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A Living Benefit-Harm Modelling Study of Glp-1 Receptor Agonists for Weight Reduction in Non-Diabetic Obese and Overweight Individuals

20 Pages Posted: 1 Feb 2024

See all articles by Hannah Moll

Hannah Moll

University of Zurich - Epidemiology, Biostatistics and Prevention Institute (EBPI)

Eliane Frey

ETH Zürich - Department of Chemistry and Applied Biosciences

Philipp Gerber

University of Zurich

Bettina Geidl

University of Zurich

Marco Kaufmann

University of Zurich - Epidemiology, Biostatistics and Prevention Institute (EBPI)

Julia Braun

University of Zurich - Epidemiology, Biostatistics and Prevention Institute (EBPI)

Felix Beuschlein

University of Zurich

Milo A. Puhan

University of Zurich - Epidemiology, Biostatistics and Prevention Institute (EBPI)

Henock G. Yebyo

University of Zurich - Epidemiology, Biostatistics and Prevention Institute (EBPI)

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Abstract

Background: The benefit of GLP-1 receptor agonists (GLP-1 RAs) in weight reduction against potential harms remains uncertain. This study aimed at evaluating the benefit-harm balance of GLP-1 RAs versus placebo for weight loss in overweight and obese non-diabetic individuals. 

Methods: We performed benefit-harm balance modelling that is set up for update as new evidence emerges. We searched for randomised controlled trials (RCTs) in PubMed, controlled trials registry, drug approval, and regulatory documents, and outcome preference weights. We synthesize data using pairwise meta-anaysis to estimate the effect of GLP-1 RAs on 5% and 10% weight loss (benefit) and various harm outcomes. We predicted the absolute effects of the benefit and harm outocmes over 1 and 2 years using exponential models. We applied preference weights (0 for least concerning to 1.0 for most concerning) to the outcomes and weighed benefits against harms on a common scale. We accounted for statistical uncertainties of the treatment effets, preference weights, and outcome risks. We calculated the whether the benefits of achieving 5% and 10% weight loss with GLP-1 agonists outweighed the harms. 

Findings: We included 8 RCTs involving 8,847 participants. The pooled averaged age was 46·7 years, with the majority being female (74%) and obese (96%). Of 1000 persons treated with GLP-1 for 2 years, 375 (95% confidence interval 352 to 399) achieved a 10% weight loss, and 318 (296 to 339) achieved a 5% weight loss, compared to those treated with placebo. In the GLP-1 group, several harm outcomes were more frequent, including abdominal pain (41, 19 to 69), cholelithiasis (8, 1 to 21), constipation (118, 78 to 164), diarrhoea (100, 42 to 173), alopecia (57, 10 to 176), hypoglycaemia (17, 1 to 68), injection site reaction (4, -3 to 19), and vomiting (110, 80 to 145) per 1000 persons in 2 years, among others.  Achieving a 10% weight loss with GLP-1 treatment outweighed the cumulative harms, with a net benefit probability of 0·97 at year 1·00 and 0·91 at year 2. The absolute net benefit was equivalent to 104 (100 to 112) per 1,000 persons achieving a 10% weight loss over 2 years without experiencing any worrisome harms. A 5% weight loss did not show net benefit, with probabilities of 0·13 and 0·01 at years 1 and 2 years. However, these benefits were sensitive to  preference weights, suggesting that even achieving a 5% weight loss could be beneficial for individuals with less concern about harm outcomes. The net benefit for a 10% weight loss was highest for semaglutide, followed by liraglutide and tirzepatide, with 2-year probabilities of 0·96, 0·72, and 0·60, respectively.  

Interpretations: The benefit of GLP-1 agonists exceeded the harms for weight loss in the first 2 years of treatment, yet the net benefit is dependent on individual’ treatment goals (10% or 5% weight loss) and willingness to accept harms in pursuit of weight loss. This implies the need for personalised decisions to optimise benefits and reduce harms and overuse of treatments. Given the evidence on the harm outcome vary between studies, continuous updates and monitoring benefit-harm balance of GLP-1 RAs is necessary.

Funding: HGY was supported by Swiss National Science Foundation (SNSF).

Declaration of Interest: We declare no conflict of interest related to the paper.

Keywords: Obesity, Overweight, Metabolic disease, GLP-1 RA, Weight loss, Weight management, Benefit-harm assessment

Suggested Citation

Moll, Hannah and Frey, Eliane and Gerber, Philipp and Geidl, Bettina and Kaufmann, Marco and Braun, Julia and Beuschlein, Felix and Puhan, Milo A. and Yebyo, Henock G., A Living Benefit-Harm Modelling Study of Glp-1 Receptor Agonists for Weight Reduction in Non-Diabetic Obese and Overweight Individuals. Available at SSRN: https://ssrn.com/abstract=4709105 or http://dx.doi.org/10.2139/ssrn.4709105

Hannah Moll

University of Zurich - Epidemiology, Biostatistics and Prevention Institute (EBPI) ( email )

Eliane Frey

ETH Zürich - Department of Chemistry and Applied Biosciences ( email )

Philipp Gerber

University of Zurich ( email )

Bettina Geidl

University of Zurich ( email )

Marco Kaufmann

University of Zurich - Epidemiology, Biostatistics and Prevention Institute (EBPI) ( email )

Julia Braun

University of Zurich - Epidemiology, Biostatistics and Prevention Institute (EBPI) ( email )

Felix Beuschlein

University of Zurich ( email )

Rämistrasse 71
Zürich, CH-8006
Switzerland

Milo A. Puhan

University of Zurich - Epidemiology, Biostatistics and Prevention Institute (EBPI) ( email )

Hirschengraben 84, CH-8001
Zurich
Switzerland

Henock G. Yebyo (Contact Author)

University of Zurich - Epidemiology, Biostatistics and Prevention Institute (EBPI)