COMPELL: Comparative Effects on Lipid Levels of Niaspan and Statins vs Other Lipid Therapies

Linda Brookes, MSc


July 28, 2006

Editorial Collaboration

Medscape &

Presenter: Peter H. Jones, MD (Baylor College of Medicine, Houston, Texas)

The results of the COMParative Effects on Lipid Levels of Niaspan and statins versus other lipid therapies (COMPELL) trial showed that in patients at high risk for cardiovascular events, low-density lipoprotein (LDL)-cholesterol levels can be lowered to goal and high-density lipoprotein (HDL)-cholesterol levels raised without the need for high doses of statin medications, the investigators believe. In the COMPELL study, low-dose combination therapy with extended-release niacin (Niaspan; Kos Pharmaceuticals, Cranbury, New Jersey) and either atorvastatin or rosuvastatin reduced LDL cholesterol, apolipoprotein (apo) B, and non-HDL cholesterol comparably to reductions with moderate-to-high doses of rosuvastatin monotherapy or ezetimibe-simvastatin fixed-dose combination tablet over 12 weeks.[1] In addition, the niacin plus statin combinations had greater benefits for HDL cholesterol, HDL2, triglycerides, and lipoprotein(a) [Lp(a)] than either of the other 2 regimens.


The objective of COMPELL, a phase 4, open-label, parallel-group efficacy trial sponsored by Kos, was to compare the effect of a statin plus niacin or ezetimibe vs a statin alone. The treatments used were niacin in combination with atorvastatin or rosuvastatin, ezetimibe-simvastatin fixed-dose combination, and rosuvastatin monotherapy. Treatment was given over 12 weeks and included low-to-moderate doses of atorvastatin or rosuvastatin vs moderate-to-high doses of rosuvastatin or ezetimibe-simvastatin. Doses were increased at 4 and/or 8 weeks (Table 1), and lipids were measured at baseline, week 8, and week 12 visits, with safety evaluations done at each 4-weekly visit.

Table 1. Dose Regimens (mg/day) at Randomization
Weeks Niacin +
Niacin +
1-4 500/20 500/10 10/20 10
5-8 1000/20 1000/10 10/20 20
9-12 2000/40 1000/20 10/40 40

A total of 292 patients were enrolled at 32 US centers, with an average age of 58 years, 29% aged ≥ 65 years, about 50% women, 84% white, and mean body mass index 29 kg/m2. Mean baseline lipid values were LDL 5.1 mmol/L (197 mg/dL), HDL 1.3 mmol/L (50 mg/dL), and triglycerides 1.9 mmol/L (171 mg/dL). After washout, screening, and qualification, patients were randomized to:

  • Atorvastatin plus niacin (n = 60);

  • Rosuvastatin plus niacin (n = 65);

  • Ezetimibe-simvastatin (n = 72); or

  • Rosuvastatin monotherapy (n = 73).


No difference was seen between treatment groups in percentage of LDL-cholesterol lowering from baseline to 8 weeks or 12 weeks, the primary endpoint of the study (Table 2). Greater effects with the statin plus niacin combinations were seen on HDL cholesterol and triglycerides at 12 weeks compared with ezetimibe-simvastatin or rosuvastatin monotherapy.

Table 2. Percentage of Changes in LDL Cholesterol, HDL Cholesterol, and Triglycerides at Week 12
Regimen LDL
Niacin + atorvastatin -56 +22 -47
Niacin + rosuvastatin -51 +24 -40
Ezetimibe-simvastatin -57 +10* -33*
Rosuvastatin -53 +7* -25*
HDL = high-density lipoprotein; LDL = low-density lipoprotein

*P < .05 vs atorvastatin + niacin

At 8 weeks, low-dose niacin plus either atorvastatin (20 mg) or rosuvastatin (10 mg) had already lowered LDL cholesterol by about 50%, Dr. Jones noted. The statin plus niacin combinations lowered apo B, non-HDL, and total/HDL cholesterol comparably to ezetimibe-simvastatin or rosuvastatin (Table 3).

Table 3. Percentage of Changes in apo B, Non-HDL Cholesterol, and Total Cholesterol/HDL Cholesterol at Week 12
Regimen Apo B Non-HDL
Total Cholesterol/
HDL Cholesterol
Niacin + atorvastatin -49 -55 -50
Niacin + rosuvastatin -46 -49 -48
Ezetimibe-simvastatin -45 -54 -47
Rosuvastatin -42 -50 -43
Apo = apolipoprotein; HDL = high-density lipoprotein

*P < .05 vs atorvastatin + niacin

A trend toward an increase in Lp(a) was seen with ezetimibe-simvastatin and rosuvastatin monotherapy, whereas both statin-niacin combinations showed a significant reduction in Lp(a) compared with the 2 non-niacin therapy groups. The statin plus niacin combinations showed no difference vs the other treatment groups in effects on small HDL particles (HDL3), but large HDL particles (HDL2) were significantly increased by the statin-niacin combinations.

