Extended-Release Niacin/Laropiprant Effects on Lipoprotein Subfractions in Patients with Type 2 Diabetes Mellitus

Abstract

Background:

A potentially atherogenic lipid profile often found in patients with type 2 diabetes mellitus (T2DM) includes increased concentrations of small, low-density lipoprotein (LDL) and intermediate-density lipoprotein (IDL) and decreased concentration of medium/large high-density lipoprotein (HDL) particles. Extended-release niacin/laropiprant (ERN/LRPT) lowers LDL-cholesterol (LDL-C) and triglycerides (TG), and raises HDL cholesterol (HDL-C) levels with attenuation of niacin-induced flushing.

Methods:

Plasma HDL, LDL, IDL, very-low-density lipoprotein (VLDL), and chylomicron particle concentration and size at were evaluated at baseline and week 12 using nuclear magnetic resonance (NMR). The data were acquired from a randomized, multicenter, double-blind, placebo-controlled study including 796 patients with T2DM treated with either 1 tablet of ERN 1 gram/LRPT 20 mg or matching placebo daily, increased after 4 weeks to 2 tablets daily.

Results:

ERN/LRPT significantly (P≤0.001 for all) reduced LDL-C 17.9% and TG 23.1%, and increased HDL-C levels 23.2%. Compared to placebo, ERN/LRPT decreased LDL, IDL, VLDL, and chylomicron particle concentrations [median concentration of smallest LDL particles decreased 16.6%, 95% confidence interval (CI) −22.3, −10.9, whereas the largest LDL particles decreased 11.0%, 95% CI −18.7, −3.2, and total VLDL/chylomicron mean plasma particle concentration decreased 34.7%, 95% CI −41.3, −28.1]. Compared to placebo, ERN/LRPT shifted the distribution of HDL particle diameter from smaller to larger (median concentration of the largest HDL particles increased 32.7% (95% CI 25.30, 40.58), whereas concentration of the smallest HDL particles decreased 8.2% (95% CI −11.29, −5.06).

Conclusions:

Compared with placebo in patients with T2DM, ERN/LRPT shifted the lipoprotein profile toward a potentially less atherogenic pattern with reduced atherogenic LDL and IDL particle concentrations, and increased large HDL plasma particle concentrations. (ClinicalTrials.gov: NCT00485758)

Introduction

T ype 2 diabetes mellitus (T2DM) patients are at increased risk of atherosclerotic coronary heart disease (CHD) compared with similar populations without T2DM.¹ T2DM patients often have a pattern of potentially atherogenic dyslipidemia characterized by high triglyceride (TG) levels, low high-density lipoprotein-cholesterol (HDL-C) levels, and increased proportion of smaller, more dense low-density lipoprotein (LDL) and HDL particles.^2
–4 Guidelines recommend treatment of dyslipidemia among those with T2DM,^1,4

–7 with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) most often being the first therapeutic option, followed by other lipid-altering drug therapies if dyslipidemia persists.^4,6,8

Niacin may provide complementary lipid effects to statins. Niacin reduces low-density lipoprotein cholesterol (LDL-C) levels, and is among the most effective lipid-altering drugs in raising HDL-C levels. Niacin also lowers TG levels and reduces small, lower-density LDL particles.^5,9
–11 Unfortunately, overall patient compliance and tolerance of the higher recommended doses of existing formulations of niacin are limited by flushing, which is the most common adverse effect of niacin treatment.^12

–16 Niacin-induced flushing is largely driven by prostaglandin (PG) D2 interaction with the PGD2 receptor DP1.¹⁷ The selective DP1 antagonist, laropiprant (LRPT, MK0524) reduces the incidence and intensity of niacin-induced flushing, without compromising its therapeutic effects on dyslipidemia.^18,19 Niacin may also increase fasting plasma glucose,^20,21 which may sometimes be a concern among T2DM patients. However, such an increase can largely be controlled with intensification of antihyperglycemic medication and lifestyle modification.^22

–25

A recent study supported extended-release niacin (ERN)/LRPT as improving standard plasma lipid parameters (LDL-C, TG, HDL-C) among T2DM patients.²⁵ This report presents additional data regarding the percent change from baseline within and between treatment groups at week 12 in lipoprotein particle subclass number and size, as defined by proton nuclear magnetic resonance spectroscopy (NMR).

