oxyntomodulin and Cardiovascular-Diseases

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

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

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

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

Patients with type 2 diabetes mellitus (T2DM) and obesity are at high risk of developing cardiovascular disease (CVD). Both glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter (SGLT-2) inhibitors have been shown to prevent CVD in T2DM patients. Additionally, the two drugs reduce body mass. However, it is unknown which drug is more effective at reducing the risk of CVD in such patients. We searched Medline, EMBASE, and Cochrane Library records to February 20, 2021 and performed a network meta-analysis to compare the efficacy with which the drugs reduced the risk of major adverse cardiovascular events (MACE). We included 102,728 patients in 12 studies containing data of obesity subgroup analyses. In T2DM patients with obesity, GLP-1 RAs significantly reduced the risk of MACE versus placebo (relative risk, RR [95% confidence interval, CI]: 0.88 [0.81-0.96]), whereas SGLT-2 inhibitors showed a tendency (RR [95% CI]: 0.91 [0.83-1.00]). In an indirect comparison, GLP-1 RAs were not associated with a significant difference in MACE compared with SGLT-2 inhibitors (RR [95% CI]: 0.97 [0.85-1.09]). Thus, GLP-1 RAs are effective at preventing MACE than placebo in T2DM patients with obesity, although further studies are warranted to conclude their superiority to SGLT-2 inhibitors.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Male; Network Meta-Analysis; Obesity; Randomized Controlled Trials as Topic; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; 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

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

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

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

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

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

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

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

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

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

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

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

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

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) 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

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

While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to increase heart rate (HR), it is insufficiently recognized that the extent varies greatly between the various agonists and is affected by the assessment methods employed. Here we review published data from 24-h time-averaged HR monitoring in healthy individuals and subjects with type 2 diabetes mellitus (T2DM) treated with either short-acting GLP-1 RAs, lixisenatide or exenatide, or long-acting GLP-1 RAs, exenatide LAR, liraglutide, albiglutide, or dulaglutide (N = 1112; active-treatment arms). HR effects observed in two independent head-to-head trials of lixisenatide and liraglutide (N = 202; active-treatment arms) are also reviewed. Short-acting GLP-1 RAs, exenatide and lixisenatide, are associated with a transient (1-12 h) mean placebo- and baseline-adjusted 24-h HR increase of 1-3 beats per minute (bpm). Conversely, long-acting GLP-1 RAs are associated with more pronounced increases in mean 24-h HR; the highest seen with liraglutide and albiglutide at 6-10 bpm compared with dulaglutide and exenatide LAR at 3-4 bpm. For both liraglutide and dulaglutide, HR increases were recorded during both the day and at night. In two head-to-head comparisons, a small, transient mean increase in HR from baseline was observed with lixisenatide; liraglutide induced a substantially greater increase that remained significantly elevated over 24 h. The underlying mechanism for increased HR remains to be elucidated; however, it could be related to a direct effect at the sinus node and/or stimulation of the sympathetic nervous system, with this effect related to the duration of action of the respective GLP-1 RAs. In conclusion, this review indicates that the effects on HR differ within the class of GLP-1 RAs: short-acting GLP-1 RAs are associated with a modest and transient HR increase before returning to baseline levels, while some long-acting GLP-1 RAs are associated with a more pronounced and sustained increase during the day and night. Findings from recently completed trials indicate that a GLP-1 RA-induced increase in HR, regardless of magnitude, does not present an increased cardiovascular risk for subjects with T2DM, although a pronounced increase in HR may be associated with adverse clinical outcomes in those with advanced heart failure.

