Antidiabetic agents and cardiovascular outcomes in patients with heart diseases

Abstract

Introduction: This article reviews evidence of the benefits and risk of antidiabetic agents in cardiovascular (CV) outcomes, with a focus on medications approved by the FDA since 2008.

Study selection: Peer-reviewed articles were identified from MEDLINE and Current Content databases (both 1966 to 1 October 2016) using the search terms insulin, metformin, rosiglitazone, pioglitazone, glyburide, glipizide, glimepiride, acarbose, miglitol, albiglutide, exenatide, liraglutide, lixisenatide, dulaglutide, pramlintide, meglitinide, alogliptin, linagliptin, saxagliptin, sitagliptin, canagliflozin, dapagliflozin, empagliflozin, colesevalam, bromocriptine, mortality, myocardial infarction (MI), heart failure (HF), and stroke. Trials were included if they were randomized clinical trials evaluating adult patients (≥18 years) with type 2 diabetes; had a period of intervention and follow-up of ≥12 months; and assessed CV outcomes (CV death, fatal/non-fatal MI or HF) as endpoints. Twenty-three randomized trials were included.

Antidiabetic agents: Of agents approved prior to 2008, metformin has not been associated with measurable harm in patients with diabetes in terms of mortality and CV events (and has a trend of benefit). Controversial results existed with the use of sulfonylureas and thiazolidinediones (TZDs) for CV outcomes. Among agents approved after 2008, liraglutide and empagliflozin have been shown to be superior to placebo in improving CV outcomes.

Conclusions: The FDA regulatory mandate to demonstrate CV safety in order to approve new diabetes drugs led to an increase in the number of CV outcome trials. However, these trials have placebo-controlled, non-inferiority designs aiming to show absence of CV toxicity. More studies are needed to address other questions, including comparative effectiveness, and longer-term risk versus benefits.

Keywords:

• Cardiovascular diseases
• diabetes
• dipeptidyl peptidase-4 inhibitor
• glucagon-like peptide-1 agonist
• sodium–glucose co-transporter 2 (SGLT2) inhibitors

Transparency

Declaration of funding

This manuscript was not funded.

Declaration of financial/other relationships

D.K.P. has disclosed that he has received speaker’s bureau fees from Sanofi, Novo Nordisk, Merck, AstraZeneca, Boehringer Ingelheim, and is an advisory board member/consultant for Regeneron, Novo Nordisk, Sanofi, and AstraZeneca. J.W.M.C., H.A.B. and S.H.B. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this article.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.