CLINICAL RESEARCH: ATHEROSCLEROSIS
Pleiotropic Effects of Statins: Benefit Beyond Cholesterol Reduction?
A Meta-Regression Analysis
Jennifer G. Robinson, MD, MPH*,*,
Brian Smith, MS, PhD ,
Nidhi Maheshwari, MBBS* and
Helmut Schrott, MD*
* Department of Epidemiology
Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa
Manuscript received March 9, 2005;
revised manuscript received April 25, 2005,
accepted May 15, 2005.
* Reprint requests and correspondence: Dr. Jennifer G. Robinson, 200 Hawkins Drive, SE226GH, Iowa City, Iowa 52242
(Email: jennifer-g-robinson{at}uiowa.edu).
OBJECTIVES: This study sought to determine whether statins reduce coronary heart disease (CHD) risk more than other interventions that also primarily lower low-density lipoprotein cholesterol (LDL-C).
BACKGROUND: Statins have anti-inflammatory, immunomodulatory, antithrombotic, vascular, and other non–LDL-C-lowering effects. It is unclear whether these pleiotropic effects contribute to cardiovascular risk reduction beyond that expected from LDL-C reduction alone.
METHODS: Trials published in English language journals were retrieved by searching Medline (1966 to October 2004), bibliographies, and the author's reference files. Randomized, placebo-controlled trials of interventions to primarily lower LDL-C of three or more years' duration in which clinical disease or death were primary outcomes were used. Information on sample size, treatment type and duration, participant characteristics at baseline, reduction in lipids, and outcome was independently abstracted by two authors (J.R. and N.M.) using a standardized protocol. Data from 5 diet, 3 bile acid sequestrant, 1 surgery, and 10 statin trials, with 81,859 participants, were included in the CHD meta-regression analysis.
RESULTS: The regression lines for non-statin and statin trials were similar and consistent with a one-to-one relationship between LDL-C lowering and CHD and stroke reduction over five years of treatment.
CONCLUSIONS: The pleiotropic effects of statins do not seem to contribute an additional cardiovascular risk reduction benefit beyond that expected from the degree of LDL-C lowering observed in other trials that primarily lowered LDL-C.
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Abbreviations and Acronyms
| | CHD = coronary heart disease | | LDL-C = low-density lipoprotein cholesterol | | MI = myocardial infarction | | PROSPER = PROspective Study of Pravastatin in the Elderly at Risk | | PROVE-IT = Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction-22 | | TNT = Treating to New Targets |
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|
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|
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|
|
|
|
|
|
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|
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|
|
|
|
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178(5):
576 - 584.
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|
|
|
|
|
|
|
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50(18):
1735 - 1741.
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|
|
|
|
|
|
|
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J. Am. Coll. Cardiol.,
July 31, 2007;
50(5):
419 - 420.
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|
|
|
|
|
|
|
A. A. Alsheikh-Ali, P. V. Maddukuri, H. Han, and R. H. Karas
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409 - 418.
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|
|
|
|
|
|
|
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12(2):
112 - 123.
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|
|
|
|
|
|
|
E. M. Tuzcu and S. J. Nicholls
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49(20):
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
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664 - 672.
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[Full Text]
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
I. Karp, S.-F. Chen, and L. Pilote
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176(3):
333 - 338.
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|
|
|
|
|
|
|
C. Napoli, L. O. Lerman, F. de Nigris, M. Gossl, M. L. Balestrieri, and A. Lerman
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Circulation,
December 5, 2006;
114(23):
2517 - 2527.
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|
|
|
|
|
|
|
K. B. Keller and L. Lemberg
Secondary prevention of coronary artery disease in elderly persons: a treatise on a report by the american heart association.
Am. J. Crit. Care.,
September 1, 2006;
15(5):
514 - 518.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Poli and A. Pujia
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J. Am. Coll. Cardiol.,
August 15, 2006;
48(4):
852 - 852.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. K. Berthold, S. Unverdorben, R. Degenhardt, M. Bulitta, and I. Gouni-Berthold
Effect of policosanol on lipid levels among patients with hypercholesterolemia or combined hyperlipidemia: a randomized controlled trial.
JAMA,
May 17, 2006;
295(19):
2262 - 2269.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. M. Scirica, D. A. Morrow, S. Verma, S. Devaraj, I. Jialal, B. M. Scirica, D. A. Morrow, S. Verma, S. Devaraj, and I. Jialal
The Verdict Is Still Out
Circulation,
May 2, 2006;
113(17):
2128 - 2151.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. LaRosa
At the Heart of the Statin Benefit
J. Am. Coll. Cardiol.,
November 15, 2005;
46(10):
1863 - 1863.
[Full Text]
[PDF]
|
|
|
|