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

Patients with type 2 diabetes (T2D) have a substantial increased risk for cardiovascular (CV) disease and associated mortality than those without diabetes. Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist that is approved for treatment of T2D.. This meta-analysis evaluates the CV risk in patients with T2D treated with dulaglutide in 9 randomized safety and efficacy trials. Mean (median) treatment duration was 333 (358) days. Reported CV events were independently adjudicated by a treatment-blinded clinical endpoint committee. The primary measure was a 4-component major adverse CV event (4-component MACE) composite endpoint of death due to CV causes, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina. Additional pre-specified endpoints included adjudicated coronary revascularizations, hospitalization for heart failure, and all-cause mortality. A Cox proportional hazards regression model (stratified by study) was used to estimate the hazard ratio (HR) and confidence interval (CI). Tests of treatment effects for the primary endpoint were conducted at a 2-sided alpha level of 0.0198 and a corresponding 98.02 % CI was calculated. Statistical heterogeneity between the strata (studies) was tested by including in the Cox model an interaction term between treatment and strata.. The analysis included 6010 randomized patients [dulaglutide: 3885; comparator therapy (active or placebo): 2125]; cumulative exposure to dulaglutide or comparator therapy was 3941 and 2223 patient-years, respectively. The demographic and baseline CV disease characteristics were similar across groups. Twenty-six (0.67 %) patients in the dulaglutide group versus 25 (1.18 %) in the comparator group experienced a primary 4-component MACE (HR 0.57; adjusted 98.02 % CI 0.30, 1.10). Results for the 3-component MACE (composite endpoint of death due to CV causes, nonfatal MI or stroke), 6-component MACE (composite endpoint of death due to CV causes, nonfatal MI or stroke, hospitalization for unstable angina or heart failure, or coronary revascularizations) and all-cause mortality were consistent with the primary analysis (HR < 1.0 for all).. These results suggest that dulaglutide does not increase the risk of major CV events in T2D patients. The ongoing CV outcomes study, Researching CV Events with a Weekly Incretin in Diabetes (REWIND), will further assess CV safety of dulaglutide.

Topics: Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Protective Factors; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Risk Assessment; Risk Factors; Treatment Outcome

To evaluate the literature about the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in the treatment of cardiac disorders, specifically myocardial infarction (MI) and heart failure (HF).. Searches were conducted in MEDLINE (1946-May 2016) and Excerpta Medica (1980-May 2016) using EMBASE with the search terms glucagon-like peptide 1, exenatide, albiglutide, liraglutide, dulaglutide, myocardial infarction, heart failure, and cardiovascular The references of relevant articles were reviewed to identify additional citations.. Clinical trials were limited to the English language and human trials. In all, 18 trials explored the use of GLP-1 RAs in the treatment of cardiac disorders in patients with and without diabetes mellitus.. Of the 18 trials reviewed, 11 trials studied the impact of GLP-1 RAs in MI. All showed a significant beneficial effect on various cardiac parameters. Favorable outcome improvements included myocardial blood flow, left ventricular (LV) function, and MI size. Seven trials reviewed the use of GLP-1 RAs in the treatment of HF. Three trials showed significant improvements in LV ejection fraction, cardiac index, and peak oxygen consumption.. Limited data suggest that GLP-1 RAs may be effective for the treatment of cardiac disorders in patients with and without diabetes mellitus. These studies suggest that GLP-1 RAs may have potential pleiotropic beneficial effects in patients with cardiovascular disease beyond their role in managing diabetes. These medications may be cardioprotective after a MI but are less promising in HF.

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Peptides; Recombinant Fusion Proteins; Venoms

Cardiovascular disease is a leading cause of death and reduced quality of life worldwide. Arterial vessels are a primary target for endothelial dysfunction and atherosclerosis, which is accompanied or even driven by increased oxidative stress. Recent research in this field identified different sources of reactive oxygen and nitrogen species contributing to the pathogenesis of endothelial dysfunction. According to lessons from the past, improvement of endothelial function and prevention of cardiovascular disease by systemic, unspecific, oral antioxidant therapy are obviously too simplistic an approach. Source- and cell organelle-specific antioxidants as well as activators of intrinsic antioxidant defense systems might be more promising. Since basic research demonstrated the contribution of different inflammatory cells to vascular oxidative stress and clinical trials identified chronic inflammatory disorders as risk factors for cardiovascular events, atherosclerosis and cardiovascular disease are closely associated with inflammation. Therefore, modulation of the inflammatory response is a new and promising approach in the therapy of cardiovascular disease. Classical anti-inflammatory therapeutic compounds, but also established drugs with pleiotropic immunomodulatory abilities, demonstrated protective effects in various models of cardiovascular disease. However, results from ongoing clinical trials are needed to further evaluate the value of immunomodulation for the treatment of cardiovascular disease.

