The cardiovascular safety of incretin-based therapies: a review of the evidence.
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ABSTRACT:
SUBMITTER: Petrie JR
PROVIDER: S-EPMC3847044 | biostudies-literature | 2013 Sep
REPOSITORIES: biostudies-literature
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The cardiovascular safety of incretin-based therapies: a review of the evidence.
Cardiovascular diabetology 20130906
Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in people with diabetes and therefore managing cardiovascular (CV) risk is a critical component of diabetes care. As incretin-based therapies are effective recent additions to the glucose-lowering treatment armamentarium for type 2 diabetes mellitus (T2D), understanding their CV safety profiles is of great importance. Glucagon-like peptide-1 (GLP-1) receptor agonists have been associated with beneficial effects on CV risk ...[more]
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Project description: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.
| S-EPMC5216099 | biostudies-literature
Project description:Our study aimed to evaluate the exposure-response relationship between incretin-based medications and the risk of major adverse cardiovascular events (MACE) using cardiovascular outcome trials (CVOTs). Eleven CVOTs with incretin-based medications were included. The median follow-up time, percentage of time exposure, and hazard ratio (HR) of MACE were obtained from each CVOT. The pharmacokinetic parameters of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitor (DPP-4) were obtained from published studies. Regression analysis was performed to assess the relationship between drug exposure and MACE HR. Cutoff values were determined from the ROC curves. The linear regression results indicated that log Cmax, log AUC0-24h, and log AUCCVOT are negatively correlated with MACE HR (R2 = 0.8494, R2 = 0.8728, and R2 = 0.8372, respectively; all p < 0.0001). The relationship between drug exposure (log Cmax, log AUC0-24h, and log AUCCVOT) and MACE HR strongly corresponded with the log (inhibitor) vs. response curve (R2 = 0.8383, R2 = 0.8430, and R2 = 0.8229, respectively). The cutoff values in the ROC curves for log Cmax, log AUC0-24h, and log AUCCVOT, were 2.556, 3.868, and 6.947, respectively (all p = 0.007). A Fisher's exact test revealed that these cutoff values were significantly related to cardiovascular benefits (all p < 0.05). Our study revealed a linear exposure-response relationship between drug exposure and MACE HR. We conclude that the cardiovascular benefits of incretin-based therapies may occur with higher doses of GLP-1 RAs and with increased exposure.
| S-EPMC9204533 | biostudies-literature
Project description:The prevalence of type 2 diabetes (T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance (NGT) and the clinical entity of T2D. Relentless ?-cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2D. The huge burden resulting from the complications of T2D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, on ?-cell function in patients with T2D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater ?-cell mass and function are preserved and the possibility of ?-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on ?-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2D.
| S-EPMC4265868 | biostudies-other
Project description:ObjectiveRecent large trials yield conflicting results on the association between incretin-based therapies (IBTs) and diabetic retinopathy (DR). We examined whether IBTs increase DR risk compared with other antihyperglycemics.Research design and methodsWe implemented an active comparator, new-user cohort design using a nationwide 20% random sample of fee-for-service U.S. Medicare beneficiaries aged 65 years or older with Parts A, B, and D coverage between 2007 and 2015. We identified the following cohorts without prior treatment for retinopathy: dipeptidyl peptidase 4 inhibitors (DPP4i) versus sulfonylureas (SU), DPP4i versus thiazolidinediones (TZD), glucagon-like peptide-1 receptor agonists (GLP1RA) versus long-acting insulin (LAI), and GLP1RA versus TZD. Primary outcome was advanced diabetic retinopathy requiring treatment (ADRRT), defined as a procedure code for retinopathy treatment. Incident diabetic retinopathy (IDR), identified by a diagnosis code, was a secondary outcome. We estimated propensity scores to balance confounders and adjusted hazard ratios (95% CI) using weighted Cox proportional hazards models.ResultsWe identified 213,652 eligible patients. During a median duration of 0.58 to 0.87 years across comparisons, with a rate from 6.0 to 12.8 per 1,000 person-years, IBTs were not associated with increased ADRRT or IDR risk. The adjusted hazard ratios (95% CI) for ADRRT were 0.91 (0.79-1.04) by comparing DPP4i to SU (n = 39,292 and 87,073); 0.91 (0.75-1.11), DPP4i to TZD (n = 51,410 and 22,231); 0.50 (0.39-0.65), GLP1RA to LAI (n = 9,561 and 82,849); and 0.75 (0.53-1.06), GLP1RA to TZD (n = 10,355 and 27,345).ConclusionsOur population-based cohort study of older U.S. adults with diabetes suggests that IBTs used for approximately 1 year do not increase the DR risk.
