Reduced Efficacy of Glucagon-Like Peptide-1 Receptor Agonists Therapy in People With Type 1 Diabetes and Genetic Forms of Obesity

Once weekly Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) have been shown to improve glycemic outcomes and cause significant weight loss. However, 9% to 27% of individuals have little or no response to these drugs. In this article, we investigated the efficacy of GLP-1 RA therapy among adults with type 1 diabetes and obesity likely related to genetic mutations compared with obesity likely unrelated to genetic mutations.

In this retrospective study, we compared body weight and glycated hemoglobin (HbA1c) change with the use of GLP-1 RA therapy (including a dual agonist, Tirzepatide) over six months among adults with type 1 diabetes and obesity likely (n = 11, median age 39.5 years with a median BMI of 43.0 kg/m²) versus unlikely related to genetic mutation(s) (n = 15, median age 45.8 years with a median BMI of 38.7 kg/m²).

Six months of GLP-1 RA treatment resulted in a numerically lower reduction of weight (−5.75 ± 9.46 kg vs −8.65 ± 9.36 kg, P = .44) and HbA1c (−0.28 ± 0.96% vs −0.43 ± 0.57%, P = .64) among individuals with obesity likely versus unlikely related to a genetic mutation(s), respectively. Fewer individuals with genetic obesity met goal weight loss ≥5% or HbA1c decrease ≥0.4% than did individuals with obesity unlikely related to a genetic cause (36.4% vs 80.0%, P = .04).

The weight loss and glycemic lowering effects of GLP-1 RA therapy may be decreased in people with type 1 diabetes and obesity likely related to genetic causes. Further research is needed to understand GLP-1 RA mechanisms via energy regulating genes.