Incretin-based therapies and cardiovascular risk

Abstract

Background:

Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP4) inhibitors are currently used as glucose-lowering agents in type 2 diabetes, due to their effects on insulin and glucagon secretion. These agents, which are effective in improving glucose control, could also have a beneficial effect on the incidence of cardiovascular events. The analysis of major cardiovascular events reported during trials with metabolic endpoints shows a significant reduction of risk with both classes of drugs. Longer-term trials specifically designed to assess the effects of GLP-1 receptor agonists and DPP4 inhibitors on major cardiovascular events are currently ongoing.

Scope:

In order to elucidate potential mechanisms of cardiovascular protection with incretin-based therapies, a Medline search (any date up to December 15th, 2011) was performed using the terms ‘cardiovascular’ and (‘DPP-4’ or ‘GLP-1’ or any single name of incretin-based drugs); papers which were considered relevant for the aim of this review were selected by the authors, on the basis of their judgment.

Findings:

Incretin-based drugs have beneficial effects on cardiovascular risk factors, such as blood pressure and, to a lesser extent, cholesterol and triglyceride. GLP-1 receptor agonists also reduce body weight. A number of experimental studies has suggested that GLP-1 has direct, beneficial effects on myocardial and endothelial cells, but some of these actions could be mediated via GLP-1 receptor-independent pathways. Available experimental evidence, together with a few pilot studies in humans, shows that GLP-1 receptor agonists and DPP4 inhibitors are capable of ameliorating myocardial function and protect myocardiocytes from ischemic damage, independent of their glucose-lowering effects. Furthermore, both classes of drugs enhance endothelial function. In addition, DPP4 inhibitors increase the availability of endothelial progenitor cells, via a GLP-1 receptor-independent pathway.

Conclusion:

Taken together, available data suggest that incretin-based therapies could prevent cardiovascular disease via multiple mechanisms.

Keywords::

• Cardiovascular disease
• Diabetes
• Dipeptidyl peptidase 4
• Glucagon-like peptide-1

Transparency

Declaration of funding

The preparation of this paper was not supported by any financial grant.

Declaration of financial relationships

E.M. has received consulting honoraria, speaking fees, and/or research grants from AstraZeneca (saxagliptin), Boehringer Ingelheim (linagliptin), Bristol-Myers Squibb (saxagliptin), Eli Lilly (exenatide), Glaxo SmithKline (albiglutide), Merck Sharp & Dohme (sitagliptin), Novartis (vildagliptin), Novo Nordisk (liraglutide), and Takeda (alogliptin). I.D. has received speaking fees from Merck Sharp & Dohme (sitagliptin) and Takeda (alogliptin).

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.