Mitigating Cardiovascular Risk in Type 2 Diabetes With 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 for major 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 far-three with dipeptidyl peptidase 4 inhibitors, one with 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 of MACE with 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 cause when compared with placebo. Treatment with semaglutide, another GLP-1 RA, 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…
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