-induced myocardial injury.. Effects of semaglutide on lipopolysaccharide (LPS)-induced oxidative stress injuries and inflammatory response were assessed in H9c2 cell via MTT assay and Western blot. Quiet control group, over training group and three doses of semaglutide treated overtraining groups were subjected to the swimming training with increasing load for consecutive 10 weeks. Immediately after the last training, the body weight, myocardial morphological changes, injury markers and inflammatory response related proteins of the model rats were analyzed.. Semaglutide at three concentrations in LPS treated H9c2 cells significantly increased the survival rate and inhibited the apoptosis of cardiomyocytes. Moreover, semaglutide activated AMPK pathway, improve autophagy and inhibited reactive oxygen species production in LPS treated H9C2 cells. In vivo results further revealed that chronic treatment of semaglutide induced significant increase in myocardial injury markers. The pathological histology analysis results showed that semaglutide ameliorated myocardial morphological changes, reduced area of lipid accumulation and significantly decreased the expression levels of NF-κB, TNF-α and IL-1β.. Semaglutide exert the protective effects on exercise-induced cardiomyopathy by activating AMPK pathway, increasing autophagy, reducing the production of ROS and inflammation-related proteins.

Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Cell Line; Cell Survival; Cytokines; Glucagon-Like Peptides; Heart Injuries; Inflammation; Interleukin-1beta; Lipids; Lipopolysaccharides; Male; Myocardium; NF-kappa B; Oxidative Stress; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

Semaglutide, a glucagon-like peptide 1 (GLP-1) analog, induces weight loss, lowers glucose levels, and reduces cardiovascular risk in patients with diabetes. Mechanistic preclinical studies suggest weight loss is mediated through GLP-1 receptors (GLP-1Rs) in the brain. The findings presented here show that semaglutide modulated food preference, reduced food intake, and caused weight loss without decreasing energy expenditure. Semaglutide directly accessed the brainstem, septal nucleus, and hypothalamus but did not cross the blood-brain barrier; it interacted with the brain through the circumventricular organs and several select sites adjacent to the ventricles. Semaglutide induced central c-Fos activation in 10 brain areas, including hindbrain areas directly targeted by semaglutide, and secondary areas without direct GLP-1R interaction, such as the lateral parabrachial nucleus. Automated analysis of semaglutide access, c-Fos activity, GLP-1R distribution, and brain connectivity revealed that activation may involve meal termination controlled by neurons in the lateral parabrachial nucleus. Transcriptomic analysis of microdissected brain areas from semaglutide-treated rats showed upregulation of prolactin-releasing hormone and tyrosine hydroxylase in the area postrema. We suggest semaglutide lowers body weight by direct interaction with diverse GLP-1R populations and by directly and indirectly affecting the activity of neural pathways involved in food intake, reward, and energy expenditure.

Topics: Animals; Body Weight; Brain; Eating; Energy Metabolism; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Mice; Neural Pathways; Rats

In spite of the evidence that inadequately controlled glycemia is associated with worse clinical outcomes, cystic fibrosis-related diabetes (CFRD) is not well controlled in a majority of patients. The objective of this report is to demonstrate the effect of the addition of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), to basal insulin to control glycemia in one such patient.. The replacement of rapidly acting prandial insulin with semaglutide weekly with continuation of basal insulin. Glycated hemoglobin A1c (HbA1c) was measured and continuous glucose monitoring (CGM) was conducted.. There was a significant improvement in glycemic control, reduction in HbA1c from 9.1% to 6.7% and stable euglycemic pattern on CGM (mean glucose, 142 mg/dL; SD, 51) within 3 months of starting treatment. There was no increase in plasma pancreatic enzyme concentrations.. Semaglutide at a low dose was able to replace prandial insulin and control glycemia in combination with basal insulin.

Topics: Blood Glucose; Cystic Fibrosis; Diabetes Mellitus; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Treatment Outcome; Young Adult

Once-weekly semaglutide 1 mg is a novel glucagon-like peptide-1 receptor agonist (GLP-1 RA) for the treatment of type 2 diabetes that has demonstrated significantly greater reductions in glycated haemoglobin (HbA1c) and body weight than the GLP-1 RA once-daily liraglutide 1.2 mg in the SUSTAIN 10 trial. The present analysis aimed to evaluate the long-term cost-effectiveness of once-weekly semaglutide 1 mg versus once-daily liraglutide 1.2 mg from a UK healthcare payer perspective.. Long-term outcomes were projected using the IQVIA CORE Diabetes Model (version 9.0), with baseline characteristics and treatment effects sourced from SUSTAIN 10. Patients were assumed to initiate treatment with GLP-1 RAs and continue treatment until HbA1c exceeded 7.5%, at which point GLP-1 RAs were discontinued and basal insulin was initiated. Pharmacy costs and costs of complications were measured in 2018 pounds sterling (GBP), with future costs and outcomes discounted at 3.5% per annum. Utilities were taken from published sources.. In the base-case analysis, once-weekly semaglutide 1 mg was associated with an increase in discounted life expectancy of 0.21 years and discounted quality-adjusted life expectancy of 0.30 quality-adjusted life-years, compared with once-daily liraglutide 1.2 mg. Clinical benefits were achieved at reduced costs, with lifetime cost savings of GBP 140 per patient with semaglutide versus liraglutide, owing to a reduction in diabetes-related complications, in particular cardiovascular disease (mean cost saving of GBP 279 per patient). Therefore, once-weekly semaglutide 1 mg was dominant compared with once-daily liraglutide 1.2 mg. The results of the sensitivity analyses were similar, demonstrating the robustness of the base-case analysis.. Once-weekly semaglutide 1 mg is a cost-effective treatment option versus once-daily liraglutide 1.2 mg, based on the SUSTAIN 10 trial, from a UK healthcare payer perspective.

Topics: Aged; Body Weight; Cost-Benefit Analysis; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Models, Econometric; Quality-Adjusted Life Years; United Kingdom

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents

Novel methods for peptides structural modification and bioactivity optimization are highly needed in peptide-based drug discovery. Herein, we explored the use gemfibrozil (GFZ) as an albumin binder to enhance the stability and improve the bioactivity of peptides. Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice. Moreover, GFZ endowed 3b with strong lipid-regulating ability in DIO and db/db mice. In a twelve-week study, chronic administration of 3b in db/db mice resulted in sustained glycemic control, to a greater extent than liraglutide and semaglutide. In addition, 3b showed comparable therapeutic efficacies to liraglutide and semaglutide on HbA1c and pancreas islets protection. Our studies reveal 3b as a potential candidate for the treatment of metabolic diseases and indicate dimeric-GFZ modification as a novel method for peptide optimization.

Topics: Albumins; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Development; Gemfibrozil; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Tolerance Test; HEK293 Cells; Humans; Hypoglycemic Agents; Liraglutide; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Rats, Sprague-Dawley; Xenopus laevis

Manufacturing processes for polypeptide/protein drugs are designed to ensure robust quality, efficacy and safety. Process differences introduced by follow-on manufacturers may result in changes in quality and clinical outcomes. This study investigated the impact of production methods on the stability and impurities of liraglutide and semaglutide drug substances/products, and the potential impact on drug quality, efficacy and safety.. State-of-the-art analytical methods were used to compare physical and chemical stability, and impurity profiles of drug substances/products from different suppliers. Identified polypeptide-related impurities were evaluated for immunogenicity potential by in silico T cell epitope prediction. Semaglutide immunogenicity in clinical trials (SUSTAIN) was evaluated using a tiered antibody analysis.. Manufacturing scale and process strongly impacted the physical stability of the products. Trace metals increased high-molecular-weight protein formation for liraglutide and semaglutide. Synthetic and recombinant liraglutide produced by five suppliers had distinct impurity profiles compared with the originator. In silico evaluation suggested that new impurities could be immunogenic. Immunogenicity of semaglutide in clinical trials was lower than for liraglutide.. Differences in manufacturing processes affect chemical/physical stability and impurity profile, and may impact immunogenicity. Follow-on versions of liraglutide and semaglutide, and possibly other polypeptides, should be clinically evaluated for efficacy and safety.

