Fenofibrate and Metabolic Syndrome

Abstract

The fibric acid derivative, fenofibrate (FF) has been used in the US since 1998 to manage patients with dyslipidemia. Typical changes in serum lipids as a result of FF treatment include clinically important mean reductions of serum triglycerides (TG) by a mean change of −93.7 mg/dL (−39.3%), increases of high density lipoprotein cholesterol (HDLC) by +5.5 mg/dL (+12.4%), and reductions in low density lipoprotein cholesterol (LDLC) by −17.9 mg/dL (−12.3%). The greatest reductions in serum TG are usually observed in subjects with elevated baseline TG including those with the metabolic syndrome (MetS). Although statins remain the mainstay of therapy for most dyslipidemic patients, their combined use with FF would be expected to address residual risk resulting from less than optimal TG and HDLC levels in such patients. Clinical trials examining the cardiovascular benefits of FF alone or combined with statins have produced mixed results. These observations underscore our lack of understanding of which patients may benefit from FF therapy and which do not. Although FF’s basic mechanism of action is known to involve PPAR-α agonist activity resulting in altered transcription of several genes, the actual genetic bases for variability in lipid response is poorly understood. Studies, such as our GOLDN study and others were designed to better understand the genetic determinants of variability in the response to FF treatment and lipid levels. As a result several important genetic determinants of lipid levels have been identified. For example, in the GOLDN study SNPs from different genes were significantly associated with baseline lipid levels before treatment (APOA5-rs662799, rs3135506; APOC3-rs5128, rs2854117, rs4520); APOA4-rs5104; PPARA-rs9626730, rs135543, rs11703495; LPL-rs1801177), after treatment PPARA-rs11708495; LPL-rs1801177, and appeared to modulate overall response to FF treatment (NOS3-rs1799983). In this article, we will review the literature leading up to the contemporary use of FF as an agent to manage patients with dyslipidemia and focus on emerging understanding of the genetic variability in response to FF treatment. On the basis of the available evidence, we conclude that FF is of benefit in the treatment of dyslipidemia, especially among those with MetS. However, more work is needed to specifically identify which individuals derive a benefit from FF administration in terms of clinical outcomes and which do not – particularly in the context of type 2 diabetes.

Long-term effects intensive medical therapy on the development and progression of subclinical atherosclerosis and the metabolic syndrome in Chinese patients with type 2 diabetes mellitus

“…However, the success rate in the intensive medical therapy group did not differ significantly from that of conventional treatment group in the latter years of the follow-up period, and a Kaplan–Meier analysis did not show a significant difference in MetS risk between the treatment groups. Studies in both animals and humans have suggested that treatment with metformin, [28] captopril, [29,30] valsartan, [31,32] simvastatin, [33] or fenofibrate [34,35] alone reduced the development of MetS, which is largely consistent with our findings. Because MetS increases the risk of cardiovascular disease, [36–38] it seems unlikely that improvements in MetS indicators contributed to a lower risk of subclinical atherosclerosis in the intensive medical therapy group, compared with that in the conventional treatment group.…”

Peroxisome proliferator-activated receptor agonists (PPARs): a promising prospect in the treatment of psoriasis and psoriatic arthritis

“…49-52 Clinical studies suggested that the therapeutic benefits of PPARγ ligands are mediated in part by the release of adiponectin. 53 Diabetic patients and patients with coronary heart disease have elevated levels of adiponectin after exposure to thiazolidinediones, which reduce cholesterol levels and improve hypertension control.…”

Management of Residual Cardiovascular Risk in Dyslipidaemic Patient with Metabolic Syndrome

“…These two organisations including ADA advocated the use of fibrates to reduce TG and elevate HDL-C in patients with the MS or diabetes and suggested that fenofibrate combination with statin may be an effective and safer alternative than statin alone. In 2010, in a review, fenofibrate is of benefit in the treatment of dyslipidemia, especially among those with MS [12]. Another study, the same year, reported that both atorvastatin and fenofibrate exhibited multidirectional pleiotropic effects in subjects with MS [13].…”