Glucagon‐like peptide‐1/glucagon receptor agonism associates with reduced metabolic adaptation and higher fat oxidation: A randomized trial

Abstract 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.