The European Society of Cardiology
Evolution of statin therapy: an ongoing story
University of Aarhus, Aarhus, Denmark
* Ole Faergeman, MD, DMSc, Professor of Preventive Cardiology, Department of Internal Medicine and Cardiology, Faculty of Health Sciences, Aarhus Amtssygehus University Hospital, University of Aarhus, Tage Hansens Gade 2, DK-8000 Aarhus C, Denmark. Tel.: +45-8949-7600; fax: +45-8949-7619
ole.faergeman{at}aas.auh.dk
Abstract
Major clinical end-point trials of cholesterol lowering with statins have shown consistent benefits in prevention of cardiovascular disease. Lessons from these trials include the findings that cardiovascular risk reduction is: (1) dependent on baseline cardiovascular risk; (2) dependent on magnitude of low-density lipoprotein cholesterol (LDL-C) reduction achieved with treatment; and (3) independent of initial LDL-C level. Ongoing studies will help to identify new markers of higher risk/higher treatment benefit and to define the merits of more aggressive LDL-C lowering.
Key Words: Statins • Cholesterol lowering • Cardiovascular disease risk • Low-density lipoprotein • Coronary heart disease
Introduction
Nine major randomized clinical trials of low-density lipoprotein cholesterol (LDL-C) lowering have taught us that statins reduce cardiovascular risk effectively and safely.1–9 These studies offer strong evidence regarding the benefits of statins in clinical practice when the following factors are taken into account: the patient’s baseline risk, the degree of LDL-C reduction achieved and the patient’s baseline LDL-C level.
Baseline risk
The degree of benefit in reducing cardiovascular risk observed with statin therapy in placebo-controlled clinical trials is related to baseline risk. As shown in Fig. 1, greater absolute percentage reductions in coronary heart disease (CHD) events have been observed in statin vs placebo arms in trials in patients with prior CHD than in patients without prior CHD.1–6 Moreover, as shown in Table 1, absolute reductions in all-cause mortality are higher in trials with higher overall mortality rates, reflecting greater underlying risk of the population studied.1–6,9
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A number of analyses of effects of risk factors on outcome in the Scandinavian Simvastatin Survival Study (4S) trial emphasize the relationship between risk and degree of benefit.10 Absolute risk reductions for mortality for the simvastatin vs placebo arms according to patient age were 3.0% in those aged
59 years, 3.9% in those aged 60–65 years and 6.2% in those aged 66–70 years. Simvastatin treatment was associated with a 55% reduction in risk for CHD death or non-fatal myocardial infarction among diabetic patients, which was greater than the risk reduction observed with statin treatment among non-diabetic patients.11 Placebo patients in the highest triglyceride quartile (
1.85 mmol/l [164 mg/dl]) had greater mortality, and statin patients in the highest quartile had the greatest reduction in mortality (13.7% vs 8.4%) compared with lower quartiles (1.45–1.85 mmol/l [129–164 mg/dl], 10.6% vs 7.5%; 1.15–1.45 mmol/l [102–129 mg/dl], 10.2% vs 7.2%; and 1.15 mmol/l [102 mg/dl], 11.5% vs 8.9%). The same was true for placebo vs simvastatin patients in the lowest high-density lipoprotein cholesterol (HDL-C) quartile (1.0 mmol/l [40 mg/dl], 14.3% vs 8.9% mortality) compared with higher quartiles (1.1–1.15 mmol/l [43–44 mg/dl], 11.5% vs 8.6%; 1.15–1.30 mmol/l [44–50 mg/dl], 10.3% vs 6.0%; and 1.3 mmol/l [50 mg/dl], 9.7% vs 8.2%).