Topics: Amino Acid Sequence; Animals; Cell Line; Chemistry, Pharmaceutical; Computer Simulation; Cricetinae; Drug Contamination; Drug Stability; Glucagon-Like Peptides; Humans; Kidney; Liraglutide; Metals; Molecular Weight; Peptides

To investigate real-world short-term clinical outcomes in adults with type 2 diabetes (T2D) who initiated semaglutide in a specialist endocrinology practice in Canada.. This study was a retrospective observational study using data from the Canadian LMC Diabetes Registry. Adults with T2D who were naïve to glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy, initiated semaglutide therapy as usual standard of care between February 2018 and February 2019, and maintained semaglutide therapy during follow-up, were eligible for analysis. The primary outcome was mean change in glycated haemoglobin (HbA1c) at 3- to 6-month follow-up.. In the final analytical cohort (n = 937), there was a statistically significant mean ± SD reduction in HbA1c of -1.03 ± 1.24% (11.3 ± 13.6 mmol/mol, P < 0.001) and weight of -3.9 ± 4.0 kg (P < 0.001), with no significant change in self-reported incidence of hypoglycaemia. There was a significant reduction in HbA1c and weight regardless of number of co-therapies or semaglutide dose. However, adults using the 1.0-mg dose had a significantly greater reduction in HbA1c compared to adults using the 0.25- to 0.5-mg dose (between-group difference - 0.24 ± 0.06%, 2.6 ± 0.7 mmol/mol; P < 0.001). Adults using basal-bolus therapy required a significantly lower median total daily dose of insulin after adding semaglutide (0.82 vs. 0.93 U/kg; P < 0.001).. This retrospective observational study demonstrated that GLP-1RA-naïve adults with T2D initiating semaglutide in a real-world clinical practice had a statistically and clinically significant reduction in HbA1c and body weight after 3 to 6 months, regardless of semaglutide dose or order of semaglutide therapy, with no significant change in reported incidence of hypoglycaemia.

Topics: Adult; Canada; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Registries

The aggregation properties of semaglutide, a lipidated peptide drug agonist of the Glucagon-like peptide 1 receptor recently approved for the treatment of type 2 diabetes, have been investigated by spectroscopic techniques (UV-Vis absorption, steady-state and time-resolved fluorescence, and electronic circular dichroism) and molecular dynamics simulations. We show that in the micromolar concentration region, in aqueous solution, semaglutide is present as monomeric and dimeric species, with a characteristic monomer-to-dimer transition occurring at around 20 μM. The lipid chain stabilizes a globular morphology of the monomer and dimer species, giving rise to a locally well-defined polar outer surface where the lipid and peptide portions are packed to each other. At very long times, these peptide clusters nucleate the growth of larger aggregates characterized by blue luminescence and a β-sheet arrangement of the peptide chains. The understanding of the oligomerization and aggregation potential of peptide candidates is key for the development of long acting and stable drugs.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Molecular Dynamics Simulation; Peptides

Topics: Administration, Oral; Counseling; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Practice Guidelines as Topic

No funding was received for this commentary. The author has nothing to disclose.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Fazioli, Rind, and Pearson are employed by ICER. Gazauskas and Hansen have nothing to disclose.

Topics: Administration, Oral; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Treatment Outcome

Healthcare systems aim to maximize the health of the population, but must work within constrained budgets. Therefore, choosing therapies that are both effective and cost-effective is paramount. The present analysis assessed the cost-effectiveness of once-weekly semaglutide 0.5 mg and 1 mg versus once-weekly dulaglutide 1.5 mg and versus once daily sitagliptin 100 mg for the treatment of patients with type 2 diabetes with inadequate glycemic control on oral anti-hyperglycemic medications over patient lifetimes from a healthcare payer perspective in the Spanish setting.. Cost and clinical outcomes were projected over patient lifetimes using the IQVIA CORE Diabetes Model. Baseline cohort characteristics and treatment effects on initiation of semaglutide 0.5 mg and 1 mg, dulaglutide 1.5 mg and sitagliptin 100 mg were based on the once-weekly semaglutide clinical trial program (SUSTAIN 7 and 2). Captured costs included treatment costs and costs of diabetes-related complications. Projected outcomes were discounted at 3.0% annually.. Projections of long-term clinical outcomes indicated that once-weekly semaglutide 0.5 mg and 1 mg were associated with improvements in discounted life expectancy of 0.02 and 0.11 years, respectively, and discounted quality-adjusted life expectancy of 0.03 and 0.11 quality-adjusted life years (QALYs), respectively, versus dulaglutide 1.5 mg. Compared with sitagliptin, once-weekly semaglutide 0.5 mg and 1 mg were associated with improvements in discounted life expectancy of 0.17 and 0.24 years, respectively and discounted quality-adjusted life expectancy of 0.16 and 0.23 QALYs. The increased duration and quality of life with once-weekly semaglutide 0.5 mg and 1 mg resulted from a reduced cumulative incidence and delayed time to onset of diabetes-related complications. Avoided complications resulted in once-weekly semaglutide 0.5 mg and 1 mg being cost-saving versus dulaglutide 1.5 mg and versus sitagliptin 100 mg from a healthcare payer perspective.. Once-weekly semaglutide 0.5 mg and 1 mg were considered dominant (more effective and less costly) versus sitagliptin 100 mg and dulaglutide 1.5 mg for the treatment of patients with type 2 diabetes with inadequate glycemic control on oral anti-hyperglycemic medications and are likely to be a good use of healthcare resources in the Spanish setting.. Since healthcare systems aim to maximize the health of the population but must work within constrained budgets, choosing therapies that are both effective and cost-effective is paramount. We assessed the cost-effectiveness, from a Spanish healthcare payer perspective, of the newly marketed once-weekly semaglutide 0.5 mg and 1 mg versus two established therapies (dulaglutide 1.5 mg and sitagliptin 100 mg) for the treatment of patients with type 2 diabetes with inadequate glycemic control on oral anti-hyperglycemic medications over patient lifetimes.Outcomes were projected using a computer simulation model, based on two trials conducted as part of the once-weekly semaglutide clinical trial program (SUSTAIN 2 and SUSTAIN 7). Captured costs included treatment costs and costs of diabetes-related complications.Projections of long-term clinical outcomes indicated that once-weekly semaglutide 0.5 mg and 1 mg were associated with improvements in quality-adjusted life expectancy of 0.03 and 0.11 quality-adjusted life years (QALYs), respectively, versus dulaglutide 1.5 mg, and 0.16 and 0.23 QALYs, respectively, versus sitagliptin 100 mg. The increased duration and quality of life with once-weekly semaglutide 0.5 mg and 1 mg resulted from a reduced cumulative incidence and delayed time to onset of diabetes-related complications. Avoided complications resulted in once-weekly semaglutide 0.5 mg and 1 mg being cost-saving versus dulaglutide 1.5 mg and versus sitagliptin 100 mg.Once-weekly semaglutide 0.5 mg and 1 mg were more effective and less costly and therefore were considered dominant in both comparisons, and are likely to be a good use of healthcare resources in the Spanish setting.

Topics: Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Quality of Life; Recombinant Fusion Proteins; Sitagliptin Phosphate

In the head-to-head trial (SUSTAIN 7), the novel, injectable, once-weekly GLP-1 analogue semaglutide showed superiority in both glycemic outcomes and body weight reduction, compared with once-weekly dulaglutide in the treatment of type 2 diabetes (T2D). However, no economic evaluation using these data has yet been conducted in the Japanese setting. The objective of this analysis was to assess the short-term cost-effectiveness in Japan of once-weekly semaglutide 0.5 mg (the approved maintenance dose in Japan) compared with once-weekly dulaglutide 0.75 mg (the only licensed dose in Japan) over a 1-year period using Japanese cost data.. Responder endpoints were obtained from the SUSTAIN 7 trial to assess the cost of successfully treating patients to these targets ("cost of control"). Responder endpoint definitions consisted of single, dual, and triple composite endpoints related to glycemic control, body weight, and hypoglycemia outcomes. The cost of treatment was accounted from a healthcare payer perspective, capturing drug costs only.. Treatment with once-weekly semaglutide 0.5 mg was associated with a lower cost and a lower cost per patient treated to target for all endpoints, compared with once-weekly dulaglutide 0.75 mg. For each JPY 1 spent on bringing patients to target with once-weekly semaglutide 0.5 mg, JPY 1.58, JPY 1.44, JPY 1.60, JPY 2.10, and JPY 2.33 would need to be spent on once-weekly dulaglutide 0.75 mg to achieve an equivalent outcome for endpoints of HbA1c ≤ 6.5%, HbA1c < 7.0%, HbA1c < 7.0% without hypoglycemia, and no weight gain, weight loss ≥ 5%, and ≥ 1.0% HbA1c reduction and ≥ 3.0% weight loss, respectively.. These findings suggest that once-weekly semaglutide is a cost-effective treatment option compared with once-weekly dulaglutide for patients with T2D in Japan. In the future, this finding should be extrapolated to traditional long-term cost-effectiveness analysis, using common outcomes such as quality-adjusted life years.

