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Systematic review
High-density lipoprotein cholesterol increase and non-cardiovascular mortality: a meta-analysis
  1. Elena Burillo1,
  2. Eva Maria Andres2,
  3. Rocio Mateo-Gallego1,
  4. Sarah Fiddyment1,
  5. Estibaliz Jarauta1,
  6. Ana Cenarro1,
  7. Fernando Civeira1
  1. 1Unidad de Lípidos and Laboratorio de Investigación Molecular, Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud (I+CS), Zaragoza, Spain
  2. 2Unidad de Investigación – Epidemiología Clínica, Hospital Universitario 12 de Octubre, CIBER de Epidemiología y Salud Pública, Edificio Materno-Infantil (planta-2) CEIC, Madrid, Spain
  1. Correspondence to Ms Elena Burillo, Laboratorio de Investigación Molecular, Hospital Universitario Miguel Servet, Avda, Isabel La Católica,1-3, Zaragoza 50009, Spain; eburilloi.iacs{at}aragon.es

Abstract

Context Many observational prospective studies have confirmed the inverse relationship between high-density lipoprotein (HDL) cholesterol and coronary heart disease. However, the potential benefit of the pharmacological increase in HDL cholesterol has not been clearly demonstrated. Moreover, in some interventions an increase in total mortality has been reported.

Objective The objective of this meta-analysis was to determine the relationship between HDL cholesterol increase and non-cardiovascular mortality in randomised trials.

Data sources Authors searched Medline up to December 2008.

Study selection Four reviewers identified randomised trials in which, through different types of interventions, HDL cholesterol increase in the treatment group was >4% compared to control group, both groups reported separately non-cardiovascular mortality and the duration of the study was, at least, one year.

Data extraction Data of HDL cholesterol concentrations and deaths were collected as they appeared in the original studies. If necessary, reviewers calculated data by using trial information.

Results Meta-regression analysis included 44 articles corresponding to 107 773 participants. Analysis showed an association between HDL cholesterol increase and non-cardiovascular mortality (p=0.023), however, the correlation disappeared when we excluded the ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerosis Events) trial from the analysis (p=0.972).

Conclusions Meta-regression analysis results suggest that increases in HDL cholesterol up to 40% are not associated with higher non-cardiovascular death. The increase in adverse events observed in some trials where HDL cholesterol was raised in large amounts could be related with the drug mechanisms more than the HDL cholesterol increase itself.

  • HDL
  • systematic review
  • meta-analysis
  • non-cardiovascular mortality
  • lipid trials
  • community cardiology

https://doi.org/10.1136/hrt.2010.195396

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    Introduction

    Many observational prospective studies have confirmed the inverse relationship between high-density lipoprotein (HDL) cholesterol and coronary heart disease.1 2 For this reason, major clinical guidelines for the prevention and treatment of cardiovascular disease3 4 recognise HDL cholesterol as an independent risk factor. However, although various clinical trials have tried to improve cardiovascular prognosis by increasing HDL concentration using different approaches, the results of these trials have been mostly unsuccessful.5 6 Moreover, one recent meta-analysis concluded that increasing HDL cholesterol concentration does not reduce the risk of coronary disease events.7 The explanation of this discrepancy between observational and intervention studies is unknown.

    A well-studied function of HDL lipoprotein that has been associated with an atheroprotective effect is the reverse cholesterol transport from peripheral tissues to the liver.8 However, HDL particles have other interesting functions related to innate immunity, endothelial vascular function, protease activity regulation, oxidation, thrombosis and inflammation.9 If these other functions that are not directly associated with lipid transport have adverse clinical implications, they might explain the lack of benefit found in the clinical trials. The recent ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerosis Events) study,5 in which HDL cholesterol levels rose more than 70% using the cholesteryl ester transfer protein inhibitor torcetrapib, had to be prematurely suspended because of a substantial increase in the non-cardiovascular mortality in the torcetrapib group, raising the possibility that some interventions associated with increased HDL cholesterol might have deleterious effects. Therefore, this analysis tries to explore the relationship between HDL cholesterol increase and non-cardiovascular mortality in order to discard possible negative effects derived from the interventions.

    To achieve the aim of the study we used meta-analysis techniques in a systematic review of randomised trials covering interventions with marked increase in HDL cholesterol concentration.

    Methods

    Clinical studies published in the Medline database were identified using combinations of the following key words: HDL cholesterol or high-density lipoprotein cholesterol, and year; and these limits: human, randomised clinical trial, English language and published before 31 December 2008. To be considered for the meta-analysis, the studies had to meet the following inclusion criteria: the allocation of participants in the treatment and control group was random and blind; the duration of the study was at least 1 year; HDL cholesterol was measured at baseline and after randomisation; HDL cholesterol increase in the treatment group was >4% compared with the control group and they were published as part of full articles in peer-reviewed journals.

