Long-term effects of fenofibrate on VLDL and HDL subspecies in participants with type 2 diabetes mellitus

Abstract

Aims/hypothesis Low HDL-cholesterol (HDL-C) is frequently accompanied by high triacylglycerol levels in diabetic dyslipidaemia, increasing the risk of CHD. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, fenofibrate treatment lowered triacylglycerol levels, but the initial 5% increase in HDL-C attenuated over 5 years. We explored the changes in VLDL and HDL subspecies during fenofibrate treatment in a statin-free FIELD cohort. Methods We randomised 171 participants with type 2 diabetes mellitus, who had been recruited to the FIELD study in Helsinki, to micronised fenofibrate (200 mg/day) or placebo in double-blind study design. VLDL and HDL subspecies were separated by ultracentrifugation at baseline and at the second and fifth year. Apolipoprotein (apo)A-I and apoA-II were measured by immunoturbidometric methods and lipoprotein (Lp)A-I and LpAI-AII particles by differential immunoassay. Results Fenofibrate reduced plasma triacylglycerol levels by 26%, resulting from a marked reduction in VLDL1 triacylglycerol (0.62 vs 0.29 mmol/l, p<0.001). Fenofibrate caused an increase in LDL size (Δ0.80 nm, p<0.001). HDL-C was similar between the groups. HDL2-C was decreased by fenofibrate (−27.5% at 5th year, p<0.001) and HDL3-C increased (13.0% at 5th year, p<0.001). Fenofibrate had no effect on apoA-I, whereas apoA-II increased. Thus, LpA-I decreased while LpAI-AII increased. Activities of cholesteryl ester transfer protein, phospholipids transfer protein and lecithin:cholesterylacyl transferase were unchanged by fenofibrate. High homocysteine levels were associated with a slight decrease in HDL-C and apoA-I. Conclusions/interpretation Fenofibrate markedly reduced large VLDL particles and produced a clear shift in HDL subspecies towards smaller particles. The HDL3-C increase in conjunction with unchanged apoA-II levels is a dilemma with regard to cardiovascular disease.

Fibrates and future PPARα agonists in the treatment of cardiovascular disease

“…Further analysis showed the key changes in HDL-cholesterol fraction caused by fenofibrate were an increase in small dense HDL 3 -C (+13.0% compared with placebo; 95% CI 7.5-18.3%; P <0.001), together with a decrease in HDL 2 -C (-27.5%, 95% CI 18.3-37.3%; P <0.001). 69 Fenofibrate decreased mostly large buoyant VLDL 1 -triglyceride (-46.5%, 95% CI 31.3-63.2%; P <0.001), but also VLDL 2 -triglyceride concentrations (-33.3, 95% CI 20.6-45.8%; P <0.001).…”

Long-Term Effects of Fenofibrate on Carotid Intima-Media Thickness and Augmentation Index in Subjects With Type 2 Diabetes Mellitus

“…Commercially available enzyme-linked immunosorbent assay kits were used to determine ICAM-1 (coefficient of variance [CV] 7.4%), VCAM-1 (CV 9.2%), E-selectin (CV 7.3%), and IL-6 (CV 15.1%) (R&D Systems, Minneapolis, Minnesota); ultra-sensitive CRP (CV 12.8%) (Medix Biochemica, Kauniainen, Finland); SAA (CV 21.9%) (Biosource International, Camarillo, California); and secretory phospholipase A2 IIA (SPLA2) (CV 22.1%) (Cayman Chemical Company, Ann Arbor, Michigan). Lipids, plasma glucose, and glycosylated hemoglobin were measured as described (27). Measurement of carotid IMT.…”

RPE barrier breakdown in diabetic retinopathy: seeing is believing

“…Fenofibrate is a drug against cardiovascular risk in diabetes through the reduction of cholesterol by downregulating the levels of low-density lipoprotein, very low-density lipoprotein, and triglyceride and by upregulating the level of highdensity lipoprotein level [67]. In ARPE-19 cells grown in high-glucose media, fenofibrate upregulated the expression of fibronectin and collagen IV, basement membrane components known to cause endothelial barrier breakdown [68].…”