Changes in HDL Cholesterol and Cardiovascular Outcomes After Lipid Modification Therapy

Study Questions:

Are increases in high-density lipoprotein cholesterol (HDL-C) after starting lipid-modifying therapy (LMT) associated with a reduction in cardiovascular outcomes, independent of changes in low-density lipoprotein cholesterol (LDL-C)?


A total of 1,148 participants, 446 from the EPIC-Norfolk and 702 from the Rotterdam general population studies conducted between 1993 and 1997, were assessed for lipids before and after starting LMT. Subsequent risk of cardiovascular events, ascertained through linkage with mortality records and hospital databases, was investigated using Cox proportional hazards regression. Random-effects meta-analysis was used to combine results across studies.


Mean age was 63 years, about 50% were female, and mean HDL at first visit was 50 ± 13 mg/dl. Based on combined data from the EPIC-Norfolk and Rotterdam studies, there was some evidence that change in HDL-C resulting from LMT was associated with reduced cardiovascular risk (hazard ratio per pooled standard deviation [=0.34 mmol/L = 13.1 mg/dl] increase = 0.74; 95% confidence interval, 0.56-0.99; adjusted for age, sex, and baseline HDL-C). However, this association was attenuated and was not (statistically) significant with further adjustments for non-HDL-C and for cigarette smoking history, prevalent diabetes, systolic blood pressure, body mass index, use of antihypertensive medication, previous myocardial infarction, prevalent angina, and previous stroke.


Following adjustment for conventional non-lipid risk factors of cardiovascular disease, this study provides no evidence to support a significant benefit from increasing HDL-C independent of the effect of lowering non-HDL-C.


The ‘good cholesterol’ hypothesis is taking a beating from many fronts, several of which are concerning. But this analysis of the effect raising HDL-C by LMT in a population study is among the least valuable. Lessons learned from many clinical trials developed based upon epidemiologic data are that a specific population (e.g., defined by cardiovascular risk, lipid phenotype, diabetes) needs to be treated with specific drugs (placebo-controlled) to be able to demonstrate the value of a targeted strategy. To draw conclusions about the value of a change in HDL-C when the mean HDL-C is 50 mg/dl at baseline provides little to no information of value. Also, the findings are not consistent with a recent analysis of observational data from the Framingham Offspring Study, which suggests that HDL-C differences resulting from LMT may be relevant to cardiovascular benefit after adjusting for changes in LDL-C.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: Cardiovascular Diseases, Cholesterol, HDL

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