1. The two-year risk of developing cardiovascular death, nonfatal myocardial infarction (MI) or stroke was approximately 25% less in patients taking semaglutide compared to placebo.
2. Two-year use of semaglutide linked to significantly lower levels for glycated hemoglobin (HbA1c) levels, weight and systolic blood pressure compared to placebo.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Semaglutide is an extended half-life glucagon-like peptitde 1 analogue that has not yet been approved for treatment of type 2 diabetes (T2DM). Its long-term cardiovascular side effects remain unknown. In this randomized, double-blind, placebo controlled trial, researchers attempt to understand if semaglutide treatment in patients greater than 50 years of age with established cardiovascular disease was noninferior to placebo with regards to cardiovascular death, nonfatal MI and/or stroke.
The result indicated that over the course of two years, participants on semaglutide were 25% less likely to experience the primary outcome composite of cardiovascular death, nonfatal MI or stroke. The decrease in risk was driven primarily by a significant decrease in the two-year risk of nonfatal stroke and a nonsignificant decrease in the two-year risk of nonfatal MI. However, there were no significant differences between groups for cardiovascular death, possibly due to the two year timeframe of the study. Additional significant differences in the semaglutide group included sustained decreases in HbA1c levels, weight loss and reduction in systolic blood pressures over the two-year study period. Overall, data from the study demonstrated not only noninferiority of semaglutide compared to placebo, but also significant clinical benefits compared to placebo.
Relevant Reading: Impact of Diabetes on Cardiovascular Disease: An Update
In-Depth [randomized controlled trial]: Researchers randomized 3297 patients to receive either semaglutide (n = 1648) or placebo (n = 1649), once-weekly at a doses of 0.5 mg or 1.0 mg. At baseline, 2735 (83%) of participants had established cardiovascular disease. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal MI or stroke. The primary outcome occurred in 6.6% of the semaglutide group and 8.9% in the placebo group (HR 0.74; 95%CI 0.58-0.95; p < 0.001). Differences in nonfatal MI between semaglutide (47 patients, or 2.9%) and placebo (44 patients, 2.7%) groups were nonsignificant (HR 0.74; 95%CI 0.51-1.08; p = 0.12). However, nonfatal stroke occurred at a significantly lower rate in the semaglutide (27 patients, 1.6%) compared to the placebo (44 patients, 2.7%) group (HR 0.61; 95%CI 0.38-0.99; p = 0.04). In terms of adverse effects, rates of new or worsening nephropathy were lower in the semaglutide group (HR 0.64; 95%CI 0.46-0.88; p = 0.005), while rates of retinopathic complications were significantly higher in the semaglutide group (HR 1.76; 95%CI 1.11-2.78; p = 0.02). The mean glycated hemoglobin level at the study end-point was also significantly lower in the semaglutide compared to placebo group. The NNT to prevent one event of the primary outcome over 2 years was 45 patients.
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