High density lipoprotein complete list of trials

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

Landmark Trials

VA-HIT Trial

• OBJECTIVE: To conclude if changes in plasma lipid levels due to gemfibrozil is the cause for reduction in major cardiovascular events in VA-HIT trial.
• METHOD: VA-HIT (Veterans Affairs HDL Intervention Trial) trial is a multicentered, randomized, double-blinded, placebo-controlled trial wherein 2531 patients with CAD along with LDL levels ≤140 mg/dL (mean 111 mg/dL) and HDL ≤40 mg/dL (mean 32 mg/dL) were randomly assigned to treatment with gemfibrozil or placebo.
• RESULTS: At one year the following findings were noted in the group treated with gemfibrozil:
  • Mean HDL-C level was higher by 6%
  • 31% lower mean TG concentration
  • Mean total cholesterol was 4% lower

At five years, the combined primary end point of cardiac death and non-fatal myocardial infarction occurred in 17.3% versus 21.7% in the placebo group. Acute coronary events reduced by 11% with gemfibrozil for every 5 mg/dL rise in HDL-C, but the reduction was independent of changes in LDL-C and triglyceride levels.

• CONCLUSION: Low HDL-C levels strongly and independently predict the occurrence of coronary events which were reduced by treatment with gemfibrozil.

AIM-HIGH Trial

• OBJECTIVE: To assess if niacin + simvastatin combination is superior to simvastatin alone in raising low levels of high density lipoprotein (HDL).
• METHOD: AIM-HIGH is a randomized trial wherein 3414 patients randomly received either extended release niacin (1500 to 2000 md per day) or a matching placebo. All patients received simvastatin 40 to 80 mg daily to maintain an LDL-C level in the range of 40-80 mg/dL. Ezetimibe 10 mg daily was added, if needed, to achieve the LDL goal. The primary end point was the first event of the composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization.
• RESULTS: The trial was stopped prematurely for futility after a follow-up of 36 months. At two years compared to placebo, niacin increased HDL-C levels and reduced triglyceride and LDL-C levels but there was no reduction in the rate of primary endpoint or all-cause mortality with niacin. Moreover, there was a trend towards more ischemic strokes in the niacin group. This led to the decision to halt the trial prematurely.
• CONCLUSION: No incremental clinical benefit was observed from addition of niacin to simvastatin during a 36 month follow-up. Also, elevations in HDL-C levels in the placebo group were higher than expected which may have reduced the competency of the trial to detect a real benefit with niacin therapy.

Trial of Simvastatin Plus Niacin

• OBJECTIVE: To suggest that additional benefits may be observed in patients with low HDL-C by combining a statin with a drug that elevates HDL-C.
• METHOD: This was a three year randomized trial that enrolled 160 patients with clinical and angiographic evidence of coronary artery disease who had an HDL-C <35 mg/dL and an LDL-C <145 mg/dL. Patients were randomly assigned into 4 groups: simvastatin plus niacin; antioxidants; simvastatin plus niacin plus antioxidants or placebo.
• RESULTS: Mean serum LDL and HDL levels changed substantially in the simvastatin plus niacin group while levels in the antioxidants and placebo groups remained unaltered. Also, patients receiving simvastatin and niacin sustained lower cardiovascular events and experienced angiographic regression of the most significant coronary artery stenosis compared with patients receiving antioxidants or placebo.
• CONCLUSION: Addition of a drug that increases HDL-C levels to a statin proves to have additional protection over just statin alone.

ARBITER 2 Trial

• OBJECTIVE: To assess if treatment with extended release niacin when added to statin monotherapy slows progression of atherosclerosis among individuals with known coronary artery disease (CAD) and moderately low HDL-C.
• METHOD: ARBITER (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol) 2 was a double blinded randomized placebo controlled study of once daily extended release niacin (1000 mg). 167 patients with known CAD and moderately low HDL-C were enrolled in this study and were assessed for the primary end-point carotid intima-media thickness (CIMT) at the end of one year.
• RESULTS: At the end of 12 months mean CIMT significantly increased in the placebo group but not in the niacin group. Niacin significantly reduced the rate of IMT progression in patients without insulin resistance. Patients treated with niacin had a significant increase in HDL levels from a mean of 39 mg/dL to 47 mg/dL.
• CONCLUSION: The addition of extended-release niacin to statin therapy slowed the progression of atherosclerosis among individuals with known coronary heart disease and moderately low HDL-C.

ARBITER 3 Trial

• OBJECTIVE: To study the effects of long term treatment with extended release niacin (ERN) on HDL levels and carotid intima- media thickness in patients who participated in ARBITER 2.
• METHODS: 88% (149) of patients enrolled in ARBITER trial participated in ARBITER 3 trial, those who either were continued or crossed over to the placebo group. The long term effects of ERN on HDL cholesterol and carotid intima- media thickness were examined during 12- 24 months of treatment.

