Raising HDL-c levels via distinct mechanisms does not lower CV morbidity and mortality

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

Literature - Keene D et al., BMJ. 2014 - BMJ. 2014 Jul 18;349:g4379

Keene D, Price C, Shun-Shin MJ et al.,
BMJ. 2014 Jul 18;349:g4379


Several targeted drug treatments have been developed, to lower LDL-c levels and to raise HDL-c levels, in an attempt to prevent an increase in cardiovascular (CV) disease. While reduction of LDL-c levels with statins has repeatedly been shown to reduce cardiac events and all cause mortality, both as secondary and primary prevention [1]. Attention and hope is now directed at achieving similar benefits by targeting HDL.
Niacin, fibrates and CETP inhibitors are agents proposed to increase HDL levels, via which CV morbidity and mortality may be reduced. This meta-analysis of randomised controlled trials evaluated the effects of these three classes of agents, with or without statin treatment, on mortality and CV events. 11 eligible trials of niacin, 20 of fibrates and 8 of CETP inhibitors were used for this analysis.

Main results


  • Niacin showed no net effect on all cause mortality (OR: 1.03, 95%CI: 0.92-1.15, P=0.59). This did not change whether people were on concomitant statin treatment (OR: 1.10, 95%CI: 1.00-1.21, P=0.06) or not (OR: 0.86, 95%CI: 0.65- 1.14, P=0.29).
  • No significant effect of niacin across all trials was seen for the secondary outcomes of coronary heart disease mortality, non-fatal myocardial infarction (MI) or stroke.
  • Risk difference in the development of adverse skin effects was 0.05 (95%CI: 0.03-0.07, P<0.001), showing significant heterogeneity between trials (I2=86%). The HPS2-THRIVE reported multiple new signals for possible harm.
  • Fibrate treatment did not significantly affect all cause mortality (OR: 0.98, 95%CI: 0.89-1.08, P=0.66), with moderate heterogeneity across all trials (I2=33%). No differences were seen whether people were on statin treatment or not.
  • Coronary heart disease mortality, nor stroke, were significantly affected by fibrates. Overall, non-fatal MI was however lower with fibrates (OR: 0.80, 95%CI: 0.74-0.87, P<0.001), which was statistically significant in trials without statin treatment, but not in participants with statin treatment.
  • Across all trials, fibrates were associated with a small increase in pulmonary emboli (risk difference: 0.01, 95%CI: 0.00-0.01, P=0.002).
CETP inhibitors
  • Torcetrapib significantly increased mortality (OR: 1.53, 95%CI: 1.12-2.09, P=0.007), while anacetrapib (OR: 1.38, 95%CI: 0.55-3.45, P=0.49) and dalcetrapib (OR: 0.98, 95%CI: 0.81-1.18, P=0.83) did not.
  • Coronary heart disease mortality, non-fatal MI or stroke were not significantly affected.
  • Torcetrapib was associated with an increased rate of hypertension, while the other CETP inhibitors were not. Dalcetrapib use showed a higher incidence of diarrhoea.


None of the three classes of HDL-c raising agents analysed in this meta-analysis were associated with a significantly reduced risk of all cause mortality and coronary heart disease mortality. Similar results were seen in the pre-statin era and the present era with widespread use of statins for CV event reduction. Only one agent, torcetrapib, significantly affected mortality, namely increased it.
The tested agents raise HDL-c through distinct mechanisms, and have different pleiotropic effects. It seems as though the simple hypothesis that any drug intervention that raises HDL-c levels, gives additional CV protection, is incorrect.

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1. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.

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