Levels and Changes of HDL Cholesterol and Apolipoprotein A-I in Relation to Risk of Cardiovascular Events among Statin-Treated Patients: A Meta-Analysis

Boekholdt SM, Arsenault BJ, Hovingh GK, et al.
Circulation. 2013. doi:10.1161/CIRCULATIONAHA.113.002670

Background

Both low levels of HDL-c and apolipoprotein A-I (apoA-I) are considered risk factors for coronary heart disease (CHD) [1,2]. HDL-c was found to be inversely associated with risk of cardiovascular events among people with low LDL-c levels [3], and HDL-c is still an important risk factor for patients treated with statins [4,5].
Although HDL-c and apoA-I have become adopted as important therapeutic targets, their direct biological protection against atherosclerosis or risk of CHD has never been proven. In fact, several lines of evidence question HDL-c and apoA-I as relevant therapeutic targets, since raising HDL-c might not be related to a lower risk of CHD [6,7]. Also it has been suggested that changes in HDL-c after initiation of lipid-modifying therapy are not independently associated with CHD risk [8,9]. Trials testing HDL-c raising therapies have shown lack of efficacy [10] or even excess mortality in the CETP inhibitor arm [11,12].
This study therefore tested the hypothesis that higher levels of HDL-c and apoA-I are associated with lower CV risk in statin-treated patients, even in those achieving very low LDL-c levels. The authors performed a meta-analysis of individual patient data from 8 large statin trials.

Main results

• Risk of major CV events was inversely associated with on-statin levels of HDL-c and apoA-I. Patients in the top quintile of on-statin HDL-c had an adjHR of 0.65 (95%CI: 0.59-0.71) as compared to those in the bottom quintile (P for linear trend across quintiles: <0.001).
  Patients in the top quintile of on-statin apoA-I had an adjHR of 0.53 (95%CI: 0.48-0.59, P(linear trend)<0.001) as compared to those in the bottom quintile.
• The association between on-statin HDL-c levels and risk of major CV events did not differ much between subgroups of patients achieving different levels of on-statin LDL-c.
• Statistically significant correlations were seen between baseline HDL-c and change in HDL-c (correlation coefficient: -0.198, P<0.001) and baseline apoA-I and change in apoA-I (corr.coef: -0.312, P<0.001).
• No large differences in risk of major CV events were seen between patients in the highest quintile of HDL-c change, as compared to patients in the lowest quintile.
  Patients in the top quintile of apoA-I change had a HR 0.83 (95%C(: 0.74-0.93) as compared to patients in the lowest quintile (P for trend: 0.001).
  
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Conclusion

Among statin-treated patients, on-trial HDL-c and apoA-I are both strongly and inversely correlated with the risk of CV events, even when very low LDL-c levels have been achieved. When apoA-I levels increase after patients have started taking statins, they have a lower risk of CV events as compared to patients in whom apoA-I levels decreased. No such difference for HDL-c change after initiation of statin therapy was seen. Thus, a rise in HDL-c levels is not independently associated with a lower risk of major CV events. Modifying apoA-I levels as a preventive therapy is worth further exploration.

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