Incretin-based Therapies For Type Research Articles

Benefit-risk assessment of incretin and other anti-diabetic agents in type 2 diabetes using a stochastic multicriteria acceptability analysis model.

Benefit-risk assessment of incretin and other anti-diabetic agents in type 2 diabetes using a stochastic multicriteria acceptability analysis model.

Comparison of biochemical parameters among DPP4 inhibitor users and other oral hypoglycaemic drug users: a cross-sectional study from Anuradhapura, Sri Lanka

BackgroundHigher efficacy of incretin-based therapies for type 2 diabetes mellitus has been reported from Asia. Pancreatitis and hepatitis have also been suspected to occur due to dipeptidyl peptidase-4 inhibitor (DPP4I) treatment. The present study aims at comparing selected biochemical parameters among DPP4 inhibitor users and other oral hypoglycaemic drug users.MethodsPatients were recruited from the State Pharmaceutical Corporation, Anuradhapura, Sri Lanka, for a comparative cross-sectional study. Two groups were involved: “DPP4I” user group (n = 63) and “other oral hypoglycaemic” user group (n = 126). Mann-Whitney U test was performed to find a significant difference (p < 0.05) in the distributions of HbA1C, pancreatic amylase, serum lipase, AST and ALT levels between the two groups.ResultsContradicting to previous Asian studies, distribution of HbA1C (p = 0.569) between anti-diabetic regimes with and without DPP4 inhibitors showed no significant difference. Also, amylase (p = 0.171), AST (p = 0.238) and ALT (p = 0.347) failed to show significance. However, lipase was significantly (p = 0.012) high in the DPP4I group.ConclusionThe study showed a significantly higher lipase level among the DPP4I users in comparison to other oral hypoglycaemic drug users, and possible reasons were discussed.

Use of Canagliflozin in Combination With and Compared to Incretin-Based Therapies in Type 2 Diabetes.

In Brief Sodium–glucose cotransporter 2 (SGLT2) inhibitors and incretin-based therapies (dipeptidyl peptidase-4 [DPP-4] inhibitors and glucagon-like peptide-1 [GLP-1] receptor agonists) are widely used to treat patients with type 2 diabetes. In clinical and real-world studies, canagliflozin, an SGLT2 inhibitor, has demonstrated superior A1C lowering compared to the DPP-4 inhibitor sitagliptin. Canagliflozin can also promote modest weight/fat loss and blood pressure reduction. The addition of canagliflozin to treatment regimens that include a DPP-4 inhibitor or a GLP-1 receptor agonist has been shown to further improve glycemic control, while still maintaining beneficial effects on cardiometabolic parameters such as body weight and blood pressure. Overall, the available clinical and real-world evidence suggests that canagliflozin is a safe and well-tolerated treatment option that can be considered either in addition to or instead of incretin-based therapies for patients with type 2 diabetes.

Cardiovascular Safety of Incretin-Based Therapies in Type 2 Diabetes: Systematic Review of Integrated Analyses and Randomized Controlled Trials.

IntroductionRegulatory requirements mandate that new drugs for treatment of patients with type 2 diabetes mellitus (T2DM), such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, are evaluated to show that they do not increase cardiovascular (CV) risk.MethodsA systematic review was undertaken to evaluate the association between DPP-4 inhibitor and GLP-1 receptor agonist use and major adverse cardiac events (MACE). The National Institutes of Health Medline database was searched for pooled analyses, meta-analyses, and randomized controlled trials (RCTs) of DPP-4 inhibitors and GLP-1 receptor agonists that included CV endpoints.ResultsThirty-six articles met the inclusion criteria encompassing 11 pooled analyses, 17 meta-analyses, and eight RCTs (including secondary analyses). Over the short term (up to 4 years), patients with T2DM exposed to a DPP-4 inhibitor or GLP-1 receptor agonist were not at increased risk for MACE (or its component endpoints) compared with those who received comparator agents. Two meta-analyses showed a significant reduction in the incidence of MACE associated with DPP-4 inhibitor therapy as a drug class, but this beneficial effect was not observed in other meta-analyses that included large RCT CV outcome studies. In four RCTs that evaluated alogliptin, saxagliptin, sitagliptin, or lixisenatide, there was no overall increased risk for MACE relative to placebo in T2DM patients at high risk for CV events or with established CV disease, although there was an increased rate of hospitalization for heart failure associated with saxagliptin. A fifth RCT showed that liraglutide reduced MACE risk by 13% versus placebo.ConclusionOverall, incretin therapy does not appear to increase risk for MACE in the short term.