Topics: Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Drug Costs; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Japan; Recombinant Fusion Proteins

Semaglutide is an oral glucagon-like peptide receptor agonist approved in 2019 by the U.S. Food and Drug Administration. It is marketed under the brand name Rybelsus and was approved to be used in conjunction with lifestyle modifications to treat individuals with type 2 diabetes. It is the first in its drug class to be administered in a once-daily oral form. Through its actions on glucose control and body weight, this once-daily oral medication could contribute to better glycemic control and healthier lives for many women with type 2 diabetes.

Topics: Administration, Oral; Body Weight; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Male

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Semaglutide is a glucagon-like peptide-1 (GLP-1) analog treatment for type 2 diabetes (T2D) available in subcutaneous (s.c.) and oral formulations. Two cardiovascular (CV) outcomes trials showed that in subjects with T2D at high risk of CV events there were fewer major adverse CV events (MACE; defined as CV death, non-fatal stroke, non-fatal myocardial infarction) with semaglutide than with placebo (hazard ratio [95% CI]: 0.74 [0.58;0.95] for once-weekly s.c. semaglutide and 0.79 [0.57;1.11] for once-daily oral semaglutide). However, there is little evidence for an effect of semaglutide on MACE in subjects not at high risk of CV events. This post hoc analysis examined CV effects of semaglutide in subjects across a continuum of baseline CV risk.. Data from the s.c. (SUSTAIN) and oral (PIONEER) semaglutide phase 3a clinical trial programs were combined according to randomized treatment (semaglutide or comparators) and analyzed to assess time to first MACE and its individual components. A CV risk model was developed with independent data from the LEADER trial (liraglutide vs placebo), considering baseline variables common to all datasets. Semaglutide data were analyzed to assess effects of treatment as a function of CV risk predicted using the CV risk prediction model.. The CV risk prediction model performed satisfactorily when applied to the semaglutide data set (area under the curve: 0.77). There was a reduced relative and absolute risk of MACE for semaglutide vs comparators across the entire continuum of CV risk. While the relative risk reduction tended to be largest with low CV risk score, the largest absolute risk reduction was for intermediate to high CV risk score. Similar results were seen for relative risk reduction of the individual MACE components and also when only placebo comparator data were included.. Semaglutide reduced the risk of MACE vs comparators across the continuum of baseline CV risk in a broad T2D population. Trial registrations ClinicalTrials.gov identifiers: NCT02054897, NCT01930188, NCT01885208, NCT02128932, NCT02305381, NCT01720446, NCT02207374, NCT02254291, NCT02906930, NCT02863328, NCT02607865, NCT02863419, NCT02827708, NCT02692716, NCT02849080, NCT03021187, NCT03018028, NCT03015220.

Topics: Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Male; Middle Aged; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Considering the high cost of the production of semaglutide, which is currently the most promising antidiabetic drug especially for the treatment of type 2 diabetes mellitus, a new synthetic route of semaglutide production that possesses excellent yield and high purity is of vital importance. Herein, we reported a newly developed synthetic route of semaglutide that is simple and efficient, based on a soluble hydrophobic-support-assisted liquid-phase synthetic method by applying Alloc-chemistry to the synthesis of the main chain peptide and side chain peptide of semaglutide. With careful optimization of the reaction conditions and innovative strategy of post-synthetic treatments, the total yield and purity of the crude semaglutide was improved satisfactorily.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hydrophobic and Hydrophilic Interactions; Hypoglycemic Agents; Lipids; Molecular Structure; Solubility

Gastrointestinal (GI) adverse events (AEs) are the most common AEs with glucagon-like peptide-1 receptor agonists (GLP-1RAs). Weight loss (WL) is slightly greater in people who experience GI AEs than those who do not. A previous mediation analysis of the SUSTAIN 1-5 trials indicated minor contribution of nausea/vomiting to the greater WL with once-weekly semaglutide versus comparators. Semaglutide demonstrated superior glycated hemoglobin and body weight (BW) reductions versus other GLP-1RAs in SUSTAIN 3 (versus exenatide extended release 2.0 mg), SUSTAIN 7 (versus dulaglutide) and SUSTAIN 10 (liraglutide 1.2 mg). The objective of this analysis was to assess if significantly greater WL with semaglutide versus other GLP-1RAs is mediated by nausea/vomiting and other GI AEs (diarrhea, constipation, dyspepsia) during dose escalation (baseline to week 12, when GI AEs are generally most prevalent) and from baseline to end of treatment (EOT: week 56 (SUSTAIN 3), 40 (SUSTAIN 7) or 30 (SUSTAIN 10)).. Subjects within trials were subdivided into those who reported (yes/no) nausea/vomiting or any other GI AE. Change from baseline in BW was assessed within each trial and subgroup. A mediation analysis separated WL into direct or indirect (mediated by GI AEs) effects.. From baseline to week 12 or EOT, the nausea/vomiting-mediated difference in WL was, respectively: 0.05 or 0.09 kg of 3.78 kg at EOT (SUSTAIN 3); 0.06 or 0.03 kg of 2.26 kg at EOT (low-dose comparison) and 0.08 or 0.04 kg of 3.55 kg at EOT (high-dose comparison) (SUSTAIN 7) and 0.05 or 0.09 kg of 3.82 kg at EOT (SUSTAIN 10).. In SUSTAIN 3, 7 and 10, nausea/vomiting by week 12 (end of dose escalation) or throughout treatment contributed minimally (<0.1 kg) to the superior WL with semaglutide versus GLP-1RA comparators at EOT.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Weight Loss

Topics: Acute Kidney Injury; Administration, Oral; Carcinoma, Neuroendocrine; Constipation; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Diarrhea; Dyspepsia; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemia; Hypoglycemic Agents; Nausea; Pancreatitis; Thyroid Neoplasms; Vomiting

Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue with an extended half-life of approximately 1 week has being come into clinic trial to treat parkingson's disease but little is known about its effect to prevent against Alzheimer's disease (AD). The goal of the present study was to explore the potential mechanisms of semaglutide to protect against AD.. We treated SH-SY5Y cell line with Aβ. Semaglutide enhanced autophagy by increasing the expression of LC3II, Atg7, Beclin-1 and P62 which were inhibited by Aβ. Our results provide a clue for the hypothesis that autophagy enhancement and apoptosis inhibition may be involved in the effect of semaglutide to protect against Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Apoptosis; Autophagy; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Glucagon-Like Peptides; Humans; Neuroprotective Agents; Peptide Fragments

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Managed Care Programs

Patient-reported outcomes (PROs), including treatment satisfaction, patient well-being, and quality of life, are becoming increasingly important contributors to treatment decisions in clinical practice and the evaluation of health care services. PROs have been included in a number of clinical trials in patients with type 2 diabetes (T2D), including those investigating glucagon-like peptide-1 receptor agonists (GLP-1RAs). The first oral GLP-1RA, oral semaglutide, was approved in the United States in 2019. Four PROs were included in the PIONEER clinical study program that evaluated oral semaglutide in patients with T2D across the full diabetes disease spectrum. PRO findings in the PIONEER studies were generally similar for oral semaglutide and comparators, with some exceptions. Improvements in a number of the 36-item Short Form Survey domains were observed for oral semaglutide versus placebo, including general health, bodily pain, physical component summary, social functioning, and mental health. For general health and social functioning, differences significantly favored oral semaglutide versus empagliflozin, whereas role-physical and the physical component summary significantly favored empagliflozin compared with oral semaglutide. The Diabetes Treatment Satisfaction Questionnaire findings indicated that oral semaglutide improved feelings of unacceptably high blood sugars versus placebo (in PIONEER 4, 5, and 8) and sitagliptin (in PIONEER 7). Significant improvements in craving control and craving for savory were observed with oral semaglutide versus empagliflozin in the Control of Eating Questionnaire (in PIONEER 2). These data provide valuable information that can facilitate a patient-centered approach and guide decision-making in managed care to optimize each patient's treatment experience.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Patient Reported Outcome Measures; Quality of Life

