Significant body weight reduction with cagrilintide-semaglutide therapy

1. In this randomized controlled trial, the combination cagrilintide-semaglutide (CagriSema) resulted in significantly greater body weight reduction compared to either agent alone or placebo.

2. CagriSema also demonstrated significant superiority over placebo in reducing waist circumference, lowering systolic blood pressure, and improving physical function.

Evidence Rating Level: 1 (Excellent)

Study Rundown: The prevalence of overweight and obesity is projected to rise, increasing the burden of mechanical, metabolic, and psychological complications. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has been shown in phase 3 trials to significantly reduce body weight, while cagrilintide, an amylin analogue, promotes weight loss through appetite suppression. This trial evaluated the efficacy and safety of a combination therapy of cagrilintide and semaglutide, known as CagriSema, in individuals with overweight or obesity and at least one associated complication. At week 68, CagriSema produced a significantly greater percentage of body weight loss compared to placebo. The co-primary endpoint—the proportion of participants achieving ≥5% weight reduction—also favored CagriSema. CagriSema was superior to placebo in several secondary outcomes, including changes in waist circumference, systolic blood pressure, IWQOL-Lite-CT Physical Function scores, and SF-36 Physical Functioning scores. In participants with prediabetes, normoglycemia was more frequently achieved with CagriSema than with placebo. The incidence of adverse events was comparable across CagriSema, semaglutide-only, cagrilintide-only, and placebo groups. Discontinuation due to adverse events was rare but occurred most often with CagriSema, which also had the highest frequency of serious adverse events. Limitations included a relatively homogenous population, several normal baseline values (e.g., blood pressure, HbA1c, lipids), and potential selection bias, as participants who completed the study may have been more motivated than the general population. Overall, this trial supports the efficacy and safety of CagriSema for the treatment of overweight and obesity.

Click here to read the study in NEJM

Relevant Reading: Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes

In-Depth [randomized controlled trial]: CagriSema is a combination of 2.4 mg semaglutide, a GLP-1 receptor agonist, and 2.4 mg cagrilintide, an amylin analogue. Both agents have demonstrated individual efficacy in promoting weight loss, and this study aimed to evaluate the combined effects of CagriSema on body weight reduction and its safety profile. Eligibility criteria included adults with a BMI ≥30, or ≥27 with an obesity-related complication, and at least one prior unsuccessful attempt at weight loss. Exclusion criteria were a diagnosis of diabetes, previous bariatric surgery, or use of glucose-lowering drugs, GLP-1 receptor agonists, or anti-obesity medications within three months of screening. A total of 3,417 participants were randomized in a 23:3:3:7 ratio to four groups: CagriSema (n = 2,108), semaglutide alone (n = 302), cagrilintide alone (n=302), and placebo (n=705). After 68 weeks, mean percent body weight reduction was most significant in the CagriSema group (-20.4%) compared with semaglutide alone (-14.9%; difference -5.5; 95% CI, -6.7 to -4.3; p<0.001), cagrilintide alone (-11.5%; difference -8.9; 95% CI, -10.1 to -7.7; p<0.001), and placebo (-4.0%; difference -13.4; 95% CI, -14.3 to -12.5; p<0.001). Additionally, 91.4% of CagriSema-treated participants achieved ≥5% weight loss compared to 31.5% in the placebo group (difference 60.4; 95% CI, 56.4–64.5; p < 0.001). CagriSema was also superior to placebo across secondary outcomes, including reductions in systolic blood pressure (-6.7 mmHg; 95% CI, -7.8 to -5.6; p<0.001) and waist circumference (-13.4 cm; 95% CI, -14.3 to -12.5; p<0.001), as well as improvements in IWQOL-Lite-CT Physical Function (difference 11.9; 95% CI, 10.0–13.8; p < 0.001) and SF-36 Physical Functioning scores (difference 3.5; 95% CI, 2.8–4.1; p < 0.001). Adverse events were reported in 92.3% of CagriSema participants, most commonly gastrointestinal (79.6%), with two deaths deemed unrelated to treatment. In summary, discontinuations were rare, and the study demonstrates that CagriSema is an effective and generally safe treatment for adults with overweight or obesity.

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