Genetic Predictors of Cardiovascular Mortality During Intensive Glycemic Control in Type 2 Diabetes: Findings From the ACCORD Clinical Trial

OBJECTIVE: To identify genetic determinants of increased cardiovascular mortality among subjects with type 2 diabetes who underwent intensive glycemic therapy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS: A total of 6.8 million common variants were analyzed for genome-wide association with cardiovascular mortality among 2,667 self-reported white subjects in the ACCORD intensive treatment arm. Significant loci were examined in the entire ACCORD white genetic dataset (n = 5,360) for their modulation of cardiovascular responses to glycemic treatment assignment and in a Joslin Clinic cohort (n = 422) for their interaction with long-term glycemic control on cardiovascular mortality. RESULTS: Two loci, at 10q26 and 5q13, attained genome-wide significance as determinants of cardiovascular mortality in the ACCORD intensive arm (P = 9.8 × 10^-9 and P = 2 × 10^-8, respectively). A genetic risk score (GRS) defined by the two variants was a significant modulator of cardiovascular mortality response to treatment assignment in the entire ACCORD white genetic dataset. Participants with GRS = 0 experienced a fourfold reduction in cardiovascular mortality in response to intensive treatment (hazard ratio [HR] 0.24 [95% CI 0.07-0.86]), those with GRS = 1 experienced no difference (HR 0.92 [95% CI 0.54-1.56]), and those with GRS ≥2 experienced a threefold increase (HR 3.08 [95% CI 1.82-5.21]). The modulatory effect of the GRS on the association between glycemic control and cardiovascular mortality was confirmed in the Joslin cohort (P = 0.029). CONCLUSIONS: Two genetic variants predict the cardiovascular effects of intensive glycemic control in ACCORD. Further studies are warranted to determine whether these findings can be translated into new strategies to prevent cardiovascular complications of diabetes.