It is important to consider the safety profile of new medications in type 2 diabetes (T2D) when selecting the most appropriate treatment option for each patient. This can help ensure that patients achieve optimal response, that those experiencing adverse events are appropriately managed, and that treatment is tailored for those with pre-existing conditions such as cardiovascular disease (CVD), which is the leading cause of death in patients with T2D. The American Diabetes Association and American Association of Clinical Endocrinologists/American College of Endocrinology recommend a glucagon-like peptide-1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter 2 inhibitor with proven cardiovascular (CV) benefit in patients with established CVD or those at high risk of CVD. Injectable semaglutide is approved by the FDA for reducing the risk of major CV events in adults with T2D and established CVD. In PIONEER 6, the CV safety of the first GLP-1RA tablet, oral semaglutide, was noninferior to placebo, and a longer-term study (SOUL; NCT03914326) powered to assess a potential CV benefit is ongoing. The safety and tolerability profile of oral semaglutide across the PIONEER clinical trial program was consistent with the GLP-1RA class. The most common adverse events were gastrointestinal (GI) (eg, nausea, diarrhea, and vomiting), which were typically mild to moderate and transient. In clinical practice, oral semaglutide expands the treatment options available to patients with T2D and can be considered in patient populations suitable for injectable GLP-1RAs.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Managed Care Programs

Topics: Adult; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Metformin; Sitagliptin Phosphate

Stroke is a condition with few medical treatments available. Semaglutide, a novel Glucagon-like peptide-1 (GLP-1) analogue, has been brought to the market as a treatment for diabetes. We tested the protective effects of semaglutide against middle cerebral artery occlusion injury in rats. Animals were treated with 10 nmol/kg bw ip. starting 2 h after surgery and every second day for either 1, 7, 14 or 21 days. Semaglutide-treated animals showed significantly reduced scores of neurological impairments in several motor and grip strength tasks. The cerebral infarction size was also reduced, and the loss of neurons in the hippocampal areas CA1, CA3 and the dentate gyrus was much reduced. Chronic inflammation as seen in levels of activated microglia and in the activity of the p38 MAPK - MKK - c-Jun- NF-κB p65 inflammation signaling pathway was reduced. In addition, improved growth factor signaling as shown in levels of activated ERK1 and IRS-1, and a reduction in the apoptosis signaling pathway C-raf, ERK2, Bcl-2/BAX and Caspase-3 was observed. Neurogenesis had also been normalized by the drug treatment as seen in increased neurogenesis (DCX-positive cells) in the dentate gyrus and a normalization of biomarkers for neurogenesis. In conclusion, semaglutide is a promising candidate for re-purposing as a stroke treatment.

Topics: Animals; Apoptosis; Brain; Disease Models, Animal; Doublecortin Protein; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Hippocampus; Hypoglycemic Agents; Infarction, Middle Cerebral Artery; Inflammation; Insulin Receptor Substrate Proteins; Microglia; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases; Motor Activity; Neurogenesis; Neurons; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-jun; Rats; Stroke; Transcription Factor RelA

Semaglutide (Ozempic®) is a new once-weekly agonist of glucagon-like peptide-1 receptors (GLP-1 AR) indicated in the treatment of type 2 diabetes (T2D). Phase III clinical trials of the SUSTAIN programme demonstrated both the efficacy and safety of semaglutide in patients with T2D treated by diet and exercise, oral antidiabetic agents or even insulin. Direct and indirect comparative clinical trials showed that semaglutide (subcutaneous 0.5 or 1.0 mg once weekly) exerts a better glucose-lowering activity and a greater weight loss than other GLP-1 AR. Presented as prefilled pens for subcutaneous injection, semaglutide is currently reimbursed in Belgium after failure of antidiabetic therapy including metformin (HbA1c superior to 7,5 % or 58 mmol/mol) in T2D patients with body mass index ? 30 kg/m².. Le sémaglutide (Ozempic®) est un nouvel agoniste des récepteurs du glucagon-like peptide-1 (AR GLP-1), en injection sous-cutanée hebdomadaire, indiqué dans le traitement du diabète de type 2 (DT2). Les études cliniques du programme de phase 3 SUSTAIN ont démontré l’efficacité et la sécurité d’emploi du sémaglutide chez des patients DT2 traités par régime et exercice, par antidiabétiques oraux ou encore par insuline. Les études comparatives directes et indirectes indiquent que le sémaglutide (0,5 ou 1,0 mg une fois par semaine) exerce un effet anti-hyperglycémiant plus puissant et provoque une perte pondérale plus importante que les autres AR GLP-1. Le sémaglutide a démontré sa sécurité cardiovasculaire chez des patients DT2 à risque. Présenté sous forme d’un stylo pré-rempli pour injection sous-cutanée, Ozempic® est actuellement remboursé en Belgique après échec d’un traitement antidiabétique (dont la metformine; HbA1c sup�rieur a 7,5 % ou 58 mmol/mol) chez des patients DT2 avec un indice de masse corporelle ? 30 kg/m².

Topics: Belgium; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Risk Factors

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide

Topics: Canagliflozin; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Metformin; Sodium-Glucose Transporter 2

Topics: Double-Blind Method; Glucagon-Like Peptides; Humans; Liraglutide; Obesity; Weight Loss

Topics: Double-Blind Method; Glucagon-Like Peptides; Humans; Liraglutide; Obesity; Weight Loss

Choosing therapies for type 2 diabetes that are both effective and cost-effective is vital as healthcare systems worldwide aim to maximize health of the population. The present analysis assessed the cost-effectiveness of once-weekly semaglutide (a novel glucagon-like peptide-1 (GLP-1) receptor agonist) versus insulin glargine U100 (the most commonly used basal insulin) and versus dulaglutide (an alternative once-weekly GLP-1 receptor agonist), from a societal perspective in the Netherlands.. The IQVIA CORE Diabetes Model was used to project outcomes for once-weekly semaglutide 0.5 mg and 1 mg versus insulin glargine U100, once-weekly semaglutide 0.5 mg versus dulaglutide 0.75 mg, and once-weekly semaglutide 1 mg versus dulaglutide 1.5 mg. Clinical data were taken from the SUSTAIN 4 and SUSTAIN 7 clinical trials. The analysis captured direct and indirect costs, mortality, and the impact of diabetes-related complications on quality of life.. Projections of outcomes suggested that once-weekly semaglutide 0.5 mg was associated with improved quality-adjusted life expectancy by 0.19 quality-adjusted life years (QALYs) versus insulin glargine U100 and 0.07 QALYs versus dulaglutide 0.75 mg. Once-weekly semaglutide 1 mg was associated with mean increases in quality-adjusted life expectancy of 0.27 QALYs versus insulin glargine U100 and 0.13 QALYs versus dulaglutide 1.5 mg. Improvements came at an increased cost versus insulin glargine U100, with incremental cost-effectiveness ratios from a societal perspective of €4988 and €495 per QALY gained for once-weekly semaglutide 0.5 mg and 1 mg, respectively, falling below Netherlands-specific willingness-to-pay thresholds. Improvements versus dulaglutide came at a reduced cost from a societal perspective for both doses of once-weekly semaglutide.. Once-weekly semaglutide is cost-effective versus insulin glargine U100, and dominant versus dulaglutide 0.75 and 1.5 mg for the treatment of type 2 diabetes, and represents a good use of healthcare resources in the Netherlands.

