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.