incretins and Hypoglycemia

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been the most widely used for type 2 diabetes (T2D) available worldwide since 2006. DPP-4 inhibitors exert their effects by inhibiting dipeptidyl peptidase-4 to increase the concentration of endogenous incretin hormones (incretin hormone analogues and incretin potentiators) and promote insulin secretion, thereby acting as a glucose regulator. Evogliptin is a new member of the DPP-4 inhibitor family with high selectivity and low risk of hypoglycemia, and extensive clinical data has been accumulated in its treatment of T2D since its introduction in October 2015.. This review summarized the recently reported studies associated with the pharmacokinetics, pharmacodynamics, safety and tolerability, and clinical application of evogliptin for managing T2D. We searched the MEDLINE and PubMed databases with the titles 'evogliptin' to identify all the information. The abstracts and posters of the annual meetings of ADA and EASD and clinicalTrials.gov. have been searched up to now.. Evogliptin is a potent, orally effective, and highly selective DPP-4 inhibitor that is not only indicated for the treatment of T2D but may also be beneficial to arterial inflammation and atherosclerosis, with good safety and tolerance.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins

Although there are many different methods of treating type 2 diabetes (T2D), it is still difficult to draw coincident conclusions concerning the efficacy and safety of different classes of new drugs, and the recommendation level of them has still kept uncertain as second anti-diabetic agents. Therefore, the aim of this study was to summarize evidence on the efficacy and safety of DPP-4is, GLP-1RAs and SGLT-2is as monotherapy or add-on to metformin (Met) for treatment of T2D.. We searched PubMed, Embase, Cochrane library and ClinicalTrials.gov for relevant articles in keeping with established methods using terms associated with anti-diabetic agents up to February, 2020, with no start date restriction. Weighted mean difference and risk ratios with 95% confidence intervals were calculated within traditional and network meta-analysis. Primary outcomes were the mean change in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG) change and the frequency of hypoglycemic events from baseline after 12 weeks of treatment.. In total, 64 eligible studies comprising 37,780 patients and 7 treatment strategies were included. The results of primary outcomes showed that GLP-1RAs were significantly more effective than DPP-4is or SGLT-2is in reducing HbA1c when add-on to Met. For FPG, both GLP-1RAs and SGLT-2is significantly reduced FPG compared with DPP-4is whether add-on to Met or not. For hypoglycemia, monotherapy has a lower risk than combination therapy except for SGLT-2is. Ranking probability analysis indicated that GLP-1RAs and SGLT-2is, respectively, reduced HbA1c and FPG most when add-on to Met. Meanwhile, GLP-1RAs took the lowest risk to induce the hypoglycemia, whereas GLP-1RAs plus Met the highest.. Both GLP-1RAs and SGLT-2is have their own advantages in efficacy and safety. Monotherapy is beneficial for reducing the risk of hypoglycemia. The recommendation should be a patient-centered approach when selecting treatment choices.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Metformin; Network Meta-Analysis; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Glucose levels in blood must be constantly maintained within a tight physiological range to sustain anabolism. Insulin regulates glucose homeostasis via its effects on glucose production from the liver and kidneys and glucose disposal in peripheral tissues (mainly skeletal muscle). Blood levels of glucose are regulated simultaneously by insulin-mediated rates of glucose production from the liver (and kidneys) and removal from muscle; adipose tissue is a key partner in this scenario, providing nonesterified fatty acids (NEFA) as an alternative fuel for skeletal muscle and liver when blood glucose levels are depleted. During sleep at night, the gradual development of insulin resistance, due to growth hormone and cortisol surges, ensures that blood glucose levels will be maintained within normal levels by: (a) switching from glucose to NEFA oxidation in muscle; (b) modulating glucose production from the liver/kidneys. After meals, several mechanisms (sequence/composition of meals, gastric emptying/intestinal glucose absorption, gastrointestinal hormones, hyperglycemia mass action effects, insulin/glucagon secretion/action, de novo lipogenesis and glucose disposal) operate in concert for optimal regulation of postprandial glucose fluctuations. The contribution of the liver in postprandial glucose homeostasis is critical. The liver is preferentially used to dispose over 50% of the ingested glucose and restrict the acute increases of glucose and insulin in the bloodstream after meals, thus protecting the circulation and tissues from the adverse effects of marked hyperglycemia and hyperinsulinemia.

Topics: Adipose Tissue; Blood Glucose; Fasting; Fatty Acids, Nonesterified; Gastric Emptying; Glucose; Homeostasis; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Incretins; Insulin; Insulin Resistance; Kidney; Liver; Meals; Muscle, Skeletal; Postprandial Period

Recent advances in anti-diabetic medications and glucose monitoring have led to a paradigm shift in diabetes care. Newer anti-diabetic medications such as DPP-4 inhibitors, GLP-1 receptor agonists (GLP-1RAs), and SGLT2 inhibitors have enabled optimal glycemic control to be achieved without increasing the risk of hypoglycemia and weight gain. Treatment with GLP-1RAs and SGLT2 inhibitors has been demonstrated to improve cardiorenal outcomes, positioning these agents as the mainstay of treatment for patients with type 2 diabetes (T2DM). The development of these newer agents has also prompted a paradigm shift in the concept of T2DM, highlighting the importance of beta cell dysfunction in the pathophysiology of T2DM.. Recent advances in pharmacotherapy for diabetes are summarized with a focus on the role of incretin-based drugs and SGLT2 inhibitors. The importance of a paradigm shift from a glucose-centric to a beta cell-centric concept of T2DM is also discussed, given from an Asian perspective.. Management of T2DM including lifestyle modification as well as pharmacotherapy should be focused on reducing beta cell workload, to preserve functional beta cell mass. A paradigm shift from a glucose-centric to a beta cell-centric concept of T2DM enhances the implementation of person-centered diabetes care.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin-Secreting Cells; Precision Medicine; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds

The role of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in the treatment of type 1 diabetes mellitus (T1DM), including efficacy and safety evidence, is reviewed.. Currently approved treatment options for glycemic control in T1DM include insulin, which combats insulin deficiency but does not effectively target disease progression or alpha cell dysfunction; and pramlintide, whose use requires multiple daily doses and involves a high likelihood of gastrointestinal side effects. GLP-1 RAs have a unique mechanism of action in T1DM, addressing alpha cell dysfunction and thereby suppressing inappropriate glucagon secretion. GLP-1 RA dosing varies from once weekly to twice daily, and the class is well tolerated in patients with type 2 diabetes. Among the GLP-1 RAs, exenatide and liraglutide have been studied in patients with T1DM, with published evidence consistently demonstrating weight loss, decreases in total daily insulin requirements, and modest improvements in glycemic control. GLP-1 RA therapy appears to be well tolerated in patients with T1DM and is associated with nonsignificant increases in hypoglycemia risk.. GLP-1 RA therapy represents an important add-on therapy option for achieving decreased insulin doses, weight loss, and modest improvements in HbA1c levels without significantly increasing hypoglycemia risk in patients with T1DM. Patients who have detectable C-peptide and/or are overweight or cannot achieve glycemic goals without hypoglycemia have been found to benefit the most from GLP-1 RA therapy. Further studies are warranted to evaluate these agents' potential impact on clinical outcomes such as microvascular and macrovascular complications.

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Exenatide; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucagon-Secreting Cells; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Treatment Outcome; Weight Loss

Hypoglycaemia is common in both type 1 and type 2 diabetes and has both acute and long-term consequences. Therefore, a key to proper glucose-lowering therapy in diabetes is to avoid or prevent hypoglycaemia. Incretin therapy (DPP-4 inhibitors and GLP-1 receptor agonists) offers an advantage in this respect, because it reduces glucose with a low risk of hypoglycaemia, both in monotherapy and in combination with other therapies. The reason for this low risk of hypoglycaemia is the glucose dependency of action of incretin therapy and the sustainment of glucose counter-regulatory hormone responses to hypoglycaemia, in particular the glucagon response. Incretin therapy is also associated with a low risk of hypoglycaemia in patient groups which are especially vulnerable and susceptible for hypoglycaemia, e.g., subjects with renal impairment, elderly subjects and subjects with on-going insulin therapy. This review summarizes how incretin therapy may meet the challenges of hypoglycaemia and suggests that incretin therapy is a therapy of choice to avoid hypoglycaemia, both in the general diabetes population and in subjects with increased risk or vulnerability for hypoglycaemia.

Topics: Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins

As Type 2 diabetes progresses, treatment is intensified with additional therapies in an effort to manage hyperglycaemia effectively and therefore avoid complications. When greater efficacy is required, options for injectable treatments include glucagon-like peptide-1 receptor agonists and insulin, which may be added on to oral glucose-lowering treatments. Among individuals receiving long-acting basal insulin as their first injectable treatment, ~40-60% are unable to achieve or maintain their target HbA

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Glargine; Insulin, Long-Acting; Peptides; Postprandial Period; Treatment Outcome

Since 2005, several glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been approved to treat people with type 2 diabetes. These agents are considered for use at the same point in the treatment paradigm as basal insulins. A comprehensive comparison of these drug classes, therefore, can help inform treatment decisions. This systematic review and meta-analysis assessed the clinical efficacy and safety of GLP-1 RAs compared with basal insulins.. MEDLINE, EMBASE, CENTRAL and PubMed databases were searched. Randomized clinical trials (RCTs) of ≥16 weeks' duration comparing GLP-1 RAs vs basal insulins in adults with type 2 diabetes inadequately controlled with oral antihyperglycemic drugs were included. Data on the change from baseline to 26 weeks (±10 weeks) of treatment in hemoglobin A1c (HbA1c) and weight, as well as the proportion of patients experiencing hypoglycaemia, were extracted. Fixed-effect pairwise meta-analyses were conducted where data were available from ≥2 studies.. Fifteen RCTs were identified and 11 were meta-analysed. The once-weekly GLP-1 RAs, exenatide long acting release (LAR) and dulaglutide, led to greater, statistically significant mean HbA1c reductions vs basal insulins (exenatide: -0.31% [95% confidence interval -0.42, -0.19], dulaglutide: -0.39% [-0.49, -0.29]) whilst once-daily liraglutide and twice-daily exenatide did not (liraglutide: 0.06% [-0.06, 0.18], exenatide: 0.01% [-0.11, 0.13]). Mean weight reduction was seen with all GLP-1 RAs while mean weight gain was seen with basal insulins. Interpretation of the analysis of hypoglycaemia was limited by inconsistent definitions and reporting. Because of the limited number of available studies sensitivity analyses to explore heterogeneity could not be conducted.. Although weight reduction is seen with all GLP-1 RA's, only the once-weekly agents, exenatide LAR and dulaglutide, demonstrate significant HbA1c reductions when compared to basal insulins.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Insulin; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Peptides; Recombinant Fusion Proteins; Venoms

To study differences in clinical outcomes between initiating glucagon-like peptide-1 receptor agonist (GLP-1 RAs) vs insulin treatment in patients with type 2 diabetes treated with oral glucose-lowering medications (OGLM).. Prospective, randomized trials comparing GLP-1 RA and insulin treatment head-to-head as add-on to OGLM were identified (PubMed). Differences from baseline values were compared for HbA1c, fasting plasma glucose, bodyweight, blood pressure, heartrate and lipoproteins. Proportions of patients reporting hypoglycaemic episodes were compared.. Of 712 publications identified, 23 describing 19 clinical trials were included in the meta-analysis. Compared to insulin, GLP-1 RAs reduced HbA1c more effectively (Δ -.12%, P < .0001). Basal insulin was more effective in reducing fasting plasma glucose (Δ -1.8 mmol/L, P < .0001). GLP-1 RAs reduced bodyweight more effectively (Δ -3.71 kg; P < .0001). The proportion of patients experiencing hypoglycaemic episodes was 34% lower with GLP-1 RAs ( P < .0001), with a similar trend for severe hypoglycaemia. Systolic blood pressure was lower and heartrate was higher with GLP-1 RAs ( P < .0001). Triglycerides and LDL cholesterol were significantly lower with GLP-1 RAs. Long-acting GLP-1 RAs were better than short-acting GLP-1 RAs in reducing HbA1c and fasting glucose, but were similar regarding bodyweight.. Slightly better glycaemic control can be achieved by adding GLP-1 RAs to OGLM as compared to insulin treatment, with added benefits regarding bodyweight, hypoglycaemia, blood pressure and lipoproteins. These differences are in contrast to the fact that insulin is prescribed far more often than GLP-1 RAs.

Topics: Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Fasting; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Peptides; Treatment Outcome; Venoms

To compare efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in people with type 2 diabetes.. We electronically searched, up to June 3, 2016, published randomized clinical trials lasting between 24 and 32 weeks that compared a GLP-1RA (albiglutide, dulaglutide, twice-daily exenatide and once-weekly exenatide, liraglutide, lixisenatide, semaglutide and taspoglutide) with placebo or another GLP-1RA. Data on cardiometabolic and safety outcomes were analysed using a mixed-treatment comparison meta-analysis.. A total of 34 trials (14 464 participants) met the inclusion criteria; no published data for semaglutide were available. Compared with placebo, all GLP-1RAs reduced glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels (reductions ranged from -0.55% and -0.73 mmol/L, respectively, for lixisenatide to -1.21% and -1.97 mmol/L, respectively, for dulaglutide). There were no differences within short-acting (twice-daily exenatide and lixisenatide) or long-acting (albiglutide, dulaglutide, once-weekly exenatide, liraglutide and taspoglutide) groups. Compared with twice-daily exenatide, dulaglutide treatment was associated with the greatest HbA1c and FPG reduction (0.51% and 1.04 mmol/L, respectively), followed by liraglutide (0.45% and 0.93 mmol/L, respectively) and once-weekly exenatide (0.38% and 0.85 mmol/L, respectively); similar reductions were found when these 3 agents were compared with lixisenatide. Compared with placebo, all GLP-1RAs except albiglutide reduced weight and increased the risk of hypoglycaemia and gastrointestinal side effects, and all agents except dulaglutide and taspoglutide reduced systolic blood pressure. When all GLP-1RAs were compared with each other, no clinically meaningful differences were observed in weight loss, blood pressure reduction or hypoglycaemia risk. Albiglutide had the lowest risk of nausea and diarrhoea and once-weekly exenatide the lowest risk of vomiting.. The RCTs in the present analysis show that all GLP-1RAs improve glycaemic control, reduce body weight and increase the risk of adverse gastrointestinal symptoms compared with placebo. Although there were no differences when short-acting agents were compared with each other or when long-acting agents were compared with each other, dulaglutide, liraglutide and once-weekly exenatide were superior to twice-daily exenatide and lixisenatide at lowering HbA1c and FPG levels. There were no differences in hypoglycaemia between these 3 agents, whilst once-weekly exenatide had the lowest risk of vomiting. These results, along with patient's preferences and individualized targets, should be considered when selecting a GLP-1RA.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Liraglutide; Male; Middle Aged; Peptides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Treatment Outcome; Venoms

