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55th Annual Scientific Sessions of the American College of Cardiology

Atlanta, Georgia / March 11-14, 2006

Published data have been limited on the relationship between on-treatment HDL-C levels and major cardiovascular (CV) events in statin trials. Furthermore, there are no published data on the connection between on-treatment HDL-C levels and major CV events at lower on-treatment levels of LDL-C.

The Framingham and PROCAM (Prospective Cardiovascular Münster, Circulation 1997;96:2128-36) studies have demonstrated that the risk of coronary heart disease (CHD) was lower in persons with higher levels of HDL-C, even when LDL-C levels were low. Furthermore, the most recent National Cholesterol Education Program and European Joint Commission treatment guidelines recognize HDL-C as an important independent marker for increased risk of CHD.

HDL-C as CV Event Risk Predictor: A TNT Analysis

A new analysis of the TNT (Treating to New Targets) study finds that HDL-C remains an important predictor of CV risk in those patients who achieve LDL-C reductions with statin treatment, thus representing an important additional therapeutic target. “Even with the most intensive statin therapy, a residual risk for CV disease is apparent,” noted lead investigator of the analysis, Dr. Philip Barter, Director, The Heart Research Institute, Sydney, Australia. “Reductions in the residual risk apparent with statin therapy may be achieved by complementing statins with treatments that target other components of the dyslipidemic state.”

TNT was a randomized, double-blind, parallel-group, multicentre study that included 10,001 men and women aged 35 to 75 years with clinically evident CHD. The patients entered an eight-week, open-label, run-in phase with atorvastatin 10 mg/day. Following the open-label run-in, patients with LDL-C <3.36 mmol/L were randomized to double-blind treatment with atorvastatin 10 or 80 mg/day and followed for a median of 4.9 years.

Major CV events were calculated by quintiles of on-treatment HDL-C: <0.98 mmol/L; 0.98 to <1.11 mmol/L; 1.11 to <1.24 mmol/L; 1.24 to <1.42 mmol/L; and ³1.42 mmol/L. Patients in each HDL-C quintile were also grouped according to on-treatment LDL-C level (£2.06 mmol/L or >2.06 mmol/L).

An inverse relationship was found between the incidence of major CV events and HDL-C quintile. The incidence ranged from approximately 12% in the lowest two quintiles of HDL-C to <8% with HDL-C levels in the highest quintile.

“Based on these data, a 1-mg/dL [0.03 mmol/L] increment in HDL-C concentration in the TNT study was associated with an approximate 2% decrement in the relative risk of a major CV event,” stated Dr. Barter. “To put this result into context, a 1-mg/dL reduction in LDL-C during this study resulted in a reduction of 0.7% in the incidence of major CV events.”

The relationship between on-treatment HDL-C levels and the frequency of major CV events was maintained in both treatment groups. The inverse relationship between HDL-C and major CV events was also maintained in the £2.06 mmol/L and >2.06 mmol/L LDL-C subgroups. “Having low HDL-C is a risk, whether LDL-C is above or below 80 mg/dL [2.06 mmol/L],” remarked Dr. Barter. “From what we know epidemiologically, we suspect that if you raise HDL-C artificially, it will reduce the event rate.”

In TNT, the lowest risk was observed in those patients who attained low LDL-C and high HDL-C levels. This dual achievement was associated with a 58% reduction in the event rate compared with the patients who had high LDL-C and low HDL-C levels.

HDL-C Levels as Predictor of Mortality in Acute MI Patients

Data from a registry of 155 hospitals in Germany showed that HDL-C levels influence in-hospital and one-year outcomes in patients admitted with myocardial infarction (MI). Over a 29-month period (June 2000 to November 2002), consecutive patients with acute coronary syndromes (ST-segment elevation and non-ST-segment elevation MI) were enrolled in the registry, and the impact of HDL-C on in-hospital and one-year mortality was evaluated in 10,690 participants for whom cholesterol levels were available.

Led by Dr. Frank Towae, MI Research Institute, Ludwigshafen, Germany, the investigators compared patients with high HDL-C (>1.3 mmol/L for females and >1.03 mmol/L for males) with those with low HDL-C (£1.3 mmol/L for females and £1.03 mmol/L for males) on admission.

Patients with high HDL-C had a lower prevalence of concomitant diseases, such as diabetes and hypertension, compared with patients with low HDL-C levels (P<0.01). In-hospital mortality was 6.1% in the group with low HDL-C and 4.7% in the group with high HDL-C (P<0.01). At one year, mortality was again significantly higher in the patients with low vs. high HDL-C (9.9% vs. 6.9%; P<0.01). “Independent of the level of LDL-C, high HDL-C levels were associated with a 19% decreased hospital mortality and with a 25% decreased one-year mortality,” observed Dr. Towae.

Atheroprotective Shift in Lipoproteins

According to data presented by Dr. Jeffrey T. Kuvin, Tufts-New England Medical Center, Boston, Massachusetts, in patients with stable CHD receiving extended-release (ER) niacin, the ratio of small to large HDL particles undergoes a favourable shift, and the distribution of HDL and LDL subparticles and inflammatory markers is improved.

In this study, 54 patients with stable CHD and LDL-C levels <2.6 mmol/L received ER niacin 1000 mg/day or placebo for three months.

Lipoproteins and particle distribution were analyzed by proton nuclear magnetic resonance spectroscopy. HDL subparticles were divided into subclasses ranging from the largest diameter (11.5 nm) to the smallest (7.5 nm), as were LDL subparticles (largest, 22 nm; smallest, 19 nm).

Compared with placebo, three months of active treatment increased total HDL-C by 7.5% and decreased triglycerides by 15% (P<0.005). It also resulted in a 32% increase in large-particle HDL and an 8% decrease in small-particle HDL (P<0.05 for both). Large HDL particles are associated with lower risk of CHD whereas small HDL particles are a part of a more atherogenic dyslipidemia.

In patients receiving active treatment, there was also an 82% increase from baseline in the less atherogenic large-particle LDL vs. a 33% increase in the placebo cohort (P=0.09) and a 12% decrease in the more atherogenic small-particle LDL (P<0.05).

The inflammatory markers lipoprotein-associated phospholipase A2 (Lp-PLA2) and high-sensitivity C-reactive protein (hs-CRP) were also measured. Lp-PLA2 levels decreased by 20% (P<0.05) and hs-CRP decreased by 15% (P<0.05) in patients assigned to active treatment relative to those given placebo.

Hyper-responder Study Population

A database of users of ER niacin reveals a subset of hyper-responders who achieve a >50% increase in HDL-C levels over baseline. Findings were presented by Dr. Leonard M. Keilson, Maine Center for Lipids, Portland, which has maintained a database of 270 patients for whom the compound was provided for treatment periods as long as 10 years continuously.

Of these 270 patients, 13 were identified as hyper-responders, who experienced average increases in HDL-C of 90%. Sixty-nine per cent of the hyper-responders were treated with statin therapy for the entire treatment interval; all were treated with statins for at least two years. Triglycerides in the hyper-responders also decreased by 43% from baseline, noted Dr. Keilson. He added that a 30% improvement in HDL-C is expected with niacin and in a subset of patients there was a much greater response.

Summary

Although statins have become a first-line strategy in reducing CV events, a residual risk for CV disease still remains. Recent findings from large CV outcomes trials suggested the role of increasing HDL-C levels to further reduce event rates. Studies support the use of ER niacin in addition to statin-based therapy for producing an atheroprotective shift in lipoprotein subclasses, inflammatory markers and reducing triglyceride levels.