ABSTRACT
Title
Niacin Extended-Release and Fenofibrate improve HDL ability to preserve endothelial cell homeostasis: results from the HiFun Study
Authors
M. Gomaraschi1, S. Pozzi1, K. Coutant2, S. Rossomano2, F. Lamour2, R. Benghozi2, G. Franceschini1, L. Calabresi1
1Center Enrica Grossi Paoletti, Dept. of Pharmacological Sciences, Università degli Studi di Milano, Italy
2F. Hoffmann-La Roche Ltd, Basel, Switzerland
1Center Enrica Grossi Paoletti, Dept. of Pharmacological Sciences, Università degli Studi di Milano, Italy
2F. Hoffmann-La Roche Ltd, Basel, Switzerland
Abstract
Background: Niacin and fenofibrate are to date the most effective available therapies to increase high density lipoprotein-cholesterol (HDL-C) levels. A direct comparison of drugs’ effects on HDL composition/distribution and on HDL atheroprotective functions is still lacking.
Methods: A multicenter, randomized, open-label, cross-over study was performed on 66 dyslipidemic patients, 24 with low HDL-C levels (36±6 mg/dl) and 42 with normal HDL-C (47±7) mg/dl. Patients received 6 weeks’ treatment with niacin extended-release (niacin ER, 0.5 g/d then 1.0 g/d) and fenofibrate (160 mg/d), with 4 weeks’ wash-out period between the two treatments. Plasma levels of HDL-C, apolipoprotein A-I and A-II and HDL distribution into small, medium and large particles by NMR were determined. In a subset of 37 patients (18 with low HDL-C and 19 with normal HDL-C), HDL ability to preserve endothelial cell homeostasis was assessed in vitro by incubating endothelial cells with HDL isolated from plasma collected at baseline and after treatment. Control HDL were obtained from 18 healthy subjects with high HDL-C levels (73±12 mg/dl). The anti-inflammatory potential of HDL was tested as their ability to inhibit cytokine-induced vascular cell adhesion molecule 1 (VCAM-1) expression in endothelial cells; HDL ability to increase the expression of the endothelial nitric oxide synthase (eNOS) was also tested.
Results: Niacin ER and fenofibrate similarly increased plasma levels of HDL-C (+15.9% and +16.0%, respectively) and apolipoprotein A-I (ApoA-I, +7.0% for both). On the contrary, apoA-II increased only after fenofibrate treatment (+27.6%). Niacin ER and fenofibrate differently affected HDL particle size distribution: a shift from baseline was observed from small (-0.7%) to medium (+101.9%) and large (+20.2%) particles with fenofibrate and from medium (-35.9%) to large (+61.5%) particles with niacin ER. Niacin ER and fenofibrate both increased HDL ability to inhibit VCAM-1 expression in endothelial cells, with a significantly higher effect of niacin ER (+12.4% after niacin ER vs +7.8% after fenofibrate, p=0.027). Interestingly, post-niacin HDL anti-inflammatory potential was higher than that of Control HDL (p=0.002). Niacin ER and fenofibrate similarly improved HDL ability to induce eNOS expression in endothelial cells (+10% and +11.4%, respectively).
Conclusions: Niacin ER and fenofibrate similarly increased HDL-C levels, but differently affected HDL distribution: niacin ER mainly increased large apoA-I-containing HDL, while fenofibrate increased medium-sized particles containing both apoA-I and apoA-II. Both treatments improved HDL ability to preserve endothelial cell homeostasis. The superior effect of niacin ER on HDL ability to inhibit VCAM-1 expression suggests that increasing large apoA-I-containing HDL could be a possible therapeutic approach to improve HDL anti-inflammatory potential.
Methods: A multicenter, randomized, open-label, cross-over study was performed on 66 dyslipidemic patients, 24 with low HDL-C levels (36±6 mg/dl) and 42 with normal HDL-C (47±7) mg/dl. Patients received 6 weeks’ treatment with niacin extended-release (niacin ER, 0.5 g/d then 1.0 g/d) and fenofibrate (160 mg/d), with 4 weeks’ wash-out period between the two treatments. Plasma levels of HDL-C, apolipoprotein A-I and A-II and HDL distribution into small, medium and large particles by NMR were determined. In a subset of 37 patients (18 with low HDL-C and 19 with normal HDL-C), HDL ability to preserve endothelial cell homeostasis was assessed in vitro by incubating endothelial cells with HDL isolated from plasma collected at baseline and after treatment. Control HDL were obtained from 18 healthy subjects with high HDL-C levels (73±12 mg/dl). The anti-inflammatory potential of HDL was tested as their ability to inhibit cytokine-induced vascular cell adhesion molecule 1 (VCAM-1) expression in endothelial cells; HDL ability to increase the expression of the endothelial nitric oxide synthase (eNOS) was also tested.
Results: Niacin ER and fenofibrate similarly increased plasma levels of HDL-C (+15.9% and +16.0%, respectively) and apolipoprotein A-I (ApoA-I, +7.0% for both). On the contrary, apoA-II increased only after fenofibrate treatment (+27.6%). Niacin ER and fenofibrate differently affected HDL particle size distribution: a shift from baseline was observed from small (-0.7%) to medium (+101.9%) and large (+20.2%) particles with fenofibrate and from medium (-35.9%) to large (+61.5%) particles with niacin ER. Niacin ER and fenofibrate both increased HDL ability to inhibit VCAM-1 expression in endothelial cells, with a significantly higher effect of niacin ER (+12.4% after niacin ER vs +7.8% after fenofibrate, p=0.027). Interestingly, post-niacin HDL anti-inflammatory potential was higher than that of Control HDL (p=0.002). Niacin ER and fenofibrate similarly improved HDL ability to induce eNOS expression in endothelial cells (+10% and +11.4%, respectively).
Conclusions: Niacin ER and fenofibrate similarly increased HDL-C levels, but differently affected HDL distribution: niacin ER mainly increased large apoA-I-containing HDL, while fenofibrate increased medium-sized particles containing both apoA-I and apoA-II. Both treatments improved HDL ability to preserve endothelial cell homeostasis. The superior effect of niacin ER on HDL ability to inhibit VCAM-1 expression suggests that increasing large apoA-I-containing HDL could be a possible therapeutic approach to improve HDL anti-inflammatory potential.