Methods

Patient selection criteria

Patient eligibility criteria and list of exclusionary medications were reported elsewhere.²⁵ Briefly, eligible patients included men and women from 18 to 80 years of age with T2DM, LDL-C ≥60 and <115 mg/dL, and TG concentration ≤500 mg/dL at visit 1. Lipid-altering drugs such as fish oils, statins, fibrates, ezetimibe, ezetimibe/simvastatin combination tablet, bile acid sequestrants, and supplements taken for lipid-altering purposes were permitted as long as doses were stable prior to study entry, and no changes in lipid-altering drugs or doses were planned during study conduct. Exclusion criteria included T2DM patients with poorly controlled glucose levels [glycosylated hemoglobin (HbA1c) >8.5% at visit 1], newly diagnosed T2DM (within 3 months of visit 1), or medical and/or laboratory abnormalities that might adversely affect study participant safety or confound study analysis. Exclusionary medications included the combined use of statin and fibrate, cyclical or intermittent hormonal therapy, systemic corticosteroids, and anabolic steroids.

Study design

This was a worldwide, multicenter, double-blind, randomized, placebo-controlled, parallel study with a 36-week double-blind treatment period, preceded by a 4-week lipid-modifying run-in period to attain LDL-C <115 mg/dL, if necessary. Patients were randomized in a ratio of 4:3 to ERN/LRPT (one tablet of ERN 1 gram/LRPT 20 mg) or placebo. After 4 weeks of double-blind treatment, doses were doubled for the remainder of the study. Approximately 78% of patients in the study were taking statins and 98% were on an antihyperglycemic regimen at baseline.

In this post hoc analysis of the original study, lipoprotein subfraction analysis by proton NMR was assessed at week 1 (before treatment began) and at week 12.^26,27 No adjustments to the patients' lipid-modifying regimens were allowed for the first 12 weeks of the study.

The following laboratory abnormalities were prespecified as values that warranted study discontinuation: persistent (two or more consecutive measurements) alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations ≥3×the upper limit of normal (ULN); TG levels >600 mg/dL; persistent creatine kinase (CK) elevations ≥5×and <10×ULN with muscle symptoms; persistent CK elevations ≥10×ULN with or without muscle symptoms; or single CK elevations ≥20×ULN with or without muscle symptoms. Prespecified discontinuation was also defined for patients who had a positive pregnancy test or experienced hypersensitivity or severe intolerance to study therapy or who required continuous treatment with systemic corticosteroids.

All study participants underwent the informed consent process, and provided written informed consent prior to any study related procedures. The study (Tredaptive Protocol 069; ClinicalTrials.gov: NCT00485758) was conducted under the guidelines of the principles of Good Clinical Practice, and the protocol was approved by the appropriate institutional review boards and regulatory agencies.

Laboratory analysis

Blood samples from 12-h fasting patients were collected into 3-mL EDTA tubes on day 1 of the study, before treatment began, and at week 12 of the study. Plasma was collected and shipped on freezer packs to LipoScience (Raleigh, North Carolina) for lipoprotein subfraction analysis by proton NMR.^26,27 This method employs the distinct NMR spectral properties of lipoprotein subclasses and a decomposition algorithm to quantitate 10 different particle sizes (Table 1) in plasma.

Table 1.

Baseline Plasma Concentrations and Sizes and of Lipoprotein Particles Quantitated by Nuclear Magnetic Resonance

Lipoprotein particle	Placebo (N=382) ^a	ERN/LRPT (N=303) ^a
	Baseline particle concentration (median±SE)
HDL (μM)	31.4±0.43	32.1±0.34
LDL (nM)	1,128.0±19.99	1126.0±17.80
VLDL and chylomicron (nM)	58.4±2.38	57.85±2.32
	Baseline mean particle diameter (median±SE)
HDL (nm)	8.6±0.03	8.7±0.03
LDL (nm)	20.7±0.05	20.8±0.06
VLDL and chylomicron (nm)	48.7±0.59	48.2±0.54

N, number of randomized patients with available data. N can vary by parameter due to missing data.

ERN/LRPT, extended-release niacin/laropiprant; SE, standard error; HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.

