Search

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) shuttles low-density lipoprotein (LDL) receptors for degradation, thus upregulates LDL plasma clearance. Although PCSK9 loss of function is cardioprotective, its role in metabolic risks remains unknown. Increased apoB-lipoproteins uptake into nonhepatic tissues such as white adipose tissue (WAT) induces their dysfunction, which may be favored by lower plasma PCSK9. We hypothesized that lower plasma PCSK9 relative to apoB, or higher apoB-to-PCSK9 ratio, is a better predictor of metabolic disturbances than PCSK9 alone in humans. Methods Thirty-three men and 48 postmenopausal women (>27 kg/m 2 , aged 45–74 years, normoglycemic) underwent in-depth assessment of glucose and fat metabolism using high-fat meals, WAT biopsies, intravenous glucose-tolerance tests, and hyperinsulinemia clamps. Results Plasma apoB correlated positively with fasting and postprandial triglycerides and chylomicron clearance (R = 0.44–0.66) and glucose-stimulated insulin secretion (R = 0.24) and negatively with insulin sensitivity (R = −0.28) and gynoid WAT in situ lipoprotein lipase activity (ie, ex vivo WAT function, R 2 = 0.34). Neither PCSK9 nor LDL cholesterol associated with these risks. In regression analysis that adjusted for body mass index, lower plasma PCSK9 strengthened the association of apoB to WAT dysfunction and insulin resistance. Moreover, plasma apoB-to-PCSK9 ratio correlated positively with all these metabolic risks and further associated positively with android-to-gynoid fat ratio (R = 0.41) and negatively with gynoid fat mass (R = −0.23, all P ≤ .05). No significant sex differences existed in these associations. Conclusions Lower plasma PCSK9 relative to apoB associates with metabolic risks and WAT dysfunction in normoglycemic obese subjects. We hypothesize that the plasma apoB-to-PCSK9 ratio provides a better clinical index than PCSK9 alone for monitoring early metabolic disturbances that may be promoted by reduction in plasma PCSK9. [ABSTRACT FROM AUTHOR]

Background Icosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid ethyl ester approved at a dose of 4 g/day as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe hypertriglyceridemia (TG ≥ 500 mg/dL). Objective In this prespecified exploratory analysis from the ANCHOR study of patients at high cardiovascular risk with TG ≥ 200 and <500 mg/dL despite statin control of low-density lipoprotein cholesterol, we assessed the effects of IPE on lipoprotein particle concentration and size and examined correlations of atherogenic particles with apolipoprotein B (ApoB). Methods Nuclear magnetic resonance spectroscopy was used to measure lipoprotein particle concentration and size. Results Compared with placebo (n = 211), IPE 4 g/day (n = 216) significantly reduced concentrations of: total (12.2%, P = .0002), large (46.4%, P < .0001), and medium (12.1%, P = .0068) very-low-density lipoprotein (VLDL) particles; total (7.7%, P = .0017) and small (13.5%, P < .0001) LDL particles; and total (7.4%, P < .0001) and large (31.0%, P < .0001) high-density lipoprotein particles. Atherogenic lipoprotein particles (total VLDL and total LDL) correlated with ApoB at baseline ( R 2 = 0.57) and week 12 ( R 2 = 0.65) as did total LDL particle concentration at baseline ( R 2 = 0.53) and week 12 ( R 2 = 0.59). Compared with placebo, IPE 4 g/day significantly reduced VLDL (7.7%, P < .0001) and high-density lipoprotein (1.2%, P = .0014) particle sizes with a modest but significant increase in LDL particle size (0.5%, P = .0031). Conclusions Compared with placebo, treatment with IPE 4 g/day for 12 weeks reduced key atherogenic lipoprotein particle concentrations. At both baseline and end of study, atherogenic lipoprotein concentrations correlated with ApoB. [ABSTRACT FROM AUTHOR]

Background In the Determining the Efficacy and Tolerability of cholesteryl ester transfer protein (CETP) INhibition with AnacEtrapib (DEFINE) trial, anacetrapib added to statin produced robust low-density lipoprotein cholesterol (LDL-C)-lowering and high-density lipoprotein cholesterol (HDL-C)-raising vs placebo in patients with coronary heart disease (CHD). Predictors of the degree of LDL-C and HDL-C responses to anacetrapib, however, are poorly understood. Objective Lipid effects of anacetrapib in patient subgroups within the DEFINE trial ( clinicaltrials.gov : NCT00685776 ) are reported. Methods The percent of placebo-corrected changes from baseline for LDL-C (estimated by Friedewald calculation [Fc-LDL-C]) and HDL-C after 24 weeks of anacetrapib 100 mg/day were compared among patients by age, gender, race, diabetes status, type of concomitant statin with or without other lipid therapies, and baseline HDL-C, Fc-LDL-C, and triglyceride (TG) levels. Results Percent decreases in Fc-LDL-C and increases in HDL-C with anacetrapib were similar (magnitude of difference generally <1/5 of the overall treatment effect) across subgroups by age, gender, diabetes status, lipid-modifying regimen, and baseline Fc-LDL-C, HDL-C, or TG. On the other hand, anacetrapib effects on Fc-LDL-C (−24% vs −41%) and HDL-C (+75% vs +139%) appeared to be less in black vs white patients, respectively. Conclusion Effects of anacetrapib on Fc-LDL-C and HDL-C were generally comparable across subgroups, including being relatively independent of baseline Fc-LDL-C, HDL-C, or TG levels. The clinical impact of the lipid-modifying effects of anacetrapib is being evaluated in the cardiovascular disease outcomes trial, Randomized EValuation of the Effects of Anacetrapib though Lipid-modification (REVEAL). [ABSTRACT FROM AUTHOR]