Incretin-based agents, including dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 agonists (GLP-1As), work via GLP-1 receptor for hyperglycemic control directly or indirectly, but have different effect on cardiovascular (CV) outcomes. The present study is to evaluate and compare effects of incretin-based agents on CV and pancreatic outcomes in patients with type 2 diabetes mellitus (T2DM) and high CV risk.. Six prospective randomized controlled trials (EXMAINE, SAVOR-TIMI53, TECOS, ELIXA, LEADER and SUSTAIN-6), which included three trials for DPP-4Is and three trials for GLP-1As, with 55,248 participants were selected to assess the effect of different categories of incretin-based agents on death, CV outcomes (CV mortality, major adverse CV events, nonfatal myocardial infarction, nonfatal stroke, heart failure hospitalization), pancreatic events (acute pancreatitis and pancreatic cancer) as well as on hypoglycemia.. When we evaluated the combined effect of six trials, the results suggested that incretin-based treatment had no significant effect on overall risks of CV and pancreatic outcomes compared with placebo. However, GLP-1As reduced all-cause death (RR = 0.90, 95% CI 0.82-0.98) and CV mortality (RR = 0.84, 95% CI 0.73-0.97), whereas DPP-4Is had no significant effect on CV outcomes but elevated the risk for acute pancreatitis (OR = 1.76, 95% CI 1.14-2.72) and hypoglycemia (both any and severe hypoglycemia), while GLP-1As lowered the risk of severe hypoglycemia.. GLP-1As decreased risks of all-cause and CV mortality and severe hypoglycemia, whereas DPP-4Is had no effect on CV outcomes but increased risks in acute pancreatitis and hypoglycemia.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Pancreatitis; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome

Hypoglycaemia after gastric bypass can be severe, but is uncommon, and is sometimes only revealed through monitoring glucose concentrations. The published literature is limited by the heterogeneity of the criteria used for diagnosis, arguing in favour of the Whipple triad with a glycaemia threshold of 55 mg/dl as the diagnostic reference. Women who lost most of their excess weight after gastric bypass, long after the surgery was performed, and who did not have diabetes before surgery are at the greatest risk. In this context, hypoglycaemia results from hyperinsulinism, which is either generated by pancreas anomalies (nesidioblastosis) and/or caused by an overstimulation of β cells by incretins, mainly glucagon-like peptide-1 (GLP-1). Glucose absorption is both accelerated and increased because of the direct communication between the gastric pouch and the jejunum. This is a post-surgical exaggeration of a natural adaptation that is seen in patients who have not undergone surgery in whom glucose is infused directly into the jejunum. There is not always a correspondence between symptoms and biological traits; however, hyperinsulinism is constant if hypoglycaemia is severe and there are neuroglucopenic symptoms. The treatment relies firstly on changes in eating habits, splitting food intake into five to six daily meals, slowing gastric emptying, reducing the glycaemic load and glycaemic index of foods, using fructose and avoiding stress at meals. Pharmacological treatment with acarbose is efficient, but other drugs still need to be validated in a greater number of subjects (insulin, glucagon, calcium channel blockers, somatostatin analogues and GLP-1 analogues). Lastly, if the surgical option has to be used, the benefits (efficient symptom relief) and the risks (weight regain, diabetes) should be weighed carefully.

Topics: Acarbose; Adaptation, Physiological; Adult; Blood Glucose; Diet Therapy; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Jejunum; Male

The progressive nature of Type 2 diabetes necessitates treatment intensification over time in order to maintain glycaemic control, with many patients ultimately requiring insulin therapy. While insulin has unlimited potential efficacy, its initiation is often delayed and improvements in glycaemic control are typically accompanied by weight gain and an increased risk of hypoglycaemia, particularly as HbA1c approaches and falls below target levels. This may account for the sub-optimal control often achieved after insulin initiation. Combining insulin with antihyperglycaemic therapies that have a low risk of hypoglycaemia and are weight-neutral or result in weight loss is a therapeutic strategy with the potential to improve Type 2 diabetes management. Although the effects differ with each individual class of therapy, clinical trials have shown that adding a glucagon-like peptide-1 receptor agonist, dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2 inhibitor to insulin regimens can offer a significant reduction in HbA1c without substantially increasing hypoglycaemia risk, or weight. The evidence and merit of each approach are reviewed in this paper. Once-daily co-formulations of a basal insulin and a glucagon-like peptide-1 receptor agonist have been developed (insulin degludec/liraglutide) or are under development (lixisenatide/insulin glargine). Insulin degludec/liraglutide phase III trials and a lixisenatide/insulin glargine phase II trial have shown robust HbA1c reductions, with weight loss and a low risk of hypoglycaemia. With insulin degludec/liraglutide now approved in Europe, an important consideration will be the types of patients who may benefit most from a fixed-ratio combination; this is discussed in the present review, and we also take a look toward future developments in the field.

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Peptides; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Obesity is a major public health problem worldwide. Obesity-related illnesses, such as coronary heart disease, type 2 diabetes, hypertension, dyslipidemia, stroke, sleep apnea, and several forms of cancer (endometrial, breast, and colon), contribute to a significant number of deaths in the USA. Bariatric surgery, including the Roux-en-Y gastric bypass (RYGB) procedure, has demonstrated significant improvements in obesity and obesity-related co-morbidities and is becoming more popular as the number of obese individuals rises. Despite the reported benefits of bariatric surgery, there are potential complications that physicians need to be aware of as the number of patients undergoing these procedures continues to increase. One challenging and potentially life-threatening complication that to date is not well understood is post-RYGB surgery hypoglycemia (PGBH). In this review, we will present the definition, historical perspective, diagnostic approach, currently available treatment options, and anecdotal assessment and treatment algorithm for this disorder.

Topics: Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypertension; Hypoglycemia; Incretins; Obesity

Type 2 diabetes in East Asians is characterized primarily by β-cell dysfunction, and with less adiposity and less insulin resistance compared with that in Caucasians. Such pathophysiological differences can determine the appropriate therapeutics for the disease. Incretins, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, are secreted in response to meal ingestion, and enhance insulin secretion glucose-dependently. Incretin-based drugs, dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists, that ameliorate β-cell dysfunction with limited hypoglycemia risk are now widely used in type 2 diabetes management. Recent meta-analyses of clinical trials on DPP-4i and glucagon-like peptide-1 receptor agonists found that the drugs were more effective in Asians, most likely because of amelioration of β-cell dysfunction. In addition, we found increased glycated hemoglobin-lowering effects of DPP-4i to be associated with intake of fish in type 2 diabetes, which suggests that dietary customs of East Asians might also underlie the greater efficacy of DPP-4i. Despite the limited risk, cases of severe hypoglycemia were reported for DPP-4i/sulfonylureas combinations. Importantly, hypoglycemia was more frequent in patients also receiving glibenclamide or glimepiride, which activate exchange protein directly activated by cyclic adenosine monophosphate 2, a critical mediator of incretin signaling, and was less frequent in patients receiving gliclazide, which does not activate exchange protein directly activated by cyclic adenosine monophosphate 2. Prevention of insulin-associated hypoglycemia by DPP-4i has gained attention with regard to the enhancement of hypoglycemia-induced glucagon secretion by insulinotropic polypeptide, but remains to be investigated in East Asians. Despite the safety issues, which are paramount and must be carefully monitored, the incretin-based drugs could have potential as a first choice therapy in East Asian type 2 diabetes patients.

Topics: Animals; Asian People; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Tolerance Test; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Mice; Rats; Risk Factors; Sulfonylurea Compounds; Treatment Outcome

To review the use of GLP-1 agonists in patients with type 1 diabetes mellitus (T1DM).. A search using the MEDLINE database, EMBASE, and Cochrane Database was performed through March 2016 using the search terms glucagon-like peptide 1 (GLP-1) agonists, incretin, liraglutide, exenatide, albiglutide, dulaglutide, type 1 diabetes mellitus. All English-language trials that examined glycemic end points using GLP-1 agonists in humans with T1DM were included.. A total of 9 clinical trials examining the use of GLP-1 agonists in T1DM were identified. On average, hemoglobin A1C (A1C) was lower than baseline, with a maximal lowering of 0.6%. This effect was not significant when tested against a control group, with a relative decrease in A1C of 0.1% to 0.2%. In all trials examined, reported hypoglycemia was low, demonstrating no difference when compared with insulin monotherapy. Weight loss was seen in all trials, with a maximum weight loss of 6.4 kg over 24 weeks. Gastrointestinal adverse effects are potentially limiting, with a significant number of patients in trials reporting nausea.. The use of GLP-1 agonists should be considered in T1DM patients who are overweight or obese and not at glycemic goals despite aggressive insulin therapy; however, tolerability of these agents is a potential concern. Liraglutide has the strongest evidence for use and would be the agent of choice for use in overweight or obese adult patients with uncontrolled T1DM.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Liraglutide; Peptides; Recombinant Fusion Proteins; Venoms

Topics: Cholecystitis; Combined Modality Therapy; Diet Therapy; Exercise Therapy; Humans; Hypoglycemia; Incretins; Liraglutide; Obesity; Overweight; Pancreatitis

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the most recent addition to the therapeutic options available for the treatment of type 2 diabetes and became available after the introduction of incretin-based therapies, dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs). These agents have potential advantages with regard to their weight loss-promoting effect, low risk of hypoglycemia, reduction in blood pressure, and reduction in cardiovascular events in high-risk patients (with empagliflozin). Apart from these clinically important outcomes, they may also correct core defects present in type 2 diabetes (i.e., improvement in β-cell function and insulin sensitivity). They do, however, have some adverse effects, notably, nausea with GLP-1 RAs and genital tract infections and potential for volume depletion with SGLT2i. Whether incretin-based therapies are associated with an increased risk of pancreatitis is unclear. Most recently, diabetic ketoacidosis has been reported with SGLT2i. Therefore, a key clinical question in relation to guidelines is whether these clinical advantages, in the context of the adverse effect profile, outweigh the additional cost compared with older, more established therapies. This article reviews the therapeutic rationale for the use of these newer drugs for diabetes treatment, considers their place in current guidelines, and discusses how this may change as new data emerge about their long-term efficacy and safety from ongoing outcome trials.

Topics: Algorithms; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucosides; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Receptors, Glucagon; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Critical illness afflicts millions of people worldwide and is associated with a high risk of organ failure and death or an adverse outcome with persistent physical or cognitive deficits. Spontaneous hyperglycemia is common in critically ill patients and is associated with an adverse outcome compared to normoglycemia. Insulin is used for treating hyperglycemia in the critically ill patients but may be complicated by hypoglycemia, which is difficult to detect in these patients and which may lead to serious neurological sequelae and death. The incretin hormone, glucagon-like peptide (GLP) 1, stimulates insulin secretion and inhibits glucagon release both in healthy individuals and in patients with type 2 diabetes (T2DM). Compared to insulin, GLP-1 appears to be associated with a lower risk of severe hypoglycemia, probably because the magnitude of its insulinotropic action is dependent on blood glucose (BG). This is taken advantage of in the treatment of patients with T2DM, for whom GLP-1 analogs have been introduced during the recent years. Infusion of GLP-1 also lowers the BG level in critically ill patients without causing severe hypoglycemia. The T2DM and critical illness share similar characteristics and are, among other things, both characterized by different grades of systemic inflammation and insulin resistance. The GLP-1 might be a potential new treatment target in critically ill patients with stress-induced hyperglycemia.

Topics: Blood Glucose; Critical Illness; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion

Incretin-based therapies are steadily gaining clinical popularity, with many more products in the developmental pipeline. Current treatment recommendations incorporate GLP-1 RAs and DPP-4 inhibitors as important agents for consideration in the treatment of T2DM owing to their low hypoglycemia risk, ability to address postprandial hyperglycemia (DPP-4 inhibitors and short-acting GLP-1 RAs), and potential for weight reduction (GLP-1 RAs). These properties may likewise prove advantageous in older adults in whom hypoglycemia is particularly undesirable, although older adults may be more prone to the nausea and vomiting associated with GLP-1 RA therapy. Other safety issues for incretin-based therapies, such as pancreatitis, C-cell hyperplasia, and renal failure, should be considered when choosing an appropriate patient to receive such therapies. Ongoing CV outcome studies will further inform the health care community regarding the CV safety of incretin-based therapies. The availability of both short-acting and long-acting GLP-1 RAs currently allows practitioners to consider individualized blood glucose trends and therapeutic needs when choosing an optimal agent.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Monitoring; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Receptors, Glucagon; Treatment Outcome; Weight Loss

Hyperglycemia in patients with and without a prior history of diabetes is an independent marker of morbidity and mortality in critically and noncritically ill patients. Improvement of glycemic control with insulin therapy has been shown to reduce hospital complications in patients with diabetes, but also results in increased rates of hypoglycemia, which have been linked to poor outcomes. Thus, alternative treatment options that can normalize blood glucose levels without undue hypoglycemia are being sought. Incretin-based therapies, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, stimulate insulin secretion in a glucose-dependent fashion, thus not causing hypoglycemia. Alternative points of view exist regarding insulin versus incretin therapy for the care of these patients. We have brought together the authors on the opposite sides of this discussion with the objective of providing a rational synthesis on how to achieve the best possible control of glycemia in the hospital, using both standard insulin approaches and incretin-based therapies to improve patient outcomes. This review examines the benefits of incretin-based therapy in improving glycemic control in hospitalized patients with stress-induced diabetes and in diabetic patients in critical care and non-critical care settings.

Topics: Diabetes Mellitus, Type 2; Hospitalization; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin

The purpose of this review is to discuss the clinical evidence for dipeptidyl peptidase-4 (DPP-4) inhibitors and to better define their use in treating type 2 diabetes mellitus (T2DM), including in special populations, such as the elderly. DPP-4 inhibitors are incretin-based therapies that can be used as monotherapy or in combination with other antidiabetes medications to treat T2DM. As monotherapy, DPP-4 inhibitors have demonstrated a modest and comparable glycated hemoglobin-lowering effect. As initial dual therapy with other antidiabetes agents, DPP-4 inhibitors significantly improved glycated hemoglobin when compared with monotherapy arms. Similarly, in triple combinations, DPP-4 inhibitors consistently provided additive glycemic benefits. In patients who were continuing insulin, glycemic parameters were improved with the addition of a DPP-4 inhibitor, and they required less insulin uptitration. In clinical trials, the overall occurrence of adverse events was similar between DPP-4 inhibitor groups and controls, and a low occurrence of hypoglycemia was observed, except when used in combination with a sulfonylurea. A neutral effect on weight was maintained, even in combination with insulin. Similar to outcomes observed in younger patients, DPP-4 inhibitors significantly improved glycemic efficacy in older patients, without increasing the risk for hypoglycemia. Efficacy and safety in patients with renal insufficiency are also documented.. DPP-4 inhibitors are therapeutically beneficial for a diverse population of patients with T2DM, including elderly patients, based on demonstrated efficacy, tolerability, and a low risk for hypoglycemia.

Topics: Age Factors; Aged; Aged, 80 and over; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Kidney; Metformin

Patients with hyperglycemia in hospital have increased adverse outcomes compared with patients with normoglycemia, and the pathophysiological causes seem relatively well understood. Thus, a rationale for excellent glycemic control exists. Benefits of control with intensive insulin regimes are highly likely based on multiple published studies. However, hypoglycemia frequency increases and adverse outcomes of hypoglycemia accrue. This has resulted in a 'push' for therapeutic nihilism, accepting higher glycemic levels to avoid hypoglycemia. One would ideally prefer to optimize glycemia, treating hyperglycemia while minimizing or avoiding hypoglycemia. Thus, one would welcome therapies and processes of care to optimize this benefit/ risk ratio. We review the logic and early studies that suggest that incretin therapy use in-hospital can achieve this ideal. We strongly urge randomized prospective controlled studies to test our proposal and we offer a process of care to facilitate this research and their use in our hospitalized patients.

