Semaglutide Cuts Risk of Major Cardiovascular Events in Type 2 Diabetes: SUSTAIN-6

Once-weekly injection of the semaglutide, a novel glucagon-like peptide-1 (GLP-1) analogue manufactured by Novo Nordisk, significantly reduces the risk of major adverse cardiovascular events when compared with usual care in patients with type 2 diabetes, according to the results of a new study.

In a high-risk patient population—the majority of the 3,297 randomized subjects had established cardiovascular disease, chronic kidney disease, or both—treatment with semaglutide on top of usual care reduced the combined risk of nonfatal MI, nonfatal stroke, or cardiovascular death by 26% compared with usual care plus placebo after a median follow-up of 2.1 years. Overall, the primary outcome occurred in 8.9% of patients treated with placebo and 6.6% of patients treated with semaglutide (P < 0.001 for noninferiority; P = 0.02 for superiority).

The study, known as SUSTAIN-6, was presented today by Steven Marso, MD (HCA Midwest Health Research Medical Center, Kansas City, MO) at the European Association for the Study of Diabetes meeting in Munich, Germany, and published simultaneously in the New England Journal of Medicine.

Marso et al state that just 45 patients would need to be treated over 24 months to prevent one primary endpoint event. They did observe an increase in complications from retinopathy—3.0% in the semaglutide-treated patients versus 1.8% in the placebo arm (P = 0.02)—but also saw a reduction in the risk of new or worsening nephropathy. 

Of the composite primary endpoint, only the reduction in the risk of nonfatal stroke with semaglutide was statistically significant, with SUSTAIN-6 researchers reporting semaglutide lowered the risk of nonfatal stroke by 39% compared with placebo (1.6% versus 2.7%; P = 0.04). There was a decrease in the risk of nonfatal MI—2.9% in patients treated with semaglutide and 3.9% in the placebo arm—but the difference was not statistically significant. The GLP-1 agonist had no effect on cardiovascular mortality. 

In June, results from the LEADER study, a large-scale trial evaluating the safety of the GLP-1 agonist liraglutide (Victoza, Novo Nordisk), showed the drug significantly reduced the risk of death from cardiovascular causes, nonfatal MI, or nonfatal stroke by 13% compared with placebo. As reported by TCTMD at the time, there was a significant 15% relative reduction in all-cause mortality and a 22% relative reduction in cardiovascular mortality among the liraglutide-treated patients compared with the placebo-treated group. In contrast with semaglutide, which is administered once per week, liraglutide is a once-daily subcutaneous injection.

Last year, the EMPA-REG OUTCOME investigators also showed the addition of the glucose-lowering agent empagliflozin (Jardiance, Boehringer Ingelheim/Lilly), a sodium glucose cotransporter-2 (SGLT-2) inhibitor, reduced the risk of cardiovascular death, nonfatal MI, and nonfatal stroke when compared with usual care in diabetic patients. That benefit, unlike semaglutide, was driven by a decrease in cardiovascular mortality, with no significant between-group differences observed in rates of nonfatal MI and stroke.

SUSTAIN-6, along with the other cardiovascular outcomes studies with diabetic medications, was designed to meet the requirements set out by the US Food and Drug Administration following revelations the thiazolidinedione (TZD) rosiglitazone (Avandia, GlaxoSmithKline) raised the risk of MI. Based on guidance for industry issued in 2008, drug companies are required to show their medications do not result in an unacceptable increase in cardiovascular risk.

Two other cardiovascular safety studies testing other GLP-1 receptor agonists—EXSCEL with exenatide (AstraZeneca) and REWIND with dulaglutide (Lilly)—are currently ongoing.

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