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

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.