Statistical analysis

All analyses presented were carried out using the Full Analysis Set (FAS) population, which included all randomized patients who took at least one dose of postrandomization study drug and had a baseline value and at least one postrandomization lipid measurement available. Inferential testing conducted was two-sided at an alpha level of 5%. The normality of the percent change from baseline data was assessed by the Shapiro–Wilk test.

For the standard plasma lipid panel data, the percent change from baseline at week 12 for LDL-C, HDL-C, TC:HDL-C ratio, and LDL-C:HDL-C ratio was analyzed by a repeated-measures analysis that included the measurements at three study times (weeks 4, 8, and 12) and had fixed effects for treatment-by-time interaction, gender-by-time interaction, and baseline lipid data-by-time interaction. No imputation of missing data was performed for the repeated measurement model. The analyses of percent change from baseline at week 12 in apolipoprotein B (ApoB) and ApoA-I were performed using an analysis of covariance (ANCOVA) model with terms for treatment, gender, and baseline as a covariate. A 95% confidence interval (CI) for the between-group least square (LS) means was provided. Due to the nonnormal distribution associated with percent changes from baseline in TG, a nonparametric model, more specifically, an ANCOVA model with terms for treatment, gender, and Tukey normal score of the baseline as a covariate was applied to the Tukey normal scores of the percent change from baseline. The between-treatment group differences in medians were assessed using Hodges–Lehman estimates with the corresponding distribution-free 95% CI based on the Wilcoxon rank sum test. For the ANCOVA models, the last available posttitration value was carried forward to impute missing data.

For the HDL, LDL, VLDL, and chylomicron particle sizes and concentrations evaluated by NMR, due to a nonnormal distribution of the percent change from baseline to week 12, the between-treatment group median differences were based on a Hodges–Lehmann estimate with a corresponding distribution-free 95% CI based on the Wilcoxon rank sum test. No P values are provided for the particle number and size comparisons, because these were not a priori end points and because this exploratory analysis is intended to be descriptive in nature only.

Patients having a mean LDL diameter <20.5 nm were classified as exhibiting pattern B, whereas patients with a mean LDL diameter ≥20.5 nm were classified as pattern A.²⁸ The percentage of patients remaining at or changing from baseline pattern at week 12 was compared between the treatment groups with an associated 95% CI, based on Wilson score method.

Results

In total, 454 T2DM patients were randomized in the ERN/LRPT group with 382 providing samples for the week-12 particle number and size analysis; 342 T2DM patients were randomized in the placebo group with 303 providing similar samples. Details of the patient populations not randomized in the study or discontinued from the study were reported previously.²⁵ Both groups were comparable regarding demographic, anthropometric, and baseline disease characteristics.²⁵ Baseline lipid variables were generally similar in both treatment groups.²⁵

For the standard plasma lipid panel data, with regard to the percent change from baseline to week 12, compared with placebo, ERN/LRPT significantly (P≤0.001 in all cases) reduced LS mean LDL-C 17.9% (95% CI −21.4, −14.4), median triglycerides 23.1% (95% CI −27.2, −18.9), LS mean LDL-C:HDL-C ratio 32.0% (95% CI −35.5, −28.4), LS mean total cholesterol (TC):HDL-C ratio 22.9% (95% CI −25.4, −20.4), and LS mean ApoB 17.1% (95% CI −19.7, −14.5), and increased LS mean HDL-C 23.2% (95% CI 20.7, 25.7) and LS mean ApoA-I 8.2% (95% CI 6.3, 10.2).

At baseline, the mean plasma concentration and size of lipoprotein particle classes (Table 1) and the plasma concentrations of all lipoprotein particle subclasses (Table 2) were similar between treatment groups. Compared with placebo after 12 weeks of ERN/LRPT administration, the median total number of HDL lipoprotein particles did not change, but the median total particle numbers of both LDL and VLDL/chylomicrons were reduced (Fig. 1A). The greatest percentage decrease in the median particle number was observed for VLDL/chylomicron particles (34.7% reduction from the baseline median 57.85±2.32 nM); however, the greatest overall reduction in particle number was observed for LDL particles (15.6% reduction from the baseline median 1,126.0±17.8 nM).

FIG. 1.

