Abstract:

Oral semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is a novel agent that offers glycemic control in an oral formulation while extending benefits into the cardiovascular domain. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM), particularly among those with prior atherosclerotic events, heart failure, or renal impairment. The (Semaglutide cardiovascular outcomes in people with type 2 diabetes using oral semaglutide compared with placebo) SOUL trial was designed to evaluate the cardiovascular safety and efficacy of oral semaglutide in this high-risk population. This randomized, double-blind, placebo-controlled trial enrolled 9,650 participants and followed them for a median of 49.5 months. A major adverse cardiovascular event (MACE) occurred in 12.0% of semaglutide-treated patients and 13.8% of those receiving placebo (HR 0.86; 95% CI, 0.77–0.96; p=0.006). Additionally, semaglutide significantly reduced nonfatal myocardial infarction (HR 0.74; 95% CI, 0.61–0.89). Secondary outcomes included fewer major adverse limb events (HR 0.71; 95% CI, 0.52–0.96) and a favorable trend in kidney events (HR 0.91; 95% CI, 0.80–1.05). Semaglutide also improved metabolic outcomes, lowering HbA1c by 1.2% and body weight by 4.1 kg versus placebo. Serious adverse events were lower with semaglutide (47.9%) compared to placebo (50.3%). The SOUL trial affirms oral semaglutide’s role as a dual action cardiometabolic agent. Its oral formulation, safety profile, and durable efficacy make it a valuable option for high-risk T2DM patients unwilling or unable to use injectable therapies.

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