Beyond LDL-Cholesterol: The Role of Low HDL-Cholesterol and Elevated TG in Residual Cardiovascular Risk Remaining After Statin Therapy

Abstract

One of the most effective classes of medications for preventing cardiovascular events is 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, more commonly known as statins. Statin therapy has been shown to decrease cardiovascular morbidity and mortality rates in virtually every patient population studied and will likely continue to be a mainstay of cardiovascular risk prevention for years to come. However, close examination of statin clinical trial data reveals that, even though this class of drugs has been highly effective, an unacceptably large number of patients on statins still experience cardiovascular events. For example, in the Scandinavian Simvastatin Survival Study (4S) trial, which studied patients with very high levels of low-density lipoprotein cholesterol (LDL-C and known coronary heart disease (CHD), a significant risk reduction was observed with statin treatment. A greater percentage of patients on placebo (28%) experienced a major cardiovascular event than did patients on statin therapy (19%), and the relative risk of a major cardiovascular event in the statin-treated patients was 0.66.27 On the other hand, those results from 4S also indicate that, over the 5 years of the study, almost 20% of statin-treated patients still had a cardiovascular event. In several major statin trials, significant residual cardiovascular risk remained even after significant reductions in LDL-C had been achieved.27-32 Thus, despite the decrease in cardiovascular events due to statin treatment, two-thirds of the adverse cardiovascular events still occurred, which indicates that both patient lifestyle changes and new pharmacological strategies are necessary to address cardiovascular disease.33 Additional trials have included high-risk patients with CHD or diabetes who were treated with intensive LDL-lowering statin therapy. In 3 of these trials, as shown in Figure 1, lowering LDL-C to approximately 100 mg per dL was compared with more intensive LDL-C lowering to approximately 70 mg per dL to investigate cardiovascular event reduction even in high-risk patient populations.14-16,34 In the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study, 4,162 patients with acute coronary syndrome (ACS) were treated with either pravastatin 40 mg or atorvastatin 80 mg. Treatment with pravastatin reduced LDL-C to 95 mg per dL, whereas treatment with high-dose atorvastatin reduced LDL-C to 62 mg per dL.14 Clinical events were reduced in the high-dose atorvastatin group versus the pravastatin group; however, over the course of the 2-year trial, 22.4% of the individuals treated with intensive statin therapy (atorvastatin 80 mg) still suffered a major cardiovascular event.14 Similar results have been observed in the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study and the Treating to New Targets (TNT) study. After 4.8 years in the IDEAL study, 12.0% of patients experienced a major cardio vascular event even after intensive LDL-C lowering with 80 mg per day of atorvastatin.16 In the TNT trial, after 4.9 years of follow-up, 8.7% of patients receiving 80 mg per day of atorvastatin still suffered a major cardiovascular event.15 Thus, significant residual cardiovascular risk remains in patients even after intensive statin therapy that achieves LDL-C goals < 100 mg per dL.14-16,34 Patients with diabetes, another high-risk population, show significant cardiovascular risk reduction when treated with statins. A meta-analysis of 14 statin trials by the Cholesterol Treatment Trialists’ Collaborators examined data of major vascular events in patients with diabetes.2 A reduction in LDL-C in individuals with a prior history of CHD and either with or without diabetes was associated with a significant reduction in cardiovascular events. There was a 9% proportional reduction in all-cause mortality per 1 mmol per L (39 mg per dL) reduction in LDL-C in individuals with diabetes (P = 0.02) and a 13% reduction in those without diabetes (P < 0.001). Moreover, there was a significant 21% reduction in major vascular events per 1 mmol per L (39 mg per dL) reduction in LDL-C in people with diabetes (P < 0.001) and those without diabetes (P < 0.001).2 Nonetheless, in patients with diabetes treated with statin therapy, the cardiovascular event rate (i.e., residual cardiovascular risk) remained unacceptably high, and was even higher than the cardiovascular event rate of those patients without diabetes who received placebo.2 It is clear, then, that residual cardiovascular risk remains in all patients treated with statins, and that the residual cardiovascular risk is particularly high in patients with diabetes treated with statins.