Incretin-based agents in type 2 diabetic patients at cardiovascular risk: compare the effect of GLP-1 agonists and DPP-4 inhibitors on cardiovascular and pancreatic outcomes

Abstract

BackgroundIncretin-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.MethodsSix 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.ResultsWhen 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.ConclusionsGLP-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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0512-z) contains supplementary material, which is available to authorized users.

Comparative outcomes of heart failure among existent classes of anti-diabetic agents: a network meta-analysis of 171,253 participants from 91 randomized controlled trials

“…As for DDP-4 inhibitors, the signal of harm was first identified in SAVOR-TIMI 53 and EXAMINE trials [47,48], in which heart failure hospitalization was increased with the use of saxagliptin and alogliptin. Furthermore, in several meta-analyses and observational studies, DPP-4 inhibitors were reported to be associated with an increased risk of worsening heart failure [49][50][51], besides acute pancreatitis and hypoglycemia [52]. Recently, the hypothesis of adrenergically mediated cardiotoxicity mediated by DPP-4 inhibition has been proposed [53].…”

Incretin-Based Therapies and the Short-term Risk of Pancreatic Cancer: Results From Two Retrospective Cohort Studies

“…However, the latter studies included relatively small numbers of patients with pancreatic cancer (13). A recent meta-analysis of the six largest randomized trials on incretin drugs obtained a summary relative risk of pancreatic cancer of 0.71 (95% CI 0.45-1.11) after 1.5-3.8 years of follow-up (14). However, the six trials analyzed reported a total of only 75 patients with pancreatic cancer, with a high level of heterogeneity of results across trials (I 2 = 61%).…”

Comparison of the effects of twice-daily exenatide and insulin on carotid intima-media thickness in type 2 diabetes mellitus patients: a 52-week randomized, open-label, controlled trial

“…An observational study for multi-center (71 centers) demonstrated that 20 weeks of treatment with shortacting exenatide was well tolerated and showed a significant body weight and glucose reduction in T2DM patients whose glycemia had been inadequately controlled with oral hypoglycemic agents [21]. Once-weekly exenatide resulted in a nominal 9% relative reduction in major adverse cardiovascular events and a 14% relative reduction in all-cause mortality compared to placebo in T2DM with and without known cardiovascular disease [22], whereas dipeptidyl peptidase-4 inhibitors had no effect on cardiovascular risk outcomes but increased risks of acute pancreatitis and hypoglycemia [23].…”