Cardiovascular Effects of Glucose-lowering Therapies for Type 2 Diabetes: New Drugs in Perspective

Abstract

Purpose: The purpose of this study was to review the results of clinical trials assessing the cardiovascular effects of drugs for type 2 diabetes and the cardiovascular effects of newer available drugs.

Methods: We performed a detailed search of PubMed-listed publications, reports from international meetings, and ongoing studies from clinical trials.gov.

Findings: Currently available drugs have neutral or, in some cases, negative effects on cardiovascular outcomes. Modern sulfonylureas appear to be safe, although the biguanide metformin has a slightly better cardiovascular safety profile than the sulfonylureas and is the first choice for monotherapy. The cardiovascular tolerability of thiazolidinediones (glitazones) remains controversial, with particularly adverse effects in patients with cardiac failure. The cardiovascular effects of insulin in type 2 diabetes appear neutral. Newer incretin-based therapies have been closely examined in a large number of clinical trials, some of which are still ongoing. The dipeptidyl peptidase-4 inhibitor (gliptins) trials to date have all found a neutral effect. Of the glucagon-like peptide-1 (GLP-1) agonists, lixisenatide had a neutral effect, whereas liraglutide and semaglutide had a benefit on outcomes. The results of the sodium-glucose transporter-2 (SGLT-2) inhibitor empaglifozin attracted interest when it was the first to report a strong benefit on cardiovascular mortality. Liraglutide and semaglutide had a neutral effect on cardiac failure admissions, whereas empaglifozin had a benefit. In each of the trials, there was not a clear effect on myocardial infarction and stroke. The mechanism of the cardiovascular benefit is debated, and further studies with other GLP-1 agonists and SGLT-2 inhibitors are awaited.

Implications: After 2 decades of disappointment in attempting to control cardiovascular progression in type 2 diabetes with careful glycemic control, there is distinct hope that newer drugs, particularly the GLP-1 agonists and the SGLT-2 inhibitors, will have cardiovascular benefits independent of glycemic control.

Keywords: GLP agonists; SGLT-2 inhibitors; cardiovascular outcomes; glucose lowering drugs; type 2 diabetes.