Evidence for use of fibrates in diabetic dyslipidemia: are we looking hard enough?

Abstract

The metabolic syndrome is intricately linked to type 2 diabetes and in fact may be a prodrome of that condition. Both exhibit characteristic perturbations of the lipid profile namely raised triglycerides (>1.7 mmol/l) and reduced HDL cholesterol (<1 mmol/l in men and <1.3 mmol/l in women) [1]. Other conditions characterized by a degree of insulin resistance, for example, the polycystic ovarian syndrome (PCOS) also exhibit similar changes in the full lipid profile [2].Dysregulation of lipoprotein metabolism in these circumstances is caused by a combination of overproduction of VLDL-apo B 100, decreased catabolism of apo B-containing particles, and increased catabolism of apo A-I containing HDL particles [3]. Reduction in the number of apo B-containing particles using LDL cholesterol as a surrogate marker is a widely established strategy for reducing cardiovascular risk with an extensive evidence base. However, despite significant proven benefits from statin therapy, considerable residual risk remains, which is potentially attributable to increased triglyceride-rich lipoproteins and reduced levels of HDL cholesterol.A meta-analysis of 17 prospective studies showed that after adjusting for variables such as HDL cholesterol, total cholesterol, and other risk factors, the relative risk for coronary heart disease with a 1 mmol/l increase in triglyceride was 1.14 [95% confidence interval (CI) 1.05-1.28] for men and 1.37 (95% CI 1.13-1.66) for women [4]. Findings from the PROCAM study similarly support the idea that elevated triglycerides are an independent cardiovascular risk factor [5]. Thus, the potential benefits of adjunctive therapy (e.g., with fibric acid derivatives) to monotherapy with statins, particularly in those patients with triglyceriderich dyslipidemia as seen in patients with diabetes and/or the metabolic syndrome should be demonstrable following well designed randomized controlled trials.Fibrates are peroxisome proliferators activated receptor a (PPAR-a) agonists that work by transcriptionally regulating genes involved in lipid metabolism resulting in lower plasma triglycerides and elevated levels of HDL. The clinical utility of therapy with fibric acid derivatives (either as monotherapy or as adjunctive therapy with statin therapy) has been the subject of controversy for several decades. Unlike statins, which are effective throughout the range of LDL cholesterol, it appears that fibric acid derivatives may only lower cardiovascular disease events in diabetic patients with 'atherogenic dyslipidemia', characterized by elevated triglycerides and reduced levels of HDL cholesterol. Two trials involving the use of fenofibrate either as monotherapy or in combination with statin therapy have reported this in the last few years. The FIELD trial [6] was disappointingly negative with respect to cardiovascular outcomes, the potential explanation being 'drop-in' statin therapy as a confounding issue. More recently, in the ACCORD-lipid arm [7], overall, after a mean of 4.5 years, the combination of fenofibrate and s...

HIV-1 infection is associated with changes in nuclear receptor transcriptome, pro-inflammatory and lipid profile of monocytes

“…Indeed, FXR has been demonstrated to regulate insulin secretion and sensitivity and FXR ligands reduce lipid and glucose levels in murine models of diabetes [23,24]. Similar beneficial effects on glucose metabolism have been shown for PXR [25], as well as for the fibrates (PPARα agonists) that are widely used for treatment of dyslipidemic conditions [26]. In short, abrogation of the expression of these genes might provide an explanation for immune dysfunction and dyslipidemia observed in HIV disease.…”

Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice

“…Prior reports demonstrated beneficial effects of PPARg agonists, such as thiazolidinediones (5), in models of AD (6 -9), Parkinson's disease (PD) (10), amyotrophic lateral sclerosis (ALS) (11,12) and Huntington's disease (HD) (13,14). Fibrates, such as fenofibrate (15), are another class of PPAR agonists that primarily target the PPARa pathway, with smaller effects on PPARb and PPARg (16)(17)(18). Fenofibrate has shown promising neuroprotective effects in models of neurodegenerative diseases including PD (19) and brain injury (20).…”