Type 2 diabetes, dyslipidemia, and vascular risk: rationale and evidence for correcting the lipid imbalance.

Type 2 diabetes is an important cardiovascular risk factor. A significant component of the risk associated with type 2 diabetes is thought to be because of its characteristic lipid "triad" profile of raised small dense low-density lipoprotein levels, lowered high-density lipoprotein, and elevated triglycerides (TGs). Trials of statins and fibrates have included substantial numbers of patients with diabetes and indicate that lipid lowering reduces cardiovascular event rates in these patients. However, statins alone do not always address all the lipid abnormalities of diabetes. Fibrates, which have low affinity for peroxisome proliferator-activated receptor alpha (PPARalpha), improve most aspects of the atherogenic dyslipidemia of diabetes. Chronic elevations of free fatty acids (FFA) induce insulin resistance and contribute to the lipid triad of diabetes. Therefore, reducing their levels is likely to ameliorate insulin resistance and improve the lipid triad of diabetes. PPARs are intimately involved in the regulation of FFA: PPARalpha modulation increases FFA catabolism and PPARgamma agonism (eg, by thiazolidinediones) increases TG lipolysis, FFA transport, conversion of FFA to TGs, and safe storage of FFA. Integrating potent PPARalpha and PPARgamma activity may deliver greater improvement of the diabetic dyslipidemic profile and its attendant risks than selective PPAR activation.