Glucagon-like Peptide-1/glucagon Receptor Agonism Associates with Reduced Metabolic Adaptation and Higher Fat Oxidation: A Randomized Trial

Objective: This study tested the hypothesis that treatment with the glucagon-like peptide-1/glucagon receptor agonist SAR425899 would lead to a smaller decrease in sleeping metabolic rate (SMR; kilocalories/day) than expected from the loss of lean and fat mass (metabolic adaptation).

Methods: This Phase 1b, double-blind, randomized, placebo-controlled study was conducted at two centers in inpatient metabolic wards. Thirty-five healthy males and females with overweight and obesity (age = 36.5 ± 7.1 years) were randomized to a calorie-reduced diet (-1000 kcal/d) and escalating doses (0.06-0.2 mg/d) of SAR425899 (n = 17) or placebo (n = 18) for 19 days. SMR was measured by whole-room calorimetry.

Results: Both groups lost weight (-3.68 ± 1.37 kg placebo; -4.83 ± 1.44 kg SAR425899). Those treated with SAR425899 lost more weight, fat mass, and fat free mass (p < 0.05) owing to a greater achieved energy deficit than planned. The SAR425899 group had a smaller reduction in body composition-adjusted SMR (p = 0.002) as compared with placebo, but not 24-hour energy expenditure. Fat oxidation and ketogenesis increased in both groups, with significantly greater increases with SAR425899 (p < 0.05).

Conclusions: SAR425899 led to reduced selective metabolic adaptation and increased lipid oxidation, which are believed to be beneficial for weight loss and weight-loss maintenance.