Topics: Biomarkers; Blood Glucose; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin Glargine; Life Expectancy; Male; Middle Aged; Netherlands; Prognosis; Quality of Life

Oral semaglutide is the first orally administered glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes, and has been evaluated in the PIONEER clinical trial program. These trials assessed the proportions of patients achieving single and composite endpoints, encompassing glycemic control [defined in terms of glycated hemoglobin (HbA1c)], weight loss, and hypoglycemia. The present study assessed the cost of control with oral semaglutide versus empagliflozin, sitagliptin, and liraglutide in the US.. Four endpoints were evaluated: (1) HbA1c ≤ 6.5%; (2) HbA1c < 7.0%; (3) ≥ 1.0%-point HbA1c reduction and weight loss ≥ 3.0%; and (4) HbA1c < 7.0% without hypoglycemia and without weight gain. The proportions of patients achieving each endpoint were sourced from the PIONEER 2, 3 and 4 trials. Treatment costs were accounted over an annual time-period in 2019 US dollars (USD), based on wholesale acquisition cost. Cost of control was calculated by dividing treatment costs by the proportion of patients achieving each target.. Oral semaglutide was consistently associated with the lowest cost of control for all four endpoints. For the targets of HbA1c ≤ 6.5% and HbA1c < 7.0%, oral semaglutide 14 mg was associated with lower cost of control than empagliflozin 25 mg, sitagliptin 100 mg and liraglutide 1.8 mg by USD 15,036, 14,697, and 6996, respectively, and USD 931, 346 and 4497, respectively. For the double composite endpoint, cost of control was lower with oral semaglutide 14 mg by USD 525, 32,277 and 13,011, respectively versus empagliflozin 25 mg, sitagliptin 100 mg and liraglutide 1.8 mg. For the triple composite endpoint, cost of control was lower with oral semaglutide 14 mg by USD 1255, 7510 and 5774, respectively.. Oral semaglutide was associated with lower cost of bringing patients with type 2 diabetes to four clinically-relevant treatment targets versus empagliflozin, sitagliptin, and liraglutide in the US.. Novo Nordisk A/S.

Topics: Benzhydryl Compounds; Blood Glucose; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Middle Aged; Sitagliptin Phosphate; United States; Weight Loss

A substantial number of ischaemic stroke patients who receive reperfusion therapy in the acute phase do not ever fully recover. This reveals the urgent need to develop new adjunctive neuroprotective treatment strategies alongside reperfusion therapy. Previous experimental studies demonstrated the potential of glucagon-like peptide-1 (GLP-1) to reduce acute ischaemic damage in the brain. Here, we examined the neuroprotective effects of two GLP-1 analogues, liraglutide and semaglutide.. A non-diabetic rat model of acute ischaemic stroke involved 90, 120 or 180 min of middle cerebral artery occlusion (MCAO). Liraglutide or semaglutide was administered either i.v. at the onset of reperfusion or s.c. 5 min before the onset of reperfusion. Infarct size and functional status were evaluated after 24 h or 72 h of reperfusion.. Liraglutide, administered as a bolus at the onset of reperfusion, reduced infarct size by up to 90% and improved neuroscore at 24 h in a dose-dependent manner, following 90-min, but not 120-min or 180-min ischaemia. Semaglutide and liraglutide administered s.c. reduced infarct size by 63% and 48%, respectively, and improved neuroscore at 72 h following 90-min MCAO. Neuroprotection by semaglutide was abolished by GLP1-R antagonist exendin(9-39).. Infarct-limiting and functional neuroprotective effects of liraglutide are dose-dependent. Neuroprotection by semaglutide is at least as strong as by liraglutide and is mediated by GLP-1Rs.

Topics: Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Incretins; Infarction, Middle Cerebral Artery; Liraglutide; Male; Neuroprotective Agents; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Time Factors

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Topics: Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Research; Sodium-Glucose Transporter 2 Inhibitors

Martin J. Kurian, Peter J. Rentzepis, Ann M. Carracher, and Kelly L. Close are of Close Concerns (http://www.closeconcerns.com), a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Closer Look, a periodical that brings together news and insights in these areas. Each month, the Journal of Diabetes includes this News feature, in which Kurian, Rentzepis, Carracher, and Close review the latest developments relevant to researchers and clinicians.

Topics: Cardiology; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Europe; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Societies, Medical; Sodium-Glucose Transporter 2 Inhibitors

Dose titration becomes more and more common in improving drug tolerability as well as determining individualized treatment doses, thereby maximizing the benefit to patients. Dose titration starting from a lower dose and gradually increasing to a higher dose enables improved tolerability in patients as the human body may gradually adapt to adverse gastrointestinal effects. Current statistical analyses mostly focus on the outcome at the end-of-study follow-up without considering the longitudinal impact of dose titration on the outcome. Better understanding of the dynamic effect of dose titration over time is important in early-phase clinical development as it could allow to model the longitudinal trend and predict the longer term outcome more accurately. We propose a parametric model with two empirical methods of modeling the error terms for a continuous outcome with dose titrations. Simulations show that both approaches of modeling the error terms work well. We applied this method to analyze data from a few clinical studies and achieved satisfactory results.

Topics: Computer Simulation; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Models, Statistical; Randomized Controlled Trials as Topic; Treatment Outcome

Glucagon-like peptide-1 (GLP-1) receptor agonists are appealing as glucose-lowering therapy for individuals with type 2 diabetes mellitus (T2DM) as they also reduce body weight and are associated with low rates of hypoglycaemia. This analysis assessed the long-term cost-effectiveness of semaglutide 0.5 and 1 mg vs dulaglutide 1.5 mg (two once-weekly GLP-1 receptor agonists) from a UK healthcare payer perspective, based on the head-to-head SUSTAIN 7 trial, to inform healthcare decision making.. Long-term outcomes were projected using the IQVIA CORE Diabetes Model (version 9.0). Baseline cohort characteristics, changes in physiological parameters and adverse event rates were derived from the 40-week SUSTAIN 7 trial. Costs to a healthcare payer were assessed, and these captured pharmacy costs and costs of complications. Utilities were taken from published sources.. Once-weekly semaglutide 0.5 and 1 mg were associated with improvements in quality-adjusted life expectancy of 0.04 and 0.10 quality-adjusted life years, respectively, compared with dulaglutide 1.5 mg. Clinical benefits were achieved at reduced costs, with lifetime cost savings of GBP 35 with once-weekly semaglutide 0.5 mg and GBP 106 with the once-weekly semaglutide 1 mg, resulting from fewer diabetes-related complications due to better glycaemic control. Therefore, both doses of once-weekly semaglutide were considered dominant vs dulaglutide 1.5 mg (improving outcomes and reducing costs).. Compared with treatment with dulaglutide, once-weekly semaglutide represents a cost-effective option for treating individuals in the UK with T2DM who are not achieving glycaemic control with metformin, projected to both improve clinical outcomes and reduce costs.

Topics: Clinical Trials as Topic; Cost-Benefit Analysis; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glucagon-Like Peptides; Health Care Costs; Health Resources; Humans; Immunoglobulin Fc Fragments; Models, Economic; Quality-Adjusted Life Years; Recombinant Fusion Proteins; Time Factors; United Kingdom

This article reviews seven drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations.

Topics: Aminophenols; Aminopyridines; Antibodies, Monoclonal, Humanized; Benzoates; Benzodioxoles; beta-Alanine; Bridged Bicyclo Compounds, Heterocyclic; cis-trans-Isomerases; Drug Approval; Drug Combinations; Glucagon-Like Peptides; Humans; Indoles; Quinolones; United States; United States Food and Drug Administration

Parkinson's disease (PD) is a progressive neurological motor control disorder. A key feature is the loss of midbrain dopaminergic neurons and the accumulation of aggregated alpha-synuclein (α-syn). No current treatment is on the market that slows or halts disease progression. Previous studies have shown that glucagon-like peptide-1 (GLP-1) receptor agonists have neuroprotective effects in animal models of PD. In addition, in a phase II clinical trial, the GLP-1 receptor agonist exendin-4 has shown good protective effects in PD patients. In the present study, we have investigated the neuroprotective effects of the GLP-1 analogues semaglutide (25 nmol/kg ip. once every two days for 30 days) and liraglutide (25 nmol/kg ip. once daily for 30 days) in the chronic MPTP mouse model of PD. Both drugs are currently on the market as a treatment for Type II diabetes. Our results show that both semaglutide and liraglutide improved MPTP-induced motor impairments. In addition, both drugs rescued the decrease of tyrosine hydroxylase (TH) levels, reduced the accumulation of α-syn, alleviated the chronic inflammation response in the brain, reduced lipid peroxidation, and inhibited the mitochondrial mitophagy signaling pathway, and furthermore increased expression of the key growth factor GDNF that protects dopaminergic neurons in the substantia nigra (SN) and striatum. Moreover, the long- acting GLP-1 analogue semaglutide was more potent compared with once daily liraglutide in most parameters measured in this study. Our results demonstrate that semaglutide may be a promising treatment for PD. A clinical trial testing semaglutide in PD patients will start shortly.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Glucagon-Like Peptides; Hypoglycemic Agents; Liraglutide; Mice; MPTP Poisoning; Neuroprotective Agents; Oxidative Stress

