pitavastatin and Hypertriglyceridemia

Pitavastatin (nisvastatin) is an HMG CoA reductase inhibitor being developed jointly by Nissan, Kowa Kogyo, Novartis and Sankyo for the potential treatment of atherosclerosis and hyperlipidemia.

Topics: Animals; Clinical Trials as Topic; Drug Industry; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertriglyceridemia; Quinolines

Substantial residual cardiovascular risks remain despite intensive statin treatment. Residual risks with high triglyceride and low high-density lipoprotein cholesterol are not the primary targets of statins. K-877 (pemafibrate) demonstrated robust efficacy on triglycerides and high-density lipoprotein cholesterol and a good safety profile as a monotherapy. The aim of these studies was to evaluate the efficacy and safety of K-877 add-on therapy to treat residual hypertriglyceridaemia during statin treatment.. The objectives were investigated in two, multicentre, randomised, double-blind, placebo-controlled, parallel group comparison clinical trials: (A) K-877 0.1, 0.2, and 0.4 mg/day in combination with pitavastatin for 12 weeks in 188 patients, (B) K-877 0.2 (fixed dose) and 0.2 (0.4) (conditional up-titration) mg/day in combination with any statin for 24 weeks in 423 patients.. In both studies, we found a robust reduction in fasting triglyceride levels by approximately 50% in all combination therapy groups, which was significant compared to the statin-monotherapy (placebo) groups (p < 0.001). High-performance liquid chromatography analysis for lipoprotein subfractions revealed that atherogenic lipoprotein profiles were ameliorated by K-877 add-on therapy, i.e. small low-density lipoproteins decreased whereas larger ones increased, and larger high-density lipoproteins decreased whereas smaller ones increased. The incidence rates of adverse events and adverse drug reactions in K-877 combination therapy groups were comparable to those in statin-monotherapy groups without any noteworthy event in both studies.. These results strongly support the favourable benefit-to-risk ratio of K-877 add-on therapy in combination with statin treatment.

Topics: Adult; Aged; Benzoxazoles; Biomarkers; Butyrates; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertriglyceridemia; Hypolipidemic Agents; Japan; Male; Middle Aged; PPAR alpha; Quinolines; Signal Transduction; Time Factors; Treatment Outcome; Triglycerides; Young Adult

Obesity is a well-established risk factor for the development and progression of coronary heart disease. Moreover, endothelial dysfunction is an early event in atherosclerosis and is known to be associated with postprandial hypertriglyceridemia. The purpose of this study was to determine whether a statin might have an effect on postprandial hypertriglyceridemia, and thereby on endothelial function in obese subjects. Twenty-four obese male subjects were recruited for this study. They were randomly assigned to receive pitavastatin (2 mg/day) or placebo for 2 weeks. The oral fat loading test using OFTT cream was performed pre- and post-treatment, in which the lipid profile and flow-mediated dilation (FMD) were assessed before and 4 h after an oral fat load. In the oral fat loading test conducted pretreatment, the oral fat load induced a marked increase of the serum triglyceride (TG) level and decrease in FMD in the pitavastatin and placebo group. In the test conducted post-treatment, the increase in postprandial TG was attenuated (+183 vs. +81 mg/dL, P < 0.001) and decrease in postprandial FMD was completely abolished (-1.1 vs. +0.1%, P < 0.01) by pitavastatin treatment. Moreover, there was a good correlation between the change in postprandial TG and the change in postprandial FMD after the 2 weeks of treatment (r = -0.737, P < 0.001). Pitavastatin might prevent endothelial dysfunction caused by postprandial hypertriglyceridemia within 2 weeks of therapy in obese subjects.

Topics: Adult; Aged; Biomarkers; Dietary Fats; Down-Regulation; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertriglyceridemia; Japan; Male; Middle Aged; Obesity; Postprandial Period; Quinolines; Regression Analysis; Time Factors; Treatment Outcome; Triglycerides; Ultrasonography; Vasodilation

Atherogenic remnant lipoproteins (RLPs) are known to induce foam cell formation in macrophages in vitro and in vivo. We examined the involvement of apoB48 receptor (apoB48R), a novel receptor for RLPs, in that process in vitro and its potential regulation by pitavastatin.. THP-1 macrophages were incubated in the presence of RLPs (20 mg cholesterol/dL, 24 hours) isolated from hypertriglyceridemic subjects. RLPs significantly increased intracellular cholesterol ester (CE) and triglyceride (TG) contents (4.8-fold and 5.8-fold, respectively) in the macrophages. Transfection of THP-1 macrophages with short interfering RNA (siRNA) against apoB48R significantly inhibited RLP-induced TG accumulation by 44%. When THP-1 macrophages were pretreated with pitavastatin (5 micromol/L, 24 hours), the expression of apoB48R was significantly decreased and RLP-induced TG accumulation was reduced by 56%. ApoB48R siRNA also inhibited TG accumulation in THP-1 macrophage induced by beta-very-low-density lipoprotein derived from apoE-/- mice by 58%, supporting the notion that apoB48R recognizes and takes-up RLPs in an apoE-independent manner.. RLPs induce macrophage foam cell formation via apoB48R. Pitavastatin inhibits RLP-induced macrophage foam cell formation. The underlying mechanism involves, at least in part, inhibition of apoB48R-dependent mechanism. Our findings indicate a potential role of apoB48R in atherosclerosis. RLPs induced macrophage foam cell formation via apoB48R. Pitavastatin inhibited RLP-induced macrophage foam cell formation, at least in part, via inhibition of apoB48R expression. Our findings indicate a potential role of apoB48R in atherosclerosis.

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Biological Transport; Cell Line; Cholesterol Esters; Foam Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertriglyceridemia; Lipoproteins, VLDL; Macrophages; Mice; Mice, Knockout; Quinolines; Receptors, Lipoprotein; rhoA GTP-Binding Protein; RNA, Small Interfering; Signal Transduction; Triglycerides