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Review
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Effect on Cardiovascular Risk of High Density Lipoprotein Targeted Drug Treatments Niacin, Fibrates, and CETP Inhibitors: Meta-Analysis of Randomised Controlled Trials Including 117,411 Patients

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Review

Effect on Cardiovascular Risk of High Density Lipoprotein Targeted Drug Treatments Niacin, Fibrates, and CETP Inhibitors: Meta-Analysis of Randomised Controlled Trials Including 117,411 Patients

Daniel Keene et al. BMJ.

Abstract

Objective: To investigate the effects on cardiovascular outcomes of drug interventions that increase high density lipoprotein levels.

Design: Meta-analysis.

Studies reviewed: Therapeutic benefit of niacin, fibrates, and cholesteryl ester transfer protein (CETP) inhibitors on cardiovascular events (all cause mortality, coronary heart disease mortality, non-fatal myocardial infarction, and stroke).

Results: 117,411 patients were randomised in a total of 39 trials. All interventions increased the levels of high density lipoprotein cholesterol. No significant effect was seen on all cause mortality for niacin (odds ratio 1.03, 95% confidence interval 0.92 to 1.15, P=0.59), fibrates (0.98, 0.89 to 1.08, P=0.66), or CETP inhibitors (1.16, 0.93 to 1.44, P=0.19); on coronary heart disease mortality for niacin (0.93, 0.76 to 1.12, P=0.44), fibrates (0.92, 0.81 to 1.04, P=0.19), or CETP inhibitors (1.00, 0.80 to 1.24, P=0.99); or on stroke outcomes for niacin (0.96, 0.75 to 1.22, P=0.72), fibrates (1.01, 0.90 to 1.13, P=0.84), or CETP inhibitors (1.14, 0.90 to 1.45, P=0.29). In studies with patients not receiving statins (before the statin era), niacin was associated with a significant reduction in non-fatal myocardial infarction (0.69, 0.56 to 0.85, P=0.0004). However, in studies where statins were already being taken, niacin showed no significant effect (0.96, 0.85 to 1.09, P=0.52). A significant difference was seen between these subgroups (P=0.007). A similar trend relating to non-fatal myocardial infarction was seen with fibrates: without statin treatment (0.78, 0.71 to 0.86, P<0.001) and with all or some patients taking statins (0.83, 0.69 to 1.01, P=0.07); P=0.58 for difference.

Conclusions: Neither niacin, fibrates, nor CETP inhibitors, three highly effective agents for increasing high density lipoprotein levels, reduced all cause mortality, coronary heart disease mortality, myocardial infarction, or stroke in patients treated with statins. Although observational studies might suggest a simplistic hypothesis for high density lipoprotein cholesterol, that increasing the levels pharmacologically would generally reduce cardiovascular events, in the current era of widespread use of statins in dyslipidaemia, substantial trials of these three agents do not support this concept.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work, no financial relationships with any organisations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work. DPF receives funding from the British Heart Foundation but this study is an unrelated independent academic activity. No author has a competing interest to declare.

Figures

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Fig 1 Forest plot showing effect of niacin on risk of all cause mortality, stratified by use of statin in trial
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Fig 2 Forest plot showing effect of fibrates on risk of all cause mortality stratified by different fibrate agents
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Fig 3 Forest plot showing effect of cholesteryl ester transfer protein (CETP) inhibitors on risk of all cause mortality stratified by CETP inhibitors
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Fig 4 The statin revolution: without background statin treatment, fibrates and niacin were found to reduce non-fatal myocardial infarction. In the modern era, however, when background treatment of patients with dyslipidaemia typically includes statins, this effect was not apparent

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