    Four abstractors independently extracted information on sample size, treatment type and duration, cardiovascular prevention type, increase in HDL cholesterol concentration and non-cardiovascular death. Data of HDL cholesterol concentrations and deaths were collected as they appeared in the original studies. In some cases10–13 the increment percentage of the HDL cholesterol concentration from baseline to the maximum increase throughout the treatment was calculated. As a last resort, in trials that failed to report exact HDL cholesterol concentration, data were extracted from graphs.14–16 Clinical end point was non-cardiovascular death, which was calculated by subtracting the cardiovascular related death from the total number of deaths.

    Meta-analyses used the random-effects model in the metan statistical package in STATA version 10.0 (Stata Corp). This takes into consideration the within-study comparison as well as differences between studies. Heterogeneity was measured by the I2 statistic proposed by Higgins and Thompson.17

    For the comparative models, treatment–HDL cholesterol interaction was added to allow the effect of HDL cholesterol increasing to vary between groups, treatment and control. The weighted mean difference was calculated based on weighting of individual results by the inverse variance; this limits the impact of studies with wide confidence intervals (CIs). Likewise, relative risk (RR) was weighted by the inverse variance; Mantel–Haenszel estimates were calculated across individual studies. The study-specific standard errors for the estimated RR were used to account for within-study variation. Between-study variation was estimated in the analysis. Overall analyses of type of treatments combined and subgroup analyses based on each type of drug were carried out.

    We also performed a meta-regression analysis using the metareg package of STATA version10.0 to examine whether the estimate of RR depends on the HDL cholesterol increasing. The natural log-transformed RR was modelled as a linear function of the study-specific mean difference in HDL cholesterol between the two groups and the mean length of follow-up.

    To address the optimal reporting of meta-analyses, we used the recent revision of the QUORUM (Quality Of Reporting Of Meta-analyses) statement renamed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) and we adopted the definitions proposed by the Cochrane Collaboration.18

    Results

    Literature searches identified 538 articles describing double-blinded studies in which HDL cholesterol was measured. Information obtained from the abstract was enough to discard 470 studies, mainly because the duration of the trial was <1 year and because there were several reports from the same study. Full report analysis was performed in the remaining 68 articles. Another 24 articles were further excluded for the reasons reported in figure 1. Therefore, the final analysis included 44 articles corresponding to 44 different clinical studies.

    Figure 1
    Figure 1

    Flowchart of trials. HDL, high-density lipoprotein.

    For the statin trials group, 14 met inclusion criteria (N=51 017). All of them used statin as a monotherapy except Derosa et al19 who used a combination of fluvastatin and orlistat. For fibrate trials, seven met inclusion criteria (N=20 199) and all of them used fibrate as a monotherapy. Two used gemfibrozil,10 20 three used bezafibrate21–23 and two used fenofibrate.15 24 In the niacin trials group (N=785), none of the studies used niacin as a monotherapy, all of them used drug combinations. HARP (Harvard Atherosclerosis Reversibility Project),25 ARBITER 2 (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol)26 and HATS (HDL-Atherosclerosis Treatment Study)27 used niacin combined with statins, the Armed Forces Regression Study28 used niacin, gemfibrozil and cholestyramine, and CLAS (Cholesterol Lowering Atherosclerosis Study)29 and FATS (Familial Atherosclerosis Treatment Study)30 used niacin and colestipol. Six hormone replacement trials were included in the meta-analysis (N=5270). In these trials, combinations of oestrogen and progestin and oestradiol were used. In addition, other trials (other treatments) met inclusion criteria (N=31 287), all compared with placebo except ILLUMINATE,5 in which torcetrapib plus atorvastatin was compared with atorvastatin, and CELL (Cost Effectiveness of Lipid Lowering),31 in which the comparison was made between intensive and usual advice. Two studies used rimonabant32 33; two used cholestyramine16 34; one xuezhikang,13 an extract of Chinese red yeast rice; two sibutramine,35 36 one used calcium37 and one used policosanol38 (table 1).

    View this table:
    Table 1

    Effects of different interventions on HDL cholesterol increment

    The increases in HDL cholesterol in the treatment and control groups obtained in each trial are also shown in table 1. To explore the potential interaction of the different lipid lowering interventions we performed a study-specific and grouped RR associated with the type of treatment with the 95% CI (figure 2). The statin trials reported 4.0–10.0% increases in HDL cholesterol and the estimated RR for non-cardiovascular death was 1.00 (95% CI 0.89 to 1.12). The fibrate trials reported 4.0–14.4% and the RR was 1.07 (95% CI 0.93 to 1.22). The niacin trials showed an increase in HDL cholesterol from 10.0% to 38.0% and reported an RR value of 1.01 (95% CI 0.06 to 15.90). The hormone replacement trials increased HDL cholesterol from 8.0% to 11.4% and the RR was 0.91 (95% CI 0.65 to 1.27) and, finally, the other treatments group had an increase of 4.2–72.1% in HDL cholesterol, and the RR associated with non-cardiovascular death was 1.10 (95% CI 0.82 to 1.47). In this group, statistically significant differences were found in the ILLUMINATE study (RR=2.00, 95% CI 1.17 to 3.42) and in the Lu Z et al study (RR=0.53, 95% CI 0.31 to 0.89). Heterogeneity was found among this latter group (I2=84.2%, p=0.002), probably owing to the very different nature of the treatments. Heterogeneity was not found in the other groups.

