Frail HDLs and Stiff Arteries in Type 2 Diabetes in Juveniles

Abstract

Lowering of LDL cholesterol plasma levels with statins reduces coronary heart disease (CHD) event rates by up to 50% (1), implying a residual cardiovascular risk of the same magnitude despite treatment. Moreover, statins increase the risk of type 2 diabetes mellitus (T2DM), especially in patients showing components of the metabolic syndrome (2). Hence, there is considerable need for novel therapeutic regimens improving CHD prevention without increasing the risk of T2DM. HDLs are an interesting target for this objective. Most observational studies and meta-analyses thereof demonstrated the inverse relationship of HDL cholesterol (HDL-C) levels with the CHD risk (3) as well as T2DM and its vascular complications (4,5). HDL particles exert various potentially antiatherogenic (6–8) and antidiabetogenic activities (4). Atherosclerotic lesions were decreased or even reversed in animals by transgenic overexpression or application of exogenous apolipoprotein (apo) A-I, which constitutes the most abundant protein of HDL (6). Animal experiments also provided evidence that HDL improves the function and survival of pancreatic β-cells and glucose uptake into muscle, liver, and adipose tissue (4). In humans, artificially reconstituted HDL particles reduced coronary plaque volume (9,10) and improved glycemia (11). In contrast to these promising results, addition of fenofibrate, niacin, torcetrapib, or dalcetrapib to statins failed to reduce cardiovascular risk beyond that provided by statin treatment alone despite increasing HDL-C (12–15). Moreover, alterations in HDL-C, either associated with mutations in the human genome or provoked in genetic mouse models, did not consistently translate into opposite changes of cardiovascular risk and atherosclerotic plaque load, respectively (16,17). Because of these controversial data, the suitability of HDL as a therapeutic target has been increasingly questioned. However, it is important to emphasize that interventional trials and …