Post-hoc Analysis of 4S Trial Highlights Additional Risk of Low HDL-C
It is becoming more widely recognized that simply treating elevated levels of low-density lipoprotein cholesterol (LDL-C) fails to protect all patients against future cardiovascular disease (CVD) events. This failure occurs despite the fact that statins are among the safest and most efficacious drugs available to clinicians, and thus to go "beyond statin therapy" will probably require going beyond simply seeking ever more potent statin doses for lowering LDL-C to even lower circulating serum levels. Intuitively, based on the widely verified epidemiologic observation that elevated high-density lipoprotein cholesterol (HDL-C) levels are generally associated with protection against CVD events, therapeutically raising HDL-C should be an attractive goal. Although there were no updates at the 2008 European Society of Cardiology (ESC) Congress on drugs currently in development to raise levels of HDL-C, new data were presented on results with well-established drugs as well as on some of the newer therapies in the field, as well as highlighting the residual risk in patients in whom low-density lipoprotein cholesterol (LDL-C) is already well-controlled.
It has been found that of the roughly half of all patients with coronary heart disease (CHD) who fail to achieve protection against events, despite being on an optimal regimen of statin therapy, over one third have low serum HDL-C levels. In fact, low HDL-C is a significant independent risk factor whether patients are enrolled with high, or even low levels of LDL-C (< 100 mg/dL; < 2.6 mmol/L). Now a post-hoc analysis of patients with CHD in the famous Scandinavian Simvastatin Survival Study (4S) has shown showed that for patients with low HDL-C and high LDL-C (≥ 100 mg/dL; ≥ 2.6 mmol/L), there was a 50% increased risk for major cardiovascular events (MCEs) compared to patients who had elevated LDL-C alone.
Original 4S. The original 4S trial randomized patients with CHD (angina pectoris or previous myocardial infarction [MI]) and serum total cholesterol 5.5 to 8.0 mmol/L (213-310 mg/dL), triglycerides ≥ 2.5 mmol/L (220 mg/dL) to double-blind treatment with simvastatin 20 to 40 mg or placebo once daily. Over a median follow-up of 5.4 years, the risk of MCEs was reduced by 34% in the patients treated with simvastatin compared with placebo (P < .00001). The reduction in MCEs was shown to be highly correlated with the degree of LDL-C lowering, ie, on-treatment cholesterol levels, as well as with the magnitude of change from baseline in total cholesterol, LDL-C, apolipoprotein B, and less so with increases in HDL-C.
Post-hoc Analysis. For the latest post-hoc analysis, researchers from the University of Oslo (Norway) and Merck & Co (Whitehouse Station, N J) analyzed data from patients on the simvastatin arm of 4S with elevated LDL-C at year 1 of treatment. Elevated LDL-C at year 1 was defined according to National Cholesterol Education Program (NCEP) Adult treatment Panel (ATP) I (1988) as ≥ 3.4 mmol/L (130 mg/dL) or NCEP ATP II (1993) as ≥ 2.6 mmol/L (100 mg/dL). Low HDL-C at year 1 was defined as < 1 mmol/L (< 40 mg/dL) for men and < 1.3 mmol/L (< 50 mg/dL) for women. MCEs were evaluated from year 1 to the end of follow-up, over 4 years on average.
After exclusion of patients with missing LDL-C or HDL-C measurements or already with MCEs at year 1, a total of 2069 patients on simvastatin were included in the analysis. Hazard ratios were adjusted for baseline age, gender, history of hypertension, MI, and diabetes, smoking, and 1-year LDL-C and triglyceride values.
A total of 1450 patients on simvastatin had LDL-C ≥ 100 mg/dL at year 1, and of these, 37% had low HDL-C. Compared with patients with elevated LDL-C alone, patients who also had low HDL-C were younger, had more diabetes, and had slightly lower LDL-C on average (P < .05).
Overall patients with LDL-C ≥ 100 mg/dL had a higher incidence rate of MCEs (26.3%) compared to patients with LDL-C < 100 mg/dL (21.2%%, P < .05). Multivariable analysis showed that low HDL-C in addition to LDL-C ≥ 100 mg/dL was associated with a 50% increased risk for MCEs ( Table 1 ). In a sensitivity analysis in patients with LDL-C < 130 mg/dL, low HDL-C was associated with a statistically significant 70% increased risk for MCEs.
As the first of the major statin trials, 4S was instrumental in establishing the principle that lowering LDL-C levels is protective against CHD events. It is therefore important that this original cohort now further reinforces the epidemiologic observation that higher HDL-C levels are more protective than lower ones, independent of what a patient's LDL-C values are. Being a post-hoc analysis, this study suffers from the usual limiations, specifically that it was restricted by inclusion and exclusion criteria of the 4S trial, so that, for example, only patients with triglycerides ≥ 2.5 mmol/L and CHD were included in the analysis. Nevertheless, this post-hoc analysis offers yet another bit of evidence supporting the importance of HDL-C levels as an independent risk factor.
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Cite this: Studies of Raising HDL Cholesterol: Updates at ESC 2008 - Medscape - Jan 05, 2009.