Topics: Hospitalization; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin

Suboptimal blood glucose control among patients with type 2 diabetes continues to support the need for new pharmacologic approaches.. The purpose of this commentary was to highlight newly available and soon-to-be available agents that are promising tools for targeting specific pathophysiologic pathways in the management of diabetes.. Published evidence to support the application of novel incretin-based therapies, dipeptidyl peptidase (DPP)-4 inhibitors, sodium-glucose cotransporter (SGLT)-2 inhibitors, other oral agents and insulins for managing specific aspects of type 2 diabetes, as well as disadvantages associated with those novel medications, are discussed.. Several new glucagon-like peptide (GLP)-1 receptor agonists with different time frames of action, although each has unique advantages and disadvantages, have been through clinical trials. Examples of these are lixisenatide and albiglutide. Currently available DPP-4 inhibitor agents, important for inhibiting the breakdown of endogenous GLP-1, have not been associated with weight gain or hypoglycemia. SGLT-2 inhibitors, which do not depend on insulin secretion or insulin action, may be advantageous in that they appear to be broadly efficacious at all stages of diabetes. New insulin analogues, such as degludec and U-500, improve glycemic control without contributing to hypoglycemia.. Advances in pharmacologic options offer the promise of improving glycemic control for longer periods, with limited glycemic fluctuations, hypoglycemia, and weight gain. However, the effectiveness of these agents ultimately depends on their availability to providers managing the health care of patients at high risk for poor diabetes outcomes and patients' use of them as directed. Long-term effectiveness and safety trials are ongoing.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin, Long-Acting; Male; Peptides

Recently, incretin-based therapy was introduced for the treatment of type 2 diabetes (T2D). In particular, dipeptidyl peptidase-4 inhibitors (DPP-4i) (sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin) play an increasing role in the management of T2D.. An extensive literature search was performed to analyze the pharmacological characteristics of DPP-4i and their clinical implications.. DPP-4i present significant pharmacokinetic differences. They also differ in chemical structure, in the interaction with distinct subsites of the enzyme and in different levels of selectivity and potency of enzyme inhibition. Moreover, disparities in the effects on glycated hemoglobin, glucagon-like peptide-1 and glucagon levels and on glucose variability have been observed. However, indirect comparisons indicate that all DPP-4i have a similar safety and efficacy profiles. DPP-4i are preferred in overweight/obese and elderly patients because of the advantages of minimal or no influence on weight gain and low risk of hypoglycemia. For the same reasons, DPP-4i can be safely combined with insulin. However, currently cardiovascular outcomes related to DPP-4i are widely debated and the available evidence is controversial. Today, long-term studies are still in progress and upcoming results will allow us to better define the strengths and limits of this therapeutic class.

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Weight Gain

Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer.

Topics: Cardiovascular Diseases; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Nausea; Pancreatic Neoplasms; Pancreatitis; Thyroid Neoplasms

GLP-1 receptors agonists have been a substantial change in treatment of type 2 diabetes mellitus, and its weekly administration has broken pre-established schemes. Daily exenatide is administered every 12 hours (BID) subcutaneously, while weekly exenatide is administered once a week. Both molecules share a common mechanism of action but have differential effects on basal and postprandial glucose. We review the major clinical trials with both exenatide BID and weekly exenatide. It can be concluded that exenatide BID shows a hypoglycemic effect similar to other treatments for type 2 DM but adding significant weight loss with low incidence of hypoglycemia. Weekly exenatide decreases HbA1c similar to liraglutide but larger than exenatide BID, both glargine and biphasic insulin, sitagliptin, and pioglitazone, maintaining weight loss and adding to gastrointestinal intolerance the induration at the injection site as a side effect.

Topics: Delayed-Action Preparations; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Exenatide; Female; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Male; Metformin; Peptides; Pioglitazone; Receptors, Glucagon; Thiazolidinediones; Venoms; Weight Loss

Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer.

Topics: Animals; Antibody Formation; Blood Pressure; Carcinoma, Medullary; Cardiotonic Agents; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Gastrointestinal Motility; Glucagon-Like Peptide-1 Receptor; Heart; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Lipids; Meta-Analysis as Topic; Nausea; Pancreatitis; Receptors, Glucagon; Rodentia; Species Specificity; Thyroid Neoplasms; Vomiting

Noninsulin antidiabetic medications coupled with diet and exercise are effective in managing most patients with type 2 diabetes. However, it is essential to evaluate the safety and effectiveness of the home antidiabetic medication regimen when the patient is hospitalized. Prescribers need to be aware of the mechanism of action of each class, contraindications, precautions, and adverse effects to formulate a safe and effective management plan. This article details the different classes of noninsulin antidiabetic medications, the mechanism of action, metabolism, elimination, dose form, usual and maximum doses, contraindications, precautions, common adverse reactions, and implications for use in the hospitalized patient.

Topics: Benzamides; Biguanides; Bromocriptine; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glycoside Hydrolase Inhibitors; Hospitalization; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Islet Amyloid Polypeptide; Metformin; Sulfonylurea Compounds; Thiazolidinediones

Once lifestyle measures implemented, if hyperglycemia persists, above individual HbA1c targets, a medication should be started in type 2 diabetic patients (T2DM). First, unless exception, an oral antidiabetic drug. Except in case of intolerance, the initial monotherapy, metformin remains the strengthening treatment. Latter, combination of two oral drugs, now offers several options, mainly the choice to associate a "conventional insulin-secretor", sulfonylureas, glinide, or a "new one" belonging the class of "incretin", more readily a gliptine (DPP-4 inhibitors) rather than injectable GLP-1 analogue which can also be sometimes chosen at this stage. These options are mostly new and have the advantage a neutral or favourable (for GLP-1) effect on body weight in obese type 2 DM patient and the absence of any hypoglycaemic risk in both classes of incretins. But this risk varies depending on the patient profile, much higher if the target HbA1c is low (6 to 6.5 or 7%), or in the elderly, fragile and/or in case of renal insufficiency. These two different situations with a high risk of hypoglycaemia, define best indications of this new class. If dual oral therapy does not achieve the goals we are faced with three options: triple oral therapy: metformin-sulfonylurea-gliptine or one of two approaches with injections, insulin or GLP-1 analogues. The use of GLP-1 analogues is often delayed today and put wrongly in balance with the transition to insulin, a use already delayed in France and insufficient. The use of incretins is new and needs to be validated by studies of sustainability on glycemic control, prevention of microvascular and macrovascular complications and after years on the market security of use, primarily on the exocrine pancreas. In short, individualization of strategies and HbA1c targets are required, the new molecules can help us in this process. This individualization can easily be done through the handy guide proposed by the experts ADA EASD statement, endorsed by the SFD, abandoning the complex algorithm recently again proposed by HAS and ANSM in 2013. A recommendation that prioritizes the costs of the strategies. An absolutely critical issue, while admitting not to have the tools to measure them in all their dimensions. Finally, we must reconsider every treatment after a maximum of 6 months of use, if the results are deemed inadequate substitute rather than adding drugs.

Topics: Administration, Oral; Body Weight; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Management; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Goals; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Kidney; Metformin; Obesity; Practice Guidelines as Topic; Risk; Societies, Medical; Sulfonylurea Compounds

Abstract Diet, lifestyle modification, and pharmacotherapy with metformin are appropriate initial treatments for many patients with type 2 diabetes (T2DM). However, most individuals do not maintain glycemic control with metformin alone. Addition of other oral antidiabetes drugs (OADs), including sulfonylurea, meglitinide, or thiazolidinedione, is often the next step. Newer options, including incretin-based glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, offer important benefits as monotherapies or in combination with OADs, with low risk for hypoglycemia. Reductions in glycated hemoglobin (A1C) have been reported among patients treated with GLP-1 RAs (exenatide, -0.8 to -1.1%; liraglutide, -0.8 to -1.6%), as has weight loss (exenatide, -1.6 to -3.1 kg; liraglutide, -1.6 to -3.2 kg). GLP-1 RAs also stimulate β-cell responses and have positive effects on cardiovascular risk factors often present in patients with T2DM. The most common adverse events associated with GLP-1 RAs are nausea, which diminishes over time, and hypoglycemia (when used in combination with a sulfonylurea). A large number of trials demonstrated benefits of GLP-1 RAs, suggesting they could provide suitable treatment options for patients with T2DM.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Liraglutide; Peptides; Receptors, Glucagon; Venoms

The role of glucagon-like peptide (GLP)-1-based treatment approaches for type 2 diabetes mellitus (T2DM) is increasing. Although self-monitoring of blood glucose (SMBG) has been performed in numerous studies on GLP-1 analogs and dipeptidyl peptidase-4 inhibitors, the potential role of SMBG in GLP-1-based treatment strategies has not been elaborated. The expert recommendation suggests individualized SMBG strategies in GLP-1-based treatment approaches and suggests simple and clinically applicable SMBG schemes. Potential benefits of SMBG in GLP-1-based treatment approaches are early assessment of treatment success or failure, timely modification of treatment, detection of hypoglycemic episodes, assessment of glucose excursions, and support of diabetes management and diabetes education. Its length and frequency should depend on the clinical setting and the quality of metabolic control. It is considered to play an important role for the optimization of diabetes management in T2DM patients treated with GLP-1-based approaches.

Topics: Biomarkers; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Europe; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Practice Guidelines as Topic; Predictive Value of Tests; Time Factors; Treatment Outcome

Although several classes of pharmacotherapy are available for type 2 diabetes, glycaemic control is often hampered by medication-related adverse effects and contraindications such as renal impairment. Glucagon-like peptide-1 (GLP-1) receptor agonists provide a new pharmacotherapeutic option based on the multiple glucose-lowering effects of the human hormone GLP-1. This mechanism of action not only provides therapeutic efficacy but also suggests that GLP-1 receptor agonists have distinct safety and tolerability concerns compared with other diabetes therapies. Stimulation of pancreatic insulin secretion by GLP-1 receptor agonists is glucose dependent, conferring a lesser risk of hypoglycaemia than that seen with sulfonylureas. Individual GLP-1 receptor agonists differ in their metabolism and excretion profiles, affecting the choice of agent for patients with renal impairment. As with other protein-based therapies, GLP-1 receptor agonists may induce the formation of antibodies that may attenuate therapeutic efficacy and affect safety. Conclusions on cardiovascular safety must await outcomes studies, but at present no signal of harm has been reported, and preclinical data and effects on risk markers suggest a potential for benefit. Current data on thyroid medullary cancer in humans and pancreatic malignancy in rodents do not suggest that there is any reason to restrict the clinical use of GLP-1 analogues in most people with diabetes. It is currently difficult to ascertain the possible contributory role of GLP-1 receptor agonists in increasing the risk of pancreatitis, and vigilance for signs and symptoms is prudent. Primary tolerability issues include transient gastrointestinal symptoms, common with GLP-1 receptor agonists, which can be reduced through dose titration.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug-Related Side Effects and Adverse Reactions; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Incretins; Liraglutide; Nausea; Pancreatitis; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Thyroid Gland; Venoms; Vomiting

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a clinically validated target for treatment of insulin resistance. PPARgamma activation by full agonists such as thiazolidinediones has shown potent and durable glucose-lowering activity in patients with type 2 diabetes without the concern for hypoglycemia or gastrointestinal toxicities associated with some other medications used to treat this disease. However, thiazolidinediones are linked to safety and tolerability issues such as weight gain, fluid retention, edema, congestive heart failure, and bone fracture. Distinctive properties of PPARgamma provide the opportunity for selective modulation of the receptor such that desirable therapeutic effects may be attained without the unwanted effects of full activation. PPARgamma is a nuclear receptor that forms a complex with coreceptor RXR and a cell type- and cell state-specific array of coregulators to control gene transcription. PPARgamma affinity for these components, and hence transcriptional response, is determined by the conformational changes induced by ligand binding within a complex pocket with multiple interaction points. This molecular mechanism thereby offers the opportunity for selective modulation. A desirable selective PPARgamma modulator profile would include high-affinity interaction with the PPARgamma-binding pocket in a manner that leads to retention of the insulin-sensitizing activity that is characteristic of full agonists as well as mitigation of the effects leading to increased adiposity, fluid retention, congestive heart failure, and bone fracture. Examples of endogenous and synthetic selective PPARgamma modulator (SPPARM) ligands have been identified. SPPARM drug candidates are being tested clinically and provide support for this strategy.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gluconeogenesis; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Resistance; Pioglitazone; PPAR gamma; Quinolines; Retinoid X Receptors; Rosiglitazone; Sulfonamides; Thiazolidinediones

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Nitriles; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Vildagliptin

Established therapies for type-2 diabetes effectively reduce blood glucose, but are often associated with adverse effects that pose risks to patient's health or diminish adherence to treatment. Weight gain, hypoglycaemia and gastrointestinal symptoms are commonly reported and some agents may not be safe for use in patients with renal impairment or elevated cardiovascular risk. New treatments based on the action of the endogenous human hormone glucagon-like peptide-1 (GLP-1), including exenatide and liraglutide, are available. These therapies provide a novel pharmacological approach to glycaemic control via multiple mechanisms of action, and accordingly exhibit different safety and tolerability profiles than conventional treatments. GLP-1 receptor agonists stimulate insulin release only in the presence of elevated blood glucose and are therefore associated with a fairly low risk of hypoglycaemia. Gastrointestinal symptoms are common but transient, and there appears to be little potential for interaction with other drugs. GLP-1 receptor agonists are associated with weight loss rather than weight gain. As protein-based therapies, these agents have the potential to induce antibody formation, but the impact on efficacy and safety is minor. GLP-1 receptor agonists thus offer a new and potentially useful option for clinicians concerned about some of the common adverse effects of type-2 diabetes therapies.

Topics: Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Drug Interactions; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Diseases; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Kidney Diseases; Pancreatitis; Receptors, Glucagon; Sulfonylurea Compounds; Thiazolidinediones; Thyroid Diseases

Type 2 diabetes mellitus (DM) is a prevalent disorder that affects children, adolescents, and adults worldwide. In addition to risks of microvascular disease, patients with type 2 DM often have multiple risk factors of macrovascular disease; for example, approximately 90% of patients with type 2 DM are overweight/obese. Type 2 DM is a complex disease that involves a variety of pathophysiologic abnormalities, including insulin resistance, increased hepatic glucose production, and abnormalities in the secretion of hormones, such as insulin, glucagon, amylin, and incretins. Incretins are gut-derived peptides with a variety of glucoregulatory functions. Incretin dysfunction can be treated with glucagon-like peptide 1 (GLP-1) receptor agonists (eg, exenatide and liraglutide) or inhibitors of dipeptidyl peptidase 4 (DPP-4) (eg, sitagliptin and saxagliptin), the enzyme that degrades GLP-1. The GLP-1 receptor agonists and DPP-4 inhibitors both elevate GLP-1 activity and substantially improve glycemic control. The GLP-1 receptor agonists are more effective in lowering blood glucose and result in substantial weight loss, whereas therapy with DPP-4 inhibitors lowers blood glucose levels to a lesser degree, and they are weight neutral. Treatment with GLP-1 receptor agonists has demonstrated durable glycemic control and improvement in multiple cardiovascular disease risk factors. In addition, unlike insulin or sulfonylureas, treatment with a GLP-1 receptor agonist or a DPP-4 inhibitor has not been associated with substantial hypoglycemia. These factors should be considered when selecting monotherapy or elements of combination therapy for patients with type 2 DM who are overweight/obese, for patients who have experienced hypoglycemia with other agents, and when achieving glycemic targets is difficult.

