Highlights
- •Variability of LDL-C lowering response to ezetimibe + statins vs statins was compared.
- •Absolute variability was not greater with ezetimibe + statin vs statins.
- •Relative variability was lower for ezetimibe + statin vs statins attributed to larger LDL-C reductions.
- •Variability within subgroups was generally consistent with the full cohort.
- •Ezetimibe added to statins does not increase the variability of LDL-C lowering response.
Abstract
Objective
We compared the variability of LDL-C-lowering responses to treatment with ezetimibe + statins
versus statins in hypercholesterolemic patients.
Methods
An analysis of patient-level data pooled from 27 double-blind, placebo and/or active-controlled
studies in 21,671 patients treated with ezetimibe + statins versus statins on first-line
(statin-naïve/wash-out) or second-line (on statin, randomized to ezetimibe versus
placebo [add-on] or ezetimibe versus uptitrated statin [uptitrate]) for 6–24 wks.
Variances (standard deviation [SD], coefficient of variation [CV], and root mean squared
error [RMSE] adjusted for various factors) for % change from baseline in LDL-C were
compared.
Results
In first-line and second-line add-on studies, the variability (SD, RMSE) of % change
from baseline in LDL-C was lower in ezetimibe + statin-treated patients versus statin-treated
patients, ±covariates. Differences were small but statistically significant due to
the large sample size. In second-line uptitrate studies, ezetimibe + statin treatment
resulted in greater unadjusted variability (SD) versus statin therapy, while the adjusted
variability (RMSE) was significantly lower. Relative variability (CV=SD/mean) was lower for ezetimibe + statins versus statin therapy for all study types,
being more pronounced in second-line add-on and uptitrate studies, attributed to larger
mean LDL-C reductions for ezetimibe + statins versus statin groups. When assessed
by individual study/type, statin brand, potency or dose, the CVs remained lower for
ezetimibe + statins versus statins in second-line studies. The SDs showed no consistent
trend for either therapy.
Conclusion
In hypercholesterolemic patients, the absolute variability of LDL-C-lowering responses
to ezetimibe + statins was not greater versus statins alone and appeared lower when
adjusted for other factors. Relative variability was lower in patients treated with
statins + ezetimibe. A better understanding of the variability of the LDL-C lowering
response may help guide clinicians in making therapeutic decisions.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to AtherosclerosisAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.Lancet. 2005; 366: 1267-1278
- Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.Lancet. 2010; 376: 1670-1681
- 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult.Can. J. Cardiol. 2013; 29: 151-167
- ESC/EAS guidelines for the management of dyslipidaemias the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).Atherosclerosis. 2011; 217: 3-46
- An international atherosclerosis society position paper: global recommendations for the management of dyslipidemia–full report.J. Clin. Lipidol. 2014; 8: 29-60
- National lipid association recommendations for patient-centered management of dyslipidemia: part 1-executive summary.J. Clin. Lipidol. 2014; 8: 473-488
- 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.Circulation. 2014; 129: S1-S45
- Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.J. Am. Coll. Cardiol. 2014; 64: 485-494
- Variability of LDL-C response with different doses of simvastatin, atorvastatin and rosuvastatin: results from voyager.Atherosclerosis. 2014; 235 (Abstract): e295
- Reaching C-reactive protein and low-density lipoprotein cholesterol goals in dyslipidemic patients (from the Lipid Treatment Assessment Project [L-TAP] 2).Am. J. Cardiol. 2011; 107: 1639-1643
- Loss of early gains in low-density lipoprotein cholesterol goal attainment among high-risk patients.J. Clin. Lipidol. 2010; 4: 126-132
- LDL-C goal attainment in patients who remain on atorvastatin or switch to equivalent or non-equivalent doses of simvastatin: a retrospective matched cohort study in clinical practice.Postgrad. Med. 2010; 122: 16-24
- Phenotypes, genotypes and response to statin therapy.Curr. Opin. Lipidol. 2004; 15: 387-392
- Factors affecting low-density lipoprotein and high-density lipoprotein cholesterol response to pravastatin in the West of Scotland Coronary Prevention Study (WOSCOPS).Am. J. Cardiol. 2002; 90: 731-736
- Where does the interplay between cholesterol absorption and synthesis in the context of statin and/or ezetimibe treatment stand today?.Atherosclerosis. 2011; 217: 308-321