Incretin-based therapy for type 2 diabetes: A real class effect?

Incretin-based therapy for type 2 diabetes: A real class effect?

Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases.

Incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Due to their promising action on insulinotropic secretion and improving insulin resistance (IR), incretin-based therapies have become a new class of antidiabetic agents for the treatment of type 2 diabetes mellitus (T2DM). Recently, the links between neurodegenerative diseases and T2DM have been identified in a number of studies, which suggested that shared mechanisms, such as insulin dysregulation or IR, may underlie these conditions. Therefore, the effects of incretins in neurodegenerative diseases have been extensively investigated. Protease-resistant long-lasting GLP-1 mimetics such as lixisenatide, liraglutide, and exenatide not only have demonstrated promising effects for treating neurodegenerative diseases in preclinical studies but also have shown first positive results in Alzheimer's disease (AD) and Parkinson's disease (PD) patients in clinical trials. Furthermore, the effects of other related incretin-based therapies such as GIP agonists, dipeptidyl peptidase-IV (DPP-IV) inhibitors, oxyntomodulin (OXM), dual GLP-1/GIP, and triple GLP-1/GIP/glucagon receptor agonists on neurodegenerative diseases have been tested in preclinical studies. Incretin-based therapies are a promising approach for treating neurodegenerative diseases.

Incretin-based therapies for type 2 diabetes with nonalcoholic fatty liver disease: a systematic review and meta-analysis

Incretin-based therapies for type 2 diabetes with nonalcoholic fatty liver disease: a systematic review and meta-analysis

A systematic review of the safety of incretin-based therapies in type 2 diabetes

ABSTRACTIntroduction: Large randomized clinical trials have demonstrated that incretin-based therapies provide effective glycemic control in type 2 diabetes. Long-term safety assessments are ongoing.Methods: This systematic review of incretin-based therapy safety is based on 112 randomized clinical trials of duration ≥26 weeks published between January 2000 and February 2015 in patients with type 2 diabetes.Results: As expected, hypoglycemia rates were lower with dipeptidyl peptidase-4 inhibitors (DPP-4is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus other oral antidiabetic drugs and insulin. The most common adverse events were infection and infestation (DPP-4is) and gastrointestinal (GLP-1 RAs). Pancreatitis cases were rare across all studies and, in the SAVOR-TIMI and EXAMINE trials, pancreatitis rates were similar in DPP-4i- and placebo-treated patients. No thyroid tumors were reported, and increased risk of cardiovascular events was not associated with DPP-4is in SAVOR-TIMI and EXAMINE, albeit over a short follow-up period.Conclusions: Overall, incretin-based therapies were well tolerated; however, their long-term safety profile should continue to be periodically assessed.

Cardiovascular, renal and gastrointestinal effects of incretin-based therapies: an acute and 12-week randomised, double-blind, placebo-controlled, mechanistic intervention trial in type 2 diabetes

IntroductionIncretin-based therapies, that is, glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors, are relatively novel antihyperglycaemic drugs that are frequently used in type 2 diabetes management. Apart from...

Which incretin-based therapy for type 2 diabetes?

Which incretin-based therapy for type 2 diabetes?

