Cagrilintide–Semaglutide Combination Therapy Versus Monotherapy or Placebo: A Systematic Review and Meta-Analysis
This systematic review and meta-analysis (PROSPERO-registered) pooled data from four randomized controlled trials (n = 4,810 adults with overweight or obesity) to compare the fixed-dose combination of cagrilintide and semaglutide (CagriSema) against semaglutide alone, cagrilintide alone, or placebo. The authors found that, across all comparators, CagriSema was associated with statistically greater percent body weight reduction: approximately 7.4 percentage points more than semaglutide, 8.8 percentage points more than cagrilintide, and 13.9 percentage points more than placebo. The likelihood of achieving ≥15% or ≥20% weight loss was reported to be 2–3 times higher with the combination. Waist circumference was also significantly reduced with CagriSema versus placebo (mean difference approximately −10.9 cm). No consistent differences in HbA1c were observed across comparisons. Gastrointestinal adverse events were more frequent with CagriSema, and treatment discontinuation rates were correspondingly higher in the combination group. Limitations include the small number of included trials (four), preprint status introducing risk of non-peer-reviewed data, and potential heterogeneity across trial designs and populations.
Why this grade: Although the meta-analysis synthesizes RCT data in humans (n = 4,810), it is currently a preprint (not peer-reviewed) and is limited to only four trials, constraining confidence to a moderate rather than strong evidence grade.
Aim: To evaluate the efficacy and safety of the fixed-dose combination of cagrilintide and semaglutide (CagriSema) compared with semaglutide, cagrilintide, or placebo in adults with overweight or obesity, integrating current evidence from randomized controlled trials Methods: : We performed a systematic review and meta-analysis (PROSPERO CRD420251128528) of randomized controlled trials comparing CagriSema with semaglutide, cagrilintide, or placebo. The primary outcome was weight reduction (%, categorical thresholds). Secondary outcomes included glycemia, waist circumference, and safety profile. Results: : Four RCTs (n=4,810) were included. CagriSema achieved greater weight loss than semaglutide (MD: -7.44%; 95% CI -10.44 to -4.44), cagrilintide (MD: -8.75%; 95% CI -9.89 to -7.62), and placebo (MD: -13.85%; 95% CI -20.61 to -7.09). The likelihood of ≥15% and ≥20% weight loss was 2-3-fold higher with CagriSema versus monotherapy. Waist circumference was significantly reduced with CagriSema compared with placebo (MD: -10.85 cm; 95% CI -15.85 to -5.86). No consistent differences in HbA1 were observed. Gastrointestinal adverse events were more frequent with CagriSema, and discontinuations were correspondingly higher in the combination therapy group. Conclusion: CagriSema provides superior and clinically meaningful weight loss compared with semaglutide, cagrilintide, and placebo, with incremental benefits across responder thresholds, albeit at the cost of increased gastrointestinal intolerance. (Figure [1](#fig-cap-0001))
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