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REVIEW

Narrative Review: Lack of Evidence for Recommended Low-Density Lipoprotein Treatment Targets: A Solvable Problem

Rodney A. Hayward, MD; Timothy P. Hofer, MD, MSc; and Sandeep Vijan, MD, MSc

3 October 2006 | Volume 145 Issue 7 | Pages 520-530

Recent national recommendations have proposed that physicians should titrate lipid therapy to achieve low-density lipoprotein (LDL) cholesterol levels less than 1.81 mmol/L (<70 mg/dL) for patients at very high cardiovascular risk and less than 2.59 mmol/L (<100 mg/dL) for patients at high cardiovascular risk. To examine the clinical evidence for these recommendations, the authors sought to review all controlled trials, cohort studies, and case–control studies that examined the independent relationship between LDL cholesterol and major cardiovascular outcomes in patients with LDL cholesterol levels less than 3.36 mmol/L (<130 mg/dL).

For those with LDL cholesterol levels less than 3.36 mmol/L (<130 mg/dL), the authors found no clinical trial subgroup analyses or valid cohort or case–control analyses suggesting that the degree to which LDL cholesterol responds to a statin independently predicts the degree of cardiovascular risk reduction. Published studies had avoidable limitations, such as a reliance on ecological (aggregate) analyses, use of analyses that ignore statins' other proposed mechanisms of action, and failure to account for known confounders (especially healthy volunteer effects). Clear, compelling evidence supports near-universal empirical statin therapy in patients at high cardiovascular risk (regardless of their natural LDL cholesterol values), but current clinical evidence does not demonstrate that titrating lipid therapy to achieve proposed low LDL cholesterol levels is beneficial or safe.

Author and Article Information

From the Department of Veterans Affairs, VA Center for Practice Management and Outcomes Research, VA Ann Arbor Healthcare System, and University of Michigan Schools of Medicine and Public Health, Ann Arbor, Michigan.

Acknowledgments: The authors thank Robert Chang, MD, for assistance with the literature review and David Kent, MD, MSc, for reviewing an earlier draft of this manuscript.

Grant Support: By the VA Health Services Research and Development Service's Quality Enhancement Research Initiative (QUERI DIB 98-001) and by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (P60 DK-20572).

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Rodney A. Hayward, MD, VA Center for Practice Management and Outcomes Research, P.O. Box 130170, Ann Arbor, MI 48113-0170; e-mail, rhayward{at}umich.edu.

Current Author Addresses: Drs. Hayward, Hofer, and Vijan: VA Center for Practice Management and Outcomes Research, P.O. Box 130170, Ann Arbor, MI 48113-0170.

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