Incretin-based therapies for type 2 diabetes mellitus: a review of direct comparisons of efficacy, safety and patient satisfaction

Clinical trials comparing incretin-based therapies-glucagon-like peptide-1 receptor agonists (exenatide-twice daily and once weekly-and once-daily liraglutide) and dipeptidyl peptidase-4 inhibitors (vildagliptin, sitagliptin, saxagliptin and linagliptin)-with placebo and oral antidiabetic drugs show that these therapies effectively control glycaemia, with low risk of hypoglycaemia. Glucagon-like peptide-1 receptor agonists are associated with weight loss and reductions in systolic blood pressure, while dipeptidyl peptidase-4 inhibitors are weight-neutral. Based on this, the National Institute for Health and Clinical Excellence recommends using these agents in patients with type 2 diabetes for whom excess weight and/or hypoglycaemia are problematic. This review aims to help decision making when selecting and using incretin-based therapies in type 2 diabetes. A search or MEDLINE and Cochrane clinical trials databases, limited to clinical trials in humans, was performed using the search criteria 'exenatide or liraglutide or vildagliptin or sitagliptin, or saxagliptin or linagliptin'. Abstracts presented at recent American Diabetes Association and European Association for the Study of Diabetes meetings were also searched. Eighteen clinical trials directly comparing incretin-based therapies were identified. Glucagon-like peptide-1 receptor agonists achieved significantly greater reductions in glycated hemoglobin and weight than dipeptidyl peptidase-4 inhibitors, which have a neutral effect on weight. Between-treatment differences were clinically important. Gastrointestinal side effects were more frequent with glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors. Comparisons between glucagon-like peptide-1 receptor agonists and between dipeptidyl peptidase-4 inhibitors showed that differences within the available agents in the two sub-classes are small. Greater treatment satisfaction was reported with glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors. Glucagon-like peptide-1 receptor agonists achieve greater glycated hemoglobin reductions than dipeptidyl peptidase-4 inhibitors, with concomitant weight loss. Probably due to the greater efficacy of glucagon-like peptide-1 receptor agonists, patient satisfaction is greater with these agents compared with dipeptidyl peptidase-4 inhibitors despite injectable versus oral administration and more frequent gastrointestinal side effects with the agonists.

Cardiovascular protective properties of incretin-based therapies in type 2 diabetes

Type 2 diabetes mellitus is a chronic dysmetabolic condition characterized by hyperglycemia and accompanied by dyslipidemia (low HDL, high triglycerides), and hypertension associated with insulin resistance in obesity. In addition to the glucose-reducing effects, incretin-based therapies have been found to have cardiovascular protective properties. This review summarizes the best available evidence favoring these positive pleiotropic effects of incretin mimetics as well as incretin enhancers. Studies in animals and humans are accumulating showing the direct as well as indirect actions of the glucagon-like peptide 1 analogues and dipeptidyl peptidase 4 inhibitors on the cardiovascular system. This class of agents appear to have effects on the cardiomyocytes, blood vessels, adipose tissue, regulation of blood pressure, and postprandial intestinal lipoprotein metabolism. Long-term hard outcome trials are under way that investigate the effects of incretin-based treatments on elevated cardiovascular risks in patients with type 2 diabetes.

Comparison of efficacy between incretin-based therapies for type 2 diabetes mellitus

Type 2 diabetes mellitus is widely prevalent and is often coexistent with obesity. Many of the available treatment options have side effects such as weight gain which often affect patient's willingness to continue the treatment. Effective weight loss, lack of significant hypoglycaemia, and favourable cardiometabolic profile make Incretin based therapies an attractive treatment option for type 2 diabetes. Incretin based therapies are available as either incretin mimetics (also called GLP-1 agonists) or incretin enhancers (DPP-4 inhibitors). Although agents in both these classes of incretin based therapy are effective through a common GLP-1 pathway, there are many differences amongst them including the route of administration, frequency of administration, effects on body weight, extent of glycaemic improvement. There are several trials evaluating these individual incretin based agents either as monotherapy or in combination with other anti-diabetic agents, however very few have looked into direct comparison amongst the agents in these two classes. This review is aimed to look at important mechanistic differences between incretin mimetics and enhancers through direct comparison trials and impact of these differences on biochemical, metabolic and patient satisfaction parameters.

