Comparative Effectiveness of CagriSegma, Semaglutide, Cagrilintide and Tirzepatide in the Management of Overweight and Obesity: A Network Meta-Analysis of Randomized Clinical Trials.
This network meta-analysis (NMA) systematically synthesized evidence from 25 randomized controlled trials across 12 interventions to compare the weight-loss efficacy and safety of four advanced anti-obesity medications — tirzepatide, semaglutide, cagrilintide, and the combination CagriSema (cagrilintide + semaglutide) — in adults with overweight or obesity. Searches were conducted across PubMed, Scopus, and Cochrane Central. Using random-effects NMA models, the study found that tirzepatide 15 mg produced the greatest mean percent body weight reduction (−17.97%), closely followed by CagriSema (−17.84%) and semaglutide 7.2 mg (−14.66%). For achieving ≥20% body weight loss, CagriSema showed the highest relative risk (RR 27.82), followed by tirzepatide 15 mg (RR 23.70). All agents increased gastrointestinal adverse events (RR 1.33–1.91) relative to placebo, with the highest treatment discontinuation seen with semaglutide 7.2 mg (RR 3.09). Serious adverse events were comparable to placebo across all regimens. Key limitations include reliance on indirect comparisons due to absence of head-to-head trials, potential heterogeneity across trial populations and follow-up durations, and the emerging/limited trial data for CagriSema specifically. The authors conclude that both tirzepatide and CagriSema represent leading options for substantial weight loss but call for direct comparative trials.
Why this grade: Although the component trials are RCTs in humans, the conclusions rest on indirect network comparisons in the absence of direct head-to-head data, and CagriSema's evidence base within the network is limited, warranting a moderate rather than strong grade.
Background Obesity is a chronic, progressive disease affecting over 1 billion adults worldwide, linked to serious comorbidities, including diabetes, hypertension, and cardiovascular disease and associated with increased mortality. Achieving clinically meaningful weight loss is critical to reducing cardiometabolic risk. Tirzepatide, semaglutide, cagrilintide and their combination (CagriSema) have demonstrated efficacy in clinical trials; however, no direct head-to-head studies have compared all advanced anti-obesity medications. This network meta-analysis examines their comparative efficacy and safety. Methods We systematically searched PubMed, Scopus and Cochrane Central for randomized controlled trials comparing these medications with placebo in adults with overweight or obesity. Outcomes included changes in percent body weight, absolute weight, waist circumference, BMI, patients achieving ≥ 5% to ≥ 20% weight loss, HDL-C and safety outcomes (AEs, serious AEs, gastrointestinal AEs and treatment discontinuation). Random-effects model and network meta-analysis methods were employed. Results Twenty-five trials involving 12 interventions met the inclusion criteria. Tirzepatide 15 mg resulted in the greatest percent weight reduction (MD -17.97%), followed by CagriSema (MD -17.84%) and semaglutide 7.2 mg (MD -14.66%). At the ≥ 20% weight-loss threshold, CagriSema demonstrated marked superiority (RR 27.82), followed by tirzepatide 15 mg (RR 23.70). Gastrointestinal adverse events increased with all treatments (RR 1.33-1.91), and treatment discontinuation was highest with semaglutide 7.2 mg (RR 3.09). Serious adverse events remained comparable to placebo across all regimens. Conclusion Tirzepatide 15 mg and CagriSema achieve the greatest weight reduction, including ≥ 20% body weight loss. Gastrointestinal adverse events rise with treatment intensity, while serious adverse events remain comparable to placebo. These findings support dual-pathway and combination incretin therapies as preferred options for patients requiring substantial weight loss. Treatment selection should be individualized based on comorbidity burden, tolerability and weight loss goals, recognizing that ≥ 5% weight loss improves metabolic parameters while ≥ 10% is needed for meaningful comorbidity reduction. Future head-to-head trials are needed.
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