Effects of Genetic Risk on Incident Type 2 Diabetes and Glycemia: The T2D-GENE Lifestyle Intervention Trial

Abstract Context Lifestyle intervention prevents or delays type 2 diabetes (T2D) in subjects at a high risk of T2D. However, it is not known whether genetic variants modify the effect on incident T2D during lifestyle intervention. Objective To investigate whether a low or high genetic risk has effects on incident T2D in a group-based lifestyle intervention study. Methods The T2D-GENE trial involved 973 men from the Metabolic Syndrome in Men (METSIM) cohort, aged 50-75 years, body mass index ≥25 kg/m2, fasting plasma glucose 5.6-6.9 mmol/L, hemoglobin A1c < 48 mmol/mol, and either a low or high genetic risk score for T2D. There were 2 intervention groups, a low (n = 315) and high genetic risk for T2D (n = 313). They were provided with a 3-year group-based intervention with access to a web portal focused on healthy diet and physical activity. There were also corresponding population-based control groups at low (n = 196) and high (n = 149) genetic risk for T2D who had two laboratory visits (0 and 3 years) and general health advice as a part of their METSIM cohort protocol. The primary outcome was incident T2D, and a secondary outcome was glycemia. Results The intervention significantly lowered the risk of T2D among the participants with a high genetic risk for T2D [hazards ratio (HR) 0.30, 95% confidence interval (CI) 0.16-0.56, P < .001) whereas in the low genetic risk group the effect was not significant (HR 0.69, 95% CI 0.36-1.32, P = .262). The intervention effect was not significantly different between the high and low genetic risk groups (P = .135). The intervention significantly ameliorated the worsening of glycemia and decreased weight both in the low and high genetic risk groups. Conclusion Our results showed that individuals with a high genetic risk for T2D benefitted from a low-cost group-based intervention focusing on healthy diet and physical activity. Therefore, all individuals at risk of T2D should be encouraged to make lifestyle changes regardless of genetic risk.