Emerging pharmacotherapies for obesity: A systematic review.

Summary

This systematic review catalogs 53 phase 2/3 trials of emerging anti-obesity agents, highlighting the dominance of incretin-based therapies and reporting phase 2 mean weight loss ranging from 7.4% to 24.2%. Oral semaglutide 50 mg is the only agent to complete phase 3 to date, and multiple GLP-1-based combinations are in ongoing phase 3 trials. Evidence gaps include long-term safety, mortality, cardio-renal outcomes, and data in underrepresented populations.

Key Findings

• Identified 53 phase 2/3 trials with 36 emerging anti-obesity agents or combinations; 4 trials were withdrawn/terminated.
• Incretin-based therapies dominate; completed phase 2 programs report mean weight loss ranging 7.4% to 24.2%.
• Oral semaglutide 50 mg is the only agent with completed phase 3; 14 phase 3 trials (e.g., CagriSema, mazdutide, retatrutide) are ongoing.
• Critical evidence gaps include long-term safety, mortality, cardio-renal-metabolic outcomes, cost-effectiveness, and equity/availability.

Clinical Implications

Clinicians should anticipate broader availability of potent incretin-based regimens and prepare for individualized selection, monitoring of GI and metabolic AEs, and long-term weight maintenance strategies, while recognizing evidence gaps in mortality and cardio-renal endpoints.

Limitations

• Heterogeneity across trials limits quantitative synthesis and between-drug comparisons
• Limited long-term outcomes (mortality, cardio-renal events) and underrepresentation of key subpopulations

Future Directions

Prospective head-to-head trials, long-term extension studies capturing cardio-renal-mortality endpoints, pragmatic effectiveness/cost studies, and inclusion of underrepresented populations.