Lipotoxicity impairs incretin signalling

The incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide are secreted by enteroendocrine cells and augment glucose-induced insulin secretion in response to food ingestion in a glucose-dependent manner. This mechanism forms the basis for incretin-based therapies in type 2 diabetes. However, the insulinotropic effect of incretins is diminished in type 2 diabetic patients, due in part to reduced expression of incretin receptors as a consequence of glucotoxicity. In this issue of Diabetologia, Kang et al (DOI: 10.1007/s00125-012-2776-x ) provide evidence that in addition to glucotoxicity, lipotoxicity also affects incretin receptor expression and signalling in insulin-secreting cells and isolated islets. In animal models of diabetes, the authors show that co-administration of a lipid-lowering drug with a dipeptidyl peptidase-4 inhibitor or a glucagon-like peptide-1 agonist improved glucose tolerance and beta cell mass. These novel findings provide convincing support for the notion that restoring normal circulating lipid levels in type 2 diabetes might help improve the efficacy of incretin-based therapies.

Incretin-based therapies for type 2 diabetes

There are many patients with type 2 diabetes in the UK, and controlling blood glucose levels in these patients can be challenging. Brenda Capaldi discusses the use of incretin-based therapies for people with type 2 diabetes

Incretin-based therapies for type 2 diabetes

The prevalence of type 2 diabetes mellitus continues to increase both in the UK and worldwide. There is a continuing need to identify novel therapeutic agents that offer improved efficacy and safety over existing anti-diabetic treatments. An increased understanding of the incretin hormone pathway has been the catalyst for development of two new classes of drugs: the DPP-4 inhibitors (gliptins) and the GLP-1 agonists (incretin mimetics). This article provides a summary of when and how to use these agents.

9. Incretin-based Therapy for Type 2 Diabetes Mellitus

9. Incretin-based Therapy for Type 2 Diabetes Mellitus

9. Incretin-based Therapy for Type 2 Diabetes Mellitus

9. Incretin-based Therapy for Type 2 Diabetes Mellitus

The future of incretin‐based therapy: novel avenues—novel targets

Incretin-based therapy for type 2 diabetes is based on the antidiabetic effects of glucagon-like peptide-1 (GLP-1) and instituted by GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors targeting the key islet defects of the disease. The treatment is clinically efficient and safe, and associated with a low risk of adverse events. It can be used both in early and late stages of the disease and both as monotherapy and add-on to other therapies. Current research on the future of incretin-based therapy focuses on optimizing its place in diabetes treatment and examines its potential in type 1 diabetes, in subjects with obesity without type 2 diabetes and in cardiovascular and neurodegenerative disorders. Other studies aim at prolonging the duration of action of the GLP-1 receptor agonists to allow weekly administration, and to develop orally GLP-1 receptor agonists. Furthermore, other investigators focus on stimulation of GLP-1 secretion by activating GLP-1-producing L-cells or using gene therapy. Finally, also other gastro-entero-pancreatic bioactive peptides are potential targets for drug development as are synthetic peptides engineered as co-agonists stimulating more than one receptor. We can therefore expect a dynamic development within this field in the coming years.

Incretin-Based Therapy and Pancreatitis—What is the Risk?

Incretin-based therapy for type 2 diabetes mellitus with glucagonlike peptide 1 (GLP-1) receptor agonists (eg, exenatide, liraglutide) and dipeptidyl-dipeptidase 4 (DPP-4) inhibitors (eg, sitagliptin, saxagliptin, vildagliptin) has been steadily increasing since its introduction 6 years ago (1). GLP-1 receptor agonists, by virtue of their pharmacologic GLP-1 action, are associated with nausea, vomiting, suppressed appetite, delayed gastric emptying, and weight loss. DPP-4 inhibitors, by virtue of prolonged inhibition of the GLP-1 degrading peptidase, achieve physiologic GLP-1 levels without gastrointestinal adverse effects, gastric slowing, or weight loss.