COMMENTARIES

Clinical Significance of Statin Induced HDL-C Increase

Vasilios G. Athyros1, Asterios Karagiannis1, and Dimitri P. Mikhailidis2,
1Atherosclerosis and Metabolic Syndrome Units, 2nd Prop. Clinic of Internal Medicine, Hippocration Hospital,
Aristotelian University of Thessaloniki, Thessaloniki,
Greece,
2Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free Hospital, Royal Free and University College Medical School,
London, UK
Please address correspondence to:
Vasilios G. Athyros, M.D., FESC, FASA, FACS
Atherosclerosis and Metabolic Syndrome Units
2nd Prop. Department of Internal Medicine
Aristotelian University
Hippocration Hospital
15 Marmara St
Thessaloniki, 55132, Greece
Tel: +30 2310 454237
Fax: +30 2310 445220
E-mail: athyros@med.auth.gr

Apo-B100-containing lipoproteins and especially low-density lipoprotein cholesterol (LDL-C) are directly implicated in the formation and progression of atherosclerotic plaques and eventually to the pathogenesis of cardiovascular events. A large body of evidence supports a central role for lowering levels of LDL-C in the prevention of cardiovascular disease (CVD). Thus, the National Cholesterol Educational Program (NCEP) guidelines almost exclusively target LDL-C [1] and we now have the entire range of LDL-C targets for primary and secondary CVD prevention. Moreover, the available powerful statins and the dual inhibition strategy (statin plus ezetimibe) provide the means to attain these targets. However, if we want even larger CVD event reductions we have to investigate other lipid targets, besides LDL-C, that might provide additional clinical benefit.

          High-density lipoprotein cholesterol (HDL-C) might be one of these targets. Epidemiological data suggest that each 1 mg/dl increase in HDL-C is associated with a 2% to 3% decrease in the risk of CHD [2]. Despite this, evidence from large-scale, randomized clinical trials with fibrates suggest that elevating HDL-C is associated with only a minor CVD risk benefit [1]. This is probably because increases in HDL-C levels in these trials were small, while non-HDL-C levels remained high. In this context, pharmacological measures that substantially increase HDL-C levels are currently under intense investigation. Statin-fibrate combinations incur the risk of increased side effects. The statin-nicotinic acid combination seems to be promising [3], but some patients cannot tolerate nicotinic acid [4]. This created the need to look back to statin monotherapy. Statins have been reported to modestly increase HDL-C levels [5]; however, data on whether or not these small statin-induced increases in HDL-C translate into a meaningful clinical benefit are limited.

          A recent meta-analysis combined the results for patients enrolled in 4 prospective clinical trials that used intravascular ultrasound (IVUS) to determine changes in atheroma volume during treatment [5]. These were: REVERSAL (Reversal of Atherosclerosis With Aggressive Lipid Lowering, atorvastatin 80 mg versus pravastatin 40 mg) [6], ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular-Ultrasound Derived Indices of Coronary Atheroma Burden, 40 mg of rosuvastatin versus baseline) [7], CAMELOT (Comparison of Amlodipine versus Enalapril to Limit Occurrence of Thrombosis trial) [8], and ACTIVATE (ACAT Intravascular Atherosclerosis Treatment Evaluation) [9]. The objective of this meta-analysis was to determine the relative contribution of statin-induced reductions in atherogenic lipoproteins and increases in HDL-C on the rate of atheroma progression. The results of this meta-analysis showed that statin therapy is associated with regression of coronary atherosclerosis when LDL-C is substantially reduced and HDL-C is increased by more than 7.5%. However, the meta-analysis was not powered to determine whether this regression, caused by these changes in lipid levels, was associated with a reduction in clinical events [5].

          We have reported in the past that clinical outcome in the structured care arm of the secondary CVD prevention GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study [10,11] was determined in part by the extent of atorvastatin-induced HDL-C increase. This effect (after multiple regression analysis HR = 0.85, 95% CI = 0.76-0.94, p = 0.002, with each 4 mg/dL increase) was independent from the benefit induced by LDL-C reduction and use of either angiotensin converting enzyme inhibitors or beta-blockers [10,11]. Moreover, it is plausible that the HDL-C increase contributed to clinical event rate reduction not only directly but also through renal function improvement, an independent CVD factor [12,13].

          Thus, this post hoc analysis shows that the relatively small increase in HDL-C (mean increase by 7%) observed in the structured care arm during the 3-year GREACE study contributed to clinical event reduction, over and above LDL-C reduction and other secondary prevention therapies. Our findings are in agreement with those of the meta-analysis of the 4 IVUS trials [5]. In the REVERSAL trial [6] the mean on-study LDL-C levels in the atorvastatin group (80 mg/d) were 79 mg/dl, reduced by 46.3% from baseline, while HDL-C was increased by only 2.9% (NS). In the ASTEROID [7] the mean on-study LDL-C levels were 61 mg/dl, reduced by 53.2% with 40 mg of rosuvastatin from baseline, while HDL-C was increased by 14.7% (p < 0.0001). This exceptionally large (for statin-induced) HDL-C increase might have contributed to the regression in atheroma volume seen in ASTEROID [7], while in REVERSAL [6] coronary atherosclerosis progression was halted by atorvastatin but there was no regression. In the target-based GREACE we used lower doses of atorvastatin (mean dose 24 mg versus the 80 mg used in REVERSAL) and this resulted in a greater HDL-C increase (7%, p < 0.001) [10,11]. In view of the fact that HDL-C decreases at high atorvastatin doses [11], this might have made a difference. On the other hand, high-dose atorvastatin significantly boosts the antiinflammatory effects of HDL [14] and is related to constrictive (beneficial) remodeling of the coronary artery wall [15]. These and other pleiotropic effects of statins such as the reduction in the levels of proatherogenic and proinflammatory lipids [16], the direct anti-inflammatory effect on the arterial wall [17], and the promotion of both HDL-C increase and HDL particle anti-inflammatory properties [18] seem also to be beneficial. Each of these effects may potentially contribute to the rate of plaque evolution [5] and beneficially influence clinical outcome [19].

Conclusions

These findings suggest that the even a small increase in HDL-C that occurs during statin therapy is clinically relevant when combined with intensive lowering of LDL-C. It seems that optimum clinical benefit is achieved with the combination of low LDL-C, high HDL-C, and low CRP levels.

Declaration of Interest

This study was conducted independently; no company or institution supported it financially. Some of the authors have given talks, attended conferences, and participated in trials and advisory boards sponsored by various pharmaceutical companies.

References

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