With regard to potential new risk markers, analysis according to the presence or absence of the 
4 allele of the apolipoprotein (apo)E gene (a common polymorphism in the Danish and Finish populations) showed that placebo patients who were carriers of the allele had a markedly increased risk for death over follow-up than did those who were not carriers (Fig. 2).12 This difference in risk was not observed between 4 carriers and non-carriers among patients receiving simvastatin, however, suggesting that simvastatin treatment essentially removed the increased risk associated with the allele (Fig. 2). Increased concentrations of lipoprotein(a) (Lp[a]), which are also largely genetically determined, also increased mortality risk in 4S, and analysis of 4 status by high (
30 mg/dl) or low Lp(a) among placebo patients indicated markedly increased risk among 4 carriers with high Lp(a). Mortality among these patients was 21.3%, compared with 12.5% in 4-negative/high Lp(a) patients, 12.6% among 4-positive/low Lp(a) patients and 6.5% among 4-negative/low Lp(a) patients. Simvastatin treatment preferentially benefited 4-positive/high Lp(a) patients compared with the placebo counterparts, with the hazard ratio for mortality being 0.22 (95% confidence interval [CI], 0.06–0.77); by comparison, the hazard ratio associated with statin treatment was 0.48 (95% CI, 0.25–0.93) among 4-negative/high Lp(a) and 4-positive/low Lp(a) patients and was not significant among 4-negative/low Lp(a) patients (0.87, 95% CI, 0.36–2.08).
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Thus, analyses in the 4S population showed that a number of risk factors other than LDL-C identified both high risk and greatest benefit of statin treatment––including established CHD, older age, diabetes, high triglycerides, low HDL-C, apoE4 genotype and high Lp(a). These analyses also point out that the mechanisms by which risk is increased by these factors are not necessarily the mechanism by which risk is decreased by statins. For example, although statin treatment may disproportionately benefit older patients, it does not do so by making patients younger!
Degree of cholesterol lowering
A number of ongoing trials are directly addressing the question of whether greater reductions in LDL-C produce greater reductions in CHD risk. However, there is already considerable evidence that this is the case. As shown in Fig. 1, risk for CHD events decreases with lower LDL-C achieved on treatment. Table 2 shows odds ratios for mortality and CHD events in long-term statin trials. The only trial in which CHD events were not reduced significantly was the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT), and the authors of the ALLHAT-LLT report noted that the absence of a significant reduction in CHD risk in that trial was probably related to the overall small 9.6% difference in total cholesterol level achieved between the statin and placebo groups.8 It is of interest in this regard that the reduction in CHD events observed in the Program on the Surgical Control of the Hyperlipidemias (POSCH) trial13 of partial ileal bypass, a surgical procedure that lowers LDL-C, falls precisely on the regression line resulting from the plotting of relative risk for CHD events to percentage reduction in total cholesterol observed in the statin trials, consistent with the concept that it is the degree of lowering of LDL-C that determines the magnitude of reduction in CHD events.
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There has been debate over whether the relationship between risk reduction and LDL-C reduction is a threshold effect, a linear effect or a curvilinear effect. Our experience in the 4S trial suggests that the effect is curvilinear, with a gradual tapering of percent reduction in coronary events observed at greater percentage LDL-C reductions.
Baseline low-density lipoprotein cholesterol
The Heart Protection Study6 showed that degree of benefit of statin therapy is independent of initial LDL-C level in high-risk patients. As shown in Fig. 3, reduction of risk for major vascular events with statin therapy was similar among patients with baseline LDL-C 2.6 mmol/l (100 mg/dl), 2.6–3.4 mmol/l (100–130 mg/dl) and 3.4 mmol/l (130 mg/dl) in the context of reduction in LDL-C of approximately 1.0 mmol/l (40 mg/dl) in each of the subgroups. This finding indicates that LDL-C reduction is associated with benefit even in patients starting therapy at levels below those currently recognized as target levels. The 4S trial also showed that there was no threshold concentration of LDL-C below which preventive benefit was not observed and that benefit was achieved irrespective of initial LDL-C level.14 Fig. 3 shows differences in major coronary events between simvastatin and placebo patients according to quartiles of baseline LDL-C.15
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Conclusion
Clinical trials of LDL-C lowering with statins indicate that cardiovascular risk reduction is dependent on baseline risk, dependent on magnitude of LDL-C reduction achieved and independent of initial LDL-C level. Challenges remaining in the clinical setting include identifying additional markers of high risk and high benefit, establishing the equivalency or superiority of newer statins compared with the older statins that have been evaluated in the majority of clinical end-point trials and defining the merits of more robust LDL-C reduction. In addition, work remains to be done in defining mechanisms in addition to LDL-C reduction and beneficial effects on other lipid parameters by which statins reduce cardiovascular risk.
References
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