Lower diabetes rate in patients with familial hypercholesterolaemia: What is the link?

In a cross-sectional study published in this journal, Perez-Calahorra and colleagues evaluate the prevalence of lifestyle-related cardiovascular risk factors in a large cohort of patients with heterozygous familial hypercholesterolaemia (FH) (n1⁄4 2185 and 11,856 controls). In an age, sex and body mass index (BMI)-adjusted analysis they show that FH patients more often have cardio-vascular disease and hypertension but are less frequently smokers. FH patients also take antihypertensive and anti-diabetic medications more often. In a subsample with complete blood glucose information, the authors describe a lower prevalence of diabetes and smoking, a lower BMI and a higher diastolic blood pressure. The observed differences in diabetes prevalence can be explained by differences in BMI. This study confirms previous reports showing that patients with FH have a lower prevalence of diabetes and extends our knowledge with respect to possible mechanisms behind this association. The analysis indicates that patients with FH (and probably their treating physicians) are more health-conscious, therefore have a lower BMI, smoke less and are treated ‘earlier’ with anti-diabetic and anti-diabetic medications. However, is that all? Glucose and lipid metabolism are both part of the energy household and closely linked to each other, which is most obvious from the fact that glucose can be converted to fatty acids and fatty acids to glucose. However, the interaction goes far beyond this and several observations document this intimate linkage: statins increase while high density lipoprotein-increasing approaches (cholesterol ester transfer protein-inhibition) decrease the risk for diabetes in a dose dependent manner. Furthermore, genetic variants that predispose to lower low density lipoprotein (LDL)-cholesterol levels increase the risk for diabetes. The data for FH are ambiguous. Besseling et al. showed a dose-dependent effect of the severity of FH on diabetes risk, patients with more severe mutations or multiple affected genes had higher LDL-cholesterol levels and lower diabetes risk. However, this was not confirmed in other studies as Xu et al. reported no association of diabetes risk with FH causing apolipoprotein B mutations and Climent et al. showed that the association of FH with the decreased prevalence of diabetes is independent of the observed LDL-cholesterol concentrations. Most likely, several factors are responsible for the observed association of FH with lower diabetes risk. Clearly, as demonstrated in the study by PerezCalahorra and colleagues, patients with FH on average practise a healthier lifestyle and thus have lower BMIs, which then leads to a decreased diabetes rate. On the other hand, mutations resulting in FH or hypocholesterolaemia not only change plasma levels of cholesterol but may also alter the cholesterol content of certain intracellular compartments, including in cells relevant to glucose metabolism. Intracellular cholesterol may be decreased in FH due to reduced uptake (LDL-receptor defect) and increased in hypocholesterolaemia or following drug therapy with statins (increased uptake of cholesterol). If this was true, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9)-inhibitor therapy should also result in an increased diabetes prevalence, which is indeed suggested by genetic studies but was not observed in large outcome trials. Since ezetimibe and PCSK9 inhibitors were only tested in statin-treated subjects, one could assume that the additional effect (on top of statins) is too small to be detected or that there is no additional effect. In summary, the study by Perez-Calahorra et al. shows that in FH patients lifestyle is associated with BMI that is then linked to diabetes risk as is true for non-FH patients. However, it remains likely that additional physiological factors resulting in altered intracellular cholesterol concentrations are also