Treatment-associated lipoprotein median percent changes from baseline median after 12 weeks of treatment. Numbers associated with bars are treatment difference in % change with 95% confidence interval (CI). No P values are provided because these were not a priori end points, and because this exploratory analysis is intended to be descriptive in nature only. (A) Percentage changes in total particle number. (B) Percentage changes in mean particle size. HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL/Chylo, very-low-density lipoprotein/chylomicron; ERN/LRPT, extended-release niacin/laropiprant.

Table 2.

Baseline Plasma Concentrations of Lipoprotein Particle Subclasses Quantitated by Nuclear Magnetic Resonance

		Baseline concentration (median±SE)
Lipoprotein particle subclass	Diameter (nm)	Placebo (N=382)^a	ERN/LRPT (N=303)^a
Small HDL (μM)	7.3 to 8.2	23.9±0.4	23.5±0.3
Medium HDL (μM)	8.2 to 8.8	0.8±0.1	0.7±0.1
Large HDL (μM)	8.8 to 13	6.0±0.2	5.7±0.2
Very small LDL (nM)	18 to 19.8	634.0±19.0	602.0±18.7
Medium small LDL (nM)	19.8 to 21.2	163.0±4.2	148.0±4.5
Large LDL (nM)	21.2 to 23	325.0±11.9	350.0±12.4
IDL (nM)	23 to 27	20.0±2.1	15.5±1.8
Small VLDL (nM)	27 to 35	27.2±1.1	27.2±0.96
Medium VLDL (nM)	35 to 60	24.3±1.6	25.3±1.5
Large VLDL/chylomicron (nM)	>60	2.4±0.3	1.95±0.2

N, number of randomized patients with available data. N can very by parameter due to missing data.

SE, standard error; ERN/LRPT, extended-release niacin/laropiprant; HDL, high-density lipoprotein; LDL, low-density lipoprotein; IDL, intermediate-density lipoprotein; VLDL, very-low-density lipoprotein.

Compared with placebo from baseline to 12 weeks, ERN/LRPT increased the mean particle sizes of all three classes of lipoprotein particles (Fig. 1B), with the greatest increase in the mean particle size of VLDL particles (between treatment difference of VLDL particles was 5.4%, whereas the between treatment difference of HDL particles was 3.6% and of LDL particles was 0.5%).

Compared with placebo after 12 weeks, ERN/LRPT decreased the concentration of small HDL particles (between-treatment difference −8.2%), whereas the concentration of both medium and large HDL particles increased from baseline, with the concentration of large HDL particles increasing more than medium HDL particles (between treatment differences 32.7% and 12.5%, respectively) (Fig. 2A).

FIG. 2.

Treatment-associated subclass particle concentration median percent change from baseline median after 12 weeks of treatment. Numbers associated with bars are treatment difference in % change with 95% confidence interval (CI). No P values are provided because these were not a priori end points, and because this exploratory analysis is intended to be descriptive in nature only. (A) High-density lipoprotein (HDL) particles; (B) low-density lipoprotein (LDL) particles; (C) intermediate-density lipoprotein (IDL), very-low-density lipoprotein (VLDL), and chylomicron (Chylo) particles. ERN/LRPT, extended-release niacin/laropiprant.

Compared with placebo after 12 weeks, ERN/LRPT reduced the concentrations of all LDL, IDL, and VLDL particles, with LDL particle concentration between treatment differences in the range of −7.6% to −16.6% and IDL/VLDL/chylomicron between treatment differences ranging from −25% to −36.1%) (Fig.2 B,C).

The ERN/LRPT treatment group began treatment with a slightly greater percentage of patients having pattern A LDL particle size (Fig. 3A). Compared to placebo at week 12, a larger proportion of patients in ERN/LRPT changed from pattern B to pattern A (Fig. 3B, 0.2% compared to 13.2%). A similar proportion of patients in ERN/LRPT compared to placebo changed from pattern A to pattern B (about 10%) or stayed in the same pattern (about 70%).

FIG. 3.

Baseline (A) and changes from baseline (B) in overall low-density lipoprotein (LDL) size patterns associated with treatment. In B, differences between mean treatment values and 95% confidence intervals (CI) are also shown. No P values are provided because these were not a priori end points and because this exploratory analysis is intended to be descriptive in nature only. ERN/LRPT, extended-release niacin/laropiprant.

