Tirzepatide 15mg and CagriSema achieve superior weight loss, including >20% reduction, in network meta-analysis

Globally, obesity is a chronic, progressive disease affecting over 1 billion adults, significantly increasing the risk of type 2 diabetes, hypertension, and cardiovascular disease. Achieving clinically meaningful and sustained weight loss is crucial for mitigating these cardiometabolic risks. While novel incretin-based therapies like tirzepatide (a GLP-1R/GIPR co-agonist), semaglutide (GLP-1R agonist), and cagrilintide (an amylin analog), alone or in combination (CagriSema), have shown promise, direct head-to-head comparisons of all these advanced anti-obesity medications have been lacking. This network meta-analysis addresses this critical gap by providing comparative efficacy and safety data.

Researchers conducted a systematic search across PubMed, Scopus, and Cochrane Central for randomized controlled trials (RCTs) evaluating CagriSema, semaglutide, cagrilintide, and tirzepatide against placebo in adults with overweight or obesity. The analysis included 25 trials covering 12 interventions. Primary outcomes assessed included changes in percent body weight, absolute weight, waist circumference, BMI, and the proportion of patients achieving ≥5% to ≥20% weight loss. Safety outcomes, such as overall adverse events (AEs), serious AEs, gastrointestinal AEs, and treatment discontinuation, were also evaluated. A random-effects model and network meta-analysis methods were employed to synthesize the indirect comparisons.

The network meta-analysis of 25 trials revealed significant differences in weight reduction among the advanced anti-obesity medications. Tirzepatide 15mg demonstrated the greatest percent body weight reduction, with a mean difference (MD) of -17.97% compared to placebo. This was closely followed by CagriSema, which achieved an MD of -17.84% weight reduction. Semaglutide 7.2mg showed a substantial, but comparatively lower, MD of -14.66% weight reduction.

For the clinically significant threshold of ≥20% body weight loss, CagriSema exhibited marked superiority with a relative risk (RR) of 27.82, meaning patients were nearly 28 times more likely to achieve this outcome compared to placebo. Tirzepatide 15mg also performed exceptionally well at this threshold, with an RR of 23.70. Gastrointestinal adverse events were consistently increased across all treatments, with RRs ranging from 1.33 to 1.91. Treatment discontinuation rates were highest with semaglutide 7.2mg (RR 3.09). Importantly, serious adverse events remained comparable to placebo across all evaluated regimens, suggesting a favorable overall safety profile despite increased GI side effects.