CagriSema Versus Semaglutide Monotherapy or Placebo for Obesity: A Systematic Review and Meta-Analysis of Randomized Controlled Trials with GRADE Assessment.
This systematic review and meta-analysis evaluated the efficacy and safety of CagriSema — a dual therapy combining the GLP-1 receptor agonist semaglutide with the amylin analogue cagrilintide — compared to semaglutide monotherapy or placebo in adults with obesity. The authors searched four major databases through July 2025 and identified four eligible randomized controlled trials encompassing 4,419 participants (CagriSema: 3,055; controls: 1,364). Pooled analyses found that CagriSema was associated with significantly greater percent body weight loss (Cohen's d: −1.38; 95% CI: −1.84 to −0.91), greater absolute weight reduction (mean difference: −11 kg), reductions in waist circumference (−9.41 cm), and lower systolic blood pressure (−7.06 mmHg) versus comparators. However, gastrointestinal adverse events occurred more frequently with CagriSema (relative risk: 1.32). Notable limitations include high statistical heterogeneity (I² = 94.8%) across the included trials, the small number of studies (n = 4), and the absence of long-term safety and cardiovascular outcomes data. The authors conclude that CagriSema demonstrates superior weight reduction compared with semaglutide or placebo, but that tolerability monitoring and longer-term evidence are warranted.
Why this grade: Meta-analysis of four RCTs in humans (n = 4,419) with GRADE assessment, though conclusions are tempered by very high heterogeneity (I² = 94.8%) and a limited number of contributing trials.
The obesity epidemic is a major health burden that enhances susceptibility to a broad spectrum of metabolic-associated comorbidities, ranging from fatty liver disease and endocrine dysfunction to traditional risks like type 2 diabetes mellitus and cardiovascular disease. Glucagon-like peptide-1 receptor agonists, including semaglutide, facilitate weight loss alongside glucose metabolism. The dual therapy CagriSema, which combines semaglutide with cagrilintide was developed. We systematically searched MEDLINE (via PubMed), Web of Science, Scopus, and Cochrane Library, from inception to July 2025, for randomized controlled trials (RCTs) comparing CagriSema with semaglutide monotherapy or placebo in patients with obesity. Four RCTs (n = 4,419) were included (CagriSema: 3,055; control: 1,364). Pooled analysis showed that CagriSema significantly reduced percent weight loss (Cohen's d: -1.38; 95% CI: -1.84 to -0.91; I² = 94.8%). CagriSema also resulted in greater absolute weight loss (MD: -11 kg), waist circumference (MD: -9.41 cm), and systolic blood pressure (MD: -7.06 mmHg). Gastrointestinal adverse events were more frequent (RR: 1.32). CagriSema therapy was associated with superior weight reduction compared with semaglutide or placebo. In conclusion, CagriSema achieves greater weight loss than semaglutide or placebo but increases gastrointestinal adverse events, warranting careful tolerability monitoring and longer-term data.
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