A systematic review and meta-analysis of the efficacy and safety of pharmacological treatments for obesity in adults: 2026 Update
Ciudin Mihai A, Baker JL, Belancic A, Busetto L, Dicker D, Fabryova L
medRxiv (preprint) (2026) · n=63,909
A network meta-analysis pooling 66 RCTs and 63,909 patients across six obesity management medication classes finds tirzepatide and semaglutide as the only compounds exceeding 10% total body weight loss, with semaglutide reducing MACE and all-cause mortality, both incretins benefiting heart-failure outcomes and MASH remission, tirzepatide improving obstructive sleep apnoea, semaglutide improving knee osteoarthritis pain remission and liver fibrosis — and no OMM associated with increased serious adverse events.
Ciudin Mihai and colleagues, writing on behalf of a multinational European-led obesity research group, updated the systematic review and network meta-analysis of pharmacological treatments for obesity in adults. Medline and Embase were searched through 21 November 2025 for randomised controlled trials comparing obesity management medications (OMMs) versus placebo or active comparators in adults. The primary endpoint was percentage total body weight loss (TBWL%) at the end of the study; secondary endpoints covered TBWL% at 1, 2, and ≥3 years, anthropometric, metabolic, mental health and quality-of-life outcomes, cardiovascular morbidity and mortality, remission of obesity-related complications, serious adverse events, and all-cause mortality.
Sixty-six RCTs (66 comparisons) met inclusion criteria, distributed across six OMM classes: orlistat (22), semaglutide (18), liraglutide (11), tirzepatide (8), naltrexone/bupropion (5), and phentermine/topiramate (2). The pooled cohort comprised 63,909 patients — 34,861 in active-compound arms and 29,048 in placebo arms.
All OMMs produced significantly greater TBWL% than placebo. Tirzepatide and semaglutide were the only compounds to exceed 10% TBWL and demonstrated the most favourable glycaemic effects. On cardiovascular and mortality endpoints, semaglutide reduced major adverse cardiovascular events and all-cause mortality. In complication-specific trials, semaglutide and tirzepatide both showed benefit on heart-failure-related outcomes; tirzepatide was associated with improved obstructive sleep apnoea syndrome, and semaglutide with knee osteoarthritis pain remission. Both incretins improved metabolic dysfunction-associated steatohepatitis remission, and semaglutide additionally improved liver fibrosis. No OMM was associated with an increased risk of serious adverse events. The authors frame the synthesis as support for individualised OMM selection based on weight-loss efficacy, complication profile, and safety — rather than a one-size-fits-all ranking.
- Preprint, not peer-reviewed — methodology and findings have not undergone external editorial review. Cited here at tier 3 to flag the provenance gap.
- Network meta-analysis pools across heterogeneous trial designs, doses, durations, comparators, and patient populations; indirect comparisons inherit transitivity assumptions that the abstract does not fully describe, and between-trial heterogeneity in baseline characteristics and run-in protocols is not quantified at the abstract level.
- The 66 included RCTs span a wide range of trial durations and study qualities; the primary endpoint is "at end of study," which conflates short and long studies and may favour compounds with shorter trial portfolios.
- Trial counts are uneven across compounds: orlistat dominates (22 trials), tirzepatide is sparsest (8 trials), and within-class effect-size precision varies accordingly; the cardiovascular and mortality findings for semaglutide are driven by a small number of large CVOT-style trials.
- Complication-specific outcomes (HFpEF, OSA, knee osteoarthritis, MASH, liver fibrosis) are reported as derived from "dedicated complication-specific trials," which are typically single-trial readouts within the broader network — one-trial-dominant effect estimates require cautious interpretation.
- Industry funding is the norm for the included RCTs (SURPASS, SURMOUNT, STEP, SUSTAIN, SCALE families), and the abstract does not report stratification by sponsorship or risk-of-bias domain.
- The "no increased serious adverse events" claim is a class-level aggregate; signal-specific safety questions (pancreatitis, gallbladder, NAION, gastroparesis, suicidality) require dedicated pharmacovigilance analyses and are not addressed by a TBWL-anchored network meta-analysis.
- Tier 3 strength rating reflects the preprint status; the methodology and trial inclusion approach would warrant a stronger reading if the paper survives peer review at a credible obesity-medicine journal.
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