Effect of liraglutide on thigh muscle fat and muscle composition in adults with overweight or obesity: Results from a randomized clinical trial

Abstract

Background: Excess muscle fat is observed in obesity and associated with greater burden of cardiovascular risk factors and higher risk of mortality. Liraglutide reduces total body weight and visceral fat but its effect on muscle fat and adverse muscle composition is unknown.

Methods: This is a pre-specified secondary analysis of a randomized, double-blind, placebo-controlled trial that examined the effects of liraglutide plus a lifestyle intervention on visceral adipose tissue and ectopic fat among adults without diabetes with body mass index ≥30 kg/m² or ≥27 kg/m² and metabolic syndrome. Participants were randomly assigned to a once-daily subcutaneous injection of liraglutide (target dose 3.0 mg) or matching placebo for 40 weeks. Body fat distribution and muscle composition was assessed by magnetic resonance imaging at baseline and 40-week follow-up. Muscle composition was described by the combination of thigh muscle fat and muscle volume. Treatment difference (95% confidence intervals [CI]) was calculated by least-square means adjusted for baseline thigh muscle fat. The association between changes in thigh muscle fat and changes in body weight were assessed using Spearman correlation coefficients. The effect of liraglutide versus placebo on adverse muscle composition, denoted by high thigh muscle fat and low thigh muscle volume, was explored.

Results: Among the 128 participants with follow-up imaging (92.2% women, 36.7% Black), median muscle fat at baseline was 7.8%. The mean percent change in thigh muscle fat over median follow-up of 36 weeks was -2.87% among participants randomized to liraglutide (n = 73) and 0.05% in the placebo group (absolute change: -0.23% vs. 0.01%). The estimated treatment difference adjusted for baseline thigh muscle fat was -0.24% (95% CI, -0.41 to -0.06, P-value 0.009). Longitudinal change in thigh muscle fat was significantly associated with change in body weight in the placebo group but not the liraglutide group. The proportion of participants with adverse muscle composition decreased from 11.0% to 8.2% over follow-up with liraglutide, but there was no change with placebo.

Conclusions: In a cohort of predominantly women with overweight or obesity in the absence of diabetes, once-daily subcutaneous liraglutide was associated with a reduction in thigh muscle fat and adverse muscle composition compared with placebo. The contribution of muscle fat improvement to the cardiometabolic benefits of liraglutide requires further study.

Keywords: Body composition; Liraglutide; Muscle fat; Muscle volume; Obesity; Overweight.

Figure 1

Participant‐level relative change in muscle fat across treatment groups. Individual participant percent change in muscle fat is shown for all participants randomized to liraglutide (red) and placebo (blue). Individual participants were ordered on the x‐axis from greatest relative decrease to increase in muscle fat.

Figure 2

Association of change in body weight with change in muscle fat (panel A) or muscle volume z‐score (panel B) across treatment groups. The absolute difference in muscle fat and muscle volume z‐score from baseline to follow‐up were plotted against the corresponding absolute difference in weight for participants stratified by treatment group. Data are shown for participants randomized to liraglutide (red) and placebo (blue). The solid line represents the linear association between change in weight and muscle fat/muscle volume z‐score.

Figure 3

Muscle composition before and after treatment with liraglutide or placebo. Participants were analysed according to treatment group at both baseline and follow‐up. Participants were stratified based on muscle volume (low [<25th percentile of the cohort/z‐score <0.68] vs. high [≥25th percentile of the cohort/z‐score ≥0.68]) and sex‐specific muscle fat (low [women ≤8.82%, men ≤7.69%]] vs. high [women >8.82%, men >7.69%]). Adverse muscle composition was defined as low muscle volume z‐score and high muscle fat.