1091-P: Genetic Ancestry Influences Metformin Treatment Response in Youth with Type 2 Diabetes
Authors: SRINIVASAN SHYLAJA , CHEN LING , KELSEY MEGAN M. , TODD JENNIFER , ARSLANIAN SILVA A. , CHANG NANCY T. , LAFFEL LORI M. , LEVITSKY LYNNE L. , SPRAGUE JENNIFER E. , POLLIN TONI I. , MANNING ALISA , FLOREZ JOSE C. 
Published: June 2023

In youth with type 2 diabetes (T2D), glycemic response to metformin varies by racial and ethnic group. In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study metformin failure rates were lower in non-Hispanic White (NHW) youth by self-report compared with non-Hispanic Black (NHB) and Hispanic youth. Understanding and addressing the mechanisms for differences in response are critical to reducing health disparities. We aimed to examine the association between genetic ancestry and risk for metformin treatment failure and evaluate whether individual global ancestry proportions predict metformin response in TODAY participants. Global ancestry proportions were estimated using FastStructure. Cox-proportional hazards analysis with genetic ancestry as a covariate was performed with the primary outcome the need for insulin or A1C ≥ 8%. Age, sex, BMI Z score, baseline A1C, and treatment arms were the other covariates. After quality control, 506 participants of mean age 14±2 y, 65% female, mean BMI Z score 2.2±0.5 kg/m2 and mean baseline A1C 6.0±0.7% were analyzed. Similar to by self-report, when stratified by genetic ancestry NHB youth had significantly higher treatment failure rates compared with other groups (P=0.02). The proportion of European ancestry in self-reported ethnic strata of admixed participants was associated with improved metformin response in the NHB (n=185) and Hispanic (n=208) groups (HR 0.4, 95% CI 0.16-0.98, P=0.04). Proportion of Native American ancestry was associated with worse response (HR 1.5, 95% CI 1.02-2.2, P=0.04) across all participants and associations with proportion African ancestry were not significant. In sum, genetic ancestry influences metformin response with greater proportion of European and Native American ancestry associated with improved and worse glycemic response respectively in TODAY. These differences could be related to biological, social or cultural factors and should be examined to reduce health disparities in T2D.

Disclosure
S.Srinivasan: None. T.I.Pollin: None. A.Manning: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. L.Chen: None. M.M.Kelsey: Other Relationship; Boehringer Ingelheim Inc., Janssen Pharmaceuticals, Inc., Rhythm Pharmaceuticals, Inc., Lilly. J.Todd: None. S.A.Arslanian: Advisory Panel; Novo Nordisk, Eli Lilly and Company, Consultant; Société des Produits Nestlé SA,, Other Relationship; Eli Lilly and Company, AstraZeneca, Research Support; Novo Nordisk, Eli Lilly and Company. N.T.Chang: None. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. L.L.Levitsky: None. J.E.Sprague: Research Support; Eli Lilly and Company, Rhythm Pharmaceuticals, Inc.

Funding
National Institutes of Health (K23DK120932)