Intensive lifestyle intervention (ILS) targeting diet, physical activity (PA), and weight loss is efficacious for diabetes mellitus (DM) prevention, but not all high-risk individuals benefit. We tested whether DM genetic risk helps identify persons for whom ILS had a greater influence on DM risk. We studied 823 individuals in the ILS arm of the Diabetes Prevention Program with genetic and lifestyle data who were free of DM at one year after study enrollment. We estimated the associations of a DM genetic risk score (GRS) based on 67 loci from a recent genome-wide association study and achievement of three ILS goals at one year (7% weight loss, 150 minutes/week of self-reported moderate to strenuous leisure-time PA, and a goal for self-reported daily total fat intake) with incident DM using multivariable proportional hazards regression, including multiplicative interaction terms (i.e., on rate ratios) between GRS and each ILS goal. We used multivariable Poisson regression to estimate absolute risk reduction (ARR) in DM from ILS goal achievement across tertiles of the GRS, including tests for additive interaction (i.e., on rate differences) between GRS and each ILS goal. The GRS, and achieving each ILS goal and achieving all three ILS goals were associated with incident DM (all p<0.05; mean follow-up 3.0 years). There were no significant multiplicative interactions between GRS and achievement of any or all ILS goals. There were significant additive interactions between GRS and achievement of the weight loss (p<0.001), PA (p=0.03), and all three ILS goals (p<0.001). The ARR in incident DM associated with achievement of all three ILS goals increased across GRS tertiles: 1.8 [0.3, 3.4], 3.1 [1.5, 4.7], 3.9 [1.6, 6.2] fewer DM cases/100-person-years from the 1st to 3rd tertile. Genetic risk may identify high-risk subgroups for whom successful lifestyle modification is associated with greater absolute risk reduction of DM and a lower number needed to treat with lifestyle interventions.


S. Raghavan: None. K.A. Jablonski: None. L.M. Delahanty: Advisory Panel; Self; Jana Care Inc., Omada Health, Inc., Weight Watchers International, Inc. N. Maruthur: Other Relationship; Self; Johns Hopkins HealthCare Solutions. A. Leong: None. P.W. Franks: Board Member; Self; Zoe Ltd. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Novo Nordisk Foundation, Sanofi, Servier. W.C. Knowler: None. J.C. Florez: None. D. Dabelea: None. DPP Research Group: None.


National Institute of Diabetes and Digestive and Kidney Diseases

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