Topics: Adolescent; Adult; Blood Glucose; Child; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Male; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Treatment Outcome; Young Adult

The demonstration that the incretin hormone glucagon-like peptide 1 can improve glycaemic control in patients with type 2 diabetes has led to the rapid development during the last decade of promising new classes of agent for the management of type 2 diabetes. These agents possess a range of physiological effects that are associated with improved glycaemic control in diabetes including stimulation of glucose-dependent insulin secretion, suppression of glucagon secretion, slowing of gastric emptying, and reduction of food intake. In addition, preclinical studies suggest that incretin-based therapies may improve beta-cell function via enhancement of beta-cell mass and induction of genes important for differentiated beta-cell function. Exenatide, and the dipeptidyl peptidase-4 inhibitors, sitagliptin and vildagliptin are already approved, and liraglutide is currently completing Phase 3 trials. As these agents and standard oral therapies for type 2 diabetes lower glucose levels through different, but potentially complementary mechanisms, their use in combination should provide effective, potentially additive, glycaemic control. The incretin-based therapies also offer other advantages such as weight loss with exenatide and liraglutide, a reduced risk of hypoglycaemia, and as suggested by preclinical studies, a potential beta-cell preserving effect. Long-term outcome and safety data are not available for these agents, but they appear generally well-tolerated in comparison with existing therapies for type 2 diabetes. The multiple underlying glucose-lowering actions of the incretin-based therapies, as well as a lack of weight gain or even weight loss, make these important new additions to available antidiabetic agents expanding the treatment options available for patients.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Incretins; Insulin; Risk Factors; Weight Loss

Topics: Animals; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Receptors, Glucagon

One of the challenges facing health care providers in the treatment of patients with type 2 diabetes mellitus is maintaining the balance between achieving hemoglobin A(1c) targets while simultaneously minimizing adverse events-most notably hypoglycemia and weight gain-that may negatively affect adherence to therapy and thus treatment outcomes. Incretin-based treatments, such as glucagon-like peptide-1 (GLP-1)-receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, are the newest class of therapies for the management of patients with type 2 diabetes. Data from clinical trials in which liraglutide, exenatide, saxagliptin, or sitagliptin were employed as monotherapy or added to ongoing antidiabetic treatment indicate that the incretin-based therapies have very low risk for the development of hypoglycemia and either decrease body weight (GLP-1-receptor agonists) or are weight neutral (DPP-4 inhibitors). Decreased risk for hypoglycemia and weight gain may improve adherence. Avoiding weight gain, which is commonly associated with older oral antidiabetic agents and some insulins, also has the potential to decrease the risk for cardiovascular disease. Future pharmacoeconomic studies may demonstrate translation of these benefits into good cost-effectiveness for these therapies.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Incretins; Patient Compliance; Randomized Controlled Trials as Topic; Weight Gain

Maintaining an adequate metabolic control is still a challenge in many patients with type 2 diabetes. Among the many factors advocated to explain the failure to achieve recommended goals, clinical inertia is increasingly recognised as a primary cause of poor glycaemic control. The existence of a "metabolic memory" strongly supports the adoption of a more aggressive treat-to-target approach, instead of waiting for treatment failure. This approach may be particularly important in the initial phases of the disease, to slow the progressive decline of beta-cell function and improve overall outcomes. The fear of hypoglycaemia and weight gain associated with most of the available treatments are among the main causes of clinical inertia, and strongly affect the attitudes of providers and patients toward therapy intensification. The incretin-based therapies represent a new potential goal-oriented treatment approach. Two classes of incretin-based drugs have been developed: GLP-1 mimetics (exenatide and liraglutide) and DPP-IV inhibitors (sitagliptin and vildagliptin). Incretino-mimetics have a peculiar mechanism of action that is associated with lack of hypoglycaemia and weight loss or neutrality; these characteristics may facilitate therapy intensification and help to attain established goals. Furthermore, they can induce benefits in terms of post-prandial hyperglicemia control and beta-cell function preservation. An early use of this class of drugs may show a positive impact on the disease progression and a delay in the need of insulin injections.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Since Diabetes Control and Complications Trial (DCCT), intensive therapy has been directed at achieving glucose and glycosylated hemoglobin (HbA1c) values as close to normal as possible regarding safety issues. However, hyperglycemia (especially postprandial hyperglycemia) and hypoglicemia continue to be problematic in the management of type 1 diabetes. The objective of associating other drugs to insulin therapy is to achieve better metabolic control lowering postprandial blood glucose levels. Adjunctive therapies can be divided in four categories based on their mechanism of action: enhancement of insulin action (e.g. the biguanides and thiazolidinediones), alteration of gastrointestinal nutrient delivery (e.g. acarbose and amylin) and other targets of action (e.g. pirenzepine, insulin-like growth factor I and glucagon-like peptide-1). Many of these agents have been found to be effective in short-term studies with decreases in HbA1c of 0.5-1%, lowering postprandial blood glucose levels and decreasing daily insulin doses.

Topics: Acarbose; Amyloid; Blood Glucose; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin-Like Growth Factor I; Islet Amyloid Polypeptide; Metformin; Muscarinic Antagonists; Pirenzepine; Postprandial Period; Thiazolidinediones

Exenatide is an incretin mimetic, while sitagliptin and vildagliptin are incretin enhancers used as adjunctive therapy in patients with type 2 diabetes failing oral agents. Sitagliptin and vildagliptin can also be used as monotherapy in patients with type 2 diabetes uncontrolled by diet.. To provide a critical review of clinical trials of exenatide, sitagliptin and vildagliptin.. Review of Phase III clinical trials based on Medline search published up to April 2008.. The use of exenatide is associated with reduction in average hemoglobin A1c (HbA1c) levels of approximately 0.8% compared with baseline. The corresponding reduction with either sitagliptin or vildagliptin is 0.7%. The actions of incretin-based drugs predominantly target postprandial hyperglycemia. Treatment-related hypoglycemia is generally mild, and mainly occurs when used with sulfonylureas (SUs). Exenatide treatment leads to a mild weight loss of around 2 kg after 30 weeks, whereas sitagliptin and vildagliptin have generally neutral effect on weight. Sitagliptin and vildagliptin are well tolerated in trials lasting up to 52 weeks. Meanwhile, 5 - 10% of patients cannot tolerate exenatide due to adverse effects, mainly nausea and vomiting. The three drugs are limited by the lack of long-term safety and efficacy data, as well as by their high cost.. Exenatide, sitagliptin and vildagliptin are useful add-on therapy for type 2 diabetes that is suboptimally controlled on oral agents, particularly when there is concern about weight gain and hypoglycemia, or when postprandial hyperglycemia is the major cause of inadequate glycemic control. Sitagliptin and vildagliptin may be used as monotherapy in patients who cannot tolerate metformin or SU, and sitagliptin may be used as alternative to metformin in renal insufficiency.

Topics: Adamantane; Body Weight; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Nausea; Nitriles; Peptides; Pyrazines; Pyrrolidines; Randomized Controlled Trials as Topic; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin; Vomiting

Management of elderly patients with type II diabetes is complicated by age-related changes in physiology, comorbidities, polypharmacy and heterogeneity of functional status. A minimum goal in antidiabetic treatment in this population is to achieve a level of glycaemic control that avoids acute complications of diabetes, adverse effects and reduction in quality of life. Hypoglycaemia is a particular problem in elderly patients, and many antidiabetic agents pose increased risk for hypoglycaemia. In addition, many standard agents pose risks for older patients because of reduced renal function and common comorbidities. Newer agents based on enhancing incretin activity, including the glucagon-like peptide-1 mimetics exenatide and liraglutide and the oral dipeptidyl peptidase-4 inhibitors sitagliptin and vildagliptin, may offer particular advantages in elderly patients with diabetes.

Topics: Aged; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Middle Aged

The aim of the study was to explore the role of GLP-1 receptor activation on the counter-regulation and symptoms of hypoglycemia in subjects who have undergone gastric bypass surgery (GBP).. Experimental hyperinsulinemic-hypoglycemic clamp study.. Twelve post-GBP subjects participated in a randomized cross-over study with two hyperinsulinemic, hypoglycemic clamps (glucose nadir 2.7 mmol/L) performed on separate days with concomitant infusions of the GLP-1 analog exenatide or with saline, respectively. Continuous measurements of metabolites and counter-regulatory hormones as well as assessments of heart rate variability and symptoms of hypoglycemia were performed throughout the clamps.. No effect of GLP-1 receptor activation on counter-regulatory hormones (glucagon, catecholamines, cortisol, GH) or glucose infusion rate was seen, but we found indications of a downregulation of the sympathetic relative to the parasympathetic nerve activity, as reflected in heart rate variability. No significant differences in symptom of hypoglycemia were observed.. Short-term exposure to a GLP-1 receptor agonist does not seem to impact the counter-regulatory hormonal and metabolic responses in post-GBP subjects during hypoglycemic conditions, suggesting that the improvement in symptomatic hypoglycemia post-GBP seen following treatment with GLP-1 receptor agonists may be mediated by mechanism not directly involved in counter-regulation.

Topics: Adult; Blood Glucose; Catecholamines; Cross-Over Studies; Exenatide; Female; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Heart Rate; Human Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Incretins; Male; Middle Aged; Parasympathetic Nervous System; Postoperative Period; Sympathetic Nervous System

Topics: Anti-Obesity Agents; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Drug Combinations; Drug Monitoring; Drug Resistance, Multiple; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Metformin; Obesity; Overweight; Weight Gain; Weight Loss

To simplify administration of aqueous exenatide once weekly, which requires reconstitution, the exenatide microspheres have been reformulated in a ready-to-use autoinjector with a Miglyol diluent (exenatide QWS-AI). This study compared the efficacy and safety of exenatide QWS-AI with the first-in-class glucagon-like peptide-1 receptor agonist exenatide twice daily (BID).. This randomized, open-label, controlled study in patients with type 2 diabetes using diet and exercise or taking stable oral glucose-lowering medication randomized patients 3:2 to either exenatide QWS-AI (2 mg) or exenatide BID (10 μg) for 28 weeks. The primary outcome was the 28-week change in glycated haemoglobin (HbA1c). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments.. A total of 375 patients (mean HbA1c, 8.5% [69 mmol/mol]; body mass index, 33.2 kg/m. Exenatide QWS-AI was associated with a greater reduction in HbA1c, similar weight loss and a favorable gastrointestinal AE profile compared with exenatide BID.

Topics: Cardiovascular Diseases; Cohort Studies; Combined Modality Therapy; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Jet; Intention to Treat Analysis; Male; Middle Aged; Patient Dropouts; Peptides; Risk Factors; Severity of Illness Index; Suspensions; United States; Venoms

To investigate the effects of 24 weeks of treatment with liraglutide added to basal/bolus insulin on anthropometric and metabolic parameters in overweight participants with type 1 diabetes.. In a double-blinded cross-over fashion, 15 participants were randomly assigned (1:1) to receive placebo (saline solution) or liraglutide for 24 weeks including a 1-month titration period from 0.6 to 1.2 to 1.8 mg, in addition to their insulin. The treatment was followed by a 1-month wash-out period. Participants were then assigned to the other treatment for another 24 weeks. Paired rank tests were used to compare the metabolic parameters.. There was no treatment effect on HbA1c nor on insulin dose. Heart rate was increased by about 8 beats per minute with liraglutide. There were significant reductions in metabolic measures: weight, body mass index, waist and hip circumferences, body fatness, computed tomography scan abdominal and mid-thigh measurements, systolic and diastolic blood pressures (all P ≤ .05). There was no increase in time spent in hypoglycaemia with liraglutide.. The addition of liraglutide to basal/bolus insulin therapy for 24 weeks in overweight/obese individuals with type 1 diabetes improved the anthropometric and metabolic profiles without an increase in hypoglycaemia. Clinical Trials.gov No: NCT01787916.

Topics: Adiposity; Adult; Anti-Obesity Agents; Body Mass Index; Cohort Studies; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin; Liraglutide; Male; Overweight

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

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

To compare the efficacy and safety of adding the glucagon-like peptide-1 receptor agonist exenatide once weekly (QW) 2 mg or placebo among patients with type 2 diabetes who were inadequately controlled despite titrated insulin glargine (IG) ± metformin.. This multicentre, double-blind study (ClinicalTrials.gov identifier: NCT02229383) randomized (1:1) patients with persistent hyperglycaemia after an 8-week titration phase (glycated haemoglobin [HbA1c] 7.0%-10.5% [53-91 mmol/mol]) to exenatide QW or placebo. The primary endpoint was HbA1c change from baseline to week 28. Secondary endpoints included body weight, 2-hour postprandial glucose, and mean daily IG dose.. Of 464 randomized patients (mean: age, 58 years; HbA1c, 8.5% [69 mmol/mol]; diabetes duration, 11.3 years), 91% completed 28 weeks. Exenatide QW + IG vs placebo + IG significantly reduced HbA1c (least-squares mean difference, -0.73% [-8.0 mmol/mol]; 95% confidence interval, -0.93%, -0.53% [-10.2, -5.8 mmol/mol]; P < .001; final HbA1c, 7.55% [59 mmol/mol] and 8.24% [67 mmol/mol], respectively); body weight (-1.50 kg; -2.17, -0.84; P < .001); and 2-hour postprandial glucose (-1.52 mmol/L [-27.5 mg/dL]; -2.15, -0.90 [-38.7, -16.2]; P < .001). Significantly more exenatide QW + IG-treated patients vs placebo + IG-treated patients reached HbA1c <7.0% (<53 mmol/mol) (32.5% vs 7.4%; P < .001); daily IG dose increased by 2 and 4 units, respectively. Gastrointestinal and injection-site adverse events were more frequent with exenatide QW + IG (15.1% and 7.8%, respectively) than with placebo + IG (10.8% and 3.0%, respectively); hypoglycaemia incidence was similar between the exenatide QW + IG (29.7%) and placebo + IG (29.0%) groups, with no major hypoglycaemic events.. Among patients with inadequate glycaemic control, exenatide QW significantly improved glucose control and decreased body weight, without increased hypoglycaemia or unexpected safety findings.

Topics: Aged; Body Mass Index; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Exenatide; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Glargine; Male; Middle Aged; Obesity; Weight Loss

Sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are antihyperglycaemic agents with weight-lowering effects. The efficacy and safety of the SGLT2 inhibitor canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control with a GLP-1RA (≥12 weeks) were evaluated in this phase IV study. Patients received canagliflozin 100 mg once daily for 52 weeks. Efficacy endpoints included change in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight, systolic blood pressure (SBP) and HDL cholesterol from baseline to week 52. Safety endpoints included adverse events (AEs), hypoglycaemia and laboratory tests. Of the 71 patients treated with canagliflozin, 63 completed the study. At 52 weeks, HbA1c was significantly reduced from baseline (-0.70%; paired t test, P < .001). Significant changes were also observed in FPG (-34.7 mg/dL), body weight (-4.46%), SBP (-7.90 mm Hg), and HDL cholesterol (7.60%; all P < .001). The incidence of AEs, adverse drug reactions and hypoglycaemia was 71.8%, 32.4% and 9.9%, respectively. All hypoglycaemic events were mild. These findings suggest that the long-term combination of canagliflozin with a GLP-1RA is effective and well tolerated in Japanese patients with T2DM.

