Risk factor control and type 2 diabetes event risks in people with high genetic susceptibility to diabetes

To explore whether the excess risk of type 2 diabetes (T2D) attributable to genetic predisposition could be mitigated by controlling modifiable risk factors and whether this mitigation is attenuated in individuals with prediabetes. We included 382,313 participants from the UK Biobank for T2D analyses. The main exposure was the number of optimally controlled risk factors including non-smoker, high level of physical activity, healthy diet, healthy sleep, low BMI, and non-hypertension. Genetic risk groups were defined as low and high categories based on a median of the T2D polygenic risk score. Cox proportional hazard models were employed to explore the associations of joint risk factor control with T2D. During a median of 13.5 years of follow-up, 9210 incident T2D cases were identified in the high genetic risk group. Among individuals with high genetic risk, those who achieved control of all six risk factors had a lower incidence of T2D than those with low genetic risk (hazard ratio [HR]: 0.79, 95% confidence interval [CI]: 0.68, 0.92). However, even with all six risk factors were controlled, participants with prediabetes still had a higher risk of developing T2D, compared with those who had low genetic risk and normal glucose levels. Our results indicated that optimal risk factor control may mitigate the genetic-related excess risk of T2D, but it cannot fully mitigate the prediabetes-related risk of T2D.