Topics: Animals; Antioxidants; Cardiovascular Diseases; Endothelium, Vascular; Glucagon-Like Peptides; Humans; Immunologic Factors; Inflammation; Oxidative Stress

Type 2 diabetes (T2D) imparts an increased risk of adverse health outcomes in patients unable to achieve glycemic control. Patient education and individualization of treatment are important for effective management of T2D. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of injectable glucose-lowering agents that lower A1C with added benefits of weight loss and improved cardiovascular risk markers. This review discusses the role of GLP-1RAs currently approved in the United States (exenatide, liraglutide, albiglutide, dulaglutide) for T2D management and characterizes the efficacy and safety profiles of individual GLP-1RAs.. GLP-1RAs are recommended as a preferred add-on agent to existing metformin monotherapy, as first-line therapy if metformin is contraindicated or poorly tolerated, and for use in combination with other oral glucose-lowering agents or basal insulin. Shorter-acting GLP-1RAs (exenatide and liraglutide) offer improved coverage of postprandial hyperglycemia, while longer-acting GLP-1RA formulations (exenatide extended-release, dulaglutide, and albiglutide) further improve fasting plasma glucose, which can result in additional A1C lowering. Reductions in body weight and blood pressure appear similar among individual agents, and small increases in heart rate are of unknown clinical relevance. Gastrointestinal adverse events abate over time with continued treatment and are less frequent with longer-acting GLP-1RAs. Hypoglycemia incidence is low but increased when GLP-1RAs are used with insulin secretagogues or insulin. GLP-1RAs target multiple pathophysiologic mechanisms in patients with T2D and improve glycemic control, although there are some differences within this drug class that may be relevant in clinical practice. Therefore, selection of the most appropriate treatment for individual patients is important.

Topics: Blood Glucose; Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin; Liraglutide; Metformin; Peptides; Recombinant Fusion Proteins; Risk Factors; Venoms

The current epidemics of excessive weight and type 2 diabetes mellitus (T2DM) cause significant morbidity and mortality. T2DM frequently coexists with excess weight as well as hypertension and dyslipidemia, placing a significant percentage of the population at an elevated risk of cardiovascular disease. Maintaining effective glycemic control is linked with a diminished risk of developing microvascular complications, and recent studies have shown it may also reduce overall macro vascular complications. Reduction of associated risk factors, including those related to excessive weight, high blood pressure, and dyslipidemia, are also necessary to meaningfully decrease cardiovascular risk. Agents that can improve glycemia with weight neutrality or weight loss could offer additional benefit to overweight patients with T2DM. Although the major pathophysiologic defects in T2DM are recognized to be beta-cell dysfunction and peripheral insulin resistance, derangements in the incretin system may contribute as well. Antidiabetes agents targeting this system include dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Both classes have been shown to significantly reduce hyperglycemia. GLP-1 receptor agonists also promote significant weight loss and have potentially beneficial effects on cardiovascular risk markers.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptides; Humans; Hyperglycemia; Hypoglycemic Agents; Risk Factors; Treatment Outcome

