Advances in lipid-lowering therapy in atherosclerosis.

The accrued evidence that lipid-lowering therapy limits the progression of atherosclerosis and reduces CAD events is overwhelming. The focus has been on LDL-C reduction with statins, but recent evidence also stresses the importance of raising HDL-C and reducing triglyceride-rich lipoproteins (TRL). Treatment should take into account the type of dyslipidemia, combination therapy, drug interactions and pleiotropic effects of drugs (multiple effects in different systems). Statins and fibrates are the most widely prescribed. Fibrates have a major impact on plasma TRL and HDL-C levels. They enhance lipoprotein lipase, apoAI and apoAII transcription and reduce that of apoCIII. The discovery that their multiple actions are in large part mediated by the PPAR alpha pathway is a breakthrough. Fibrates also lower plasma fibrinogen and plasma viscosity but their ability to inhibit smooth muscle cell activation is one of their most promising pleiotropic effects. Statins are safe and potent LDL-C-lowering agents but also lower TRL and raise HDL. Their pleiotropic effects are numerous, and include vasodilatory, anti-thrombotic, antioxidant, anti-proliferative, anti-inflammatory and plaque stabilizing properties. Many findings make a case for their early use in CAD to improve myocardial perfusion after a myocardial infarction, and they are indicated in heart transplant recipients to improve survival and reduce graft rejection. Fibrates and statins have complementary lipid modifying and pleiotropic effects so that their combination, carried out with caution to avoid potential untoward effects, should provide the highest cardiovascular benefit. This hypothesis is currently being tested in the Lipid in Diabetes Study (LDS), an outcome trial comparing monotherapy with fenofibrate and cerivastatin to combination therapy conducted in England.