Mitigating cardiovascular risk in type 2 diabeteswith antidiabetes drugs: A review of principal cardiovascular outcome results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 trials

Abstract

The U.S. Food and Drug Administration (FDA) issued a diabetes guidance in 2008 mandating that all new antidiabetes drugs rule out excess cardiovascular (CV) risk, defined as an upper bound of the two-sided 95% CI formajor adverse CV events (MACE) of less than 1.80 preapproval and 1.30 postapproval. Over 25 large, prospective, randomized, controlled clinical trials involving nearly 195,000 subjects thus far have been completed or are ongoing in accordance with this guidance. The results of seven trials have been presented so fardthree with dipeptidyl peptidase 4 inhibitors, onewith a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and three with glucagon-like peptide 1 receptor agonists (GLP-1 RA).While all seven trials showed noninferiority in the rate ofMACEwith the use of these agents compared with placebo, three of them revealed CV benefits. Treatment with empagliflozin (an SGLT2 inhibitor) and treatment with liraglutide (a GLP-1 RA) both significantly reduced the risk of MACE, mortality from CV causes, and mortality from any causewhen comparedwith placebo. Treatment with semaglutide, anotherGLP-1RA, showed a significantly lower rate of MACE but not mortality from CV or any cause compared with placebo. In all of the trials, the effects of treatment on outcomes were out of proportion to the small differences in glycemic control levels, suggesting that the effects observed were likely unrelated to differences in the glucose-lowering efficacy. Overall, the results of these trials yield a favorable benefit-risk balance for these therapies in mitigating CV risk in patients with type 2 diabetes. More research is needed to elucidate the underlying mechanisms and confirm whether the CV benefits are a class effect or whether the benefits persist in patients without established CV disease or are evident even in patients without diabetes.