Effect of oral semaglutide on cardiometabolic risk factors in overweight and obese individuals with or without diabetes: a systematic review and meta-analysis.

BACKGROUND: Obesity is linked to cardiometabolic risk, and semaglutide, a glucagon-like peptide-1 receptor agonist, has emerged as a promising option for weight and metabolic control. This systematic review and meta-analysis evaluated the effects of oral semaglutide, compared with placebo, on cardiometabolic risk factors in overweight and obese adults with or without diabetes. MATERIALS AND METHODS: In this systematic review and meta-analysis, following PRISMA 2020 guidelines, PubMed, Embase, and Scopus were searched through 25 August 2025. Randomized controlled trials (RCT) with overweight and obese populations, with or without diabetes, were included. The treatment and control groups received oral semaglutide and placebo, respectively. Outcomes were cardiometabolic factors and adverse events at baseline and follow-up. We pooled data using a random-effects model to estimate changes in outcomes by reporting Estimated Treatment Difference (ETD) as mean difference. Subgroup analyses were conducted based on dosage and follow-up duration. RESULTS: Thirteen RCTs involving 26,284 participants met the criteria (52% received semaglutide). Female ratio of the semaglutide group was 30.1% and for the placebo group weas 33.3%. Compared with placebo, semaglutide showed significant reductions in body weight (ETD - 2.85 kg; 95% CI [- 4.03 to - 1.66]; p < 0.001), BMI (ETD - 0.66 kg/m²; 95% CI [- 0.95 to - 0.36]; p < 0.001), waist circumference (ETD - 1.79 cm; 95% CI [- 2.63 to - 0.95]; p < 0.001), HbA1c (ETD - 0.94%; 95% CI [- 1.13 to - 0.76]; p < 0.001), fasting plasma glucose (ETD - 26.91 mg/dL; 95% CI [- 33.56 to - 20.26]; p < 0.001), systolic blood pressure (ETD - 2.71 mmHg; 95% CI [- 3.70 to - 1.72]; p < 0.001), and diastolic blood pressure (ETD - 0.77 mmHg; 95% CI [- 1.38 to - 0.17]; p = 0.01) over 6 months. Benefits were consistent across different follow-up durations and doses. Gastrointestinal symptoms remained the most common adverse events (OR for GI issues = 2.69; nausea = 3.13; vomiting = 6.25; all p < 0.001). Semaglutide also showed a protective effect on cardiovascular events (OR = 0.64; p = 0.006). CONCLUSION: Oral semaglutide demonstrates meaningful improvements in cardiometabolic outcomes and a favorable safety profile, supporting its use as a non-invasive therapy for obesity and related metabolic disorders.