Heterogeneity of Treatment Effects of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss in Adults

Importance: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a novel class of therapeutics approved to treat chronic conditions such as cardiovascular disease, diabetes, and/or obesity. However, whether GLP-1 RAs' efficacy varies by age, sex, race and ethnicity, baseline body mass index (BMI), and baseline hemoglobin A1c (HbA1c) is unclear. Objective: To quantify the heterogeneity of treatment effects (HTE) of GLP-1 RAs, including semaglutide, liraglutide, exenatide, lixisenatide, and dulaglutide, by patient characteristics. Data Sources: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, from inception through July 26, 2024. Study Selection: Pairs of investigators independently screened titles and abstracts and then reviewed eligible full-text articles reporting on randomized clinical trials (RCTs) that compared GLP-1 RAs to placebo or other medications. Data Extraction and Synthesis: Study design, interventions, and comparators, and patient baseline weight and weight change over time (overall and by age, sex, race and ethnicity, BMI, and HbA1c level) were extracted from the data. Risk of bias was assessed using the Cochrane risk of bias tool and meta-analyses were conducted using random-effects models. For each subgroup, RCTs were meta-analyzed where quantitative synthesis was possible, while additional relevant studies were narratively incorporated in the analysis. Main Outcomes and Measures: Change in body weight measured in kg (by age, baseline BMI, baseline HbA1c) or percentage change from baseline (by sex, race and ethnicity). Results: Of 7705 unique records, 41 articles representing 64 RCTs were included in the meta-analysis. Of these, 48 RCTs could be individually characterized: they had a mean (SD) study population of 1181 (2513) participants; 51 trials were parallel (98.1%); 51 multicenter (98.1%); and 21 evaluated semaglutide (43.8%) and 9, dulaglutide (18.8%). HTE was most commonly evaluated using baseline BMI (36 RCTs [75.0%]), HbA1c (24 [50.0%]), and age (21 [43.8%]), and less commonly, ethnicity (12 [25.0%]), race (11 [22.9%]), and sex (10 [20.8%]). Among 6 trials (19 906 patients) analyzed by sex, weight loss was greater among women (10.9%; 95% CI, 7.0%-14.8%) than men (6.8%; 95% CI, 4.6%-9.0%). We found no significant HTE by age (7 trials with 4314 patients), race (9 trials, 25 229 patients), ethnicity (7 trials, 8328 patients), baseline BMI (15 trials, 9473 patients across 3 analyses), or baseline HbA1c (4 trials, 1886 patients). Conclusions and Relevance: In this systematic review and meta-analysis, GLP-1 RAs produced greater weight loss among women than men; however, their efficacy was consistent across other important subpopulations. These findings may inform clinical decision-making.