Abstract & Commentary
Synopsis: The addition of niacin to patients with known CAD on statins raised HDL cholesterol and reduced atherosclerosis progression.
Source: Taylor AJ, et al. Circulation. 2004;110: 3512-3517.
Although good at lowering LDL cholesterol, statins do not raise HDL enough in many patients. Niacin is the most effective therapy for low HDL, but little information exists about combination niacin and statin therapy on cardiovascular outcomes. Thus, the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study was conducted at Walter Reed Army Medical Center to evaluate the effect of adding niacin to statins on carotid intima-media thickness (CMT) in patients with known coronary artery disease (CAD). This was a double-blind, randomized, placebo-controlled study in 167 patients with CAD documented by myocardial infarction or coronary revascularization. Patients on statins with LDL < 130 and HDL < 45, and no known contraindication to niacin, were randomized to placebo or extended-release niacin starting at 500 mg for 30 days, then 1000 mg for 11 months. Only 4 patients had their statin dose changed during the study. The primary end point of CMT change at 1 year was increased in the placebo group by 0.044 mm (P < .001) and was unchanged in the niacin group, 0.014; P = 0.23. LDL was 89 at baseline and was unchanged by niacin therapy. HDL averaged 39 in the niacin group at baseline and increased to 47 (P < .001); there were no changes in the placebo group. Triglycerides also decreased in the niacin group (164 to 134; P < .01), but fasting glucose increased (107 to 123; P = 0.017). CRP measures were unchanged by niacin. Patients without insulin resistance (diabetes or metabolic syndrome) on niacin had the lowest progression rate of CMT. Cardiovascular events occurred in 3 niacin patients and in 7 placebo patients (P = NS). Study drug adherence was > 90%, and not different between placebo and niacin. No patient had liver tests > 3 times the upper normal limit, and none had myositis. The majority of patients on niacin noted skin flushing. Taylor et al concluded that the addition of niacin to patients with known CAD on statins raised HDL cholesterol and reduced atherosclerosis progression.
Comment by Michael H. Crawford, MD
Although it is well-known that niacin raises HDL levels, the value of this effect, in addition to statins and its tolerability, has been poorly defined. The coronary drug project evaluated niacin monotherapy and showed a reduction in nonfatal myocardial infarction and 15-year mortality, but other studies employing niacin included it with other agents, making it difficult to tease out the effects of niacin alone. This is the first study of moderate-dose niacin added to statins in a systematic, controlled fashion. The study was not powered for clinical outcomes, but rather used CMT as a surrogate. Despite an average duration of statin therapy of about 5 years and average LDL levels of 85 to 90, the placebo group showed progression in CMT. There are several explanations for this: The low HDLs, high triglycerides (average > 150), or failure to drive the LDL below 80 in all the statin patients. Niacin addressed the first 2 issues and showed a lack of progression, thus, indirectly supporting the value of raising HDL and lowering triglycerides. These results are also concordant with the results of a small study of the effect on vessel walls of infusing man-made HDL.
Niacin seemed to be well-tolerated at this dose. Although most patients had skin flushing, few discontinued therapy. Also, liver tests were not alarmingly elevated (> 3 times the upper limit), but the report did not give the actual liver function test data. So elevations < 3 times the upper limit probably were observed. No muscle problems were reported. Thus, this long-acting niacin preparation given at bedtime in moderate doses seems like a reasonable approach to those with low HDL on adequate statin therapy.
Since most of the subjects were on simvastatin, we do not know if more potent statins with greater LDL-lowering would have worked just as well. Also, the role of fibrates, which also increase HDL and reduce triglycerides, either alone or in combination with statins, is unclear. However, the fibrate statin combination probably has more potential for adverse effects. Finally, the suggestion that patients with diabetes or the metabolic syndrome do not do as well on the statin and niacin combination requires more study.
Dr. Crawford is Professor of Medicine, Chief of Clinical Cardiology; University of California, San Francisco.