The glucagon-like peptide-1 receptor agonist dulaglutide reduced MACE in the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. This article expores the relationship of selected biomarkers to both dulaglutide and major adverse cardiovascular events (MACE).. In this post hoc analysis, stored fasting baseline and 2-year plasma samples from 824 REWIND participants with MACE during follow-up and 845 matched non-MACE participants were analyzed for 2-year changes in 19 protein biomarkers. Two-year changes in 135 metabolites were also analyzed in 600 participants with MACE during follow-up and in 601 matched non-MACE participants. Linear and logistic regression models were used to identify proteins that were associated with both dulaglutide treatment and MACE. Similar models were used to identify metabolites that were associated with both dulaglutide treatment and MACE.. Compared with placebo, dulaglutide was associated with a greater reduction or lesser 2-year rise from baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), high-sensitivity C-reactive protein, and a greater 2-year rise in C-peptide. Compared with placebo, dulaglutide was also associated with a greater fall from baseline in 2-hydroxybutyric acid and a greater rise in threonine (P < 0.001). Increases from baseline in two of the proteins (but neither metabolite) were associated with MACE, including NT-proBNP (OR 1.267; 95% CI 1.119, 1.435; P < 0.001) and GDF-15 (OR 1.937; 95% CI 1.424, 2.634; P < 0.001).. Dulaglutide was associated with a reduced 2-year rise from baseline of NT-proBNP and GDF-15. Higher rises of these biomarkers were also associated with MACE.

Topics: Biomarkers; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptides; Growth Differentiation Factor 15; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins

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

In a phase 2 trial of once-weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo, the dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide dose-dependently reduced HbA1c and body weight in patients with type 2 diabetes. In this post hoc analysis, inflammation, endothelial dysfunction, and cellular stress biomarkers were measured at baseline, 4, 12, and 26 weeks to evaluate the additional effects of tirzepatide on cardiovascular risk factors. At 26 weeks, tirzepatide 10 and 15 mg decreased YKL-40 (also known as chitinase-3 like-protein-1), intercellular adhesion molecule 1 (ICAM-1), leptin, and growth differentiation factor 15 levels versus baseline, and YKL-40 and leptin levels versus placebo and dulaglutide. Tirzepatide 15 mg also decreased ICAM-1 levels versus placebo and dulaglutide, and high-sensitivity C-reactive protein (hsCRP) levels versus baseline and placebo, but not dulaglutide. GlycA, interleukin 6, vascular cell adhesion molecule 1, and N-terminal-pro hormone B-type natriuretic peptide levels were not significantly changed in any group. YKL-40, hsCRP, and ICAM-1 levels rapidly decreased within 4 weeks of treatment with tirzepatide 10 and 15 mg, whereas the decrease in leptin levels was more gradual and did not plateau by 26 weeks. In this hypothesis-generating exploratory analysis, tirzepatide decreased several biomarkers that have been associated with cardiovascular risk.

Topics: Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins; Risk Factors

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

The REWIND trial demonstrated cardiovascular (CV) benefits to patients with type 2 diabetes and multiple CV risk factors or established CV disease. This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial.. Potential mediators of established CV risk factors that were significantly reduced by dulaglutide were assessed in a post hoc analysis using repeated measures mixed models and included glycated hemoglobin (HbA1c), body weight, waist-to-hip ratio, systolic blood pressure, low-density lipoprotein (LDL), and urine albumin/creatinine ratio (UACR). These factors, for which the change in level during follow-up was significantly associated with incident MACE, were identified using Cox regression modeling. Each identified variable was then included as a covariate in the Cox model assessing the effect of dulaglutide on MACE to estimate the degree to which the hazard ratio of dulaglutide vs placebo was attenuated. The combined effect of the variables associated with attenuation was assessed by including all variables in an additional Cox model.. Although all evaluated variables were significantly improved by treatment, only changes in HbA1c and UACR were associated with MACE and a reduction in the effect of dulaglutide on this outcome was observed. The observed hazard ratio for MACE for dulaglutide vs placebo reduced by 36.1% by the updated mean HbA1c, and by 28.5% by the updated mean UACR. A similar pattern was observed for change from baseline in HbA1c and UACR and a reduction of 16.7% and 25.4%, respectively in the hazard ratio for MACE with dulaglutide vs placebo was observed. When HbA1c and UACR were both included, the observed hazard ratio reduced by 65.4% for the updated mean and 41.7% for the change from baseline with no HbA1c-UACR interaction (P interaction = 0.75 and 0.15, respectively).. Treatment-induced improvement in HbA1c and UACR, but not changes in weight, systolic blood pressure, or LDL cholesterol, appear to partly mediate the beneficial effects of dulaglutide on MACE outcomes. These observations suggest that the proven effects of dulaglutide on cardiovascular disease benefit are partially related to changes in glycemic control and albuminuria, with residual unexplained benefit. Clinicaltrials.gov; Trial registration number: NCT01394952. URL: https://clinicaltrials.gov/ct2/show/NCT01394952.