| S-EPMC6105327 | biostudies-literature
Project description:Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are incretins secreted from enteroendocrine cells postprandially in part to regulate glucose homeostasis. Dysregulation of these hormones is evident in type 2 diabetes mellitus (T2DM). Two new drugs, exenatide (GLP-1 mimetic) and sitagliptin [dipeptidyl peptidase (DPP) 4 inhibitor], have been approved by regulatory agencies for treating T2DM. Liraglutide (GLP-1 mimetic) and vildagliptin (DPP 4 inhibitor) are expected to arrive on the market soon.The background of incretin-based therapy and selected clinical trials of these four drugs are reviewed. A MEDLINE search was conducted for published articles using the key words incretin, glucose-dependent insulinotropic polypeptide, GLP-1, exendin-4, exenatide, DPP 4, liraglutide, sitagliptin, and vildagliptin.Exenatide and liraglutide are injection based. Three-year follow-up data on exenatide showed a sustained weight loss and glycosylated hemoglobin (HbA(1c)) reduction of 1%. Nausea and vomiting are common. Results from phase 3 studies are pending on liraglutide. Sitagliptin and vildagliptin are orally active. In 24-wk studies, sitagliptin reduces HbA(1c) by 0.6-0.8% as monotherapy, 1.8% as initial combination therapy with metformin, and 0.7% as add-on therapy to metformin. Vildagliptin monotherapy lowered HbA(1c) by 1.0-1.4% after 24 wk. Their major side effects are urinary tract and nasopharyngeal infections and headaches. Exenatide and liraglutide cause weight loss, whereas sitagliptin and vildagliptin do not.The availability of GLP-1 mimetics and DPP 4 inhibitors has increased our armamentarium for treating T2DM. Unresolved issues such as the effects of GLP-1 mimetics and DPP 4 inhibitors on beta-cell mass, the mechanism by which GLP-1 mimetics lowers glucagon levels, and exactly how DPP 4 inhibitors lead to a decline in plasma glucose levels without an increase in insulin secretion, need further research.
| S-EPMC2579648 | biostudies-other
Project description:Type 2 diabetes is associated with a high prevalence of comorbidities resulting from hypertension, dyslipidemia, and hyperglycemia. Inadequate management of these risk factors will eventually result in detrimental health consequences. Thus, the effect of a drug on factors such as weight, cardiovascular (CV) risk factors, and adherence is important to consider. A review was undertaken of the recent medical literature describing the extraglycemic characteristics of the two classes of incretin-based therapies-glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors. PubMed searches were performed to identify published data on incretin therapies that describe their effects on CV risk factors, CV events, and factors related to medication adherence. The maintenance or loss of weight associated with the use of GLP-1RAs and DPP-4 inhibitors is well described in the medical literature. These agents also appear to be associated with a modest decrease in blood pressure and a reduced risk of CV events. In addition, several characteristics of incretin therapies may improve rates of medication adherence, such as generally favorable tolerability profiles (particularly with DPP-4 inhibitors), the availability of formulations that simplify treatment regimens, and a low risk for hypoglycemia. The literature on incretin therapies describes a number of clinical characteristics that are relevant to the management of extraglycemic risk factors. As part of a holistic treatment strategy, these properties constitute important considerations for tailoring therapy to individual patients with type 2 diabetes.
| S-EPMC3889321 | biostudies-literature
Project description:There is limited comparative effectiveness evidence to guide approaches to managing diabetes in individuals failing metformin monotherapy. Our aim was to compare the incidence of all-cause mortality and major adverse cardiovascular events (MACEs) among new metformin monotherapy users initiating a dipeptidyl-peptidase-4 inhibitor (DPP4i), glucagon-like peptide-1 receptor agonist (GLP-1RA), sulfonylurea (SU), thiazolidinedione, or insulin.We conducted a cohort study using the UK-based Clinical Practice Research Datalink. Participants included a cohort of 38,233 new users of metformin monotherapy who initiated a 2nd antidiabetic agent between January 1, 2007 and December 31, 2012 with follow-up until death, disenrollment, therapy discontinuation, or study end-date. A subcohort of 21,848 patients with linked hospital episode statistics (HES) and Office of National Statistics (ONS) data were studied to include MACE and cardiovascular-related death. The primary exposure contrasts, defined a priori, were initiation of a DPP4i versus an SU and initiation of a GLP-1RA versus an SU following metformin monotherapy. Cox proportional hazards models were used to assess the relative differences in time to mortality and MACE between exposure contrasts, adjusting for important baseline patient factors and comedications used during follow-up.The main study cohort consisted of 6213 (16%) patients who initiated a DPP4i, 25,916 initiated an SU (68%), 4437 (12%) initiated a TZD, 487 (1%) initiated a GLP-1RA, 804 (2%) initiated insulin, and 376 (1%) initiated a miscellaneous agent as their 2nd antidiabetic agent. Mean age was 62 years, 59% were male, and mean glycated hemoglobin was 8.8% (92.6 mmol/mol). Median follow-up was 2.7 years (interquartile range 1.3-4.2). Mortality rates were 8.2 deaths/1000 person-years for DPP4i and 19.1 deaths/1000 person-years for SU initiators. Adjusted hazards ratio (aHR) for mortality in DPP4i versus SU initiators = 0.58, 95% CI 0.46 to 0.73, P < 0.001. MACE rates were 19.1/1000 person-years for DPP4i initiators, 15.9/1000 person-years for GLP1-RA initiators versus 33.1/1000 person-years for SU initiators (aHR: DPP4i vs SU initiators = 0.64, 95%CI 0.52-0.80; GLP1RA vs SU initiators = 0.73, 95% CI 0.34-1.55).In this cohort of metformin monotherapy users, 2nd-line DPP4i use was associated with a 42% relative reduction in all-cause mortality and 36% reduction in MACE versus SUs, the most common 2nd-line therapy in our study. GLP-1RAs were not associated with adverse events in this cohort.