    Figure 2
    Figure 2

    Relative risk (RR) of non-cardiovascular mortality associated with type of treatment. M–H, Mantel–Haenszel test.

    Non-cardiovascular mortality risk was slightly higher in primary prevention trials than in those focused on secondary prevention (RR=1.24, 95% CI 0.96 to 1.60 and RR=1.00, 95% CI 0.92 to 1.09, respectively figure 3).

    Figure 3
    Figure 3

    Relative risk (RR) of non-cardiovascular mortality associated with type of cardiovascular prevention. M–H, Mantel–Haenszel test.

    The meta-regression analysis performed in order to find a relationship between the increase of HDL cholesterol and non-cardiovascular mortality is shown in figure 4A, B. The log RR was modelled as a linear function of HDL cholesterol increasing percentage. An association between HDL cholesterol and non-cardiovascular mortality was seen (p=0.023. figure 4A); however, the association observed disappeared when we excluded the ILLUMINATE trial from the meta-regression analysis (p=0.972. figure 4B) because it was the only study in which heterogeneity was found in the meta-analysis.

    Figure 4
    Figure 4

    (A) Meta-regression analysis of the correlation between HDL cholesterol increase and non-cardiovascular mortality including the ILLUMINATE study. (B) Meta-regression analysis of the correlation between HDL cholesterol increase and non-cardiovascular mortality without the ILLUMINATE study. HDL, high-density lipoprotein; RR, relative risk.

    Discussion

    Raising HDL cholesterol is a potential therapeutic goal for cardiovascular disease prevention, but the impact on non-cardiovascular events has remained uncertain. In this meta-analysis of the published results we provide consistent information about this topic. We performed a meta-regression analysis to confirm whether or not a relationship exists between the increase of HDL cholesterol and non-cardiovascular mortality. The regression showed a correlation between HDL cholesterol increase and non-cardiovascular mortality when we included all the studies in the analysis, but this correlation disappear when we excluded the ILLUMINATE study. This latter study is the only trial in which we observed a higher RR of non-cardiovascular mortality in the treatment group (torcetrapib plus atorvastatin) than in the control group (atorvastatin). We analysed different types of treatment: statins, fibrates, niacin combinations, hormone replacement treatments, resins and others, and no study reported higher RR for non-cardiovascular mortality in the treatment group (in which the HDL cholesterol was higher). The results of our meta-analysis could indicate that the increase in non-cardiovascular disease adverse events found in the ILLUMINATE trial, in which HDL cholesterol concentration was >70% in the treatment group, cannot be explained as a negative effect of increasing HDL cholesterol itself. Mechanisms associated with the inhibition of the cholesteryl ester transfer protein, or mechanisms of action of torcetrapib, might be responsible and should be further studied. However, our study does not exclude the possibility that very large increases in HDL cholesterol over 50% might have an effect on non-cardiovascular death.

    Briel et al recently published7 a meta-analysis studying the effects of HDL interventions on cardiovascular mortality. Our study further increases the knowledge of the effects of HDL interventions on non-cardiovascular mortality, an aspect that has not been previously studied. Another important difference between Briel's study and ours is that we selected only studies in which a clinically relevant increase in HDL cholesterol was obtained.3 In contrast, Briel et al studied the association between treatment-induced change in HDL cholesterol and coronary heart disease and total death.7 Our study more potently identifies the effect of an increase of HDL cholesterol, the main goal of the therapeutic interventions in HDL until now, on non-cardiovascular death.

    Strengths and limitations

    We used aggregated data from the studies rather than individual subject data. We excluded 24 studies from the analysis because they did not contain the necessary information. However, all the excluded studies were small, and therefore, the weight of these studies would be light and we think their inclusion would not have caused our results to vary. Even so, our meta-analysis limits possible associations which are a product of small sample sizes, multiple statistical comparisons and emphasis on particular findings in certain studies. We included a wide variety of patients with and without cardiovascular disease and several types of interventions, powering the meta-analysis. We incorporated studies with small increases in HDL cholesterol as well as studies in which the increase was larger. Variability was sufficient to detect any effect of HDL cholesterol increase on non-cardiovascular mortality. Finally, publication bias was not present in the analysis.

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    Footnotes

    • All authors had access to the data and all authors had a role in writing the manuscript.

    • Funding Grant from the Spanish Ministry of Health FIS PI06/0365, PI07/1221, RETIC C06/01 (RECAVA) supported this work.

    • Competing interests None.

    • Ethics approval Each study included in this meta-analysis was conducted with approval of the corresponding ethics committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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