Topics: Aged; Blood Glucose; Blood Pressure; Body Weight; Canagliflozin; Cholesterol, HDL; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Incretins; Japan; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

We performed a randomized controlled trial with the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide as add-on to standard peri-operative insulin therapy in patients undergoing elective cardiac surgery. The aims of the study were to intensify peri-operative glucose control while minimizing the risk of hypoglycaemia and to evaluate the suggested cardioprotective effects of GLP-1-based treatments. A total of 38 patients with decreased left ventricular systolic function (ejection fraction ≤50%) scheduled for elective coronary artery bypass grafting (CABG) were randomized to receive either exenatide or placebo in a continuous 72-hour intravenous (i.v.) infusion on top of standard peri-operative insulin therapy. While no significant difference in postoperative echocardiographic variables was found between the groups, participants receiving exenatide showed improved peri-operative glucose control as compared with the placebo group (average glycaemia 6.4 ± 0.5 vs 7.3 ± 0.8 mmol/L; P < .001; percentage of time in target range of 4.5-6.5 mmol/L 54.8% ± 14.5% vs 38.6% ± 14.4%; P = .001; percentage of time above target range 39.7% ± 13.9% vs 52.8% ± 15.2%; P = .009) without an increased risk of hypoglycaemia (glycaemia <3.3 mmol/L: 0.10 ± 0.32 vs 0.21 ± 0.42 episodes per participant; P = .586). Continuous administration of i.v. exenatide in patients undergoing elective CABG could provide a safe option for intensifying the peri-operative glucose management of such patients.

Topics: Aged; Cardiotonic Agents; Coronary Artery Bypass; Czech Republic; Drug Therapy, Combination; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Heart; Hospitals, University; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Incretins; Infusions, Intravenous; Insulin; Intraoperative Complications; Male; Peptides; Perioperative Care; Postoperative Complications; Proof of Concept Study; Risk; Single-Blind Method; Venoms; Ventricular Dysfunction, Left

We have previously reported that once-weekly albiglutide was noninferior to thrice-daily lispro for glycemic lowering, with decreased weight and risk of hypoglycemia, in patients inadequately controlled on basal insulin over 26 weeks. Findings after 52 weeks reveal similar responses to albiglutide as an add-on to insulin glargine.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Monitoring; Drug Resistance; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Incretins; Insulin Glargine; Insulin Lispro; Meals; Risk; Weight Gain; Weight Loss

To characterize gastrointestinal adverse events (AEs) with different glucagon-like peptide-1 receptor agonists (GLP-1RAs).. Two retrospective intention-to-treat analyses of 6-month patient-level data were conducted. Data from three studies comparing exenatide once weekly (n = 617) with exenatide twice daily (n = 606) were pooled, and one (DURATION-6) comparing exenatide once weekly (n = 461) with liraglutide (n = 450) was analysed separately. Patient-reported gastrointestinal AEs were classified as upper or lower, AE incidences and timing were determined, subgroups were analysed, and associations of gastrointestinal AEs with efficacy were examined.. Nausea was the most common gastrointestinal AE for all treatments. Fewer exenatide once-weekly-treated vs exenatide twice-daily- or liraglutide-treated patients reported gastrointestinal AEs (34% vs 45% and 25% vs 41%, respectively; both P  < .0001). Fewer exenatide once-weekly-treated patients reported upper plus lower events than liraglutide-treated patients ( P  < .001); the difference between exenatide once weekly and twice daily was not significant. Within each group, more women than men reported gastrointestinal AEs. Events occurrred early and were predominantly mild. Glycated haemoglobin reductions were similar for patients with or without gastrointestinal AEs. Weight loss was greater for patients with gastrointestinal AEs with exenatide once weekly and exenatide twice daily ( P  < .05); no difference was observed in DURATION-6.. Gastrointestinal AEs were less frequent with exenatide once weekly vs exenatide twice daily or liraglutide, and combined upper and lower events occurred less often. Gastrointestinal AEs were typically mild and occurred early. Gastrointestinal AEs did not affect glycaemic control but may be associated with greater weight loss.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Gastrointestinal Diseases; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Incidence; Incretins; Intention to Treat Analysis; Liraglutide; Male; Nausea; Patient Dropouts; Peptides; Retrospective Studies; Self Report; Severity of Illness Index; Sex Factors; Venoms; Weight Loss

Sustained exogenous stimulation of a hormone-specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon-like peptide-1 (GLP-1) agonists on the endogenous GLP-1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years' duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP-1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUC

Topics: Adult; Diabetes Mellitus, Type 2; Double-Blind Method; Enteroendocrine Cells; Enzyme-Linked Immunosorbent Assay; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin-Secreting Cells; Liraglutide; Time Factors

To evaluate the efficacy and safety of fasiglifam, an orally active G-protein-coupled receptor 40 agonist, in combination with the dipeptidyl peptidase-4 inhibitor sitagliptin, in patients with type 2 diabetes inadequately controlled with diet/exercise (± metformin).. In this randomized, double-blind, phase II study, 368 patients received once-daily placebo, sitagliptin 100 mg, fasiglifam 25 or 50 mg, or the combination of sitagliptin 100 mg plus fasiglifam 25 or 50 mg. The primary endpoint was change from baseline glycated haemoglobin (HbA1c) at 12 weeks; a key secondary endpoint was change in fasting plasma glucose (FPG).. The fasiglifam 25 and 50 mg combination regimens produced significantly greater HbA1c reductions than sitagliptin (treatment differences of -0.45% and -0.61%; P < .01, respectively) or respective doses of fasiglifam monotherapy (-0.43% and -0.48%; P < .01) and significantly greater FPG reductions than sitagliptin (-1.1 mmol/L for both combination regimens; P < .01). Improved glycaemic control occurred by week 1 for FPG and week 4 for HbA1c in all groups. Hypoglycaemia rates were low (≤3.3%) and similar across treatments. Liver enzymes >3 × upper limit of normal occurred in four patients (fasiglifam 25 mg, n = 1; fasiglifam 50 mg, n = 2; 1 fasiglifam/sitagliptin 50/100 mg, n = 1).. Combination of fasiglifam and sitagliptin provided significant additional effects on glycaemic control, with hypoglycaemia rates similar to placebo with or without metformin. This study provides supportive clinical evidence for the complementary mechanism of actions of this GPR40 agonist and DPP-4 inhibitor.

Topics: Benzofurans; Combined Modality Therapy; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Hemoglobins, Abnormal; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Incretins; Male; Metformin; Middle Aged; Receptors, G-Protein-Coupled; Sitagliptin Phosphate; Sulfones; United States

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) stimulate the incretin system and lower glycaemic parameters in type 2 diabetes mellitus (T2DM). This analysis of clinical studies of up to 3years evaluated the safety of albiglutide, a GLP-1 RA, in people with T2DM.. Integrated safety analysis included seven phase-3 T2DM studies of albiglutide compared with placebo and/or active comparators (a dipeptidyl peptidase-4 inhibitor, GLP-1 RA, insulin, sulphonylurea, and thiazolidinedione).. Studies of 32months (HARMONY 7), 1year (HARMONY 6), and 3years (HARMONY 1-5), reported similar rates of adverse events (AEs) (84.8%, 82.3%), and serious AEs (13.1%, 12.9%) between albiglutide and all comparators, respectively. AEs that did not differ between the groups included symptomatic or severe hypoglycaemia as well as nausea (12.0%, 11.3%) and vomiting (5.3%, 4.7%) for albiglutide and all comparators, respectively. According to the Medical Dictionary for Regulatory Activities preferred terms, only diarrhoea (13.7%, 9.9%), injection-site reaction (9.0%, 2.0%), and peripheral oedema (4.5%, 6.8%) had at least 2% difference between the albiglutide and all-comparator groups. In a similar integrated analysis, pancreatitis occurred more often with albiglutide (0.3%, 0.1%). Renal and cardiac function did not differ between the two groups.. In an integrated analysis of seven phase 3 clinical trials, albiglutide-treated patients experienced frequencies of AEs (including cardiovascular and renal) similar to the all-comparators group treated with other T2DM medications or placebo. Albiglutide treatment was associated with higher rates of diarrhoea and injection-site reactions, but not increased nausea and vomiting, versus all comparators.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections; Insulin; Male; Middle Aged; Sulfonylurea Compounds

The aim of this study was to evaluate the efficacy and safety of sitagliptin administered to elderly patients with type 2 diabetes mellitus (T2DM) for 1 year as compared with glimepiride. Patients aged ≥60 years with T2DM and inadequately controlled blood glucose were randomly assigned to sitagliptin 50 mg once daily or glimepiride 0.5 mg once daily for 52 weeks. The primary efficacy endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 52. Secondary efficacy endpoints included self-monitored blood glucose and weight. Safety endpoints were adverse events including hypoglycaemia. Administration of sitagliptin or glimepiride to elderly patients with T2DM resulted in a significant decrease in HbA1c change from baseline. At 52 weeks, the least squares mean difference between the treatments was 0.11% (95% confidence interval [CI] -0.02 to 0.24; P = .087) (1.2 mmol/mol [-0.2 to 2.6]). The upper limit of the CI was below the predefined non-inferiority margin (0.3% [3.3 mmol/mol]), demonstrating non-inferiority of sitagliptin to glimepiride for the primary endpoint. Sitagliptin resulted in a significantly lower incidence rate of non-serious hypoglycaemia than glimepiride during the 52 weeks (4.7% vs 16.1%; P = .002); thus, sitagliptin is a useful therapeutic option for elderly patients with T2DM.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Aging; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Equivalence Trials as Topic; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Incretins; Japan; Middle Aged; Reproducibility of Results; Severity of Illness Index; Sitagliptin Phosphate; Sulfonylurea Compounds; Weight Loss

To compare the addition of weekly dulaglutide vs the addition of placebo to titrated glargine in patients with type 2 diabetes (T2D) with sub-optimum glycated haemoglobin (HbA1c) concentration.. Patients (N = 300) from this phase III, double-blind, parallel-arm, placebo-controlled study were randomized to weekly subcutaneous injections of dulaglutide 1.5 mg or placebo with titrated daily glargine (mean ± standard deviation baseline dose: 39 ± 22 U), with or without metformin (≥1500 mg/d). The primary endpoint was superiority of dulaglutide/glargine to placebo/glargine with regard to change from baseline in HbA1c level at 28 weeks.. Least squares (LS) mean ± standard error (s.e.) HbA1c changes from baseline were -1.44 ± 0.09% (-15.74 ± 0.98 mmol/mol) with dulaglutide/glargine and -0.67 ± 0.09% (-7.32 ± 0.98 mmol/mol) with placebo/glargine at 28 weeks (LS mean difference [95% confidence interval] -0.77% [-0.97, -0.56]; P < .001). Body weight decreased with dulaglutide/glargine and increased with placebo/glargine (LS mean difference: -2.41 ± 0.39 kg; P < .001). Increases from baseline in mean glargine dose were significantly smaller with dulaglutide/glargine vs placebo/glargine (13 ± 2 U [0.1 ± 0.02 U/kg] vs 26 ± 2 U [0.3 ± 0.02 U/kg], respectively; P < .001; LS mean ± s.e. final dose: dulaglutide/glargine, 51 ± 2 U; placebo/glargine, 65 ± 2 U). The hypoglycaemia rate (≤3.9 mmol/L threshold) was 7.69 ± 15.15 and 8.56 ± 16.13 events/patient/year, respectively (P = .488). One episode of severe hypoglycaemia occurred in the dulaglutide/glargine group. Common gastrointestinal adverse events with dulaglutide were nausea (12.0%), diarrhoea (11.3%) and vomiting (6.0%).. Weekly dulaglutide 1.5 mg added to basal insulin is an efficacious and well tolerated treatment option for patients with T2D.

Topics: Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Drug Resistance; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Injections, Subcutaneous; Insulin Glargine; Intention to Treat Analysis; Male; Middle Aged; Patient Dropouts; Recombinant Fusion Proteins

To assess the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase-4 (DPP-4) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist].. CANVAS is a double-blind, placebo-controlled study that randomized participants to canagliflozin 100 or 300 mg or placebo added to routine therapy. The present post hoc analysis assessed the efficacy and safety of canagliflozin 100 and 300 mg compared with placebo in subsets of patients from CANVAS who were taking background DPP-4 inhibitors or GLP-1 receptor agonists with or without other antihyperglycaemic agents at week 18.. Of the 4330 patients in CANVAS, 316 were taking DPP-4 inhibitors and 95 were taking GLP-1 receptor agonists. At 18 weeks, canagliflozin 100 and 300 mg provided larger placebo-subtracted reductions in glycated haemoglobin (HbA1c) in patients taking DPP-4 inhibitors [-0.56% (95% confidence interval [CI]: -0.77, -0.35), and -0.75% (95% CI: -0.95, -0.54), respectively] and GLP-1 receptor agonists [-1.00% (95% CI: -1.35, -0.65), and -1.06% (95% CI: -1.43, -0.69), respectively]. Body weight and blood pressure (BP) reductions were seen with canagliflozin versus placebo in both subsets. Higher incidences of genital mycotic infections and osmotic diuresis-related adverse events (AEs) were seen with canagliflozin compared with placebo. The incidence of hypoglycaemia was numerically higher with canagliflozin versus placebo; nearly all events occurred in patients on background insulin or insulin secretagogues.. In patients on background incretin mimetics, canagliflozin improved HbA1c, body weight and BP, with an increased incidence of AEs related to SGLT2 inhibition.

Topics: Aged; Biomimetics; Blood Pressure; Canagliflozin; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Urologic Diseases; Weight Loss

To assess whether the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin affects glucagon and other counter-regulatory hormone responses to hypoglycaemia in patients with type 1 diabetes.. We conducted a single-centre, randomized, double-blind, placebo-controlled, three-period crossover study. We studied 16 male patients with type 1 diabetes aged 18-52 years, with a diabetes duration of 5-20 years and intact hypoglycaemia awareness. Participants received sitagliptin (100 mg/day) or placebo for 6 weeks and attended the hospital for three acute hypoglycaemia studies (at baseline, after sitagliptin treatment and after placebo). The primary outcome was differences between the three hypoglycaemia study days with respect to plasma glucagon responses from the initialization phase of the hypoglycaemia intervention to 40 min after onset of the autonomic reaction.. Sitagliptin treatment significantly increased active levels of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. No significant differences were observed for glucagon or adrenergic counter-regulatory responses during the three hypoglycaemia studies. Growth hormone concentration at 40 min after occurrence of autonomic reaction was significantly lower after sitagliptin treatment [median (IQR) 23 (0.2-211.0) mEq/l] compared with placebo [median (IQR) 90 (8.8-180) mEq/l; p = 0.008].. Sitagliptin does not affect glucagon or adrenergic counter-regulatory responses in patients with type 1 diabetes, but attenuates the growth hormone response during late hypoglycaemia.