- Benefits of pravastatin on cardiovascular events and mortality in older patients with coronary heart disease are equal to or exceed those seen in younger patients: results from the LIPID trial.Ann. Intern. Med. 2001; 134: 931-940
- Pharmacogenomics of statin response.Curr. Opin. Mol. Ther. 2008; 10: 555-561
- Phenotypic predictors of response to simvastatin therapy among African-Americans and Caucasians: the Cholesterol and Pharmacogenetics (CAP) Study.Am. J. Cardiol. 2006; 97: 843-850
- Low density lipoprotein-cholesterol variability in patients with type 2 diabetes taking atorvastatin compared to simvastatin: justification for direct measurement?.Diabetes Obes. Metab. 2010; 12: 540-544
- Use of lipid-lowering medications and the likelihood of achieving optimal LDL-cholesterol goals in coronary artery disease patients.Cholesterol. 2012; 2012: 861924
- Attainment of low-density lipoprotein cholesterol goals in coronary artery disease.J. Clin. Lipidol. 2010; 4: 173-180
- a survey on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary patients from 22 European countries.Eur. J. Cardiovasc. Prev. Rehabil. 2009; 16: 121-137
- Mathematical Statistics with Applications.PWS-KENT Publishing Company, Boston, MA1990: 1-752
- Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial.Circulation. 2003; 107: 2409-2415
- Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients.Curr. Med. Res. Opin. 2006; 22: 2041-2053
- Effects of ezetimibe, simvastatin, atorvastatin, and ezetimibe-statin therapies on non-cholesterol sterols in patients with primary hypercholesterolemia.Curr. Med. Res. Opin. 2008; 24: 249-259
- Applicability of non-cholesterol sterols in predicting response in cholesterol metabolism to simvastatin and fluvastatin treatment among hypercholesterolemic men.Nutr. Metab. Cardiovasc. Dis. 2010; 20: 308-316
- Indices of cholesterol metabolism and relative responsiveness to ezetimibe and simvastatin.J. Clin. Endocrinol. Metab. 2010; 95: 800-809
- Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.Atherosclerosis. 2007; 194: e116-e122
- The efficacy and safety of ezetimibe co-administered with statin therapy in various patient groups.Clin. Lipidol. 2013; 8: 13-41
Merck & Co. Inc., Vytorin (ezetimibe/simvastatin) [package insert]. USA. North Wales, PA, Merck/Schering-Plough Pharmaceuticals, 2012.
- Zetia (Ezetimibe) [package Insert]. USA.North Wales, PA, Merck/Schering-Plough Pharmaceuticals, 2012
- Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials.Atherosclerosis. 2012; 66: 800-812
- Update on the efficacy and safety of combination ezetimibe plus statin therapy.Clin. Lipidol. 2010; 5: 655-684
- LDL-cholesterol targets after the ACC/AHA 2013 guidelines: evidence that lower is better?.J. Am. Coll. Cardiol. 2014; 64: 495-497
- Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1094-1100
- Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial.J. Lipid Res. 2010; 51: 755-762
- Headed in the right direction but at risk for miscalculation: a critical appraisal of the 2013 ACC/AHA risk assessment guidelines.J. Am. Coll. Cardiol. 2014; 63: 2789-2794
- Achievement of 2011 European low-density lipoprotein cholesterol (LDL-C) goals of either <70 mg/dl or >/= 50% reduction in high-risk patients: results from VOYAGER.Atherosclerosis. 2013; 228: 265-269
- Risk factors: new risk-assessment guidelines-more or less personalized?.Nat. Rev. Cardiol. 2014; 11: 136-137
- 2013 ACC/AHA cholesterol treatment guideline: what was done well and what could be done better.J. Am. Coll. Cardiol. 2014; 63: 2674-2678
- Attainment of the anticipated >=50% reduction in LDL-C in the four ACC/AHA guidelines statin benefit groups: a voyager meta-analysis.Atherosclerosis. 2014; 235 (Abstract): e11-e12
- Statins for all?.Am. J. Cardiol. 2014; 114: 1443-1446
- Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18,144 patients after acute coronary syndromes: final baseline characteristics of the IMPROVE-IT study population.Am. Heart J. 2014; 168: 205-212
M.A. Blazing, R. Guigliano, C.P. Cannon, et al. IMProved Reduction of Outcomes: Vytorin Efficacy International Trial: On-treatment analysis. Presented at the American Heart Association Scientific Sessions 2014; November 15–19, 2014; Chicago, IL (Abstract).
C.P. Cannon, On behalf of the IMPROVE-IT investigators. IMProved Reduction of Outcomes: Vytorin Efficacy International Trial. Presented at the American Heart Association Scientific Sessions 2014; November 15–19, 2014; Chicago, IL (Abstract).
Article info
Publication history
Published online: March 10, 2015
Accepted:
March 3,
2015
Received in revised form:
February 20,
2015
Received:
December 24,
2014
Identification
Copyright
© 2015 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
