Nov 10, 2004

New Orleans - Results from the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER-2) study have shown that the addition of extended-release niacin to statin therapy slowed the progression of atherosclerosis as measured by carotid intima-media thickness (IMT) among coronary heart disease patients with low HDL cholesterol levels. After one year of treatment, mean carotid IMT increased significantly in those not treated with niacin, while no significant increase in IMT was found in the niacin-treated patients.

Dr Allen Taylor

Presenting the data at the 2004 American Heart Association (AHA) Scientific Sessions, lead investigator Dr Allen Taylor (Walter Reed Army Medical Center, Washington, DC) said the results of the study are encouraging, especially given that niacin was able to significantly increase HDL cholesterol levels and slow disease progression in appropriately treated statin-therapy patients.

"Patients with known coronary heart disease treated with statin therapy who are at their LDL cholesterol goal still demonstrated substantial progression of atherosclerosis in the setting of moderately low HDL cholesterol," said Taylor. "This is the first trial to show that combination therapy targeting HDL cholesterol slows the progression of atherosclerosis, and it calls for the standard inclusion of prescription niacin to improve HDL cholesterol levels."

To coincide with the AHA presentation, the study is also published online before print in Circulation.[1]

The ARBITER-2 study was a randomized, double-blind, placebo-controlled study of once-daily extended-release niacin (1000 mg) added to a background of lipid-lowering therapy in 167 patients with known coronary heart disease and low HDL cholesterol levels, those with levels <45 mg/dL. At baseline, a majority of patients were at their NCEP ATP III goal for LDL cholesterol of <100 mg/dL, with an average LDL cholesterol level of 89 mg/dL. Before enrollment, patients were treated predominantly with simvastatin, average dose 35 mg, for 4.5 years.

The primary end point of the study was change in carotid IMT after one year as assessed within each study medication group.

After 12 months, HDL cholesterol levels increased significantly in patients treated with niacin, increasing from 39 mg/dL to 47 mg/dL, a statistically significant 21% increase. Mean carotid IMT increased significantly in the placebo group but was unchanged in those patients randomized to niacin, increasing 0.044 mm in the placebo-treated patients and 0.014 mm in the niacin group. When investigators compared IMT progression between the study arms—a prespecified end point—they found that niacin slowed atherosclerotic progression 68% compared with the placebo-treated patients, although this result did not achieve statistical significance.

The one that's here and mature, and we know its safety and efficacy profile, is niacin.

"We've had niacin in use for over four decades now," said Taylor. "We turned away from it as statins emerged because they were so easy to apply and they had hard outcomes evidence. That was an appropriate clinical response. But the recognition that there are events still occurring is leading to interest in other drugs for combination therapy. This increasing focus on increasing HDL is consistent with the guidelines; even if the guidelines don't recommend treating HDL cholesterol, they do increase our focus on it. Coupled with that are the emerging therapeutics directed at HDL. But the one that's here and mature, and we know its safety and efficacy profile, is niacin."

There were nine patients who withdrew from the niacin arm, two out of concern for adverse drug effects. Flushing occurred in a majority of patients treated with niacin and appeared to be a side effect that was managed fairly effectively with aspirin and nighttime dosing, said Taylor.

Addressing the issue of the surrogate IMT end point, Taylor pointed out that IMT is a valid surrogate accepted by the Food and Drug Administration to demonstrate the ability of a drug to prevent the progression of atherosclerosis. He added that despite the lack of hard clinical outcome data, he is encouraged by the increase in HDL cholesterol. "We know that at any level of LDL, the lower your HDL cholesterol, the greater the risk," he said.

Interestingly, in 88 subjects with diabetes or metabolic syndrome, the lowest progression rate was observed in patients with normal glycemic status. A statistically significant difference in carotid IMT progression was observed between patients with normal glycemic index treated with niacin and those treated with placebo (p=0.026), although Taylor stressed the numbers are very small and the result could be a statistical anomaly. No significant differences were observed in patients with insulin resistance.

"The strongest effect was seen in patients without diabetes and metabolic syndrome," said Taylor. "Within that group, there actually was a statistical difference between groups, although this wasn't a prespecified analysis and should be hypothesis generating only."

Commenting on the study during the late-breaking clinical-trials session, Dr Phillip Greenland (Northwestern University, Chicago, IL) said the study is important because it focuses on the concept that there is more to lipid management than just LDL cholesterol but stressed that the end point was a surrogate, and not a clinical, end point.

Patient management should not necessarily be changed on the basis this single, well-done, surrogate-end-point study.

"Patient management should not necessarily be changed on the basis this single, well-done, surrogate-end-point study," said Greenland.

Greenland added that with the new NCEP cholesterol guidelines—those requiring clinicians to treat to much lower LDL targets—it remains to be seen whether the same benefit would be seen in patients with LDL levels <70 mg/dL. Also, it is not known how many patients who reach the LDL cholesterol target of less than 70 mg/dL would require additional lipid-lowering therapy, such as HDL-raising niacin therapy. Still, he added, the study reinforces conventional wisdom that lowering to LDL cholesterol <100 mg/dL is "not good enough," as patients in the placebo arm who achieved this target but did not receive niacin had significant atherosclerosis worsening.

"What we know today is that HDL metabolism is complex, and more research on this topic is definitely needed," said Greenland. "This study raises the possibility that existing drugs, already within our clinical armamentarium, could play an even larger role in some proportion of coronary patients. A clinical trial in patients similar to those in this study, in which coronary events are the primary end point, would be well justified."