Fibrates and future PPARα agonists in the treatment of cardiovascular disease

Abstract

Statins lower cardiovascular risk in patients with diabetes; however, as these patients are at higher risk than other cardiovascular patients, statins merely decrease coronary event rates to the level seen in untreated nondiabetic individuals at risk for cardiovascular disease, indicating the existence of substantial residual risk. One reasonable explanation resides in the fact that statins have only limited effectiveness on hypertriglyceridemia and low HDL cholesterol, and they do not normalize the LDL size-distribution pattern. Peroxisome proliferator-activated receptor (PPAR)alpha agonists, which include fibrates, normalize this atherogenic lipid profile, as well as several cardiovascular risk markers associated with the metabolic syndrome and type 2 diabetes. In particular, hypertriglyceridemia and the ratio of small dense:large buoyant LDL particles are significantly improved. Outcome trials of PPARalpha agonists have demonstrated reductions in cardiovascular morbidity in patients with diabetes and in those with the metabolic syndrome; plaque progression is diminished, diabetic nephropathy and retinopathy are counteracted and amputation-risk decreased. The combination of fibrates with statins improves overall lipoprotein profile further. PPARalpha agonists seem particularly indicated in patients with diabetes who have residual dyslipidemia (high triglyceride and/or low HDL) despite receiving statin therapy, and patients who are nondiabetic, overweight, insulin-resistant and who have hypertriglyceridemia and/or low HDL cholesterol and chronic inflammation.

Porównanie wpływu leczenia hipolipemicznego na wydzielanie cytokin prozapalnych u kobiet i mężczyzn z cukrzycą typu 2 i dyslipidemią aterogenną

“…In the case of fenofibrate, the presence of these correlations is a logical consequence of the involvement of FFA in the development of insulin resistance in both men and women [26], as well as the role of endogenous ligands for PPAR-a [27]. Finding that a similar reduction in FFA was induced by simvastatin is in agreement with the hypothesis that the molecular mechanisms of the action of statins and fibrates partially overlap [28,29]. An inhibitory effect of simvastatin-induced inhibition of protein prenylation on the activity of glucose transporter 4 [30], responsible for insulinregulated glucose transport into the cell [31], may explain why, despite a reduction in FFA, simvastatin did not improve insulin sensitivity.…”

Diabetic Nephropathy: A Cardiovascular Risk Factor

“…Outcome trials of PPARalpha agonists have shown decreased cardiovascular morbidity in patients with diabetes and in those with the metabolic syndrome. In addition, plaque progression is diminished, and there is a decrease in both microvascular (including diabetic nephropathy and retinopathy) and macrovascular complications (reviewed by Staels et al, 2008). Two trials worth mentioning are the FIELD study and the DAIS study.…”

Apolipoprotein CIII

“…1 These disorders are characterized by abnormalities in glucose and lipid metabolism, putting patients at increased risk for macro-and microvascular complications. 2 Although statin treatment, which primarily targets elevated plasma low-density lipoprotein (LDL)-cholesterol levels, lowers cardiovascular morbidity and mortality in patients with type 2 diabetes, 3 it is increasingly clear that a significant residual cardiovascular risk remains in these patients, [3][4][5] which is partly attributable to the typical atherogenic lipoprotein profile (ALP) characterized by hypertriglyceridemia and low high-density lipoprotein (HDL)-cholesterol concentrations. 6 Post hoc analysis of statin trials, such as PROVE-IT TIMI 22, have identified plasma triglycerides as a determinant of cardiovascular risk in patients achieving LDL-cholesterol goals.…”

“…Peroxisome proliferator-activated receptor ␣ agonists, such as the currently used fibrates, are drugs used in the treatment of hypertriglyceridemia. 3 These compounds are potent downregulators of apoCIII expression. 11 Interestingly, fibrates have been found to be most efficacious in those patients with the ALP associated with the metabolic syndrome and type 2 diabetes, 3 and these novel findings regarding apoCIII may provide a mechanistic explanation for these effects of peroxisome proliferator-activated receptor ␣ ago-nists.…”