Meta-analysis
Effects of HDL-modifiers on cardiovascular outcomes: A meta-analysis of randomized trials

https://doi.org/10.1016/j.numecd.2014.09.003Get rights and content

Highlights

  • A total of 69,515 patients from 18 randomized trials treated with niacin of CETP-inhibitors were included in meta-analysis.

  • HDL-modifiers did not significantly reduce cardiovascular mortality.

  • Niacin but not CETP significantly reduced myocardial infarction and coronary revascularization.

  • No relationship was observed between the extent of HDL changes and benefits from HDL-modifiers.

  • HDL-modifiers, increased serious adverse events, as new onset of diabetes mellitus and worsening of hypertension with CETP inhibitors.

Abstract

Background and aim

High density lipoproteins (HDL) have been addressed as a potential strategy for cardiovascular prevention, with great controversies on pharmacological approaches for HDL-elevation.

Our aim was to compare HDL-rising treatment with niacin or CETP-inhibitors with optimal medical therapy in cardiovascular outcome.

Methods and results

Randomized trials were searched. Primary endpoint was cardiovascular death, secondary were: non fatal myocardial infarction; coronary revascularization; cerebrovascular accidents and safety endpoints.

As many as 18 randomized trials, for a total of 69,515 patients, were included. HDL-modifiers did not reduce cardiovascular mortality (2.3%vs3.4%; OR [95%CI] = 0.96 [0.87–1.05], p = 0.37, phet = 0.58), with no benefit from niacin/CETP inhibitors according to patients' risk profile (beta [95%CI] = −0.14 [−0.29 to 0.02], p = 0.09) or the amount of HDL increase (beta [95%CI] = 0.014 [−0.008 to 0.04], p = 0.21). Niacin but not CETP-I reduced myocardial infarction and coronary revascularization, but higher rate of SAE occurred with HDL-modifiers (OR [95%CI] = 1.24 [1.18–1.31], p < 0.00001, phet = 0.02), in particular new onset of diabetes with niacin and worsening of hypertension with CETP-inhibitors.

Conclusions

Niacin and CETP inhibitors do not influence cardiovascular mortality. Significant benefits in MI and coronary revascularization were observed with niacin, despite the higher occurrence of diabetes.

Section snippets

Background

Cardiovascular disease still represents the leading cause of mortality in developed countries. In fact, despite the great achievements in treating acute myocardial infarction [1], [2], [3], [4], the results are still unsatisfactory in some high-risk subsets of patients [5], [6], [7]. Dyslipidemia has been addressed as one of the most prominent risk factors for Coronary Artery Disease (CAD) and the reduction of low-density lipoprotein cholesterol (LDL-C) still remains the primary objective of

Eligibility and search strategy

The literature was scanned by formal searches of electronic databases (MEDLINE, Cochrane and EMBASE) for clinical studies and furthermore the scientific session abstracts, searched on the American College of Cardiology (www.acc.org), American Heart Association (www.aha.org), and European Society Congress (www.escardio.org) websites, for oral presentations and/or expert slide presentations from January 1970 to March 2013. In addition, manual search of unpublished data of registered clinical

Eligible studies

Among 9297 potentially relevant publications, a total of 18 randomized clinical trials were finally included, 12 trials comparing niacin to optimal medical therapy and 6 trials with CETP inhibitors (Fig. 1) [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45]. A total of 69,515 patients were included, 34,042 (48.9%) receiving a HDL-modifier, either niacin or CETP inhibitor, and 35,473 (51%) optimal medical therapy plus eventual placebo

Primary endpoint

Follow-up length ranged from 3 to 95 months. In particular, the duration of follow-up was shorter than 1 year in 3 trials [37], [41], [42], between 1 and 3 years in 11 trials [28], [30], [32], [33], [34], [35], [36], [38], [40], [43], [44], and longer than 3 years in 4 trials [29], [31], [39], [45]. Data on cardiovascular mortality were available in 69,515 patients (100%). Cardiovascular death was observed in a total of 2002 patients (2.9%). As shown in Fig. 2, HDL-modifiers did not

Discussion

Present meta-analysis represents the first attempt to define a role of HDL-rising therapies, both with niacin or CETP-inhibitors, in the prevention of cardiovascular events, after the publication of large randomized trials with these drugs. Our main finding is that these pharmacological strategies do not provide significant benefits in cardiovascular mortality. However, a reduction in myocardial infarction and coronary revascularization was observed with niacin. No relationship was observed

Limitations

Some limitations should be addressed in present study. In particular, a major one relates to the synthesis of data from heterogeneous trials. In fact, although the study populations might seem relatively similar with regard to their high cardiovascular risk, a significant heterogeneity was found for secondary endpoints (mainly coronary revascularization). However, no heterogeneity was observed for primary endpoint. In fact, sensitivity analysis showed stability of the results of the primary

Conclusions

The present meta-analysis has shown that both niacin and CETP inhibitors do not provide significant benefits in cardiovascular mortality and are associated with higher risk of new onset diabetes (niacin) or hypertension (CETP). Significant, but modest benefits in myocardial infarction and coronary revascularization were observed with niacin, independently from the extent of HDL raising, at the expense of higher risk of new-onset diabetes. Therefore, based on current available trials,

Funding

None.

Conflict of interest

None.

Authorship contribution

MV; AS; HS; GDL; provided to data collection, GDL to project management; GDL and HS to production and scientific revision of the manuscript.

Prof. Giuseppe De Luca is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data analysis.

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