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Meta-analysis: Statin Therapy Does Not Alter the Association Between Low Levels of High-Density Lipoprotein Cholesterol and Increased Cardiovascular Risk

Haseeb Jafri, MD; Alawi A. Alsheikh-Ali, MD, MS; and Richard H. Karas, MD, PhD
[+] Article and Author Information

From Molecular Cardiology Research Institute, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, and Tufts University School of Medicine, Boston, Massachusetts, and Institute of Cardiac Sciences, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates.


Acknowledgment: The authors thank Dr. Thomas Trikalinos for his valuable advice and assistance with statistical analysis.

Potential Conflicts of Interest: Dr. Alsheikh-Ali: Grants received: Pfizer. Grants received (money to institution): Pfizer. Dr. Karas: Consultancy: Abbott Laboratories. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-2091.

Reproducible Research Statement:Study protocol, statistical code, and data set: Not available.

Requests for Single Reprints: Richard H. Karas, MD, PhD, Molecular Cardiology Research Institute, Box 80, Tufts Medical Center, 750 Washington Street, Boston, MA 02111; e-mail, rkaras@tuftsmedicalcenter.org.

Current Author Addresses: Drs. Jafri and Karas: Molecular Cardiology Research Institute, Box 80, Tufts Medical Center, 750 Washington Street, Boston, MA 02111.

Dr. Alsheikh-Ali: Institute of Cardiac Sciences, Sheikh Khalifa Medical City, PO Box 51900, Abu Dhabi, United Arab Emirates.

Author Contributions: Conception and design: H. Jafri, A.A. Alsheikh-Ali, R.H. Karas.

Analysis and interpretation of the data: H. Jafri, A.A. Alsheikh-Ali, R.H. Karas.

Drafting of the article: H. Jafri, A.A. Alsheikh-Ali, R.H. Karas.

Critical revision of the article for important intellectual content: H. Jafri, A.A. Alsheikh-Ali, R.H. Karas.

Final approval of the article: H. Jafri, A.A. Alsheikh-Ali, R.H. Karas.

Statistical expertise: H. Jafri, A.A. Alsheikh-Ali.

Administrative, technical, or logistic support: H. Jafri, A.A. Alsheikh-Ali.

Collection and assembly of data: H. Jafri, A.A. Alsheikh-Ali.


Ann Intern Med. 2010;153(12):800-808. doi:10.7326/0003-4819-153-12-201012210-00006
Text Size: A A A

Background: Low levels of high-density lipoprotein cholesterol (HDL-C) are associated with an increased risk for myocardial infarction (MI). Although statins reduce the risk for MI, most cardiovascular events still occur despite statin treatment.

Purpose: Using meta-analysis of large randomized, controlled trials (RCTs) of statins to determine whether statins alter the relationship between HDL-C level and MI.

Data Sources: MEDLINE search to February 2010, ClinicalTrials.gov, and reference lists from eligible studies.

Study Selection: English-language RCTs of statin-treated patients versus control participants with 1000 or more person-years of follow-up and reported HDL-C levels and MI.

Data Extraction: Two independent investigators extracted data from eligible RCTs.

Data Synthesis: Twenty eligible RCTs were identified (543 210 person-years of follow-up and 7838 MIs). After adjustment for on-treatment LDL-C levels, age, hypertension, diabetes, and tobacco use, there was a significant inverse association between HDL-C levels and risk for MI in statin-treated patients and control participants. In Poisson meta-regressions, every 0.26-mmol/L (10-mg/dL) decrease in HDL-C was associated with 7.1 (95% CI, 6.8 to 7.3) and 8.3 (CI, 8.1 to 8.5) more MIs per 1000 person-years in statin-treated patients and control participants, respectively. The inverse association between HDL-C levels and MI did not differ between statin-treated patients and control participants (P = 0.57).

Limitation: The observed associations may be explained by unmeasured confounding and do not imply causality in the relationship between HDL-C level and cardiovascular risk.

Conclusion: Statins do not alter the relationship between HDL-C level and cardiovascular risk, such that low levels of HDL-C remain significantly and independently associated with increased risk despite statin treatment. The remaining risk seen in statin-treated patients may be partly explained by low HDL-C levels or other factors associated with low levels of HDL-C.

Primary Funding Source: None.

Figures

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Figure 1.
Summary of evidence search and selection.

HDL-C = high-density lipoprotein cholesterol; RCT = randomized, controlled trial.

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Appendix Figure 1.
Forest plot of statin versus control for MI and RR (95% CI) for MI.

The size of the data markers (solid squares) represents the relative weight of the trial in random-effects meta-analysis. See footnote to Tables 1 and 2 for full titles of studies. MI = myocardial infarction; RR = relative risk.

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Appendix Figure 2.
Funnel plot for myocardial infarction.

Plots represent data from 20 randomized, controlled trials of statin therapy evaluating the outcome of myocardial infarction. LN = log normal.

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Figure 2.
Associations between HDL-C levels and cardiovascular outcomes.

Black circles indicate patients who are receiving statin interventions, and green circles indicate patients who are receiving a nonstatin control. The circles represent the relative sizes of the group (that is, the weight of the group). The solid lines are the regression lines (weighted by the SE). To convert values for HDL-C to mmol/L, multiply by 0.0259. CVD = cardiovascular disease; HDL-C = high-density lipoprotein cholesterol; MI = myocardial infarction.

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Tables

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Comments

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Meta-analysis: Statin Therapy...
Posted on February 11, 2011
Nauman Qureshi
Athens Internal Medicine
Conflict of Interest: None Declared

To the Editor:

In their meta-analysis Jafri et al. elegantly showed that a high HDL level confers benefit in terms of reducing atherosclerotic risk, regardless of whether the person is on statin therapy or not.

I am suggesting a basic change in the conceptual "take" that we have at present, on HDL and LDL cholesterol, as risk factors.

Both of them are cholesterol values; however, in terms of atherosclerotic risk factor reduction, in my opinion, it is best to make a sea change in the paradigm for managing these two different cholesterols and to get in the habit of accepting each as a separate and distinct risk factor. The analogy would be that we can keep attempting to lower the hemoglobin A1c in a diabetic but there comes a point beyond which lowering it is no longer justifiable from the risk-benefit ratio in terms of preventing atherosclerotic cardiovascular disease. However, if we work on the systolic pressure and try to bring it down to 130 mm/Hg it will provide significant incremental benefit, in terms of separate risk reduction strategy which is distinct from trying to lower the LDL choleseterol. Hence, in a diabetic, a favorable improvement in the levels of systolic blood pressure; the hemoglobin A1C, the LDL cholesterol level and the HDL cholesterol level will each provide finite improvement in the atherosclerotic risk and, hopefully, in a given patient the individual benefits of those interventions will be additive and may even get us to the elusive goal of atherosclerosis regression.

References

1. Jafri H et al: Meta-analysis: Statin Therapy Does Not Alter The Association Between Low Levels of High-Density Lipoprotein Cholesterol and Increased Cardiovascular Risk, Annals of Internal Medicine 2010; 800-808.

Conflict of Interest:

None declared

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