Topics: Adolescent; Adult; Cross-Over Studies; Diabetes Mellitus, Type 1; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Growth Hormone; Humans; Hypoglycemia; Incretins; Male; Middle Aged; Sitagliptin Phosphate; Young Adult

Maturity onset diabetes of the young (MODY) designates monogenic forms of non-autoimmune diabetes characterised by autosomal dominant inheritance, non-insulin dependent diabetes at onset and diagnosis often before 25 years of age. MODY constitutes genetically and clinically heterogeneous forms of diabetes. More than 8 different genes are known to cause MODY, among which hepatocyte nuclear factor 1 alpha (HNF1A) (MODY3) and glucokinase (GCK) (MODY2) mutations are the most common. Both forms of MODY are characterised by specific beta cell dysfunction, with patients with HNF1A-diabetes having a reduced insulin secretory capacity, while patients with GCK-diabetes have a glucose-sensing defect, but preserved insulin secretory capacity. Patients with MODY are effectively treated with sulphonylurea (SU) due to very high sensitivity to these drugs, but they are also prone to develop hypoglycaemia. The objectives of this thesis were to study the pathophysiology of GCK-diabetes and HNF1A-diabetes by investigating the incretin effect, the physiological response to food ingestion and to estimate the treatment potential of a glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with HNF1A-diabetes. In Study I we investigated the incretin effect and the responses of islet hormones and incretin hormones to oral glucose tolerance test (OGTT) and isoglycaemic IV glucose infusion (IIGI) in patients with GCK-diabetes, in patients with HNF1A-diabetes, and in BMI and age matched healthy individuals (CTRLs). In Study II we investigated responses of islet hormones and incretin hormones to a more physiological stimulus consisting of a standardised meal test in patients with GCK-diabetes, in patients with HNF1A--diabetes, and in BMI and age matched CTRLs. In Study III we conducted a randomised, double-blind, crossover trial investigating the glucose lowering effect and risk of hypoglycaemia during 6 weeks of treatment with the GLP-1RA, liraglutide compared to the SU, glimepiride in 16 patients with HNF1A-diabetes. At baseline and at the end of each treatment period a standardised meal test followed by a light bicycling test was performed. The results of the studies showed that patients with HNF1A-diabetes were less glucose tolerant than patients with GCK-diabetes, but both groups were more glucose intolerant than CTRLs. In spite of glucose intolerance patients with GCK-diabetes showed normal incretin effect, whereas patients with HNF1A-diabetes showed an impaired increti

Topics: Academic Dissertations as Topic; Adult; Blood Glucose; Cross-Over Studies; Denmark; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Double-Blind Method; Female; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Islets of Langerhans; Male; Postprandial Period

The PDY6797 study evaluated efficacy, safety and pharmacodynamics of lixisenatide in Japanese and Caucasian patients with type 2 diabetes mellitus (T2DM) insufficiently controlled with sulphonylureas with/without metformin.. This randomized, double-blind, placebo-controlled trial comprised a single-dose assessment of lixisenatide 5 and 10 µg, and a 5- to 6-week repeated dose-escalation assessment of lixisenatide 5 to 30 µg once (QD) or twice daily (BID). The primary endpoint was change in postprandial plasma glucose (PPG) area under the curve (AUC)[0:29-4:30 h] after a standardized breakfast at the highest tolerated lixisenatide dose. Change from baseline in glycated haemoglobin (HbA1c), 2-h PPG and fasting plasma glucose (FPG) were assessed, as were adverse events.. Change from baseline in PPG AUC[0:29-4:30 h] with lixisenatide QD and BID was significantly greater than placebo (p < 0.0001 for all study populations), with particularly prominent effects in Japanese patients. Greater reductions in PPG AUC[0:29-4:30 h] were seen with lixisenatide QD versus BID, while the totality of evidence suggested that the lixisenatide 20 µg dose was optimal. In the overall population, changes from baseline for 2-h PPG, HbA1c and FPG were significant with lixisenatide QD and BID versus placebo (p < 0.01 for all). Lixisenatide was well tolerated.. Lixisenatide significantly reduced PPG AUC[0:29-4:30 h] versus placebo at the highest well-tolerated dose in patients with T2DM treated with sulphonylureas with/without metformin and had a good safety and tolerability profile. Japanese patients experienced particular benefits with lixisenatide in terms of reductions in PPG excursions.

Topics: Adult; Aged; Asian People; Cohort Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Drug Therapy, Combination; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Japan; Male; Metformin; Middle Aged; Peptides; Receptors, Glucagon; Sulfonylurea Compounds; White People; Young Adult

Exogenous GLP-1 slows gastric emptying in health and diabetes leading to diminished glycemic excursions. Gastric emptying is markedly accelerated by hypoglycemia. The primary objective was to determine whether GLP-1 attenuates the acceleration of gastric emptying induced by hypoglycemia.. Ten healthy volunteers were studied on four separate days in a randomized double-blind fashion. Blood glucose was stabilized using a glucose/insulin clamp at hypoglycemia (2.6 mmol/L on two occasions [hypo]) or euglycemia (6.0 mmol/L on two occasions [eu]) between T = -15 and 45 min before clamping at 6.0 mmol/L until 180 min. During hypoglycemia and euglycemia, subjects received intravenous GLP-1 (1.2 pmol/kg/min) or placebo. At T = 0 min, subjects ingested 100 g beef mince labeled with 20 MBq (99m)Tc-sulfur-colloid and 3 g of 3-O-methyl-glucose (3-OMG), a marker of glucose absorption. Gastric emptying was measured scintigraphically from T = 0 to 180 min and serum 3-OMG taken at 15-min intervals. The areas under the curve for gastric emptying and 3-OMG concentration were analyzed using one-way repeated-measures ANOVA with Bonferroni-Holm adjusted post hoc tests.. Gastric emptying was accelerated during hypoglycemia (hypo/placebo vs. eu/placebo; P < 0.001), as was glucose absorption (P < 0.03). GLP-1 slowed emptying during euglycemia (eu/placebo vs. eu/GLP-1; P < 0.001). However, hypoglycemia-induced acceleration of gastric emptying on placebo was markedly diminished by GLP-1 (hypo/placebo vs. hypo/GLP-1; P < 0.008), as was glucose absorption (P < 0.01).. Acute administration of exogenous GLP-1 attenuates, but does not abolish, the acceleration of gastric emptying by insulin-induced hypoglycemia in healthy subjects.

Topics: Aged; Blood Glucose; Double-Blind Method; Female; Gastric Emptying; Glucagon-Like Peptide 1; Glucose Clamp Technique; Healthy Volunteers; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Intravenous; Insulin; Male; Middle Aged

To show that albiglutide, a glucagon-like peptide-1 receptor agonist, is an effective and generally safe treatment to improve glycaemic control in patients with type 2 diabetes mellitus whose hyperglycaemia is inadequately controlled with pioglitazone (with or without metformin).. In this 3-year, randomized, double-blind, placebo-controlled study, 310 adult patients on a regimen of pioglitazone (with or without metformin) were randomly assigned to receive additional treatment with albiglutide [30 mg subcutaneous (s.c.) once weekly, n = 155] or matching placebo (n = 155). The primary efficacy endpoint was change from baseline to week 52 (intention-to-treat) in glycated haemoglobin (HbA1c).. The model-adjusted change from baseline in HbA1c at week 52 was significantly better with albiglutide than with placebo (-0.8%, 95% confidence interval -1.0, -0.6; p < 0.0001). Change from baseline fasting plasma glucose was -1.3 mmol/l in the albiglutide group and +0.4 mmol/l in the placebo group (p < 0.0001); a significantly higher percentage of patients reached the HbA1c goals with albiglutide (p < 0.0001), and the rate of hyperglycaemia rescue up to week 52 for albiglutide was 24.4 versus 47.7% for placebo (p < 0.0001). Albiglutide plus pioglitazone had no impact on weight, and severe hypoglycaemia was observed rarely (n = 2). With few exceptions, the results of safety assessments were similar between the groups, and most adverse events (AEs) were mild or moderate. The 52-week incidence rates for gastrointestinal AEs for albiglutide and placebo were: 31.3 and 29.8%, respectively (diarrhoea: 11.3 and 8.6%; nausea: 10.7 and 11.3%; vomiting: 4.0 and 4.0%).. Albiglutide 30 mg administered once weekly as an add-on to pioglitazone (with or without metformin) provided effective and durable glucose lowering and was generally well tolerated.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Male; Metformin; Middle Aged; Pioglitazone; Thiazolidinediones; Treatment Outcome

To test the hypothesis that acute hypoglycemia induces endothelial dysfunction and inflammation through the generation of an oxidative stress. Moreover, to test if the antioxidant vitamin C can further improve the protective effects of glucagon-like peptide 1 (GLP-1) on endothelial dysfunction and inflammation during hypoglycemia in type 1 diabetes.. A total of 20 type 1 diabetic patients underwent four experiments: a period of 2 h of acute hypoglycemia with or without infusion of GLP-1 or vitamin C or both. At baseline, after 1 and 2 h, glycemia, plasma nitrotyrosine, plasma 8-iso prostaglandin F2a (PGF2a), soluble intracellular adhesion molecule-1a (sICAM-1a), interleukin-6 (IL-6), and flow-mediated vasodilation were measured. At 2 h of hypoglycemia, flow-mediated vasodilation significantly decreased, while sICAM-1, 8-iso-PGF2a, nitrotyrosine, and IL-6 significantly increased. The simultaneous infusion of GLP-1 or vitamin C significantly attenuated all of these phenomena. Vitamin C was more effective. When GLP-1 and vitamin C were infused simultaneously, the deleterious effect of hypoglycemia was almost completely counterbalanced.. At 2 h of hypoglycemia, flow-mediated vasodilation significantly decreased, while sICAM-1, 8-iso-PGF2a, nitrotyrosine, and IL-6 significantly increased. The simultaneous infusion of GLP-1 or vitamin C significantly attenuated all of these phenomena. Vitamin C was more effective. When GLP-1 and vitamin C were infused simultaneously, the deleterious effect of hypoglycemia was almost completely counterbalanced.. This study shows that vitamin C infusion, during induced acute hypoglycemia, reduces the generation of oxidative stress and inflammation, improving endothelial dysfunction, in type 1 diabetes. Furthermore, the data support a protective effect of GLP-1 during acute hypoglycemia, but also suggest the presence of an endothelial resistance to the action of GLP-1, reasonably mediated by oxidative stress.

Topics: Acute Disease; Antioxidants; Ascorbic Acid; Blood Glucose; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelium, Vascular; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Inflammation; Infusions, Intravenous; Insulin; Male; Oxidative Stress; Vasodilation; Young Adult

Metformin monotherapy is recommended as initial treatment of type 2 diabetes. The selection of optimal second-line therapy that is often necessary due to the progressive nature of the disease is still a subject of ongoing discussions.. The aim of the international EDGE (Effectiveness of Diabetes control with vildaGliptin and vildagliptin/mEtformin) study was to prospectively compare the efficacy and safety of vildagliptin vs other oral antidiabetic agents in patients with type 2 diabetes not adequately controlled on monotherapy in a real-life clinical setting. In this paper, we present the data of patients participating in the EDGE study in the Czech Republic.. Patients with type 2 diabetes not adequately controlled on monotherapy were enrolled into the study, and randomised into either the vildagliptin arm or control arm with another OAD at the discretion of the treating physician. Patients with the addition of other incretin-based medications were not enrolled into the study. The efficiency was evaluated as a proportion of patients reaching the combined endpoint of decreasing HbA1c> 3 mmol/mol without hypoglycaemia, peripheral oedema or treatment termination due to gastrointestinal side effects during the 12 months of treatment.. 654 patients were enrolled into the study in the Czech Republic. The mean age of the patients when enrolled into the study (vildagliptin group vs control group) was 59.5 ± 10.6 vs 63.7 ± 8.5 years, mean body mass index was 32.4 ± 5.7 vs 31.7 ± 6.5 kg/m2, mean HbA1c was 62 ± 12 vs 64 ± 11 mmol/mol. The probability of reaching the combined primary endpoint (calculated using a binary logistic regression model to calculate the odds ratios with 95% confidence intervals) was higher for vildagliptin regardless of baseline HbA1c or type of medication added in the control group. Primary endpoint was reached by 60.6 % of patients in the vildagliptin group vs 51.3 % of patients in the control group, odds ratio 1.46 (1.06, 1.99); p< 0.019. The proportion of patients reaching secondary endpoint (HbA1c< 54 mmol/mol without hypoglycemic event or weight gain 3 % with baseline glycated hemoglobin > 54 mmol/mol was higher for vildagliptin 45.7 % vs 31.4 % in the control arm, odds ratio 1.84 (1.26, 2.68), p< 0.001. The rate of adverse events was comparable in both groups.. In a real-life clinical set-ting, the percentage of patients reaching the combined endpoint of decreasing HbA1c> 3 mmol/mol, without hypoglycaemia, peripheral oedema or treatment termination due to gastrointestinal side effects was higher after the addition of vildagliptin as compared to other antidiabetic agents with comparable rate of side effects.

Topics: Adamantane; Adult; Aged; Cohort Studies; Czech Republic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Male; Metformin; Middle Aged; Nitriles; Prospective Studies; Pyrrolidines; Vildagliptin; Weight Gain

Mosapride citrate, a selective agonist of the 5-hydroxytryptaine (5-HT)₄ receptor, is typically used to treat heartburn, nausea, and vomiting associated with chronic gastritis or to prepare for a barium enema X-ray examination. Mosapride citrate reportedly improves insulin sensitivity in patients with type 2 diabetes. As mosapride citrate activates the motility of the gastrointestinal tract, we hypothesized that mosapride citrate affects incretin secretion. We examined the effect of the administration of mosapride citrate on the plasma glucose, serum insulin, plasma glucagon, and plasma incretin levels before breakfast and at 60, 120, and 180 min after breakfast in men with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) to exclude gastropathy. Mosapride citrate was administered according to two different intake schedules (C: control (no drug), M: mosapride citrate 20 mg) in each of the subject groups. The area under the curve (AUC) of the plasma glucose levels was smaller in the M group than in the C group. The time profiles for the serum insulin levels at 60 and 120 min after treatment with mosapride citrate tended to be higher, although the difference was not statistically significant. The AUCs of the plasma active and total glucagon-like peptide-1 (GLP-1) levels were significantly larger in the M group than in the C group. No significant difference in the AUC of the plasma glucose-dependent insulinotropic polypeptide (GIP) level was observed between the two groups. Our results suggest that mosapride citrate may have an antidiabetic effect by increasing GLP-1 secretion.

Topics: Adult; Benzamides; Blood Glucose; Gastric Inhibitory Polypeptide; Gastrointestinal Agents; Gastrointestinal Tract; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Male; Morpholines; Postprandial Period; Serotonin 5-HT4 Receptor Agonists; Up-Regulation

To determine whether miglitol administration improves glycemic control and reduces the frequency of hypoglycemia in type 1 diabetes mellitus (T1DM) patients treated with intensive insulin therapy, we analyzed the effect of miglitol on daily insulin doses, body weight, hypoglycemia, and incretin hormone responses during meal tolerance tests (MTT). Eleven T1DM subjects (21-77 years) undergoing intensive insulin therapy, took 25 mg (weeks 0-4) and 50 mg miglitol (weeks 4-12) thrice daily, immediately before meals. At weeks 0 and 12, 9 of 11 subjects underwent MTT. In present study, mean HbA1c, glycoalbumin, and 1,5-anhydroglucitol levels were significantly improved. The blood glucose level 1 h after dinner was significantly lower at week 12 than at week 0 (p = 0.008). From week 0 to 12, there was a significant decrease in the body mass index (BMI; p = 0.0051), frequency of preprandial hypoglycemic events (p = 0.012), and daily bolus insulin dosage (p = 0.018). The change in active glucagon-like peptide-1 (GLP-1) at 120 min significantly increased at week 12 (p = 0.015). The change in total glucose-dependent insulinotropic peptide (GIP) significantly decreased in the MTT at week 12. These results demonstrate that addition of miglitol on intensive insulin therapy in T1DM patients has beneficial effects on reducing BMI, bolus and total insulin dosage, and frequency of preprandial hypoglycemic events. MTT findings suggest that this combination therapy improves blood glucose control by delaying carbohydrate absorption and modifying the responses of incretins, GIP, and GLP-1.

