Effect of Switching From Statin Monotherapy to Ezetimibe/Simvastatin Combination Therapy Compared With Other Intensified Lipid-Lowering Strategies on Lipoprotein Subclasses in Diabetic Patients With Symptomatic Cardiovascular Disease

Ngoc-Anh Le, Joanne E Tomassini, Andrew M Tershakovec, David R Neff, Peter W F Wilson, Ngoc-Anh Le, Joanne E Tomassini, Andrew M Tershakovec, David R Neff, Peter W F Wilson

Abstract

Background: Patients with diabetes mellitus and cardiovascular disease may not achieve adequate low-density lipoprotein cholesterol (LDL-C) lowering on statin monotherapy, attributed partly to atherogenic dyslipidemia. More intensive LDL-C-lowering therapy can be considered for these patients. A previous randomized, controlled study demonstrated greater LDL-C lowering in diabetic patients with symptomatic cardiovascular disease who switched from simvastatin 20 mg (S20) or atorvastatin 10 mg (A10) to combination ezetimibe/simvastatin 10/20 mg (ES10/20) therapy, compared with statin dose-doubling (to S40 or A20) or switching to rosuvastatin 10 mg (R10). The effect of these regimens on novel biomarkers of atherogenic dyslipidemia (low- and high-density lipoprotein particle number and lipoprotein-associated phospholipase A2 [Lp-PLA2]) was assessed.

Methods and results: Treatment effects on low- and high-density lipoprotein particle number (by NMR) and Lp-PLA2 (by ELISA) were evaluated using plasma samples available from 358 subjects in the study. Switching to ES10/20 reduced low-density lipoprotein-particle number numerically more than did statin dose-doubling and was comparable with R10 (-133.3, -94.4, and -56.3 nmol/L, respectively; P>0.05). Increases in high-density lipoprotein particle number were significantly greater with switches to ES10/20 versus statin dose-doubling (1.5 and -0.5 μmol/L; P<0.05) and comparable with R10 (0.7 μmol/L; P>0.05). Percentages of patients attaining low-density lipoprotein particle number levels <990 nmol/L were 62.4% for ES10/20, 54.1% for statin dose-doubling, and 57.0% for R10. Switching to ES10/20 reduced Lp-PLA2 activity significantly more than did statin dose-doubling (-28.0 versus -3.8 nmol/min per mL, P<0.05) and was comparable with R10 (-28.0 versus -18.6 nmol/min per mL; P>0.05); effects on Lp-PLA2 concentration were modest.

Conclusions: In diabetic patients with dyslipidemia, switching from statins to combination ES10/20 therapy generally improved lipoprotein subclass profile and Lp-PLA2 activity more than did statin dose-doubling and was comparable with R10, consistent with its lipid effects.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00862251.

Keywords: NMR spectroscopy; diabetes mellitus; ezetimibe; lipoprotein particle number; lipoprotein subclasses; lipoprotein‐associated phospholipase A2; rosuvastatin; simvastatin.

© 2015 The Authors. [Ngoc‐Anh Le and Peter W. F. Wilson] and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. All rights reserved. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Net changes from baseline in (A) CHOL, LDL‐C, and hsCRP and in (B) HDL‐C, TG, apoA‐I, and apoB for the more‐intensive therapies. Apo indicates apolipoprotein; ES, ezetimibe/simvastatin; HDL‐C, high‐density lipoprotein cholesterol; hsCRP, high‐sensitivity C reactive protein; LDL‐C, low‐density lipoprotein cholesterol; R, rosuvastatin; CHOL, total cholesterol; TG, triglycerides. See Table 1 for actual values and standard deviations.
Figure 2
Figure 2
Effect of more‐intensive therapy on LDL‐P. A, Reductions in LDL‐P from baseline were significant with switching to 2× statin (P<0.05), ES 10/20 (P<0.001), and R10 (P<0.001). There was a significant association between the percent changes in total LDL‐P and the percent changes in the concentration of small LDL particles with ES 10/20 (B), 2× statin (C), and with R10 (D). 2× statin indicates doubling the statin dose to simvastatin 40 mg or atorvastatin 20 mg; ES10/20, switch to ezetimibe/simvastatin 10/20 mg; LDL‐P, low‐density lipoprotein particle number; R10, switch to rosuvastatin 10 mg.
Figure 3
Figure 3
Effect of more‐intensive therapy on HDL‐P. A, Net changes (SD) from baseline in HDL‐P concentrations (μmol/L) were statistically significant only for ES 10/20 (P<0.001) and nonsignificant (P>0.05) for doubling the statin dose (2× statin) and R10. Significant associations were observed between HDL‐P and large HDL‐P with ES 10/20 in (B), 2× statin in (C), and R10 in (D). 2× statin indicates doubling the statin dose to simvastatin 40 mg or atorvastatin 20 mg; ES10/20, switch to ezetimibe/simvastatin 10/20 mg; HDL‐P, high‐density lipoprotein particle number; R10, switch to rosuvastatin 10 mg; SD, standard deviation.
Figure 4
Figure 4
Changes in Lp‐PLA2 specific activity with the 3 more‐intensive cholesterol‐reduction regimens. E/S indicates ezetimibe/simvastatin; Lp‐PLA2 lipoprotein‐associated phospholipase A2; R, rosuvastatin.
Figure 5
Figure 5
Relationship between on‐treatment levels of total plasma apoB and LDL‐P concentration based on all samples for participants stabilized on low‐dose statin (S20 or A10) as well as more‐intensive cholesterol reduction (2× statin, ES 10/20, and R10). 2× statin indicates doubling the statin dose to simvastatin 40 mg or atorvastatin 20 mg; A, atorvastatin; Apo, apolipoprotein; E/S, ezetimibe/simvastatin; LDL‐P, low‐density lipoprotein particle number; R, rosuvastatin; S, simvastatin.
Figure 6
Figure 6
Effect of more‐intensive cholesterol reducing regimens (ES 10/20, 2× statin, and R10) on the percent changes for various measures of LDL. (A) LDL‐C versus total plasma apoB, (B) LDL‐C versus LDL‐P, and (C) total plasma apoB versus LDL‐P. 2× statin indicates doubling the statin dose to simvastatin 40 mg or atorvastatin 20 mg; E/S, ezetimibe/simvastatin; LDL‐P, low‐density lipoprotein particle number; R, rosuvastatin.
Figure 7
Figure 7
Percent of individuals who reached (A) the 20th percentile target levels for LDL‐C, LDL‐P, and non–HDL‐C or (B) the 5th percentile target levels based on the Multi‐Ethnic Study of Atherosclerosis (MESA) cohort. Baseline corresponds to either simvastatin 20 mg or atorvastatin 10 mg. 2× statin indicates doubling the statin dose to simvastatin 40 mg or atorvastatin 20 mg; E/S, ezetimibe/simvastatin; LDL‐C, low‐density lipoprotein cholesterol; LDL‐P, low‐density lipoprotein particle number; non–HDL‐C, non–high‐density lipoprotein cholesterol R, rosuvastatin.

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