Abstract 13703: Patients With Familial Hypercholesterolemia Are Protected Against Type II Diabetes - a Cross-sectional Study in 63,000 Individuals Tested for the Presence of LDL Receptor Mutations

Introduction: Familial Hypercholesterolemia (FH) is a prevalent single gene disorder characterized by decreased transmembrane cholesterol transport (TCT). In clinical practice, it was noticed that FH patients are less prone to develop type 2 diabetes mellitus (T2DM). In contrast, statin use increases TCT and, intriguingly, increases risk for T2DM. Hypothesis: Hence, we hypothesized that perturbations in TCT contribute to the development of T2DM, and we investigated whether T2DM prevalence is indeed lower in FH. Methods: All Dutch individuals who underwent DNA testing for FH between 1994 and 2014 were enrolled. We compared T2DM prevalence between FH patients and unaffected relatives. Additionally, we tested whether more severe FH mutations were associated with an even lower risk for T2DM; i.e. LDLR vs. APOB, and receptor-negative vs. receptor-deficient LDLR mutations, with unaffected relatives as reference, after adjustment for potential confounders. Results: Unadjusted, the prevalence of T2DM proved to be 1.8% in 25,137 FH patients (n=440) (adjusted: 1.4%) versus 2.9% in 38,183 unaffected relatives (n=1,119) (p<0.001). The adjusted odds ratios for T2DM in LDLR vs. APOB, and in receptor-negative vs. receptor-deficient LDLR mutation carriers were 0.44 (95% CI: 0.37 - 0.52) vs. 0.63 (95% CI: 0.47 - 0.85), and 0.37 (95% CI: 0.28 - 0.47) vs. 0.48 (95% CI: 0.39 - 0.58), respectively, compared to unaffected relatives (p-for-trend<0.001 in both associations). Conclusions: The prevalence of T2DM in FH patients is 50% lower than in unaffected relatives. Moreover, the more severe the FH mutation, the lower the prevalence of T2DM. Together with the observed association between statin use and T2DM, our findings suggest a role for cholesterol metabolism in the pathogenesis of T2DM and point to novel targets for disease modification.