Topics: Aged; Albuminuria; Biomarkers; Blood Glucose; Cardiovascular Diseases; Creatinine; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Recombinant Fusion Proteins; Risk Assessment; Time Factors; Treatment Outcome

Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial.. Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular or unknown causes. Key secondary outcomes included a microvascular composite endpoint, all-cause death, and heart failure. The effect of dulaglutide in patients with and without baseline metformin was evaluated by a Cox regression hazard model with baseline metformin, dulaglutide assignment, and their interaction as independent variables. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by a Cox regression model with adjustments for factors differing at baseline between people with vs. without metformin, identified using the backward selection.. Compared to patients with metformin at baseline (n = 8037; 81%), those without metformin (n = 1864; 19%) were older and slightly less obese and had higher proportions of women, prior CV events, heart failure, and renal disease. The primary outcome occurred in 976 (12%) participants with baseline metformin and in 281 (15%) without. There was no significant difference in the effect of dulaglutide on the primary outcome in patients with vs. without metformin at baseline [HR 0.92 (CI 0.81-1.05) vs. 0.78 (CI 0.61-0.99); interaction P = 0.18]. Findings for key secondary outcomes were similar in patients with and without baseline metformin.. This analysis suggests that the cardioprotective effect of dulaglutide is unaffected by the baseline use of metformin therapy.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Metformin; Middle Aged; Recombinant Fusion Proteins; Treatment Outcome; Vascular Diseases

Dulaglutide reduced major adverse cardiovascular events (MACE) in the Researching Cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial. Its efficacy and safety in older vs younger patients have not been explicitly analyzed.. This work aimed to assess efficacy and safety of dulaglutide vs placebo in REWIND by age subgroups (≥ 65 and < 65 years).. A post hoc subgroup analysis of REWIND was conducted at 371 sites in 24 countries. Participants included type 2 diabetes patients aged 50 years or older with established cardiovascular (CV) disease or multiple CV risk factors, and a wide range of glycemic control. Patients were randomly assigned (1:1) to dulaglutide 1.5 mg or placebo as an add-on to country-specific standard of care. Main outcomes measures included MACE (first occurrence of the composite of nonfatal myocardial infarction, nonfatal stroke, or death from CV or unknown causes).. There were 5256 randomly assigned patients who were 65 years or older (mean = 71.0), and 4645 were younger than 65 years (mean = 60.7). Baseline characteristics were similar in randomized treatment groups. Dulaglutide treatment showed a similar reduction in the incidence (11% vs 13%) of MACE in older vs younger patients. The rate of permanent study drug discontinuation, incidence of all-cause mortality, hospitalizations for heart failure, severe hypoglycemia, severe renal or urinary events, and serious gastrointestinal events were similar between randomized treatment groups within each age subgroup. The incidence rate of serious cardiac conduction disorders was numerically higher in the dulaglutide group compared to placebo within each age subgroup but the difference was not statistically significant.. Dulaglutide had similar efficacy and safety in REWIND in patients65 years and older and those younger than 65 years.

Topics: Age Factors; Aged; Aged, 80 and over; Aging; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptides; Hospitalization; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Recombinant Fusion Proteins; Severity of Illness Index; Treatment Outcome

