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

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Abstract
Background: 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. Methods: 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/m 2 ) versus unlikely related to genetic mutation(s) (n = 15, median age 45.8 years with a median BMI of 38.7 kg/m 2 ). Results: 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). Conclusions: 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.

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