Shi Q, Wang Y, Hao Q, et al. Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials. Lancet. 2022 Jan 15;399(10321):259-269. doi: 10.1016/S0140-6736(21)01640-8. Epub 2021 Dec 8. (Systematic review)

BACKGROUND: Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence for the benefits and harms of weight-lowering drugs.

METHODS: This systematic review and network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) from inception to March 23, 2021, for randomised controlled trials of weight-lowering drugs in adults with overweight and obesity. We performed frequentist random-effect network meta-analyses to summarise the evidence and applied the Grading of Recommendations Assessment, Development, and Evaluation frameworks to rate the certainty of evidence, calculate the absolute effects, categorise interventions, and present the findings. The study was registered with PROSPERO, CRD 42021245678.

FINDINGS: 14 605 citations were identified by our search, of which 143 eligible trials enrolled 49 810 participants. Except for levocarnitine, all drugs lowered bodyweight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification. High to moderate certainty evidence established phentermine-topiramate as the most effective in lowering weight (odds ratio [OR] of =5% weight reduction 8·02, 95% CI 5·24 to 12·27; mean difference [MD] of percentage bodyweight change -7·97, 95% CI -9·28 to -6·66) followed by GLP-1 receptor agonists (OR 6·33, 95% CI 5·00 to 8·00; MD -5·76, 95% CI -6·30 to -5·21). Naltrexone-bupropion (OR 2·69, 95% CI 2·11 to 3·43), phentermine-topiramate (2·40, 1·69 to 3·42), GLP-1 receptor agonists (2·17, 1·71 to 2·77), and orlistat (1·72, 1·44 to 2·05) were associated with increased adverse events leading to drug discontinuation. In a post-hoc analysis, semaglutide, a GLP-1 receptor agonist, showed substantially larger benefits than other drugs with a similar risk of adverse events as other drugs for both likelihood of weight loss of 5% or more (OR 9·82, 95% CI 7·09 to 13·61) and percentage bodyweight change (MD -11·41, 95% CI -12·54 to -10·27).

INTERPRETATION: In adults with overweight and obesity, phentermine-topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide might be the most effective.

FUNDING: 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Endocrine 6 / 7
Public Health 6 / 7
Special Interest - Obesity -- Physician 5 / 7
Comments from MORE raters

Endocrine rater

Nice review with useful figures to help counsel patients regarding comparative effectiveness of different weight-loss approaches.

Family Medicine (FM)/General Practice (GP) rater

Seems nicely reassuring that these meds are useful.

General Internal Medicine-Primary Care(US) rater

The real problem is keeping the weight off after one year, which was the longest follow-up period in these studies.

General Internal Medicine-Primary Care(US) rater

The data on the GLP1ra are very promising and hopefully more providers are becoming aware of this.

Public Health rater

Many practitioners don't know about the best pharmacological treatment for weight reduction. The present review synthesizes available data in a comprehensive manner. This is definitely useful as a clinical guidance.

Special Interest - Obesity -- Physician rater

I think it's mostly well known in our institution that most drugs don't do much and that semaglutide is a potential game-changer because of its effects on 3 important endpoints: DM sugar, CVD outcomes, and weight. We don't use phentermine much due to the side effects.

Special Interest - Obesity -- Physician rater

Semagletide is pricey but for DM2 patients at a different dose, the weight loss and resultant normalization of A1C, lipids, etc is amazing.

Special Interest - Obesity -- Physician rater

Surprised at the 'win' for topiramate-phentermine over GLP1, but we must be cautious about rankings in network meta-analysis and CIs because the former were much larger due to fewer/smaller studies.
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