Topics: 1-Deoxynojirimycin; Adult; Aged; Deoxyglucose; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Enzyme Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Serum Albumin; Weight Loss; Young Adult

Hyperglycaemia occurs frequently in the critically ill, affects outcome adversely, and is exacerbated by enteral feeding. Furthermore, treatment with insulin in this group is frequently complicated by hypoglycaemia. In healthy patients and those with type 2 diabetes, exogenous glucagon-like peptide-1 (GLP-1) decreases blood glucose by suppressing glucagon, stimulating insulin and slowing gastric emptying. Because the former effects are glucose-dependent, the use of GLP-1 is not associated with hypoglycaemia. The objective of this study was to establish if exogenous GLP-1 attenuates the glycaemic response to enteral nutrition in patients with critical illness induced hyperglycaemia.. Seven mechanically ventilated critically ill patients, not previously known to have diabetes, received two intravenous infusions of GLP-1 (1.2 pmol/kg/min) and placebo (4% albumin) over 270 minutes. Infusions were administered on consecutive days in a randomised, double-blind fashion. On both days a mixed nutrient liquid was infused, via a post-pyloric feeding catheter, at a rate of 1.5 kcal/min between 30 and 270 minutes. Blood glucose and plasma GLP-1, insulin and glucagon concentrations were measured.. In all patients, exogenous GLP-1 infusion reduced the overall glycaemic response during enteral nutrient stimulation (AUC30-270 min GLP-1 (2077 +/- 144 mmol/l min) vs placebo (2568 +/- 208 mmol/l min); P = 0.02) and the peak blood glucose (GLP-1 (10.1 +/- 0.7 mmol/l) vs placebo (12.7 +/- 1.0 mmol/l); P < 0.01). The insulin/glucose ratio at 270 minutes was increased with GLP-1 infusion (GLP-1 (9.1 +/- 2.7) vs. placebo (5.8 +/- 1.8); P = 0.02) but there was no difference in absolute insulin concentrations. There was a transient, non-sustained, reduction in plasma glucagon concentrations during GLP-1 infusion (t = 30 minutes GLP-1 (90 +/- 12 pmol/ml) vs. placebo (104 +/- 10 pmol/ml); P < 0.01).. Acute, exogenous GLP-1 infusion markedly attenuates the glycaemic response to enteral nutrition in the critically ill. These observations suggest that GLP-1 and/or its analogues have the potential to manage hyperglycaemia in the critically ill.. Australian New Zealand Clinical Trials Registry number: ACTRN12609000093280.

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Critical Illness; Cross-Over Studies; Double-Blind Method; Enteral Nutrition; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Incretins; Infusions, Intravenous; Insulin; Male; Middle Aged

Exaggerated postprandial incretin and insulin responses are well documented in postbariatric surgery hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). However, less is known about PBH after sleeve gastrectomy (SG).. We sought to compare meal-stimulated hormonal response in those with PBH after SG vs RYGB.. We enrolled 23 post-SG (12 with and 11 without PBH) and 20 post-RYGB (7 with and 13 without PBH) individuals who underwent bariatric surgery at our institution. PBH was defined as plasma glucose less than 60 mg/dL on 4-hour mixed-meal tolerance test (MTT). Islet and incretin hormones were compared across the 4 groups.. Participants (N = 43) were on average 5 years post surgery, with a mean age of 48 years, mean preoperative body mass index of 48.4, 81% female, 61% White, and 53% post SG. Regardless of PBH, the SG group showed lower glucose, glucagon, and glucagon-like peptide 1 (GLP-1) responses to MTT and similar insulin and glucose-dependent insulinotropic polypeptide (GIP) responses compared to the RYGB group. Among those with PBH, the SG group following the MTT showed a lower peak glucose (P = .02), a similar peak insulin (90.3 mU/L vs 171mU/L; P = .18), lower glucagon (P < .01), early GLP-1 response (AUC0-60 min; P = .01), and slower time to peak GIP (P = .02) compared to PBH after RYGB.. Among individuals with PBH, those who underwent SG were significantly different compared to RYGB in meal-stimulated hormonal responses, including lower glucagon and GLP-1 responses, but similar insulin and GIP responses. Future studies are needed to better understand the differential contribution of insulin and non-insulin-mediated mechanisms behind PBH after SG vs RYGB.

Topics: Blood Glucose; Female; Gastrectomy; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemia; Incretins; Insulin; Male; Middle Aged; Obesity, Morbid

The enteroendocrine cell (EEC)-derived incretins play a pivotal role in regulating the secretion of glucagon and insulins in mammals. Although glucagon-like and insulin-like hormones have been found across animal phyla, incretin-like EEC-derived hormones have not yet been characterised in invertebrates. Here, we show that the midgut-derived hormone, neuropeptide F (NPF), acts as the sugar-responsive, incretin-like hormone in the fruit fly, Drosophila melanogaster. Secreted NPF is received by NPF receptor in the corpora cardiaca and in insulin-producing cells. NPF-NPFR signalling resulted in the suppression of the glucagon-like hormone production and the enhancement of the insulin-like peptide secretion, eventually promoting lipid anabolism. Similar to the loss of incretin function in mammals, loss of midgut NPF led to significant metabolic dysfunction, accompanied by lipodystrophy, hyperphagia, and hypoglycaemia. These results suggest that enteroendocrine hormones regulate sugar-dependent metabolism through glucagon-like and insulin-like hormones not only in mammals but also in insects.

Topics: Animals; Animals, Genetically Modified; Drosophila melanogaster; Enteroendocrine Cells; Female; Glucagon; Glucagon-Like Peptide 1; Hormones; Humans; Hypoglycemia; Incretins; Insulin; Insulin Secretion; Lipid Metabolism; Mutation; Neuropeptides; Receptors, Neuropeptide; Sugars

Post-prandial and oral glucose tolerance test-related hypoglycemia is common in cystic fibrosis (CF); however, the underlying mechanisms are unclear.. To understand the relationship of hypoglycemia with meal-related glucose excursion and insulin secretion, we analyzed plasma glucose, insulin, C-peptide, glucagon and incretins obtained during standardized mixed-meal tolerance tests (MMTT) in non-diabetic adolescents and young adults with pancreatic insufficient CF (PI-CF).. Hypoglycemia, defined as glucose <70 mg/dL, occurred in 9/34 subjects at 150 (range:120-210) minutes following initial meal ingestion. Hypoglycemia[+] and hypoglycemia[-] groups did not differ in gender, age, lung function, HbA1c, or BMI. While 11/14 hypoglycemia[-] individuals displayed normal glucose tolerance (NGT), only 2/9 hypoglycemia[+] had NGT. Peak glucose was higher in hypoglycemia[+] vs hypoglycemia[-]. Compared to hypoglycemia[-] NGT, hypoglycemia[+] exhibited lower early-phase insulin secretion (ISR-AUC. Hypoglycemia is common in PI-CF following MMTT and is associated with early glucose dysregulation (higher peak glucose), more impaired early-phase insulin secretion (lower ISR-AUC

Topics: Adolescent; Area Under Curve; Blood Glucose; C-Peptide; Cystic Fibrosis; Exocrine Pancreatic Insufficiency; Female; Glucagon; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemia; Incretins; Insulin; Insulin Secretion; Male; Young Adult

Patients who have undergone gastric bypass surgery (GB) have enhanced postprandial hyperinsulinaemia and a greater incretin effect is apparent. In the present study, we sought to determine the effect of vagal activation, a neural component of the enteroinsular axis, on postprandial glucose metabolism in patients with and without hypoglycaemia after GB. Seven patients with documented post-GB hypoglycaemia, seven asymptomatic patients without hypoglycaemia post-GB, and 10 weight-matched non-surgical controls with normal glucose tolerance were recruited. Blood glucose, and islet hormone and incretin secretion were compared during mixed meal tolerance tests (MMTs) with and without prior sham-feeding on two separate days. Sham feeding preceding the MMT caused a more rapid increase in prandial blood glucose levels but lowered overall glycaemia in all three groups (P < 0.05). Sham feeding had a similar effect to increase early (P < 0.05), but not overall, meal-induced insulin secretion in the three groups. Prandial glucagon concentrations were significantly greater in the GB groups, and sham feeding accentuated this response (P < 0.05). The effect of vagal activation on prandial glucose and islet-cell function is preserved in patients who have undergone GB, in those both with and without hypoglycaemia.

Topics: Blood Glucose; Gastric Bypass; Glucagon; Humans; Hypoglycemia; Incretins; Insulin; Postprandial Period; Vagus Nerve

To analyse the prevalence of severe hypoglycaemia in patients with type 2 diabetes (T2DM) treated with antihyperglycaemic agents (AHA) and requiring emergency room (ER) assistance, and to analyse the prevalence according to type of AHA therapy.. The present study, the Hypoglycaemia In Portugal Observational Study-Emergency Room (HIPOS-ER), was a cross-sectional, observational, multicentre, nationwide study, with specific hypoglycaemia source data collection.. Within the study period, a total of 425 706 admissions were recorded in the ERs of participating hospitals. The prevalence of severe hypoglycaemic episodes in patients with T2DM was 0.074%. In all, 238 patients were included, more than half of whom were on insulin-based therapy (55.0%) and a third of whom (31.5%) were on oral secretagogue-based therapy. In 61.2% of patients primary care was the main diabetes care setting. The median patient age was 77.5 years and the mean duration of diabetes was 19 years. Missing a meal or low carbohydrate meal content was the most frequent cause of hypoglycaemia (55.9%) and the most frequent triggers for seeking emergency assistance were pre-syncope (19.2%) and transient loss of consciousness (17.4%). A total of 44.1% of patients were hospitalized for a median of 5.1 days. Patients in the secretagogue group were admitted to hospital more often than patients in the insulin group (70.7% vs 29.0%; P < .001). Nine patients died.. These findings confirm that severe hypoglycaemia in patients with T2DM requiring ER assistance occurs mainly in those on insulin- and secretagogue-based therapies and is associated with a significant medical burden. Antidiabetic therapy should be individualized to minimize the risk of severe iatrogenic hypoglycaemia, and any intervention to this end should always involve primary care stakeholders.

Topics: Aged; Combined Modality Therapy; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diet, Diabetic; Drug Therapy, Combination; Elder Nutritional Physiological Phenomena; Emergency Service, Hospital; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Length of Stay; Male; Middle Aged; Patient Compliance; Portugal; Prevalence; Risk; Severity of Illness Index; Syncope

This study aimed to quantify the effect of the immediate release (IR) of exenatide, a short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA), on gastric emptying rate (GER) and the glucose rate of appearance (GluRA), and evaluate the influence of drug characteristics and food-related factors on postprandial plasma glucose (PPG) stabilization under GLP-1RA treatment. A quantitative systems pharmacology (QSP) approach was used, and the proposed model was based on data from published sources including: (1) GLP-1 and exenatide plasma concentration-time profiles; (2) GER estimates under placebo, GLP-1 or exenatide IR dosing; and (3) GluRA measurements upon food intake. According to the model's predictions, the recommended twice-daily 5- and 10-μg exenatide IR treatment is associated with GluRA flattening after morning and evening meals (48%-49%), whereas the midday GluRA peak is affected to a lesser degree (5%-30%) due to lower plasma drug concentrations. This effect was dose-dependent and influenced by food carbohydrate content, but not by the lag time between exenatide injection and meal ingestion. Hence, GER inhibition by exenatide IR represents an important additional mechanism of its effect on PPG.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Digestion; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Liberation; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Intestinal Absorption; Models, Biological; Postprandial Period; Systems Biology

To estimate the long-term cost-effectiveness of exenatide twice daily vs insulin glargine once daily as add-on therapy to oral antidiabetic agents (OADs) for Chinese patients with type 2 diabetes (T2DM).. The Cardiff Diabetes Model was used to simulate disease progression and estimate the long-term effects of exenatide twice daily vs insulin glargine once daily. Patient profiles and treatment effects required for the model were obtained from literature reviews (English and Chinese databases) and from a meta-analysis of 8 randomized controlled trials comparing exenatide twice daily with insulin glargine once daily add-on to OADs for T2DM in China. Medical expenditure data were collected from 639 patients with T2DM (aged ≥18 years) with and without complications incurred between January 1, 2014 and December 31, 2015 from claims databases in Shandong, China. Costs (2014 Chinese Yuan [¥]) and benefits were estimated, from the payers' perspective, over 40 years at a discount rate of 3%. A series of sensitivity analyses were performed.. Patients on exenatide twice daily + OAD had a lower predicted incidence of most cardiovascular and hypoglycaemic events and lower total costs compared with those on insulin glargine once daily + OAD. A greater number of quality-adjusted life years (QALYs; 1.94) at a cost saving of ¥117 706 gained was associated with exenatide twice daily vs insulin glargine once daily. (i.e. cost saving of ¥60 764/QALY) per patient.. In Chinese patients with T2DM inadequately controlled by OADs, exenatide twice daily is a cost-effective add-on therapy alternative to insulin glargine once daily, and may address the problem of an excess of medical needs resulting from weight gain and hypoglycaemia in T2DM treatment.

Topics: Administration, Oral; Cardiovascular Diseases; China; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Direct Service Costs; Drug Administration Schedule; Drug Therapy, Combination; Exenatide; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Incretins; Injections, Subcutaneous; Insulin Glargine; Middle Aged; Models, Economic; Peptides; Quality of Life; Randomized Controlled Trials as Topic; Venoms

Severe postprandial hypoglycemia with neuroglycopenia is an increasingly recognized, debilitating complication of Roux-en-Y gastric bypass (RYGB) surgery. Increased secretion of insulin and incretin hormones is implicated in its pathogenesis. Histopathologic examination of pancreas has demonstrated increased islet size and/or nuclear diameter in post-RYGB patients who underwent pancreatectomy for severe refractory hypoglycemia with neuroglycopenia (RYGB + NG). We aimed to determine whether β-cell proliferation or apoptosis is altered in RYGB + NG.. We performed an observational study to analyze markers of proliferation, apoptosis, cell cycle, and transcription factor expression in pancreatic tissue from affected RYGB + NG patients (n = 12), normoglycemic patients undergoing pancreatic surgery for benign lesions (controls, n = 6), and individuals with hypoglycemia due to insulinoma (n = 52).. Proliferative cell nuclear antigen (PCNA) expression was increased in insulin-positive cells in RYGB + NG patients (4.5-fold increase, p < 0.001 vs. controls) and correlated with β-cell mass. Ki-67 immunoreactivity was low in both RYGB + NG and controls, but did not differ between groups. Phospho-histone H3 levels did not differ between RYGB + NG and controls. PCNA and Ki-67 were both significantly lower in both controls and RYGB + NG than insulinomas. Markers of apoptosis and cell cycle (M30, p27, and p21) did not differ between groups. PDX1 and menin exhibited similar expression patterns, while FOXO1 appeared to be more cytosolic in RYGB + NG.. Markers of proliferation are heterogeneous in patients with severe post-RYGB hypoglycemia. Increased β-cell proliferation in some individuals may contribute to increased β-cell mass observed in severely affected patients.

Topics: Adult; Aged; Blood Glucose; Cell Proliferation; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Humans; Hypoglycemia; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Pancreas

The range of glycated haemoglobin (HbA1c) responses and characteristics associated with above-average response to exenatide twice daily and once weekly were examined. Data were pooled from 8 exenatide-twice-daily and 5 exenatide-once-weekly studies. A baseline HbA1c-corrected measure of change in HbA1c after 24 weeks identified high, average and low responses. Multiple linear regression and multivariate generalized estimating equation models identified factors associated with high response. Among 2355 participants (exenatide twice daily, n = 1414; exenatide once weekly, n = 941), baseline HbA1c correlated with change in HbA1c (P < .0001). Across baseline HbA1c levels, the 25th to 75th percentile of HbA1c change ranged from -0.3% to -3.2% with exenatide twice daily and from -0.5% to -3.6% with exenatide once weekly. Asian ethnicity and older age were significantly associated with high response to exenatide twice daily; no factors were significantly associated with response to exenatide once weekly. These data provide clinically useful information for estimating the likelihood that, depending on baseline HbA1c, an individual can achieve HbA1c goals. The association between Asian ethnicity, age and high response to exenatide twice daily may relate to the specific effects of exenatide twice daily on postprandial glucose.

