A network meta-analysis of 262 randomised trials in 99,791 adults with overweight or obesity found that tirzepatide produced the largest one-year weight loss (-14.9% vs lifestyle modification), followed closely by CagriSema (-14.8%). Larger weight loss was generally accompanied by more adverse events and discontinuation; only subcutaneous semaglutide showed reduced all-cause mortality, and most drugs did not meaningfully improve quality of life.
Systematic review — systematic review and network meta-analysis. Population: adults with overweight or obesity. Sample size: 99 791 participants. Follow-up: 12 to 172 weeks. Interventions: tirzepatide; cagrilintide-semaglutide (CagriSema); oral semaglutide; orforglipron; subcutaneous semaglutide; phentermine-topiramate; ecnoglutide; mazdutide. Cited by 1 other paper.
At one year, tirzepatide was associated with the largest weight loss (-14.9%, 95% CI -16.0% to -13.9%), followed by CagriSema (-14.8%, -16.9% to -12.7%), oral semaglutide (-10.9%, -12.7% to -9.1%), orforglipron (-9.9%, -12.4% to -7.5%), subcutaneous semaglutide (-9.8%, -10.6% to -9.1%), and phentermine-topiramate (-8.1%, -9.7% to -6.5%). Discontinuation due to adverse events was highest with orforglipron, naltrexone-bupropion, liraglutide, phentermine-topiramate, CagriSema, and oral semaglutide (risk ratios 1.9 to 4.2); gastrointestinal events were most increased with naltrexone-bupropion, oral semaglutide, orforglipron, and tirzepatide (risk ratios 3.1 to 4.2). Tirzepatide reduced fat mass most (-25.7%) but also lean mass most (-8.3%). Subcutaneous semaglutide was the only drug associated with reduced all-cause mortality (risk ratio 0.81, 95% CI 0.72 to 0.93) and myocardial infarction (0.72, 0.61 to 0.85); subcutaneous semaglutide and tirzepatide reduced heart failure risk (0.43, 0.21 to 0.84 and 0.49, 0.27 to 0.88, respectively). No drugs convincingly reduced kidney failure or improved quality of life beyond established minimally important differences (all mean differences <5 points; minimally important difference 10).
For researchers studying tirzepatide, this paper provides a comprehensive, head-to-head context showing it as the most potent weight-loss agent at one year, while also quantifying its harms (largest lean mass loss, increased gastrointestinal events) and a heart failure benefit. It does not establish whether tirzepatide reduces all-cause mortality or myocardial infarction, nor does it provide dosing or individualised treatment recommendations.
Peptide profiles: Tirzepatide.
All indexed evidence: Tirzepatide trials & papers.
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