A network meta-analysis of 27 trials and 15,584 patients ranked retatrutide 12mg (−22.1% body weight) and tirzepatide 15mg (−16.5%) as the most effective weight loss treatments among 7 GLP-1 agonists and polyagonists, with dual/triple receptor agonists outperforming single-receptor drugs.
−22.1% body weightRetatrutide 12mg achieved the greatest weight loss among 7 GLP-1 agonists and polyagonists — approaching bariatric surgery results
What the researchers found
Retatrutide 12mg (−22.1% body weight, −17cm waist) and tirzepatide 15mg (−16.5%) were the most effective weight loss treatments. Dual/triple receptor agonists significantly outperformed single GLP-1 receptor agonists across 27 RCTs with 15,584 patients.
Why it matters
With multiple GLP-1 weight loss drugs now available or in development, clinicians and patients need evidence-based comparisons. This analysis shows multi-receptor agonists represent the next frontier, with retatrutide potentially doubling the weight loss of earlier drugs like liraglutide.
The numbers in context
Drugs compared: mazdutide (6/4.5mg), retatrutide (12/8mg), tirzepatide (15/10mg), liraglutide 3.0mg, semaglutide (2.4/1.0mg). RCTs with ≥16-week duration.
How the study worked
Network meta-analysis of 27 RCTs (≥16 weeks duration) from Cochrane Library, PubMed, and Embase through August 2024. Compared mazdutide, retatrutide, tirzepatide, liraglutide, semaglutide, orforglipron, and beinaglutide. Frequentist random-effects model using Stata 16.1.
Who was studied
Adults with obesity or overweight
What this study cannot tell us
Some drugs (retatrutide, mazdutide) have fewer trials and shorter follow-up than established drugs like semaglutide. Long-term safety data beyond trial periods is unavailable for newer agents. The network meta-analysis relies on indirect comparisons for some drug pairs. Weight regain after discontinuation wasn't assessed.
How to read the evidence
Strong evidence from a network meta-analysis of 27 randomized controlled trials with 15,584 patients. However, newer drugs have fewer supporting trials than established agents.
When this study was published
Published in 2024 with literature search through August 2024; includes the most current trial data for all 7 drugs.
The bigger picture
The GLP-1 drug landscape is evolving rapidly from single-receptor agonists (liraglutide, semaglutide) to dual (tirzepatide) and triple (retatrutide) receptor agonists. This meta-analysis confirms the trend: each additional receptor target adds meaningfully to weight loss. Retatrutide's 22% average weight loss approaches what was previously only achievable with bariatric surgery.
Questions still open
- Will retatrutide maintain its weight loss superiority in larger phase 3 trials and real-world use?
- What is the long-term safety profile of triple receptor agonists compared to GLP-1-only drugs?
- Do patients who lose 20%+ body weight on these drugs maintain the loss, or does weight regain occur after stopping?
Common questions
Which GLP-1 drug causes the most weight loss?
Are these newer drugs safe?
Read the original research
Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials.
Metabolism: clinical and experimental, 161, 156038
Citation
Xie, Zeyu; Zheng, Guimei; Liang, Zhuoru; Li, Mengting; Deng, Weishang; Cao, Weiling. (2024). Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials.. Metabolism: clinical and experimental, 161, 156038. https://doi.org/10.1016/j.metabol.2024.156038