Abstract
Patients with heterozygous familial hypercholesterolemia (HeFH) have been reported to be less vulnerable to type 2 diabetes mellitus (T2DM), although the mechanism is unknown. The aims of the present study were to assess the effects of low density lipoprotein (LDL) cholesterol concentration and the presence of FH-causing mutations on T2DM prevalence in HeFH. Data were collected from the Dyslipidemia Registry of the Spanish Arteriosclerosis Society. Inclusion criteria were definite or probable HeFH in patients aged ≥18 years. T2DM prevalence in HeFH patients was compared with data of the general population. 1732 patients were included. The prevalence of T2DM was lower in patients with HeFH compared with the general population (5.94% vs 9.44%; OR: 0.606, 95% CI 0.486–0.755, p < 0.001). Risk factors for developing T2DM were male sex, age, body mass index, hypertension, baseline triglyceride levels and years on statin therapy. The prevalence of T2DM in HeFH patients was 40% lower than that observed in the general population. Gene mutations and LDL cholesterol concentrations were not risk factors associated with the prevalence of T2DM in patients with HeFH. The prevalence of T2DM in patients with HeFH was 40% lower than in the general population matched for age and sex.
Highlights
Heterozygous familial hypercholesterolemia (HeFH), the most frequent monogenic disorder of human metabolism caused by some mutations in the genes that encode for the low-density lipoprotein (LDL) receptor, apolipoprotein B, proprotein convertase subtilisin/kexin-type 9 (PCSK9) or apo E1, 2, entails an increased risk of premature cardiovascular disease[2]
If intracellular cholesterol uptake via the low density lipoprotein (LDL) receptor is involved in the pathogenesis of type 2 diabetes mellitus (T2DM), it would explain the hypothetical protection from diabetes in heterozygous familial hypercholesterolemia (HeFH) patients, but only in those with genetic defects affecting LDL receptor uptake, in contrast to the hypothesis that the protection would be dependent on the high plasma LDL-cholesterol concentrations observed in HeFH
The prevalence of T2DM and variables associated with the metabolic syndrome and diabetes i.e. age, body mass index (BMI), waist circumference, triglycerides, glucose and prevalence of hypertension were higher in the probable HeFH group than in definite HeFH
Summary
Heterozygous familial hypercholesterolemia (HeFH), the most frequent monogenic disorder of human metabolism caused by some mutations in the genes that encode for the low-density lipoprotein (LDL) receptor, apolipoprotein (apo) B, proprotein convertase subtilisin/kexin-type 9 (PCSK9) or apo E1, 2, entails an increased risk of premature cardiovascular disease[2]. One of the mechanisms suggested to explain www.nature.com/scientificreports/ This finding lies in potential decreased cholesterol uptake by pancreatic β cells in HeFH5. This lower T2DM risk contrasts with the fact that most HeFH patients are treated with high doses of potent statins which exert a dose-dependent diabetogenic effect[6, 7]. The aims of the present study were to assess the prevalence of T2DM in HeFH patients of the Dyslipidemia Registry of the Spanish Arteriosclerosis Society, and evaluate the impact of mutations in the LDLR, APOB and PCSK9 genes, baseline LDL cholesterol concentration and duration of statin treatment on T2DM prevalence in this population. T2DM is defined in the presence of fasting blood glucose >125 mg/dL or use of blood glucose-lowering drugs
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