Topics: Clinical Trials as Topic; Glucagon-Like Peptides; Humans; Peer Review, Health Care

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors

Cardiovascular risk reduction with liraglutide and semaglutide in patients with type 2 diabetes was demonstrated in the LEADER (ClinicalTrials.gov: NCT01179048) and SUSTAIN 6 (ClinicalTrials.gov: NCT01720446) cardiovascular outcome trials. This post hoc analysis assessed the impact of diabetes duration (<5, 5 to <15, 15 to <25 and ≥25 years at baseline) on cardiorenal efficacy of these human glucagon-like peptide-1 analogues using a Cox proportional hazards model. Proportions of patients in the LEADER trial across diabetes duration strata were 15% (<5 years, n = 1377), 50% (5 to <15 years, n = 4692), 27% (15 to <25 years, n = 2504) and 8% (≥25 years, n = 748); corresponding proportions in the SUSTAIN-6 trial were 13% (<5 years, n = 422), 48% (5 to <15 years, n = 1582), 30% (15 to <25 years, n = 977) and 10% (≥25 years, n = 316). Overall, longer diabetes duration was associated with higher age; higher prevalence of females; history of ischaemic stroke, peripheral arterial disease and insulin use; and inferior renal function. There was an increased frequency of major adverse cardiovascular events (MACE), expanded MACE and nephropathy events with increasing diabetes duration. Liraglutide and semaglutide consistently reduced the risk of cardiorenal outcomes across categories of diabetes duration (P-interaction was not significant for all endpoints analysed).

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Kidney Diseases; Liraglutide; Male; Middle Aged; Randomized Controlled Trials as Topic; Risk Factors

Topics: Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents

The SUSTAIN 3 and 7 clinical trials compared the efficacy and safety of once-weekly semaglutide relative to exenatide extended-release (ER) and dulaglutide, respectively, in the treatment of patients with type 2 diabetes (T2D). The trials included a series of clinically relevant single and composite endpoints focused on improving glycemic control and reducing body weight, while avoiding hypoglycemia. The present study combined SUSTAIN 3 and 7 outcomes with short-term treatment costs to evaluate the relative cost of control of once-weekly semaglutide versus exenatide ER and dulaglutide.. Proportions of patients reaching three endpoints were taken from SUSTAIN 3 and 7 for comparisons with exenatide ER and dulaglutide, respectively. The endpoints investigated were HbA1c < 7.0%, HbA1c < 7.0% without hypoglycemia or weight gain, and a ≥ 1.0% HbA1c reduction with ≥ 5.0% weight loss. Annual per patient treatment costs were based on US wholesale acquisition costs from July 2018. Relative cost of control was calculated by plotting the ratio of the treatment costs and the ratio of the proportions of patients reaching each endpoint on the cost-efficacy plane.. Once-weekly semaglutide 0.5 mg and 1.0 mg were most effective at bringing patients to each of the three endpoints across both SUSTAIN trials. The efficacy-to-cost ratios for once-weekly semaglutide 0.5 mg and 1.0 mg were also superior to all comparators when assessing both the single endpoint of HbA1c < 7.0% and the two composite endpoints including weight loss and hypoglycemia.. The present study showed that once-weekly semaglutide 0.5 mg and 1.0 mg offer superior cost of control versus exenatide ER and dulaglutide in terms of achieving single and composite endpoints, based on an analysis of retrieved dropout data. Once-weekly semaglutide 0.5 mg and 1.0 mg would therefore represent good value for money in the USA, particularly in the attainment of multi-model T2D treatment goals.. Novo Nordisk A/S.

Topics: Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Recombinant Fusion Proteins; Weight Loss

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Metformin; Sitagliptin Phosphate

Topics: Administration, Oral; Aged; Blood Glucose; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Injections, Subcutaneous; Italy; Male; Middle Aged; Patient Preference; Quality of Life; Recombinant Fusion Proteins

Oral semaglutide, which has undergone multiple phase 3 clinical trials, represents the first oral biologic medication for type 2 diabetes in the form of a daily capsule. It provides similar efficacy compared with its weekly injection counterpart, but it demands a dose on the order of 100 times as high and requires more frequent administration. We perform a cost effectiveness analysis using a first and second order Monte Carlo simulation to estimate quality-adjusted life expectancies associated with an oral daily capsule, oral weekly capsule, daily injection, and weekly injection of semaglutide. We conclude that the additional costs incurred to produce extra semaglutide for the oral formulation are cost effective, given the greater quality of life experienced when taking a capsule over a weekly injection. We also demonstrate that the potency of semaglutide allows the formulation to be cost effective, and less potent drugs will require increased oral bioavailability to make a cost effective oral formulation.

Topics: Administration, Oral; Biological Availability; Biological Products; Blood Glucose; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Costs; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Life Expectancy; Male; Middle Aged; Models, Economic; Monte Carlo Method; Quality-Adjusted Life Years; Time Factors; United States

Topics: Blood Glucose; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Female; Financing, Personal; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Peptides; Recombinant Fusion Proteins; Sweden

Topics: Acute Coronary Syndrome; Acute Kidney Injury; Cardiovascular Agents; Clinical Trials as Topic; Contrast Media; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Male; Practice Guidelines as Topic; Practice Patterns, Physicians'; Risk Reduction Behavior; Treatment Outcome

The SUSTAIN 6 trial demonstrated that once-weekly semaglutide (0.5 and 1.0 mg) significantly reduced major adverse cardiovascular (CV) events (MACE) vs placebo in subjects with type 2 diabetes (T2D) and high CV risk. The effects of gender, age and baseline CV risk on outcomes are important considerations for further study.. Subjects were grouped according to gender, age (50-65 years and > 65 years), and CV risk profile at baseline (prior myocardial infarction [MI] or stroke vs no prior MI or stroke, and established CV disease [CVD] vs CV risk factors alone, including subjects with chronic kidney disease). Time to MACE and its individual components (CV death, nonfatal MI, nonfatal stroke), hospitalization for unstable angina or heart failure, and revascularization (coronary and peripheral) were analyzed for all subgroups. Additional analyses were performed for gender and age to investigate change from baseline in HbA. A total of 3297 subjects were included. The majority of subjects (60.7%) were male; 43% were > 65 years of age; 41.5% had a history of MI or stroke; and 76.8% had established CVD. Compared with placebo, semaglutide reduced the risk of the first occurrence of MACE and each MACE component consistently across all subgroups (gender, age, and baseline CV risk profile). Revascularizations, HbA. In this post hoc analysis of SUSTAIN 6, once-weekly semaglutide vs placebo reduced the risk of MACE in all subjects included in the trial, regardless of gender, age, or baseline CV risk profile. Trial registry Clinicaltrials.gov, Identifying number: NCT01720446, Date of registration: October 29, 2012.

