Discussion
Our results show that there is large interindividual variation with regard to the reduction of atherogenic lipoprotein levels achieved with statin therapy. As a consequence, >40% of trial patients assigned to high-dose statin therapy did not reach an LDL-C level <70 mg/dl (Central Illustration). The clinical benefit of achieving even lower levels of atherogenic lipoproteins appears to be considerable because patients achieving an LDL-C level <50 mg/dl are at significantly lower risk for major cardiovascular events, even when compared with those reaching LDL-C levels 75 to <100 mg/dl.
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Central Illustration.
On-Statin LDL-C Levels and Risk for Major Cardiovascular Events
Distribution of achieved on-statin LDL-C levels (dark blue curve; right y-axis) and the risk of major cardiovascular events (light blue line; left y-axis). The x-axis represents achieved on-statin LDL-C levels. LDL C = low-density lipoprotein cholesterol; HR = hazard ratio.
It is well-known that there is large interindividual variation in the response to statin therapy. However, our results highlight an underappreciated aspect, namely, that some patients achieve a large reduction of atherogenic lipoprotein levels, whereas others respond poorly. Therefore, the current management of dyslipidemia continues to be suboptimal. Multiple patient characteristics, including sex, age, smoking status, body weight, diet, and physical activity have been reported to contribute to variations in statin-induced LDL-C reduction, but the impact of these factors is modest. However, nonadherence is probably one of the most important factors in the failure of patients to reach their lipid targets. Nonadherence is a complex entity and is affected by several factors, including dose-related toxicity and adverse effects, physician-related issues, and patient-related issues such as depression.
Several studies have investigated the association between genetic variants and the magnitude of LDL-C reduction achieved with a fixed-dose statin. For instance, among patients treated with pravastatin 40 mg, 2 common variants in the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene (HMGCR) were shown to have been associated with lower efficacy of pravastatin treatment. In a genetic substudy of the TNT trial, variants of APOE, PCSK9, and HMGCR also were associated with statin efficacy, in this case atorvastatin. A genome-wide association study in the JUPITER trial identified variants of ABCG2, LPA, APOE, and PCSK9 to be involved in response to rosuvastatin. Voora et al. reported that variants in the APOE and ABCA1 genes also were associated with statin efficacy. Overall, the lack of strong genetic effects on statin-induced lipid response in these large trials is likely a reflection of the complexity of lipid homeostasis and suggests that variability in response is due to a range of small effects superimposed on nonadherence. Thus, the most important causes of inadequate lipid lowering achieved with statin therapy are largely unexplained.
The U.S. Executive Summary of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults guideline recommends that for patients with CHD or a CHD risk equivalent, the LDL-C goal should be <100 mg/dl. The more recently published European guidelines recommend that for people at high CVD risk, the LDL-C goal is <2.5 mmol/l (~100 mg/dl). These guidelines also suggest a target of <70 mg/dl or <1.8 mmol/l, respectively, for patients at very high CVD risk, but these recommendations are not evidence based. Our results suggest that even in the optimal setting of a randomized controlled trial, >40% of patients assigned to high-dose statin therapy do not reach an LDL-C level <70 mg/dl. However, Phase 2 data from trials of PCSK9 inhibitors suggest that the large majority of patients treated with those agents may be able to reach LDL-C levels <70 mg/dl.
Whether achieving very low levels of atherogenic lipoproteins is indeed beneficial in terms of CVD risk is unclear. Post-hoc analyses of data from several statin trials have shown that patients achieving very low LDL-C levels on statin therapy are at lower CVD risk than are those achieving moderately low levels, although the number of patients achieving very low LDL-C levels in individual trials is usually small. As reported in a substudy of the PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) trial, there was no adverse effect and even an apparently lower cardiovascular risk in patients who reached LDL-C levels lower than the target 80 to <100 mg/dl. A post-hoc analysis of data from the TNT trial showed that there was a significant reduction in the rate of major cardiovascular events with descending quintiles of achieved on-treatment LDL-C, even down to the lowest quintile, which was defined as <64 mg/dl. In JUPITER, statin-allocated participants attaining LDL-C <50 mg/dl had a lower risk for cardiovascular events than did those not reaching LDL-C <50 mg/dl. Our large-scale meta-analysis supports the results of those studies and suggests that achieving very low levels of atherogenic lipoproteins seems to provide cardiovascular benefit beyond just treatment with a statin. With regard to the safety of very low levels of atherogenic lipoproteins, we observed that the risk for hemorrhagic stroke appeared to be somewhat higher among patients achieving very low levels of atherogenic lipoproteins than among those achieving moderately low levels. However, the number of hemorrhagic strokes was low, so statistical power was insufficient to draw definite conclusions, and this small potential relative increase in hemorrhagic stroke was outweighed by a much lower risk for other cerebrovascular events. Thus, the overall risk for major cerebrovascular events was still lowest among patients achieving very low levels of atherogenic lipoproteins.
Several aspects need to be taken into account when interpreting the results of this analysis. An important strength of this study was the availability of individual patient data, which enabled individual-level patient analyses, which in turn provide more appropriate and accurate results than do study-level analyses. A second strength was the fact that the dataset contained large numbers of patients and major cardiovascular events, allowing for more reliable analyses of the relatively small group of patients reaching very low levels of atherogenic lipoproteins, which in individual trials is usually a small number.
Study Limitations
The most important limitation was the fact that this was a post-hoc analysis on the basis of observational data, which cannot be extrapolated to treatment recommendations. A second limitation was the fact that the participating trials had different inclusion criteria. The different distributions of baseline characteristics may have affected the results of our meta-analysis. In particular, inclusion on the basis of lipid criteria may have led to the selection of specific subpopulations of patients in some trials. In addition, outcome definitions may have differed slightly between trials. The results were on the basis of patients included in trials, and these results cannot necessarily be extrapolated to patients in routine clinical practice. Another limitation was the use of on-statin lipid and apolipoprotein levels measured at 1-year follow-up. This time point was chosen because it was the first uniform time point when lipids and apolipoproteins were measured in all participating trials. Therefore, fatal cardiovascular events occurring in the first year of therapy are not accounted for in this analysis. Finally, part of the variability of LDL-C reductions observed in the trials may not have a strict biological explanation but also could be explained by drug interactions or other factors, such as noncompliance—a factor that could not be accounted for in the present analysis.