Tirzepatide delivers the most weight loss (15-21%) among incretin drugs in non-diabetic adults, followed by semaglutide (15-17%) and liraglutide (6-12%), with all three beating placebo.
Up to 20.9% weight lossTirzepatide produced the highest weight loss among the three incretin drugs reviewed, nearly double what liraglutide achieved in some trials
What the researchers found
Across 15 randomized controlled trials in adults without diabetes, all three incretin analogs produced significant weight loss compared to placebo. Tirzepatide delivered the most weight loss at 15-20.9%, followed by semaglutide at 14.9-17.4%, and liraglutide at 5.7-11.8%. All agents were superior to placebo, with gastrointestinal side effects (nausea, vomiting, diarrhea) being the most common adverse events across all three drugs.
The review establishes a clear hierarchy: tirzepatide (the dual GLP-1/GIP agonist) outperforms semaglutide (a GLP-1 agonist), which in turn substantially outperforms liraglutide (the older GLP-1 agonist). The American Gastroenterological Association already recommends GLP-1 agonists as preferred pharmacotherapy for overweight or obese patients.
Why it matters
This review provides a concise head-to-head comparison of the three approved incretin analogs for weight management in non-diabetic adults. With the weight loss drug market exploding, patients and clinicians need clear comparisons. The data shows a meaningful progression in efficacy from first-generation (liraglutide) to current-generation (tirzepatide) peptide drugs, with tirzepatide nearly quadrupling liraglutide's minimum weight loss.
The numbers in context
15 RCTs reviewed · Liraglutide: 5.7-11.8% weight loss · Semaglutide: 14.9-17.4% weight loss · Tirzepatide: 15-20.9% weight loss · GI adverse effects most common · All superior to placebo
How the study worked
Narrative review of randomized controlled trials identified through PubMed/MEDLINE, Scopus, and Embase from inception through June 2023. Included studies of adults without diabetes treated with liraglutide, semaglutide, or tirzepatide for weight management with weight loss as a primary outcome. Fifteen studies met inclusion criteria.
Who was studied
Adults without diabetes who are overweight or obese, seeking pharmacological weight management
What this study cannot tell us
Narrative review rather than a systematic review or meta-analysis, so study selection may not be fully reproducible. Direct head-to-head trials between the three drugs are limited — weight loss ranges come from different trial populations and protocols. Literature search ends June 2023, so more recent data (including newer dose formulations) is not captured. Does not address long-term weight maintenance after stopping treatment.
How to read the evidence
This is a narrative review synthesizing 15 RCTs — the strongest form of clinical evidence. Published in the Annals of Pharmacotherapy, a respected pharmacy practice journal. The underlying trial data is robust, though the review itself is narrative rather than systematic.
When this study was published
Published in 2024 with literature through June 2023. The weight loss percentages cited remain broadly accurate, though newer trial data and formulations have since emerged.
The bigger picture
The incretin drug class has evolved rapidly from liraglutide's modest weight loss to tirzepatide's near-21% reductions. This review captures a snapshot of a field in rapid motion — newer multi-agonists like retatrutide (triple agonist) are already showing even greater results in trials. The review also reflects the shift from viewing these drugs as diabetes medications to recognizing them as primary weight management tools.
Questions still open
- Will triple agonists like retatrutide push weight loss percentages even higher than tirzepatide's 20.9%?
- How do these weight loss percentages translate to long-term health outcomes like reduced cardiovascular events or cancer risk?
- What happens to weight when patients stop these medications, and should they be considered lifelong therapy?
Common questions
Which GLP-1 drug causes the most weight loss?
What are the main side effects of incretin weight loss drugs?
Read the original research
Incretin Analogs for Weight Management in Adults Without Diabetes.
The Annals of pharmacotherapy, 58(4), 398-406
Citation
Lobkovich, Alison; Kale-Pradhan, Pramodini; Lipari, Melissa. (2024). Incretin Analogs for Weight Management in Adults Without Diabetes.. The Annals of pharmacotherapy, 58(4), 398-406. https://doi.org/10.1177/10600280231190089