Diabetes is a major risk factor for erectile dysfunction, however, the effect of GLP-1 receptor agonists on erectile dysfunction is unknown. We aimed to assess the incidence, prevalence, and progression of erectile dysfunction in men treated with dulaglutide compared with placebo, and to determine whether dulaglutide's effect on erectile dysfunction was consistent with its effect on other diabetes-related outcomes.. The Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial was a double-blind, placebo-controlled randomised trial of the effect of dulaglutide on cardiovascular outcomes. REWIND was done at 371 sites in 24 countries. Men and women aged older than 50 years with type 2 diabetes, who had either a previous cardiovascular event or cardiovascular risk factors, were randomly assigned (1:1) to receive either dulaglutide or placebo. Participating men were offered the opportunity to complete the standardised International Index of Erectile Function (IIEF) questionnaire at baseline, 2 years, 5 years, and study end. We did an exploratory analysis, in which we included participants who completed a baseline and at least 1 follow-up IIEF questionnaire. The primary outcome for these analyses was the first occurrence of moderate or severe erectile dysfunction following randomisation, assessed by the erectile function subscores on IIEF. This analysis was part of the REWIND trial, which is registered with ClinicalTrials.gov, NCT01394952.. Between Aug 18, 2011, and Aug 14, 2013, 3725 (70·1%) of 5312 male participants with a mean age of 65·5 years (SD 6·4 years) were analysed, of whom 1487 (39·9%) had a history of cardiovascular disease, and 2104 (56·5%) had moderate or severe erectile dysfunction at baseline. The incidence of erectile dysfunction following randomisation was 21·3 per 100 person-years in the dulaglutide group and 22·0 per 100 person-years in the placebo group (HR 0·92, 95% CI 0·85-0·99, p=0·021). Men in the dulaglutide group also had a lesser fall in erectile function subscore compared with the placebo group, with a least square mean difference of 0·61 (95% CI 0·18-1·05, p=0·006).. Long-term use of dulaglutide might reduce the incidence of moderate or severe erectile dysfunction in men with type 2 diabetes.. Eli Lilly and Company.

Topics: Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Erectile Dysfunction; Female; Follow-Up Studies; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Prognosis; Recombinant Fusion Proteins

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 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 Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants METHODS: We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular deaths between participants randomized to dulaglutide and those randomized to placebo. Incidences were expressed as number per 1000 person-years. Hazard ratios (HR) were calculated using the conditional time gap and proportional means models.. Participants had a mean age of 66.2 years, 46.3% were women and 31% had previous cardiovascular disease. During the trial there were 1972 MACE or non-cardiovascular deaths and 3673 expanded MACE or non-cardiovascular deaths. The incidence of total MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 35.8 and 40.3 per 1000 person-years, respectively [absolute reduction = 4.5 per 1000 person-years; conditional time gap HR 0.90 (95% CI, 0.82-0.98) p = 0.020, and proportional means HR 0.89 (95% CI, 0.80-0.98) p = 0.022]. The incidence of total expanded MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 67.1 and 74.7 per 1000 person-years, respectively [absolute reduction = 7.6 per 1000 person-years; conditional time gap HR 0.93 (95% CI, 0.87-0.99) p = 0.023, and proportional means HR 0.90 (95% CI, 0.82-0.99) p = 0.028].. These findings suggest that weekly subcutaneous dulaglutide reduced total cardiovascular or fatal event burden in people with type 2 diabetes at moderate cardiovascular risk.. https://www.clinicaltrials.gouv . Unique Identifier NCT01394952).

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Male; Middle Aged; Recombinant Fusion Proteins; Risk Assessment; Time Factors; Treatment Outcome

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

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

Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A. This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952.. Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA. Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors.. Eli Lilly and Company.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Myocardial Infarction; Recombinant Fusion Proteins; Stroke

