Investigators showed that the addition of extended-release niacin to atorvastatin or rosuvastatin compared with a simvastatin/ezetimibe combination or rosuvastatin alone resulted in equivalent reductions in LDL-cholesterol levels but significantly greater increases in HDL-cholesterol levels and lower triglyceride levels.

"National and international guidelines focus on LDL lowering as the cornerstone of therapy for coronary heart disease risk reduction for very good reason," said Dr Peter Jones (Baylor College of Medicine, Houston, TX), one of the COMPELL investigators. "At least in the US, increasingly lower LDL targets are being recommended for very high-risk individuals, as low as 70 mg/dL or less. That being said, treating triglyceride levels that remain high or HDL-cholesterol levels that remain low is recognized as appropriate treatment by the US guidelines."

In COMPELL, investigators sought to determine the relative efficacy of combination therapy with a statin and niacin or ezetimibe compared with a statin alone. The 12-week, open-label, randomized, parallel-group study was conducted in 32 US centers with lipids measured at baseline, week 8, and week 12. The average age of the patients was 58 years and approximately one third were older than 65 years. A majority of the subjects were white and overweight.

Will this type of treatment, combining niacin with statin-based therapy, actually reduce coronary heart disease risk more than statins alone?

Patients were randomized to one of the four treatment regimens:

• Niacin 500 mg plus atorvastatin 20 mg—The dose of niacin doubled at week 4 to 1000 mg/day and at week 8 to 2000 mg/day, whereas the dose of atorvastatin doubled to 40 mg/day at week 8.
• Niacin 500 mg plus rosuvastatin 10 mg—The dose of niacin doubled at week 4 to 1000 mg/day and was maintained for the remainder of the study, whereas the dose of rosuvastatin was doubled to 20 mg/day at week 8.
• Simvastatin 20 mg and ezetimibe 10 mg—The dose of simvastatin was increased at week 8 to 40 mg/day.
• Rosuvastatin alone—The dose of rosuvastatin was doubled at week 4 to 20 mg and again doubled at week 8 to 40 mg.

Regarding reductions in LDL cholesterol, there was no statistically significant difference across the four treatment arms. There were, however, significant differences observed regarding changes in HDL-cholesterol and triglyceride levels. The addition of niacin to statin therapy increased HDL significantly more than the simvastatin and ezetimibe combination or rosuvastatin alone. Triglycerides were also reduced more with the addition of niacin.

"The question then becomes, Will this type of treatment, combining niacin with statin-based therapy, actually reduce coronary heart disease risk more than statins alone?" said Jones. "We're waiting for that to be seen."

Jones noted that the National Institutes of Health is sponsoring the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study, a five-year trial with 3300 patients with atherogenic dyslipidemia treated with simvastatin alone or simvastatin with extended-release niacin. Another trial, the Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), is also under way and will assess whether a new combination tablet, containing extended-release niacin with a specific blocker of prostaglandin D2 to prevent flushing, prevents cardiovascular events in patients with existing vascular disease.

In addition to the 12-week data, Jones reported the results of treatment at eight weeks. The data showed that low-dose niacin, 1000 mg/day, coupled with low-dose atorvastatin (20 mg) or rosuvastatin (10 mg) could reduce LDL-cholesterol levels by approximately 50%. The lower doses also resulted in a significant reduction in triglyceride levels compared with simvastatin/ezetimibe or rosuvastatin alone, as well as increased HDL-cholesterol levels.

Approximately 90% of patients treated with simvastatin/ezetimibe or rosuvastatin completed the trial, whereas approximately 75% of patients on the different niacin and statin combinations stayed enrolled. Patients withdrew mainly because of flushing, a commonly reported side effect with niacin, or for other cutaneous reactions.

Jones also reported that a similar number of patients in all four treatment arms reported adverse events, with approximately 3% to 4% of patients having serious adverse events. There were no cases of drug-related myopathy and no reported elevations in creatine kinase. One patient treated with rosuvastatin 40 mg/day had a reversible liver-enzyme elevation. There were small increases in fasting glucose levels of patients treated with niacin, but no changes in hemoglobin A1_C levels.

As pointed out by Dr Anthony Keech (University of Sydney, Australia), one of the concerns with niacin is the increase in glucose intolerance, which might make the drug problematic in combination therapy, especially if there is a transition from insulin resistance to diabetes. Jones agreed that balancing the benefits and risks of the drug will be important, adding that the COMPELL patients had normal glucose levels. Other data have shown a slight trend toward an increase in blood sugar and hemoglobin A1_C in patients without diabetes, although it did not affect the overall benefit of niacin. The AIM-HIGH study, with patients with the metabolic syndrome, should address these concerns, he said.

Keech told heartwire that combination therapy is "definitely coming," but it remains an issue as to who will be able to tolerate the different agents. In terms of clinical end points, he said the combination of raising HDL cholesterol and lowering LDL cholesterol should reduce coronary events, although he pointed out that such assumptions can be perilous in medicine.