Supported by a plethora of data, lowering low-density lipoprotein (LDL) cholesterol is the principal target of treatment for hyperlipidemia. Statins have subsequently emerged as the treatment of choice for both primary prevention and secondary intervention of cardiovascular disease. However, even once goal LDL levels are achieved, the risk of cardiovascular events remains quite significant.1,2 Cardiovascular risk is multifaceted, which may be estimated but ultimately very difficult to quantify. It is an aggregate of numerous risk factors that include, though not exclusive to: those defined by the Framingham Heart Study such as male gender, hypertension, and low high-density lipoprotein (HDL); life-habit risk factors, such a physical inactivity and atherogenic diet; and some emerging risk factors including lipoprotein (a) and proinflammatory markers such as C-reactive protein (CRP).3,4
The JUPITER trial specifically evaluated the effects of rosuvastatin 20 mg/day on the occurrence of primary cardiovascular events in patients with low LDL but elevated CRP levels. This multicenter, randomized, double-blind, placebo-controlled study of 17,802 patients found that when compared with placebo, rosuvastatin was associated with a 44% reduction in the primary endpoint, a composite of first non-fatal myocardial infarction (MI) or stroke, hospitalization for unstable angina, arterial revascularization, or cardiovascular death (hazard ratio [HR] for rosuvastatin, 0.56; 95% confidence interval [CI] 0.46-0.69, p <0.00001). It was estimated that 95 patients would need to be treated with rosuvastatin for 2 years to prevent one primary endpoint. Rosuvastatin treatment also resulted in a 54% reduction in MI, a 48% reduction in stroke, and a 20% reduction in total mortality.5 A recently published subgroup analysis of the JUPITER trial analyzed the residual risk of cardiovascular events and its association with HDL cholesterol levels.6
In 1977, the Framingham Heart Study determined HDL was the most potent lipid predictor of coronary artery disease (CAD) risk in men and women >49 years of age.4 Numerous studies since then have also reported a strong inverse relationship between HDL levels and cardiovascular risk.7,8 One study found that this relationship persists when LDL levels are below 60 mg/dL.9 Two other studies found that the lower pretreatment LDL levels, the greater the clinical impact of raising HDL.10,11 The subgroup analysis of the JUPITER trial contradicts many of these findings and suggests that, in at least statin-treated patients, HDL may not predict residual cardiovascular risk when very low LDL levels are achieved.
In the new subgroup analysis, patients were divided into quartiles based on their baseline and on-treatment HDL cholesterol. Hazard ratios comparing various HDL quartiles were determined for the primary endpoint and were done separately for patients receiving placebo and rosuvastatin. An analogous analysis was also repeated for baseline and on-treatment apolipoprotein A1 concentrations.
After a median follow-up of 1.9 years, rosuvastatin decreased LDL concentrations by 50% and increased HDL concentration by 4% when compared with placebo. Among patients receiving placebo, an inverse relationship between HDL quartiles and the first cardiovascular event was found. In other words, patients in quartiles representing lower HDL levels were more likely to experience a cardiovascular event than patients in quartiles representing high HDL levels. This was true for both the baseline (top quartile vs. bottom quartile HR 0.54, p = 0.0039) and on-treatment (HR 0.55, p = ...