Patients with Obesity Caused by Melanocortin-4 Receptor Mutations Can Be Treated with a Glucagon-like Peptide-1 Receptor Agonist

Abstract

Pathogenic mutations in the appetite-regulating melanocortin-4 receptor (MC4R) represent the most common cause of monogenic obesity with limited treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) cause weight loss by reducing appetite. We assessed the effect of the GLP-1 RA liraglutide 3.0mg for 16weeks in 14 obese individuals with pathogenic MC4R mutations (BMI 37.5± 6.8) and 28 matched control participants without MC4R mutation (BMI 36.8± 4.8). Liraglutide decreased body weight by 6.8kg ± 1.8kg in individuals with pathogenic MC4R mutations and by 6.1kg ± 1.2kg in control participants. Total body fat, waist circumference, and fasting and postprandial glucose concentrations similarly decreased in both groups. Thus, liraglutide induced an equal, clinically significant weight loss of 6% in both groups, indicating that the appetite-reducing effect of liraglutide is preserved in MC4R causal obesity and that liraglutide acts independently of the MC4R pathway. Thus, liraglutide could be an effective treatment of the most common form of monogenic obesity.