Evaluating the Cardiovascular Benefits of Innovator Semaglutide 2.4 mg (Recombinant DNA (r-DNA)) in Patients With Overweight or Obesity: A Critical Review of Current Evidence

Obesity and cardiovascular (CV) disease (CVD) are tightly intertwined global epidemics, with excess adiposity now recognized as a major, modifiable driver of atherosclerotic events, heart failure, and mortality. Despite advances in cardiometabolic care, residual CV risk remains high in people with obesity, underscoring the need for therapies that both reduce body weight and directly modify CV risk. Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), has emerged as a pivotal agent across the cardiometabolic spectrum, culminating in the SELECT trial, which demonstrated a reduction in three-point major adverse CV events (3P-MACE) in people with obesity and established CVD but without diabetes. Complementary evidence from heart failure with preserved ejection fraction (HFpEF) trials and real-world studies further supports a broad CV and functional benefit profile. This narrative review synthesizes data from randomized controlled trials (RCTs) and real-world evidence (RWE) on Wegovy® (semaglutide 2.4 mg, a recombinant DNA-derived GLP-1RA) in obesity with CVD, with a focus on SELECT, mediation analyses suggesting weight-independent CV effects, and outcomes in obesity-related HFpEF. We also discuss guideline positioning, regulatory milestones-including the 2025 Central Drugs Standard Control Organization (CDSCO) approval in India-and the evolving competitive landscape. Overall, semaglutide 2.4 mg represents the first and only anti-obesity medication with proven CV benefit in people with obesity without type 2 diabetes (T2D), with important implications for clinical practice and health policy.