1.) Why This Paper Matters Type 2 diabetes is ubiquitous, and cardiovascular disease is the leading cause of morbidity and mortality in diabetic patients. GLP‑1 receptor agonists have consistently shown improvements in reducing cardiovascular risk, but oral formulations were unavailable until recently. The SOUL trial examines whether oral semaglutide can reduce major adverse cardiovascular events (MACE) in high-risk adults. Key learning points for members: - How to identify what outcomes are clinically relevant - How to interpret absolute vs relative risk - How to approach papers yourself in a structured way 2.) Study Design & Population - Design: Phase III, randomized, double-blind, placebo-controlled trial - Participants: ~9,650 adults with type 2 diabetes and established cardiovascular disease, chronic kidney disease, or both - Intervention: Oral semaglutide (tablet) vs placebo (in addition to standard of care) - Follow-up: Median ~4 years - Inclusion/Exclusion: Adults age 50 or greater, with HbA1c 6.5-10%, high CV risk; excluded severe GI disease or recent major CV events 3.) Methods & Statistics - Primary outcome: Composite MACE (CV death, nonfatal MI, nonfatal stroke) - Analysis: Intention-to-treat; hazard ratios (HR) with 95% confidence intervals - Power: Designed to detect ~15% relative risk reduction - Other outcomes: HbA1c, weight, safety/adverse events - Why this matters: Learn how hazard ratios, confidence intervals, and absolute vs relative risk inform clinical interpretation 4.) Results - MACE: HR 0.86 (14% relative reduction) vs placebo - Absolute risk reduction: 1.8% over ~4 years - Weight & glycemic control: Significant reductions with semaglutide - Adverse events: Mostly mild/moderate GI events; serious events similar between groups - Subgroups: Benefits observed broadly, slightly attenuated in lower-risk populations 5.) Strengths & Limitations Strengths: - Large sample size - Double-blind, placebo-controlled - Definitive and observable cardiovascular outcomes - Long follow-up