Topics: Age Factors; Asian People; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Resistance; Exenatide; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Middle Aged; Peptides; Postprandial Period; Randomized Controlled Trials as Topic; Reproducibility of Results; Venoms

Topics: Administration, Oral; Adult; Computer Simulation; Down-Regulation; Female; Glucose; Humans; Hypoglycemia; Incretins; Insulin Resistance; Male; Middle Aged; Obesity; Weight Loss

Topics: Diabetes Complications; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin, Long-Acting; Liraglutide

Ferrets are an important emerging model of cystic fibrosis related diabetes. However, there is little documented experience in the use of advanced techniques to quantify aspects of diabetes pathophysiology in the ferret. Glycemic clamps are the gold standard technique to assess both insulin sensitivity and insulin secretion in humans and animal models of diabetes. We therefore sought to develop techniques for glycemic clamps in ferrets. To assess insulin sensitivity, we performed euglycemic hyperinsulinemic clamps in 5-6 week old ferrets in the anesthetized and conscious states. To assess insulin secretion, we performed hyperglycemic clamps in conscious ferrets. To evaluate responsiveness of ferret islet and entero-insular hormones to low glucose, a portion of the hyperglycemic clamps were followed by a hypoglycemic clamp. The euglycemic hyperinsulinemic clamps demonstrated insulin responsiveness in ferrets similar to that previously observed in humans and rats. The anesthetic isoflurane induced marked insulin resistance, whereas lipid emulsion induced mild insulin resistance. In conscious ferrets, glucose appearance was largely suppressed at 4 mU/kg/min insulin infusion, whereas glucose disposal was progressively increased at 4 and 20 mU/kg/min insulin. Hyperglycemic clamp induced first phase insulin secretion. Hypoglycemia induced a rapid diminishment of insulin, as well as a rise in glucagon and pancreatic polypeptide levels. The incretins GLP-1 and GIP were affected minimally by hyperglycemic and hypoglycemic clamp. These techniques will prove useful in better defining the pathophysiology in ferrets with cystic fibrosis related diabetes.

Topics: Analysis of Variance; Animals; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Ferrets; Glucose Clamp Technique; Hyperglycemia; Hypoglycemia; Incretins; Insulin; Insulin Resistance; Isoflurane

It is recognized that reducing hyperglycemia early on in disease progression has long-term benefits for patients with diabetes. Insulin therapy has greater potential to reduce hyperglycemia than other therapies; however, there is often a significant delay in insulin initiation and intensification. Insulin replacement therapy in type 2 diabetes should no longer be viewed as the treatment of last resort. With the development of modern insulin analogs, the field has evolved. Large clinical trials have improved our understanding of the potential benefits and risks associated with intensive glycemic control in different patient populations and highlighted the need for individualization of glycemic targets and treatment strategies. Current treatment guidelines recognize the important role of insulin therapy both early on and throughout the progression of type 2 diabetes.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Disease Management; Drug Monitoring; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections; Insulin; Practice Guidelines as Topic; Precision Medicine; Time-to-Treatment

Real-world data on emerging combination approaches for type 2 diabetes mellitus (T2DM) management are limited. The objective of the current study was to document the characteristics and clinical outcomes of patients with T2DM initiating prandial insulin or a glucagon-like peptide-1 (GLP-1) receptor agonist while on basal insulin.. This was a retrospective analysis of an electronic medical records database of patients with T2DM managed in a community practice setting in the United States. The main outcome measures were glycated hemoglobin (HbA1c), body weight, hypoglycemia, and health care resource utilization at baseline and at 6-month and 1-year follow-up.. A total of 33 810 patients were included in the study: 31 848 on prandial insulin and 1962 on a GLP-1 receptor agonist. At baseline there were significant differences in mean age (60 vs 56 years), mean Charlson Comorbidity Index score (1.1 vs 0.7), mean HbA1c (8.8% vs 8.4%), and mean body weight (99 vs 112 kg) between the prandial insulin and GLP-1 receptor agonist groups, respectively (P < 0.001 for each). After matching for baseline differences, significant and similar changes from baseline were observed between the prandial insulin and the GLP-1 receptor agonist groups during follow-up at the 6 months/1 year post-index date for HbA1c (-0.45/-0.60% vs -0.44/-0.58%, respectively; P = 0.907/0.723 between groups). Body weight changes between the groups were significantly different at 6 months/1 year (+1.7/-1.7 vs -0.9/-3.7 kg; P < 0.001). Hypoglycemia incidence and health care resource utilization were significantly greater in the prandial insulin versus GLP-1 receptor agonist group.. The results of this real-world analysis of patients with T2DM adding a GLP-1 receptor agonist or prandial insulin to basal insulin suggest an association between adding a GLP-1 receptor agonist with similar glycemic control, greater reduction in body weight, lower hypoglycemia incidence, and lower health care utilization compared with adding prandial insulin.

Topics: Aged; Community Health Services; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Endocrinology; Family Practice; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Retrospective Studies; United States; Weight Gain

Despite the availability of a number of therapeutic options, management of type 2 diabetes (T2DM) and hyperglycemia remains suboptimal. Evidence shows that physicians are not adequately individualizing incretin-based therapies as there is lack of clear understanding of the similarities and differences between various incretin-based therapies. Additionally, sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors, a very recent addition to the therapeutic armamentarium, are not adequately utilized in managing patients with T2DM due to a lack of awareness or an increased concern regarding their safety, efficacy, and the mechanism of action. Insulin therapy is also not initiated or intensified appropriately due to a lack of clear understanding on when to add and how to intensify them and, more importantly, due to fear of increasing the risk of hypoglycemia in patients. To address these gaps, in the first section of this educational activity, the expert faculty will review the current understanding of the risks associated with hypoglycemia-one of the main factors that limit the successful use of insulin therapy-and when to initiate insulin therapy, as well as the available data on the risk of hypoglycemia with emerging agents. The expert faculty will also provide practical strategies on how to minimize the risk of hypoglycemia in patients. In the second section, the expert faculty will highlight the differences between the various incretin-based therapies in addition to providing strategies for physicians to individualize their choice of incretin-based therapy. The expert faculty will also review the mechanism of action, safety, efficacy, and the appropriate place for this class of therapies in the treatment continuum. In the third section, the expert faculty will discuss the mechanism of action, safety, and efficacy of the currently available SGLT2 inhibitors as well as the appropriate use of these newer agents in T2DM management. This CME Multimedia Activity is also available through the Website of The American Journal of Medicine (www.amjmed.com). Click on the CME Multimedia Activity button in the navigation bar for full access. Or access: www.elseviercme.com/537.

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Patient-Centered Care; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Topics: Adamantane; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Drug-Related Side Effects and Adverse Reactions; Heart Failure; Heart Rate; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Myocardial Infarction; Pioglitazone; Risk Assessment; Rosiglitazone; Safety-Based Drug Withdrawals; Stroke; Thiazolidinediones; United States; United States Food and Drug Administration

The number of morbidly obese subjects submitted to bariatric surgery is rising worldwide. In a fraction of patients undergoing gastric bypass (GBP), episodes with late postprandial hypoglycemia (PPHG) develop 1-3 years after surgery. The pathogenesis of this phenomenon is not fully understood; meal-induced rapid and exaggerated increases of circulating incretins and insulin appear to be at least partially responsible. Current treatments include low-carbohydrate diets, inhibition of glucose intestinal uptake, reduction of insulin secretion with calcium channel blockers, somatostatin analogs, or diazoxide, a KATP channel opener. Even partial pancreatectomy has been advocated. In type 2 diabetes, GLP1 analogs have a well-documented effect of stabilizing glucose levels without causing hypoglycemia.. We explored GLP1 analogs as open treatment in five consecutive GBP cases seeking medical attention because of late postprandial hypoglycemic symptoms.. Glucose measured in connection with the episodes in four of the cases had been 2.7, 2.5, 1.8, and 1.6 mmol/l respectively. The patients consistently described that the analogs eliminated their symptoms, which relapsed in four of the five patients when treatment was reduced/discontinued. The drug effect was further documented in one case by repeated 24-h continuous glucose measurements.. These open, uncontrolled observations suggest that GLP1 analogs might provide a new treatment option in patients with problems of late PPHG.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Incretins; Male; Middle Aged; Obesity, Morbid; Postprandial Period; Treatment Outcome

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Resistance; Risk Factors; Treatment Outcome

Topics: Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Male; Obesity; Prevalence

The incretin effect, reflecting the enhancement of postprandial insulin secretion by factors including the intestinal hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, increases in proportion to meal size. However, it is unknown whether the incretin effect is dependent on ambient glucose. The goal of this study was to determine the effect of plasma glycemia on the incretin effect. Thirteen healthy subjects consumed 50 g oral glucose solution mixed with d-xylose during fixed hyperglycemia at 8 and 10.5 mmol/L, on 3 separate days, twice at lower glycemia (LOW) and once at higher values (HIGH). The relative increase in insulin release after glucose ingestion at fixed hyperglycemia, a surrogate for the incretin effect, was similar among all three studies. The GLP-1 response to oral glucose was significantly lower at higher plasma glycemia, as was the appearance of d-xylose after the meal. Between the two LOW studies, the reproducibility of insulin release in response to intravenous glucose alone and intravenous plus ingested glucose was similar. These findings indicate that the incretin contribution to postprandial insulin release is independent of glycemia in healthy individuals, despite differences in GLP-1 secretion. The incretin effect is a reproducible trait among humans with normal glucose tolerance.

Topics: Administration, Oral; Adult; Blood Glucose; Cohort Studies; Female; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemia; Incretins; Infusions, Intravenous; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Postprandial Period; Young Adult

The overall safety profiles of GLP-1 agonists and DPP-4 inhibitors are favorable, with a low incidence of hypoglycemia. This attribute, along with their weight and cardiovascular benefits, particularly with the GLP-1 agonists, make them appropriate choices in our 3 patient cases. Ongoing safety investigations with GLP-1 agonists and DPP-4 inhibitors will provide further clarity to the complete safety profiles of these agents.

Topics: Adamantane; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Male; Metformin; Middle Aged; Peptides; Pyrazines; Receptors, Glucagon; Risk; Sitagliptin Phosphate; Triazoles; Venoms; Weight Loss

Incretins such as glucagon-like peptide-1 (GLP-1) are gut-derived hormones that stimulate insulin secretion and suppress glucagon secretion, thus playing a key role in glucose homeostasis. While incretin mimetics and enhancers are approved for treatment of outpatients with diabetes, evidence is only starting to accumulate regarding the therapeutic potential of incretins in hospitalized patients. Small exploratory studies suggest that GLP-1 safely reduces hyperglycemia without causing hypoglycemia, a key advantage over insulin if efficacy is established in larger studies. Potential limitations include the need for a continuous infusion for delivery, attenuation but not normalization of glucose levels, increased deceleration of gastric emptying and nausea. The exact mechanism of action, dosing, adverse effects, patient subgroups that would be most suitable and safety of combination treatment with insulin remain to be studied. While promising, additional research is required studying effects on hard clinical endpoints.

Topics: Female; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Humans; Hyperglycemia; Hypoglycemia; Incretins; Insulin; Intensive Care Units; Male; Outcome Assessment, Health Care

Hyperinsulinemic hypoglycemia is newly recognized as a rare but important complication after Roux-en-Y gastric bypass (GB). The etiology of the syndrome and metabolic characteristics remain incompletely understood. Recent studies suggest that levels of incretin hormones are increased after GB and may promote excessive beta-cell function and/or growth.. We performed a cross-sectional analysis of metabolic variables, in both the fasting state and after a liquid mixed-meal challenge, in four subject groups: 1) with clinically significant hypoglycemia [neuroglycopenia (NG)] after GB surgery, 2) with no symptoms of hypoglycemia at similar duration after GB surgery, 3) without GB similar to preoperative body mass index of the surgical cohorts, and 4) without GB similar to current body mass index of the surgical cohorts.. Insulin and C-peptide after the liquid mixed meal were both higher relative to the glucose level achieved in persons after GB with NG compared with asymptomatic individuals. Glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic peptide levels were higher in both post-GB surgical groups compared with both overweight and morbidly obese persons, and glucagon-like peptide 1 was markedly higher in the group with NG. Insulin resistance, assessed by homeostasis model assessment of insulin resistance, the composite insulin sensitivity index, or adiponectin, was similar in both post-GB groups. Dumping score was also higher in both GB groups but did not discriminate between asymptomatic and symptomatic patients. Notably, the frequency of asymptomatic hypoglycemia after a liquid mixed meal was high in post-GB patients.. A robust insulin secretory response was associated with postprandial hypoglycemia in patients after GB presenting with NG. Increased incretin levels may contribute to the increased insulin secretory response.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Eating; Female; Food; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Incretins; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Morbid; Postoperative Complications

Topics: Anastomosis, Roux-en-Y; Gastric Bypass; Glucose Tolerance Test; Hormone Antagonists; Humans; Hypoglycemia; Incretins; Postoperative Complications; Somatostatin

(1) When type 2 diabetes is inadequately controlled with oral antidiabetic therapy, one option is to add subcutaneous insulin injections (or to accept less stringent glycaemic control). However, since the effects of adding insulin have only been evaluated in the short-term, effects on long-term clinical outcomes remain unknown. (2) Exenatide, a drug belonging to a new pharmacological class (incretin analogues), is marketed as a subcutaneously administered adjunct to inadequately effective oral antidiabetic therapy in adults with type 2 diabetes. (3) Three placebo-controlled trials lasting 7 months showed that adding exenatide to metformin and/or a glucose-lowering sulphonylurea yielded an HbA1c level of 7% or less in about 40% of patients treated with exenatide 10 micrograms twice a day, versus about 10% of patients on placebo. The potential impact of exenatide on morbidity and mortality is not known. (4) In two trials versus insulin glargine and in one trial versus insulin aspart (+ isophane insulin), exenatide was as effective as the various insulins in controlling HbA1c levels. (5) During clinical trials, patients receiving exenatide lost an average of about 2 kg after 6 months, while insulin was associated with a weight gain of about 2 kg. (6) There was a similar incidence of hypoglycaemia with exenatide and insulin. In patients treated with exenatide, concomitant use of glucose-lowering sulphonylurea increases the risk of hypoglycaemia. (7) More than half of patients on exenatide experienced nausea, versus fewer than 10% of patients on insulin glargine. (8) The long-term consequences of the presence of antiexenatide antibodies on the effectiveness of treatment are not known. (9) Exenatide is administered in two subcutaneous injections a day, at fixed doses. Insulin is administered in one or several injections a day, at doses adjusted to self-monitored blood glucose levels. (10) Adding insulin rather than exenatide is a better option in general when oral antidiabetic therapy fails in patients with type 2 diabetes, as we have more experience with insulin and there is no evidence of important advantages with exenatide. The latter should be reserved for situations in which weight gain is a major problem.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Metformin; Overweight; Peptides; Sulfonylurea Compounds; Venoms; Weight Gain; Weight Loss