CLAS Trial

• OBJECTIVE: To determine whether combined therapy with the lipid lowering agents colestipol hydrochloride plus niacin would produce significant change in coronary, carotid, and femoral artery atherosclerosis and coronary bypass graft lesions as determined by angiography. Also, to determine possible correlations between lesion changes and plasma lipid and lipoprotein cholesterol levels and to explore interrelationships of atherosclerosis change in femoral, coronary, and carotid arteries.
• METHOD: CLAS (Cholesterol Lowering Atherosclerosis Study) was a randomized, selectively blinded study wherein 188 men, with known previous coronary artery bypass grafts, were randomized to diet plus placebo or diet plus combined lipid lowering therapy consisting of colestipol and niacin and followed up at 2 years and 4 years.
• RESULTS: The following results were noted:
  • Treatment group had a 37% raise in HDL-C levels and a 43% reduction in LDL-C levels.
  • Regression of atherosclerosis, as measured by angiography, was greater with combined drug treatment at 2 years and at 4 years.
  • Reduction in the percentage of subjects with new atheroma formation in native coronary arteries.
  • Significantly reduced percentage of subjects with new lesions or any adverse change in bypass grafts.
  • Atherosclerosis regression occurred in 16.2% of colestipol-niacin treated vs 2.4% placebo treated
• CONCLUSION: The benefit of combined nicotinic acid and colestipol therapy was most prominent in patients with baseline plasma cholesterol levels above 240 mg/dL.

FATS Trial

• OBJECTIVE: To compare the effects of two intensive lipid altering therapies in men with familial combined hyperlipidemia as assessed by arteriography.
• METHOD: Familial Atherosclerosis Treatment Study (FATS) is a randomized, double blinded, placebo controlled study wherein 146 men with one coronary stenosis of greater than 50 percent or three lesions of greater than 30 percent were enrolled and randomized into three groups. The groups included:
  • Placebo plus low dose colestipol (if needed, to lower LDL)
  • Niacin (1 g QID) plus colestipol (10 g TID)
  • Lovastatin (20 mg BID) plus colestipol (10 g TID)

The primary endpoint was a measure of change in the severity of disease in the proximal coronary arteries as measured by quantitative arteriography.

• RESULTS: Both the intensive lipid lowering therapies were equally effective. Both reduced the frequency of progression of coronary lesions (21% and 25% versus 46% in the control group), increased the frequency of regression (32% and 39% versus 11%), and reduced the incidence of cardiovascular events in men with coronary artery disease who were at high risk for cardiovascular events.

Trials on Investigational Therapies

ERASE Trial

• OBJECTIVE: To study the effects of reconstituted HDL on atheromatous plaque volume.
• METHOD: This was a randomized placebo-controlled trial conducted in 17 centers across Canada. An intravascular ultrasound was performed at baseline and at 2 to 3 weeks after the last infusion to assess plaque burden.
• RESULTS: The group with higher doses of reconstituted HDL (CSL-111) was eliminated from the study because of mild liver function test abnormalities. The results of the study are briefed below:
  • Percentage change in plaque volume: -3.4% with CSL-111 and -1.6% with placebo (P= 0.48 between the groups, P< 0.001 vs baseline for CSL-111)
  • Nominal change in plaque volume: -5.3% with CSL-111 and -2.3% with placebo (P= 0.39 between the groups, P< 0.001 vs baseline for CSL-111)
  • Mean changes in plaque characterization on IVUS: −0.0097 for CSL-111 and 0.0128 with placebo (P = .01)
  • Mean changes in coronary score on quantitative coronary angiography: −0.039 mm for CSL-111 and −0.071 mm with placebo (P= 0.03)
• CONCLUSIONS: Short term infusions of reconstituted HDL (CSL-111) resulted in:
  • No significant reductions in percentage change and nominal change in plaque volume compared to placebo.
  • Statistically significant improvement in mean changes in plaque characterization on IVUS and coronary score on quantitative coronary angiography, compared to placebo.

Infusion of Apo A-1 Milano

• OBJECTIVE: To study the effects of Apo A-1 Milano on plaque burden on arteries.
• METHOD: Apo A-1 was infused in cholesterol fed rabbits and showed a decreased intimal thickness and macrophage content after balloon injury in femoral and iliac arteries. Based on these results, another pilot trial was designed using recombinant Apo A-1 Milano phospholipid complex (ETC-216) in 57 patients within two weeks of the onset of acute coronary syndrome. Subjects were randomly assigned to the ETC 216 infusion group at 15 mg/kg or 45 mg/kg or to placebo group. IVUS was performed at baseline and repeated at the completion of the study.
• RESULTS: Treatment with ETC-216 (in both doses) resulted in a significant decrease in mean percentage of coronary artery volume occupied by atheroma as well as the total atheroma volume. Whereas the placebo group did not show any significant change.
• CONCLUSIONS: Although Apo A-1 Milano infusions resulted in decrease in plaque burden, further study is required assess efficacy, safety and cost-effectiveness.