Topics: Age Factors; Aged; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Protective Factors; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Sex Factors; Time Factors; Treatment Outcome

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Obesity and type 2 diabetes are drivers of non-alcoholic fatty liver disease (NAFLD). Glucagon-like peptide-1 analogues effectively treat obesity and type 2 diabetes and may offer potential for NAFLD treatment.. To evaluate the effect of the glucagon-like peptide-1 analogue, semaglutide, on alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) in subjects at risk of NAFLD.. Data from a 104-week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52-week weight management trial (semaglutide 0.05-0.4 mg/day) were analysed. Treatment ratios vs placebo were estimated for ALT (both trials) and hsCRP (weight management trial only) using a mixed model for repeated measurements, with or without adjustment for change in body weight.. Elevated baseline ALT (men >30 IU/L; women >19 IU/L) was present in 52% (499/957) of weight management trial subjects. In this group with elevated ALT, end-of-treatment ALT reductions were 6%-21% (P<0.05 for doses≥0.2 mg/day) and hsCRP reductions 25%-43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day). Normalisation of elevated baseline ALT occurred in 25%-46% of weight management trial subjects, vs 18% on placebo. Elevated baseline ALT was present in 41% (1325/3268) of cardiovascular outcomes trial subjects. In this group with elevated ALT, no significant ALT reduction was noted at end-of-treatment for 0.5 mg/week, while a 9% reduction vs placebo was seen for 1.0 mg/week (P = 0.0024). Treatment ratios for changes in ALT and hsCRP were not statistically significant after adjustment for weight change.. Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Biomarkers; Body Weight; Cardiovascular Diseases; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Inflammation; Liver; Male; Middle Aged; Multicenter Studies as Topic; Non-alcoholic Fatty Liver Disease; Obesity; Randomized Controlled Trials as Topic; Retrospective Studies; Weight Reduction Programs; Young Adult

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Treatment Outcome

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Interactions; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Signal Transduction; Treatment Outcome

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Weight Loss

To evaluate dose levels for semaglutide, a glucagon-like peptide-1 analogue approved for the treatment of type 2 diabetes, by examining the effects of demographic factors on efficacy and safety in an exposure-response analysis.. We analysed data from 1552 adults from four randomized phase III trials of 30 to 56 weeks' duration, investigating once-weekly semaglutide doses 0.5 and 1.0 mg. Exposure-response relationships were investigated using graphical and model-based techniques to assess the two dose levels and subgroups with the highest and lowest exposure and response.. The population had the following demographic characteristics: baseline mean age between 53.2 and 58.4 years, glycated haemoglobin (HbA1c) between 64 and 67 mmol/mol (8.0% and 8.3%), body weight between 71.3 and 96.2 kg, and diabetes duration between 4.2 and 8.9 years. Exposure-response analysis showed a clear HbA1c and weight reduction across exposures after 30 weeks, irrespective of baseline values. The exposure-response for HbA1c was influenced by baseline HbA1c, and body weight exposure-response was influenced by sex, with limited impact of other factors. Analyses for relevant subgroups of baseline body weight, baseline HbA1c and sex indicated clinically relevant additional benefits with regard to HbA1c and weight with 1.0 vs 0.5 mg semaglutide. The proportion of participants reporting gastrointestinal (GI) side effects increased with increasing exposure, but was counteracted by tolerance development.. The analysis showed that all subgroups obtained a clinically relevant benefit with semaglutide 0.5 mg and an additional benefit with semaglutide 1.0 mg. The increase in GI side effects with higher exposure was mitigated by gradually increasing the dose.

Topics: Blood Glucose; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome; Weight Loss

GLP-1 analogs suffer from the main disadvantage of a short in vivo half-life. Lithocholic acid (LCA), one of the four main bile acids in the human body, possesses a high albumin binding rate. We therefore envisioned that a LCA-based peptide delivery system could extend the half-life of GLP-1 analogs by facilitating the noncovalent binding of peptides to human serum albumin. On the basis of our previously identified Xenopus GLP-1 analogs (1-3), a series of LCA-modified Xenopus GLP-1 conjugates were designed (4a-4r), and the bioactivity studies of these conjugates were performed to identify compounds with balanced in vitro receptor activation potency and plasma stability. 4c, 4i, and 4r were selected, and their LCA side chains were optimized to further increase their stability, affording 5a-5c. Compound 5b showed a more increased albumin affinity and prolonged in vitro stability than that of 4i and liraglutide. In db/ db mice, 5b exhibited comparable hypoglycemic and insulinotropic activity to liraglutide and semaglutide. Importantly, the enhanced albumin affinity of 5b resulted in a prolonged in vivo antidiabetic duration. Finally, chronic treatment investigations of 5b demonstrated the therapeutic effects of 5b on HbA1c, body weight, blood glucose, and pancreatic endocrine deficiencies on db/ db mice. Our studies revealed 5b as a promising antidiabetic candidate. Furthermore, our study suggests the derivatization of Xenopus GLP-1 analogs with LCA represents an effective strategy to develop potent long-acting GLP-1 receptor agonists for the treatment of type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Drug Stability; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Half-Life; HEK293 Cells; Humans; Hypoglycemic Agents; Liraglutide; Lithocholic Acid; Male; Mice; Mice, Inbred C57BL; Rats; Rats, Sprague-Dawley; Serum Albumin, Human; Treatment Outcome; Xenopus Proteins

To evaluate the potential for semaglutide to help people with type 2 diabetes (T2D) achieve glycated haemoglobin (HbA1c) targets while avoiding unwanted outcomes, such as weight gain, hypoglycaemia and gastrointestinal (GI) side effects.. Data from the phase IIIa SUSTAIN 1 to 5 clinical trials were analysed. Participants had inadequately controlled T2D and were drug-naïve (SUSTAIN 1) or on a range of background treatments (SUSTAIN 2 to 5). The main protocol-specified composite endpoint was the proportion of participants achieving HbA1c <53 mmol/mol (7.0%) at end of treatment (30 or 56 weeks) without weight gain and with no severe or blood glucose (BG)-confirmed symptomatic hypoglycaemia. A post hoc composite endpoint was the proportion of participants achieving the primary composite endpoint without moderate or severe GI adverse events (AEs).. Across the SUSTAIN trials 1 to 5, 3918 participants with T2D were randomized to once-weekly subcutaneous semaglutide 0.5 mg, 1.0 mg, or comparators (placebo, sitagliptin 100 mg, exenatide extended release 2.0 mg or insulin glargine). The proportion of participants achieving HbA1c <53 mmol/mol (7.0%) with no weight gain and no severe/BG-confirmed symptomatic hypoglycaemia was 47% to 66% (semaglutide 0.5 mg) and 57% to 74% (semaglutide 1.0 mg) vs 7% to 19% (placebo) and 16% to 29% (active comparators; all P < .0001). More participants achieved the primary composite endpoint with no moderate or severe GI AEs with semaglutide vs comparators (all P < .0001).. Semaglutide helped more people with T2D achieve HbA1c targets than did comparators in the SUSTAIN 1 to 5 trials, while avoiding unwanted outcomes such as weight gain, hypoglycaemia and GI side effects.

Topics: Adult; Aged; Blood Glucose; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Female; Gastrointestinal Diseases; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Male; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Retrospective Studies; Weight Gain

Parkinson's disease (PD) is the second most common neurodegenerative disease, and there is no recognised therapy to cure it. Recently, it has been shown that treatments to improve insulin resistance in type 2 diabetes (T2DM) may be useful for PD patients. In previous studies, the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide showed good neuroprotective effects in animal models of PD. In addition, the GLP-1 mimetic exendin-4 has shown good protective effects in PD patients in a phase II clinical trial. Here, we report the protective effects of semaglutide (25 nmol/kg ip. once-daily for 7 days), a new long-acting GLP-1 analogue, in the MPTP mouse model of PD. Moreover, we compared the neuroprotective effect of semaglutide with liraglutide given at the same dose. Our work shows that both semaglutide and liraglutide improved 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor impairments. In addition, both GLP-1 analogues rescued the decrease of tyrosine hydroxylase (TH) levels, alleviated the inflammation response, reduced lipid peroxidation, inhibited the apoptosis pathway, and also increased autophagy- related protein expression, to protect dopaminergic neurons in the substantia nigra and striatum. Moreover, the long-acting GLP-1 analogue semaglutide was superior to liraglutide in most parameters measured in this study. Our results demonstrate that the new long- acting GLP-1 analogue semaglutide may be a promising treatment for PD.

Topics: Animals; Apoptosis; Corpus Striatum; Dopaminergic Neurons; Glucagon-Like Peptides; Lipid Peroxidation; Liraglutide; Mice; Motor Activity; MPTP Poisoning; Neuroprotective Agents; Rotarod Performance Test; Substantia Nigra

Topics: Anti-Obesity Agents; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Randomized Controlled Trials as Topic; Risk Factors; Signal Transduction; Treatment Outcome; Weight Loss

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

Topics: Anti-Obesity Agents; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Hypoglycemic Agents

In recognition of the substantial prevalence of cardiovascular disease-related comorbidities among patients with diabetes and the potential for some agents to increase this risk, evaluation of cardiovascular outcomes is now a standard component of late-stage clinical trials involving antihyperglycemic agents. While most agents are evaluated in noninferiority trials to establish a lack of cardiovascular-related harm, a few agents have shown significant reductions in cardiovascular-related outcomes, including mortality.

