Role of PPAR signalling in diabetic dyslipidemia
Despite that statin treatment substantially reduces cardiovascular morbidity and mortality, many treated patients still experience a high residual risk. Statins lower LDL-cholesterol (LDL-C), with limited effects on other lipid parameters. A meta-analysis from 14 randomised trials conducted in high-risk patients reported that statin therapy is effective in reducing the proportional risk for major vascular events by 21% for each mmol/l lowering of LDL-C. However, on average 14% of patients still experienced an event despite being allocated to statin. Beyond LDL-C, other factors, including triglycerides, non-HDL-C, HDL-C and apolipoprotein B and CIII, have been identified as factors determining residual risk, and normalization of these parameters may further decrease cardiovascular disease in patients treated with statins. PPARα activation improves atherogenic dyslipidemia characterized by high triglyceride and/or low HDL-C levels and elevated concentrations of small dense LDL particles, with or without high LDL-C levels. Data from fibrate trials indicate that these drugs are particularly effective in reducing cardiovascular morbidity in patients with atherogenic dyslipidemia and the metabolic syndrome. The ACCORD trial is testing the effect of fenofibrate and statin combination therapy on cardiovascular disease in diabetic patients. In addition, results from the FIELD trial have demonstrated a beneficial action of the PPARα activation on microvacular complications (retinopathy) and amputation in diabetic patients. Moreover, PPARδ agonists improve dyslipidemia, glucose and energy homeostasis in preclinical animal models of (pre)diabetes. These observations provide a rationale to target PPARα and PPARδ in the management of patients with high residual cardiovascular risk related to atherogenic dyslipidemia and persisting after single therapy.