Cardiovascular safety of therapies for type 2 diabetes

ABSTRACT

Introduction: Dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) analogs and sodium-glucose cotransporter 2 (SGLT2) inhibitors are relatively new therapies for the treatment of type 2 diabetes mellitus. Given the high prevalence of cardiovascular complications in patients with type 2 diabetes and recent concerns questioning CV safety of newer antidiabetic medications, cardiovascular safety of these medications requires evaluation.

Areas covered: Cardiovascular effects of these drug classes from preclinical and clinical data as well as non-cardiovascular safety issues are delineated from literature searches covering the last decade and up to June 2016. Major clinical trials assessing the cardiovascular safety of GLP-1 agonists (ELIXA and LEADER), DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) and SGLT2 inhibitors (EMPA-REG OUTCOME) are reviewed and interpreted.

Expert opinion: Based on review of the present evidence, these 3 classes of antihyperglycemic therapies have acceptably safe CV safety profiles for patients with type 2 diabetes. The latest evidence from LEADER and EMPA-REG OUTCOME trials indicate that liraglutide and empagliflozin have cardiovascular benefits that may prove to be of clinical importance in the management of type 2 DM.

KEYWORDS:

• Cardiovascular safety
• DPP-4 inhibitors
• GLP-1 agonists
• SGLT-2 inhibitors
• type 2 diabetes mellitus

Article highlights

• The paper focuses on the pharmacologic and clinical cardiovascular (CV) effects of drugs for the treatment of type 2 diabetes

• The clinical pharmacology of the newer classes of therapies for the treatment of type 2 diabetes are reviewed

• Several major clinical trials that have evaluated the CV safety of these agents (SAVOR TIMI 53, EXAMINE, ELIXA, TECOS, EMPA-REG OUTCOME, LEADER] have been described.

• The results of these major studies have shown either a non-inferior or in 2 cases, a beneficial effect on major CV outcomes. It is not yet clear if those studies showing a benefit could be considered a ‘class effect’

Heart failure safety has received a great deal of attention over the past 3 years and has become a pre-specified part of the more recent studies. Only 1 study showed a small but statistically significant increase in hospitalization for heart failure. The bulk of evidence does not suggest heart failure to be of major clinical concern with the newer drugs used for the treatment of type 2 diabetes.

This box summarizes key points contained in the article.

Declaration of interest

Dr WIlliam White served a chair of the Steering Committee for the EXAMINE trial from 2009 to 2016 (sponsored by Takeda Development Center, Deerfield, IL, USA). The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper has been funded in part (not in total) by National Institutes of Health R01 AG022092.