| S-EPMC4937919 | biostudies-literature
Project description:Type 2 diabetes is the leading cause of chronic kidney disease (CKD). The prevalence of CKD is growing in parallel with the rising number of patients with type 2 diabetes globally. At present, the optimal approach to glycaemic control in patients with type 2 diabetes and advanced CKD (categories 4 and 5) remains uncertain, as these patients were largely excluded from clinical trials of glucose-lowering therapies. Nonetheless, clinical trial data are available for the use of incretin therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, for patients with type 2 diabetes and advanced CKD. This review discusses the role of incretin therapies in the management of these patients. Because the presence of advanced CKD in patients with type 2 diabetes is associated with a markedly elevated risk of cardiovascular disease (CVD), treatment strategies must include the reduction of both CKD and CVD risks because death, particularly from cardiovascular causes, is more probable than progression to end-stage kidney disease. The management of hyperglycaemia is essential for good diabetes care even in advanced CKD. Current evidence supports an individualized approach to glycaemic management in patients with type 2 diabetes and advanced CKD, taking account of the needs of each patient, including the presence of co-morbidities and concomitant therapies. Although additional studies are needed to establish optimal strategies for glycaemic control in patients with type 2 diabetes and advanced CKD, treatment regimens with currently available pharmacotherapy can be individually tailored to meet the needs of this growing patient population.
| S-EPMC7317405 | biostudies-literature
Project description:Postprandial plasma glucose concentrations are an important contributor to glycemic control. There is evidence suggesting that postprandial hyperglycemia may be an independent risk factor for cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that predominantly reduce postprandial plasma glucose levels. DPP-4 inhibitors are associated with fewer gastrointestinal side effects than GLP-1 receptor agonists and are administered orally, unlike GLP-1 analogs, which are administered as subcutaneous injections. GLP-1 receptor agonists are somewhat more effective than DPP-4 inhibitors in reducing postprandial plasma glucose and are usually associated with significant weight loss. For these reasons, GLP-1 receptor agonists are generally preferred over DPP-4 inhibitors as part of combination treatment regimens in patients with glycated hemoglobin levels above 8.0%. This article reviews the pathogenesis of postprandial hyperglycemia, the mechanisms by which GLP-1 receptor agonists and DPP-4 inhibitors reduce postprandial plasma glucose concentrations, and the results of recent clinical trials (ie, published 2008 to October 2012) that evaluated the effects of these agents on postprandial plasma glucose levels when evaluated as monotherapy compared with placebo or as add-on therapy to metformin, a sulfonylurea, or insulin. Findings from recent clinical studies suggest that both GLP-1 receptor agonists and DPP-4 inhibitors could become valuable treatment options for optimizing glycemic control in patients unable to achieve glycated hemoglobin goals on basal insulin, with the added benefits of weight loss and a low risk of hypoglycemia.
| S-EPMC3884108 | biostudies-literature
Project description:ObjectiveCombined treatment with an incretin-based drug, such as a glucagon-like peptide 1 receptor agonist (GLP-1 RA) or a dipeptidyl peptidase-4 (DPP-4) inhibitor, and basal insulin is a new strategy for improving glucose control in type 1 diabetes mellitus (T1DM). We performed a meta-analysis to assess the effect of this combined treatment on glycaemic control, insulin dose, severe hypoglycaemia, weight gain and gastrointestinal side effects in T1DM patients.MethodsWe searched PubMed, EMBASE and the Cochrane Library for relevant studies published before July 16, 2018. The primary outcome was glycosylated haemoglobin (HbA1c). Secondary outcomes included total daily insulin dose, body weight, severe hypoglycaemia and gastrointestinal side effects.ResultsNine randomized controlled trials (RCTs) involving 2389 patients were ultimately included in the meta-analysis. The pooled data suggested that incretin-based therapy was associated with a reduction in HbA1c levels (weighted mean difference (WMD) -0.17%, 95% confidence interval (CI) -0.24 to -0.11, P < 0.001), total daily insulin dose (WMD -5.53 IU/day, 95% CI -8.89 to -2.17, P = 0.001) and body weight (WMD -3.24 kg, 95% CI -4.43 to -2.04, P < 0.001). Incretins did not increase the risk of severe hypoglycaemia (odds ratio (OR) 0.83, 95% CI 0.60-1.16, P = 0.287) but increased the occurrence of gastrointestinal side effects (OR 3.46, 95% CI 2.20-5.45, P < 0.001).ConclusionsIn T1DM patients, GLP-1 RAs, but not DPP-4 inhibitors, combined with insulin appear to be an effective therapy but may increase the occurrence of gastrointestinal side effects.
| S-EPMC6410765 | biostudies-literature