Semaglutide Beyond Diabetes and Obesity: Systematic Review and Meta-Analysis of Multisystem Therapeutic Benefits.

OBJECTIVES

To evaluate semaglutide's multisystem therapeutic benefits across 12 health domains. Primary outcomes were major adverse cardiovascular events, resolution of metabolic dysfunction-associated steatohepatitis, and composite renal endpoints.

METHODS

PubMed, Embase, and Cochrane Central were searched through June 30, 2025, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Eligible studies included randomized controlled trials in adults (≥18 years) with ≥24-week follow-up comparing semaglutide (≥0.5 mg weekly subcutaneous or ≥7 mg daily oral) versus placebo or active comparators. Two reviewers independently extracted data and assessed bias (RoB 2) and certainty (GRADE).

RESULTS

Thirty-five trials (n = 36 847; mean age 54.2 years; body mass index: 34.8 kg/m2) were included. Semaglutide reduced glycated hemoglobin (-1.52%, 95% confidence interval [CI]: -1.60 to -1.44) and weight (-12.4 kg, 95% CI: -13.0 to -11.8). Non-glycemic benefits included major adverse cardiovascular events reduction (16%, risk ratio [RR]: 0.84, 95% CI: 0.77-0.92), metabolic dysfunction-associated steatohepatitis resolution (62.9%, RR: 1.84, 95% CI: 1.49-2.27), renal protection (HR: 0.76, 95% CI: 0.68-0.85), improved vascular function (+87 m walking distance), favorable body composition (87:13 fat-to-lean ratio), and better quality of life (+3.8 SF-36 points). No increase was observed in psychiatric or cancer risk.

CONCLUSIONS

Semaglutide confers robust, consistent multisystem benefits-including cardiovascular, hepatic, and renal protection-supporting its role as a transformative, disease-modifying therapy for metabolic disease beyond diabetes and obesity management. These findings support using semaglutide as a comprehensive, disease-modifying therapy for complex metabolic disorders, guiding clinicians to integrate it into patient-centered care for multisystem benefits beyond glycemic and obesity control.