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

Adv Ther. 2017 Jan;34(1):1-40. doi: 10.1007/s12325-016-0432-4. Epub 2016 Nov 14.


Introduction: Regulatory 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.

Methods: A 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.

Results: Thirty-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.

Conclusion: Overall, incretin therapy does not appear to increase risk for MACE in the short term.

Keywords: Cardiovascular risk; Dipeptidyl peptidase-4 inhibitor; Glucagon-like peptide-1 receptor agonist; MACE; Type 2 diabetes mellitus.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Adamantane / analogs & derivatives
  • Adamantane / therapeutic use
  • Cardiovascular Diseases / epidemiology
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / epidemiology
  • Dipeptides / therapeutic use
  • Dipeptidyl-Peptidase IV Inhibitors / adverse effects
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
  • Glucagon-Like Peptide-1 Receptor / antagonists & inhibitors*
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Incretins / adverse effects
  • Incretins / therapeutic use*
  • Meta-Analysis as Topic
  • Peptides / therapeutic use
  • Piperidines / therapeutic use
  • Randomized Controlled Trials as Topic
  • Sitagliptin Phosphate / therapeutic use
  • Uracil / analogs & derivatives
  • Uracil / therapeutic use


  • Dipeptides
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Incretins
  • Peptides
  • Piperidines
  • Uracil
  • lixisenatide
  • saxagliptin
  • alogliptin
  • Adamantane
  • Sitagliptin Phosphate