Summary: In adults with overweight plus a complication or obesity without diabetes, once-weekly cagrilintide-semaglutide (CagriSema) produced substantially greater weight loss than placebo at 68 weeks. Gastrointestinal adverse events were common, and the trial was not designed to establish cardiovascular outcomes or long-term weight maintenance.
PICO Summary
| Element | Detail |
|---|---|
| Population | 3417 adults without diabetes with BMI >=30 kg/m2, or BMI >=27 kg/m2 plus an obesity-related complication; 68-week phase 3a, double-blind, four-arm RCT. |
| Intervention | Once-weekly cagrilintide 2.4 mg plus semaglutide 2.4 mg with lifestyle intervention (n=2108). |
| Comparison | Placebo (n=705), with active semaglutide-only (n=302) and cagrilintide-only (n=302) groups also included. |
| Outcome | Mean body-weight change -20.4% with CagriSema versus -3.0% with placebo; estimated difference -17.3 percentage points (95% CI -18.1 to -16.6; P<0.001). Gastrointestinal events occurred in 79.6% versus 39.9%. |
CagriSema for Obesity (REDEFINE 1)
Phase 3a RCT - obesity without diabetes - 68 weeks
CagriSema produced 20.4% mean weight loss at 68 weeks versus 3.0% with placebo in adults with obesity without diabetes; gastrointestinal adverse events were frequent.
Expert Commentary
REDEFINE 1 confirms that combined amylin and GLP-1 receptor agonism can deliver weight loss in the range previously associated mainly with the most effective incretin therapies or metabolic surgery. A mean reduction of 20.4% at 68 weeks is clinically substantial, and the large, multinational phase 3 programme supports confidence in the efficacy estimate. The result should still be interpreted alongside tolerability: nearly four in five participants receiving CagriSema reported gastrointestinal adverse events, although most were transient and mild to moderate. The published primary comparison was against placebo; comparative interpretation against semaglutide alone requires attention to the full trial hierarchy and estimand rather than headline cross-arm arithmetic. Can I use this with my patients? Not yet unless the combination is locally approved and available. When it becomes available, it may suit adults with obesity or overweight plus complications who need greater weight reduction and accept injectable combination therapy, gradual escalation, and gastrointestinal monitoring. The study excluded diabetes and did not establish cardiovascular-event reduction, long-term maintenance after withdrawal, or superiority to bariatric surgery. Manufacturer sponsorship and the intensive trial setting also matter. The next clinical questions are durability, real-world persistence, cost, lean-mass effects, and whether the additional weight loss translates into fewer cardiovascular, renal, hepatic, and mechanical complications.
References
Garvey WT, Bluher M, Osorto Contreras CK, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2025;393(7):635-647. doi:10.1056/NEJMoa2502081. PMID: 40544433.