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

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

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

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

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

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

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

To determine the proportion of UK patients with type 2 diabetes (T2D) who meet the cardiovascular (CV) or combined CV/core eligibility criteria used for the CV outcome trials (CVOTs) of UK-marketed glucagon-like peptide-1 receptor agonists (GLP-1RAs) showing CV benefit (dulaglutide in REWIND, liraglutide in LEADER and injectable semaglutide in SUSTAIN-6).. Adults with T2D on/before June 2018 were identified from the UK Clinical Practice Research Datalink GOLD primary care database and linked to Hospital Episode Statistics data (Protocol 19_262). Patient CV and clinical data were evaluated against the CVOT eligibility criteria. Data were analysed descriptively.. The study cohort (N = 33 118 patients with T2D) had a mean (standard deviation) age of 66.0 (13.3) years and 56.6% were male. Almost two-thirds (64.5%) of the study cohort met the CV criteria for REWIND, versus 43.0% for both LEADER and SUSTAIN-6. The proportions of the study cohort who met the CVOT criteria of "established CV disease" and "CV risk factors only" for REWIND were 22.4% and 42.1%, respectively, versus 38.7% and 4.3%, respectively, for both LEADER and SUSTAIN-6. The proportions of patients satisfying both CV and core criteria were 44.4% for REWIND, 13.3% for LEADER and 13.5% for SUSTAIN-6. Study findings remained consistent when restricted to GLP-1RA users.. REWIND captured a trial population more representative of the real-world T2D population in the United Kingdom than LEADER or SUSTAIN-6 with regard to both CV and combined CV/core eligibility criteria.

Topics: Aged; Cardiovascular Diseases; Clinical Trials as Topic; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Male; Risk Factors

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

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

Type 2 diabetes (T2D) is a common comorbidity in people living with HIV (PLWH). Anti-hyperglycemic treatment in PLWH is still a challenge, and no randomized controlled studies using new glucose-lowering agents are currently available.. A 55-year-old-women was admitted to our Diabetes Unit because of hyperosmolar hyperglycemic state (HHS) and sepsis. The medical history included HIV infection and insulin-treated diabetes. On clinical examination, the lady appeared dehydrated with dry buccal mucosa, tachycardia, altered mental status, genital infection, and fever. On admission, plasma glucose was 54.5 mmol/L, HbA1c 155 mmol/mol, osmolarity 389.4 mOsm/kg, bicarbonate 24.6 mmol/L with no detectable serum ketones. The patient was treated with i.v. fluid and insulin, and antibiotic therapy commenced. Upon HHS and sepsis resolution, a basal-bolus insulin therapy was implemented that was followed by significant improvement of daily glucose profiles and progressive reduction of insulin requirement until complete discontinuation. A low dose of metformin plus linagliptin was started. Since a severe atherosclerotic disease was diagnosed, a GLP-1 receptor agonist, dulaglutide, was added to metformin upon linagliptin withdrawal with maintenance of good glycemic control, treatment adherence and amelioration of quality of life and no side effects.. This case suggests that GLP-1 receptor agonist therapy may be effective and safe for treatment of T2D with high cardiovascular risk in PLWH, supporting the need of clinical trials directly assessing the safety and the efficacy of GLP-1 receptor agonist in these individuals.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glucose; Glycated Hemoglobin; Heart Disease Risk Factors; HIV Infections; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin; Linagliptin; Metformin; Middle Aged; Quality of Life; Recombinant Fusion Proteins; Risk Factors; Sepsis

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

This post hoc analysis investigated the effect of dulaglutide on cardiovascular disease (CVD) risk factors in subgroups of participants at increased CVD risk in the AWARD-11 study.. Participants who received once weekly dulaglutide 1.5, 3.0 or 4.5 mg for 52 weeks were categorized according to their baseline Framingham CVD risk category [low (N = 295), medium (N = 481) and high (N = 1054) risk], as well as their baseline CVD risk according to the REWIND study eligibility criteria (N = 953). Serum lipids and vital signs were assessed at baseline and at 52 weeks. Data were analysed as least squares mean percentage change from baseline for lipids and least squares mean change from baseline for vital signs.. Demographic and baseline clinical characteristics were balanced across doses within the CVD risk groups. In the high Framingham CVD risk and REWIND-like groups, dulaglutide resulted in dose-related decreases in total cholesterol (≤6.0%), non-high-density lipoprotein cholesterol (≤8.8%), very-low-density lipoprotein cholesterol (≤19.4%) and triglycerides (≤21.5%), with little change in low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Systolic and diastolic blood pressure decreased up to 5.6 mmHg and 1.6 mmHg, respectively, and heart rate increased up to 2 beats/min.. This post hoc analysis suggests the magnitude of the favourable effects of dulaglutide 3.0 mg and 4.5 mg on several cardiometabolic CVD risk factors was similar to, if not greater than, those of dulaglutide 1.5 mg among participants with type 2 diabetes and increased CVD risk.. gov Identifier: NCT03495102.