Topics: Benzhydryl Compounds; Bromocriptine; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glucosides; Humans; Hypoglycemic Agents; Risk Reduction Behavior; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidinediones

Semaglutide is a human glucagon-like peptide-1 analogue in clinical development for the treatment of type 2 diabetes. The absorption, metabolism and excretion of a single 0.5mg/450μCi [16.7MBq] subcutaneous dose of [

Topics: Animals; Area Under Curve; Chromatography, High Pressure Liquid; Feces; Glucagon-Like Peptides; Half-Life; Humans; Macaca fascicularis; Male; Middle Aged; Rats; Rats, Wistar; Tritium

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Weight Loss

Topics: Glucagon-Like Peptides; Humans; Lipids; Non-alcoholic Fatty Liver Disease

Topics: Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Lipids; Non-alcoholic Fatty Liver Disease

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Liraglutide; Neoplasms; Randomized Controlled Trials as Topic

Hyperglycemia is the major risk factor for microvascular complications in patients with type 2 diabetes (T2D). However, cardiovascular disease (CVD) is the principal cause of death, and lowering HbA

Topics: Animals; Benzhydryl Compounds; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glucosides; Humans; Hyperglycemia; Hypoglycemic Agents; Liraglutide; Pioglitazone; Randomized Controlled Trials as Topic; Risk Factors; Thiazolidinediones; Treatment Outcome

Topics: Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glucosides; Humans; Hypoglycemic Agents; Liraglutide; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Topics: Body Weight; Diabetes Mellitus; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Product Surveillance, Postmarketing

Topics: Benzhydryl Compounds; Congresses as Topic; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptides; Glucosides; Humans; Hypoglycemic Agents; Peptides; Treatment Outcome; Venoms

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) constitute a class of drugs for the treatment of type 2 diabetes, and currently, six different GLP-1RAs are approved. Besides improving glycemic control, the GLP-1RAs have other beneficial effects such as weight loss and a low risk of hypoglycemia. Treatment with the GLP-1RA lixisenatide has been shown to be safe in patients with type 2 diabetes and recent acute coronary syndrome. Furthermore, liraglutide and semaglutide have been shown to reduce cardiovascular (CV) disease (CVD) risk in type 2 diabetes patients with established and/or high risk of CVD. The CV safety of the remaining GLP-1RAs in type 2 diabetes patients with established and/or high risk of CVD remains uncertain, but ongoing CV outcome trials (CVOTs) will elucidate this within a few years. Areas covered: The aim of this review is to provide an overview of the existing GLP-1RAs with a particular focus on their clinical effects on CV risk factors and their CV safety and benefits. Expert opinion: Data on the CV risks and benefits associated with GLP-1RA treatment in patients with type 2 diabetes and high risk of CVD are emerging - and look promising (especially for liraglutide and semaglutide). Data from ongoing CVOTs will be crucial for the positioning of the individual GLP-1RAs in the treatment of patients with type 2 diabetes and high risk of CVD. However, the long-term CV safety and the potential of GLP-1RAs to prevent CVD in type 2 diabetes patients with less risk of CVD (e.g. newly diagnosed patients) remain uncertain.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Risk Factors

Topics: Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Peptides

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Glucagon-Like Peptides; Humans; Risk; Risk Factors

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Risk Factors; Stroke; Treatment Outcome

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans

The effect of semaglutide, a once-weekly human glucagon-like peptide-1 (GLP-1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. Postmenopausal women with T2D (n = 43) on diet/exercise ± metformin received ethinylestradiol (0.03 mg)/levonorgestrel (0.15 mg) once daily for 8 days before (semaglutide-free) and during (steady-state 1.0 mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25 mg 4 weeks; 0.5 mg 4 weeks; 1.0 mg 5 weeks). Bioequivalence of oral contraceptives was established if 90%CI for the ratio of pharmacokinetic parameters during semaglutide steady-state and semaglutide-free periods was within prespecified limits (0.80-1.25). The bioequivalence criterion was met for ethinylestradiol area under the curve (AUC0-24 h ) for semaglutide steady-state/semaglutide-free; 1.11 (1.06-1.15). AUC0-24 h was 20% higher for levonorgestrel at semaglutide steady-state vs. semaglutide-free (1.20 [1.15-1.26]). Cmax was within bioequivalence criterion for both contraceptives. Reductions (mean ± SD) in HbA1c (-1.1 ± 0.6%) and weight (-4.3 ± 3.1 kg) were observed. Semaglutide pharmacokinetics were compatible with once-weekly dosing; the semaglutide dose and dose-escalation regimen were well tolerated. Adverse events, mainly gastrointestinal, were mild to moderate in severity. Asymptomatic increases in mean amylase and lipase were observed. Three subjects had elevated alanine aminotransferase levels ≥3x the upper limit of normal during semaglutide/oral contraceptive coadministration, which were reported as adverse events, but resolved during follow-up. Semaglutide did not reduce the bioavailability of ethinylestradiol and levonorgestrel.

Topics: Aged; Area Under Curve; Blood Glucose; Contraceptives, Oral, Combined; Drug Combinations; Drug Interactions; Ethinyl Estradiol; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Half-Life; Humans; Hypoglycemic Agents; Levonorgestrel; Metabolic Clearance Rate; Middle Aged; Postmenopause

Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analogue that binds to serum albumin in vivo and is approved for once-daily treatment of diabetes as well as obesity. The aim of the present studies was to design a once weekly GLP-1 analogue by increasing albumin affinity and secure full stability against metabolic degradation. The fatty acid moiety and the linking chemistry to GLP-1 were the key features to secure high albumin affinity and GLP-1 receptor (GLP-1R) potency and in obtaining a prolonged exposure and action of the GLP-1 analogue. Semaglutide was selected as the optimal once weekly candidate. Semaglutide has two amino acid substitutions compared to human GLP-1 (Aib(8), Arg(34)) and is derivatized at lysine 26. The GLP-1R affinity of semaglutide (0.38 ± 0.06 nM) was three-fold decreased compared to liraglutide, whereas the albumin affinity was increased. The plasma half-life was 46.1 h in mini-pigs following i.v. administration, and semaglutide has an MRT of 63.6 h after s.c. dosing to mini-pigs. Semaglutide is currently in phase 3 clinical testing.

Topics: Administration, Intravenous; Animals; Cell Line; Cricetinae; Crystallography, X-Ray; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Half-Life; Humans; Injections, Subcutaneous; Liraglutide; Male; Mice, Obese; Models, Molecular; Rats, Sprague-Dawley; Structure-Activity Relationship; Swine; Swine, Miniature

Increased pancreas mass and glucagon-positive adenomas have been suggested to be a risk associated with sitagliptin or exenatide therapy in humans. Novo Nordisk has conducted extensive toxicology studies, including data on pancreas weight and histology, in Cynomolgus monkeys dosed with two different human glucagon-like peptide-1 (GLP-1) receptor agonists. In a 52-week study with liraglutide, a dose-related increase in absolute pancreas weight was observed in female monkeys only. Such dose-related increase was not found in studies of 4, 13, or 87 weeks' duration. No treatment-related histopathological abnormalities were observed in any of the studies. Quantitative histology of the pancreas from the 52-week study showed an increase in the exocrine cell mass in liraglutide-dosed animals, with normal composition of endocrine and exocrine cellular compartments. Proliferation rate of the exocrine tissue was low and comparable between groups. Endocrine cell mass and proliferation rates were unaltered by liraglutide treatment. Semaglutide showed no increase in pancreas weight and no treatment-related histopathological findings in the pancreas after 13 or 52 weeks' dosing. Overall, results in 138 nonhuman primates showed no histopathological changes in the pancreas associated with liraglutide or semaglutide, two structurally different GLP-1 receptor agonists.

Topics: Animals; Body Weight; Drug Evaluation, Preclinical; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Macaca fascicularis; Male; Organ Size; Pancreas; Primates

Topics: Animals; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Male; Pancreas