What question did this study set out to answer?

To explore genetic factors influencing treatment response and weight loss in T2D medications using nonadditive analysis.

June 7, 2026

1810-P: Time-to-Event Nonadditive Analysis Identifies Novel Genetic Variants Associated with Treatment Response and Weight Loss in the GRADE Clinical Trial

Key Points

To explore genetic factors influencing treatment response and weight loss in T2D medications using nonadditive analysis.
Examined 4,538 participants on metformin randomized to four different treatments: glargine, glimepiride, liraglutide, or sitagliptin.
Conducted a time-to-event GWAS focused on treatment failure (HbA1c ≥7%).
Utilized REGENIE-v4.1 to analyze additive, dominant, and recessive genetic models, adjusting for various baseline factors.
Identified twelve additive and eleven non-additive genetic signals linked to glycemic response across treatments (p<5×10-8).
Notable finding: rs113801264 linked to better response to liraglutide (HR=0.52, p=2.4×10-8) and weight loss (β=-0.96kg, p=0.04).
rs181359782 showed improved response to glargine (HR=0.35, p=2.4×10-8), while variant rs5969895 indicated strong response to liraglutide in hemizygous males (HR=0.16, p=7.7×10-9).

Abstract

Introduction and Objective: Second-line glucose-lowering medications for T2D vary in glycemic and metabolic effects due in part to genetic factors. We previously conducted a Cox proportional hazards genome-wide association study (GWAS), identifying variants associated with glycemic response. We hypothesized that an alternative whole-genome regression including dominant (full effect by one allele copy) and recessive (only homozygous have an effect) models would increase statistical power. Methods: The GRADE Genetics Study examined 4,538 participants on metformin and randomized to glargine, glimepiride, liraglutide, or sitagliptin. We performed a time-to-event GWAS of treatment failure (HbA1c ≥7%). We used REGENIE-v4.1 to run additive, dominant, and recessive models, adjusted for baseline age, sex, HbA1c, BMI, and the first 10 principal components. Results: We found twelve additive and eleven non-additive signals associated with glycemic response across the four treatments (p5×10-8). rs113801264 had improved response to liraglutide (HR=0.52, p=2.4×10-8) and greater weight loss (β=-0.96kg, p=0.04). rs181359782 had improved response to glargine (HR=0.35, p=2.4×10-8). X-chromosome variant rs5969895 had improved response to liraglutide in hemizygous males (HR = 0.16, p = 7.7×10-9). Conclusion: To sum up, we identified novel loci associated with treatment response, which may support T2D personalized treatment. Disclosure T.Y. Wangden: None. L. Szczerbinski: Research Support; Current; Novo Nordisk. Consultant; Current; Eli Lilly and Company. M.T. Tripputi: None. A. Huerta: None. A. Kretowski: None. S. Kahn: Advisory Panel; Current; AltPep, Amgen Inc., Congruence Therapeutics, Eli Lilly and Company, General Medicines, Kayothera, Merck Ended; Jubilant Therapeutics, Inc. J.C. Florez: Research Support; Current; Novo Nordisk. Consultant; Current; Alveus Therapeutics. J. Mercader: None.

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