Type 2 Diabetes Mellitus Polygenic Score Predicts New Onset Diabetes in Patients With Established Atherosclerotic Cardiovascular Disease: A FOURIER Sub-Study

Introduction: Polygenic scores (PS) have been created to predict the risk of developing type 2 diabetes (T2D). We tested whether a contemporary T2D PS predicts new-onset T2D in individuals with established atherosclerotic cardiovascular disease (ACSVD) and across a range of HbA1c and BMI levels. Methods: We analyzed individuals without T2D at baseline with available genotyping data from the FOURIER trial. Genetic risk was characterized using a PS for T2D based on 554 previously identified genome-wide significant single nucleotide polymorphisms. PS was analyzed continuously and categorized as high (top 20%) vs. low (bottom 80%). New-onset T2D was pre-specified and adjudicated centrally according to the American Diabetes Association definitions. HRs were calculated and adjusted for baseline age, sex, BMI, HbA1c, SBP, DBP, HDL-C, and triglycerides. Results: The 9115 participants in this study had mean age of 63±9 yrs and 22.5% were women. Mean HbA1c and BMI were 5.6±0.4% and 28.7±5 kg/m 2 , respectively. A total of 641 new-onset diabetes cases occurred over a median of 2.3 years of follow up. T2D PS significantly predicted new-onset T2D (adjusted HR per 1-SD increase 1.13 95% CI 1.04-1.23, P=0.006). The rates of new-onset T2D in the high and low genetic risk categories were 10.8% vs. 6.6 %, respectively (adjusted HR 1.41 95% CI 1.18-1.69, P<0.001, Panel A). The predictive strength of high genetic risk for T2D appeared strongest in those without key clinical risk factors, namely, those without pre-diabetes [HR 2.01 (1.03-3.89); Panel B] and those with normal weight [HR 2.77 (1.65-4.66); Panel C]. There was no treatment interaction with evolocumab for new-onset T2D. Conclusions: Within a relatively short follow up, we found that a contemporary T2D PS strongly predicted new-onset T2D in patients with established ASCVD. This genetic risk appeared more discriminatory in those lacking traditional clinical risk factors.