Background: Icosapent ethyl (IPE; formerly AMR101) is a high-purity prescription form of eicosapentaenoic acid ethyl ester. In the MARINE study we evaluated the efficacy and safety of IPE in patients with very high triglycerides (TG; ≥500 mg/dL) and previously demonstrated significant reductions in TG levels with no significant increases in low-density lipoprotein (LDL) cholesterol levels. Objectives: In this follow-up, exploratory analysis, we report the effects of IPE on lipoprotein particle concentration and size. Methods: MARINE was a phase 3, multicenter, placebo-controlled, randomized, double-blind, 12-week study. Hypertriglyceridemic patients (N = 229) were randomized to three treatment groups: IPE 4 g/day, IPE 2 g/day, or placebo. Lipoprotein particle concentrations and sizes were measured by nuclear magnetic resonance spectroscopy. Results: Compared with placebo, IPE 4 g/day significantly reduced median concentrations of large very-low-density lipoprotein (VLDL; −27.9%; P = .0211), total LDL (−16.3%; P = .0006), small LDL (−25.6%; P < .0001), and total high-density lipoprotein (HDL; −7.4%; P = .0063) particles and reduced VLDL particle size (−8.6%; P = .0017). In this patient population with TG ≥500 mg/dL, IPE did not significantly change the overall sizes of LDL or HDL particles. Conclusion: IPE 4 g/day significantly reduced large VLDL, total LDL, small LDL, and total HDL particle concentrations and VLDL particle size in patients with TG ≥500 mg/dL. Changes in VLDL particle concentration and size reflect the TG-lowering effects of eicosapentaenoic acid. The reduction in LDL particle concentration with IPE is novel among ω-3 therapies and is consistent with the previously reported reduction in apolipoprotein B and lack of LDL-C increase with IPE in patients with very high TG levels. Clinical trial registration number: NCT01047683. [Copyright &y& Elsevier]

Abstract: Lipoprotein X (Lp-X) is an abnormal lipoprotein which may form in patients with intra- and extra-hepatic cholestasis. The presence of very high levels of Lp-X has been shown to be a rare cause of pseudohyponatremia. We present a patient with severe obstructive cholestasis secondary to pancreatic cancer leading to very high Lp-X concentrations resulting in pseudohyponatremia, pseudohypokalemia, pseudohypochloremia and interference with the selective micellary solubilization direct low density lipoprotein cholesterol assay. These spurious laboratory anomalies impeded the initial clinical management of the patient including the attempted correction of the electrolyte abnormalities. After relief of obstruction following biliary stent placement, the patient’s lipid levels normalized. Clinicians must be wary of laboratory artifacts and remember to correlate the laboratory values with the clinical presentation of the patient. Assays employing direct ion-selective electrodes such as those in blood gas analyzers are not subject to the interference of high concentrations of lipids or proteins, and maybe useful in situations where such interference is suspected. Furthermore the Vertical Auto Profile (VAP®) ultracentrifugation assay may be useful to detect lipoprotein X and low density lipoprotein cholesterol levels when the selective micellary solubilization technique fails to detect or quantify these lipid moieties. [Copyright &y& Elsevier]

Background Vitamin D deficiency is associated with an unfavorable lipid profile, but whether and how vitamin D supplementation affects lipid metabolism is unclear. Objective To examine the effects of vitamin D supplementation on lipid and lipoprotein parameters. Methods This is a post hoc analysis of the single-center, double-blind, randomized, placebo-controlled Styrian Vitamin D Hypertension Trial (2011–2014). Two hundred individuals with arterial hypertension and 25-hydroxyvitamin D concentrations of <75 nmol/L were randomized to 2800 IU of vitamin D daily or placebo for 8 weeks. Results One hundred sixty-three participants (62.2 [53.1–68.4] years of age; 46% women) had available lipid data and were included in this analysis. Vitamin D supplementation significantly increased total cholesterol, triglycerides, very-low-density lipoprotein (VLDL) triglycerides, low-density lipoprotein (LDL) triglycerides, high-density lipoprotein (HDL) triglycerides, apolipoprotein B (ApoB), LDL-ApoB, ApoCII, ApoCIII, phospholipids, and ApoE ( P < .05 for all). Except for ApoCII and ApoCIII and HDL-triglycerides, all other treatment effects remained statistically significant after adjustment for multiple testing with the Benjamini and Hochberg false discovery rate method. There was a nonsignificant increase in LDL cholesterol. Furthermore, no significant effects were seen on free fatty acids, lipoprotein (a), ApoAI, ApoAII, VLDL cholesterol, VLDL–ApoB, HDL cholesterol, LDL diameter, and VLDL diameter. Conclusions The effects of vitamin D on lipid metabolism are potentially unfavorable. They require further investigation in view of the wide use of vitamin D testing and treatment. [ABSTRACT FROM AUTHOR]