Discussion

This study evaluated the effect of ERN/LRPT upon particle number and size among T2DM patients. Compared to placebo, ERN/LRPT reduced LDL and VLDL particle concentrations in total, and in all subclasses (Figs. 1A and 2), and generally shifted the distribution of particles to larger sizes. Consistent with the observation that LDL particles comprise the vast majority of ApoB-containing particles in this patient population (Table 1), compared with placebo, ERN/LRPT at week 12 reduced LDL particle number approximately 16% (Fig. 1) and reduced ApoB by approximately 17%. ERN/LRPT did not significantly change HDL particle number (Fig. 1A), although ERN/LRPT did substantially increase medium and large HDL particle size (Fig. 2). These two classes comprise the minority of HDL in this patient population (Table 1), and the increase in concentrations of these particles is offset by the reduction in small HDL concentration (Fig. 2).

ERN/LRPT increased the mean particle sizes of all classes of lipoproteins relative to baseline compared with placebo (Fig. 1B), with HDL and VLDL having greater increases. ERN/LRPT also increased ApoA-1, likely due to the increased mean particle size of HDL, as larger particles accumulate more ApoA-1 than do smaller particles.²⁹

To the knowledge of the authors, this report represents the largest study to evaluate the effects of niacin on lipoprotein particle concentration and size in patients with T2DM, and its results are generally consistent with previous reports of niacin's lipid effects, not specifically in T2DM patients.^10,11 A prior study of 36 T2DM patients demonstrated that as measured by polyacrylamide gradient gel electrophoreses, ERN (without LRPT) significantly decreased small, dense LDL particles and increased LDL peak particle diameter,³⁰ which again, is consistent with the results reported here.

Individuals with a relatively high proportion of small, dense LDL particles (pattern B) may be at increased risk of myocardial infarction.³¹ As measured by NMR, patients having a mean LDL diameter <20.55 nm are often classified as exhibiting pattern B, whereas patients with pattern A (thus being at lower risk) have a mean LDL diameter ≥20.55 nm. In this study, 35%–40% of patients exhibited a mean LDL diameter of <20.55 at baseline, indicative of a proatherogenic B pattern. Compared to placebo, ERN/LRPT shifted more patients from pattern B to pattern A; but this represented a small number of patients as particle size distribution remained unchanged in most. This is because a shift in LDL size pattern from B to A with interventions that reduce LDL particle number requires the preferential reduction of small LDL particles. In this study, ERN/LRPT treatment generally resulted in the reduction of LDL particles of all sizes.

Overall the results of this study were consistent with current guidelines for the treatment of patients with both T2DM and dyslipidemia, which include niacin as a valid treatment option.³² Not only were proatherogenic lipoproteins reduced and potentially antiatherogenic lipoprotein particles increased in number, but, compared with placebo, ERN/LRPT use was associated with modest increases in FPG, which were generally manageable with adjustments in antihyperglycemic medication.²⁵

Niacin has a number of potential mechanisms whereby its administration may reduce CHD risk, and the antiflushing effects of LRPT may improve the compliance with niacin therapy.³³ Niacin's effects upon lipids and lipoprotein particle number and size^{5,9

–13,20,22

–25} are just some examples of effects that may help account for niacin's beneficial CHD effects, as evidenced by niacin CHD outcome studies (which often included T2DM patients).^34

–40 However, a limitation is that not all niacin CHD outcomes studies confirm niacin as reducing CHD. For example, in the AIM HIGH study, ERN (without LRPT) was added to ongoing simvastatin (and ezetimibe, as needed) in patients with established vascular disease and atherogenic dyslipidemia. In this study, wherein LDL-C levels in both groups were maintained less than 80 mg/dL, ERN produced no incremental CHD benefit over placebo when added to ongoing statin therapy.^41
–43 A CHD outcome study specific to LRPT includes the ongoing Heart Protection Study 2 Treatment of High-Density Lipoprotein to Reduce the Incidence of Vascular Events (HPS2-THRIVE, ClinicalTrials.gov: NCT00461630), which is designed to test the clinical efficacy and safety of ERN/LRPT in statin-treated patients.

Footnotes

Author Disclosure Statement

H.B. has received research grants as investigator and honoraria as a consultant, and has served on advisory board and speaker's bureau for Merck. H.G., E.O., and A.T. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, New Jersey, or MSD (Europe) and own stock/stock options in Merck. J.M. has no conflicts of interest to report.

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