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

The REPRESENT study aims to examine whether participants enrolled in glucagon-like peptide 1 receptor agonist cardiovascular outcome trials (CVOTs) LEADER (liraglutide), REWIND (dulaglutide), and SUSTAIN-6 (injectable semaglutide) are representative of the Spanish population with type 2 diabetes (T2D).. This retrospective observational study used the IQVIA Electronic Medical Records database in Spain to identify adults aged 18 years and older with T2D diagnosed before/between January 2013 and December 2015. Demographic and clinical characteristics were analyzed descriptively. The proportions of individuals in the Spanish cohort who met the key selection criteria of each CVOT were calculated from individuals with available database entries for estimated glomerular filtration rate and body mass index using proxies.. A total of 24,268 adults with T2D were identified from the IQVIA database. The Spanish cohort was predominantly male (55.5%) and had a mean (± SD) age of 66.8 ± 12.5 years and HbA1c of 7.2 ± 1.5%, with 14.0% having established cardiovascular disease and 2.9% having prior myocardial infarction. The characteristics of the Spanish cohort were more similar to that of REWIND than LEADER or SUSTAIN-6. The proportions of subjects in the Spanish cohort who met the CVOTs key selection criteria were 10.1% for LEADER, 53.6% for REWIND, and 10.4% for SUSTAIN-6.. Although none of the CVOTs was fully representative of the Spanish cohort, the REWIND population was found to be more representative of the real-world Spanish population with T2D than those of LEADER and SUSTAIN-6. These findings reinforce the applicability of the results of REWIND in clinical practice.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Spain

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

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

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

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 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

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

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

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

To examine the generalizability of results from glucagon-like peptide-1 receptor agonist (GLP-1 RA) cardiovascular outcome trials (CVOTs) in the US type 2 diabetes (T2D) population.. Patients enrolled or eligible for inclusion in four CVOTs (EXSCEL, LEADER, REWIND, and SUSTAIN-6) were examined in reference to a retrospective clinical database weighted to match the age and sex distribution of the US adult T2D population. We descriptively compared key baseline characteristics of the populations enrolled in each trial to those of the reference population and estimated the proportions of individuals in the reference population represented by those in the trials for each characteristic. We also estimated the proportions of individuals in the reference population that might have been enrolled in each trial based upon meeting the trial inclusion and exclusion (I/E) criteria.. No trial's enrolled population perfectly matched the reference population in key characteristics. The EXSCEL population most closely matched in mean age (62.7 vs. 60.5 years) and percentage with estimated glomerular filtration rate <60 (18.6 vs. 17.3%), while REWIND most closely matched in HbA1c, sex distribution, and proportion with a prior myocardial infarction. Based on I/E criteria, 42.6% of the reference population were eligible for enrolment in REWIND, versus 15.9% in EXSCEL, 13.0% in SUSTAIN-6, and 12.9% in LEADER.. Although none of the trials are fully representative of the general population, among the four trials examined, results from baseline REWIND were found to be more generalizable to the US adult T2D population than those of other GLP-1 RA CVOTs.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Retrospective Studies; United States

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

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: Administration, Oral; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins

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

The aim was to determine the effects of dulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world.

Topics: Aged; Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Injections, Subcutaneous; Male; Middle Aged; Mortality; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Research Design; Risk Factors

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

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

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

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: 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

In four trials including a total of more than 3000 patients, dulaglutide reduced the HbA1c concentration as effectively as other GLP-1 analogues when added to other hypoglycaemic drugs. The long elimination half-life of dulaglutide can make management of adverse effects and drug interactions more difficult. More data are needed on possible cardiac adverse effects.

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Recombinant Fusion Proteins; Risk Assessment; Treatment Outcome

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