Effects of Glucagon-Like Peptide-1 Receptor Agonists (Mono and Combination Therapy) on Energy Expenditure: A Scoping Review

Abstract

Introduction: Weight loss results in reduced energy expenditure (EE) due to body composition alterations (e.g., fat-free mass and fat mass losses) and mass-independent adaptations in EE (e.g., hormones). Glucagon-like peptide-1 receptor agonists (GLP-1RA) are indicated for obesity management; however, their effects on EE remain unclear. Methods: In this scoping review, we searched MEDLINE, EMBASE, CINAHL, Web of Science, ProQuest, and Cochrane Library (inception to October 2025) for studies that investigated the effects of GLP-1RA (mono or combination therapy) on EE in humans. Results: Twenty-three studies were included, 10 assessed GLP-1RA monotherapy (4 exenatide, 4 liraglutide, 1 semaglutide, 1 beinaglutide) and 13 combination therapy (11 dual, 2 triple agonists); drug regimen heterogeneity was high. Most studies assessed resting metabolic rate (RMR); 4 used 24-h whole-room indirect calorimetry; and none applied doubly labeled water. Eight studies (34.8%) concluded that GLP-1RA mono or combination therapy had non-significant effects on EE. Combination with glucagon produced varied impacts on EE components (RQ [n = 3], RMR [n = 1], and sleep metabolic rate [n = 1]), whereas combination with glucose-dependent insulinotropic polypeptide (GIP) decreased RQ and increased fat utilization (n = 1). Eleven studies (47.8%) produced inconclusive results due to the applied statistical analyses. Conclusion: Acute or chronic GLP-1RA monotherapy does not appear to impact EE independent of weight loss. Combining GLP-1RA with glucagon or GIP may impact EE in different ways, requiring further exploration.