Table 4. Percentage of Changes in Lp(a), HDL2, and HDL3 at Week 12
Regimen Lp(a) HDL2 HDL3
Niacin + atorvastatin -14 +93 +5
Niacin + rosuvastatin -5 +102 +10
Ezetimibe-simvastatin +7* +41* +6
Rosuvastatin +18* +31* +5
HDL2 = large high-density lipoprotein particles; HDL3 = small high-density lipoprotein particles; Lp(a) = lipoprotein(a)

*P < .05 vs atorvastatin + niacin
Safety and Tolerability

All drug regimens were generally well tolerated, with similar rates of adverse events (55% to 67%) and serious adverse events (3% to 4%) on all treatment arms. Approximately 90% of patients on ezetimibe-simvastatin or rosuvastatin completed the trial vs approximately 75% to 80% of patients on statin plus niacin combinations. Most discontinuations in patients on the niacin-containing regimens were due to flushing or other cutaneous reactions. These may have been related to a low rate (60%) of aspirin use in the study, Dr. Jones suggested.

No drug-related myopathy (myalgia plus elevated creatine kinase > 10 x upper limit of normal [ULN]) was observed, and no patient had asymptomatic creatine kinase elevation > 5 or > 10 x ULN. One patient receiving rosuvastatin had a reversible liver enzyme elevation > 3 x ULN on 2 successive measurements. Small increases in fasting glucose (+3 to +5 mg/dL) were observed with the nicotinic acid-statin combinations, but at 12 weeks there was no change in hemoglobin A1c levels. A slight increase in uric acid (approximately 0.1 mg/dL) occurred in patients on the statin plus niacin treatments compared with no change or a decrease (0.4-0.5 mg/dL) in other groups.


"The bottom line of the COMPELL study is that we can lower LDL cholesterol substantially, by 50% to 55%, with statins, but what we cannot do with statins is increase HDL-cholesterol and lower triglycerides," Dr. Jones commented later. "In patients who need substantial triglyceride lowering and HDL increases, the COMPELL study shows that you can double or triple your increase in HDL cholesterol, and you can improve your triglyceride lowering by at least 50% by adding niacin to statin therapy," he said. "So for patients who need more than LDL-cholesterol lowering, for raising HDL cholesterol and lowering triglycerides, niacin extended-release is a safe and very effective drug in combination for clinicians to consider."

He continued:

Niacin is the best HDL-cholesterol raising drug right now. Fenofibrate is good, but not as good as niacin, and the statins have only a modest effect. The cholesteryl ester transfer protein (CETP) inhibitors will come along in the next couple of years, and they can raise HDL more than any of these other drugs, but we do not have any real data to back up the benefits of raising HDL by that method. We at least have some clinical trial evidence that niacin is a safe and effective medication. We have the results of the HDL Atherosclerosis Treatment Study (HATS) trial[2]; we have data on angiographic regression using niacin; and we have data on niacin from the Coronary Drug Project,[3,4] so we know that niacin has benefits. So until the data about CETP inhibition come out, we think niacin, especially niacin extended-release, is the best for raising HDL cholesterol. Eventually the 2 ways of raising HDL cholesterol will have to be compared, but that will not happen for several years, and in the meantime we have the AIM HIGH and the HPS-THRIVE studies.
Ongoing Trials of Statin Plus Niacin

The AIM HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-cholesterol/High Triglyceride and Impact on Global Health Outcomes) and HPS-THRIVE (Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events) phase 3 trials are each investigating whether treating multiple lipid abnormalities with a statin plus niacin combination is more effective in reducing coronary heart disease (CHD) risk than statin therapy alone in patients with established cardiovascular disease.

AIM-HIGH, a US-Canadian multicenter, randomized, double-blind, parallel-group, controlled clinical trial, is comparing extended-release niacin plus simvastatin with simvastatin alone over a median follow-up of 4 years at comparable levels of on-treatment LDL cholesterol in patients with atherogenic dyslipidemia, ie, low HDL cholesterol (≤ 40 mg/dL) and high triglycerides (≥ 150 mg/dL). The study will enroll an estimated 3300 men and women aged > 45 years old. The primary composite clinical endpoint is CHD death, nonfatal myocardial infarction (MI), ischemic stroke, or hospitalization for high-risk acute coronary syndrome with objective evidence of ischemia (troponin-positive or ST-segment deviation). A secondary endpoint is the composite of CHD death, nonfatal MI, or ischemic stroke. Follow-up will extend through 2010. AIM HIGH is sponsored by the National Heart, Lung, and Blood Institute with additional support from Kos Pharmaceuticals.

HPS2-THRIVE is studying a new combination tablet containing extended-release niacin plus a specific blocker of prostaglandin D2 to prevent the flushing associated with niacin. HPS2-THRIVE will recruit 20,000 men and women aged between 50 and 80 years who have a history of MI, stroke, or peripheral arterial disease, one third of whom will also have diabetes. Patients will first have their LDL-cholesterol treatment optimized with statin-based therapy, and then they will be randomly allocated to receive the new combination HDL-raising tablets or matching placebo daily for ≥ 4 years. Centers in the United Kingdom, China, and Scandinavia are participating in the study, which is being coordinated at Oxford University, Oxford, United Kingdom, under a grant from Merck & Co., Inc. (Whitehouse Station, New Jersey), developer of the combined HDL-cholesterol raising tablet, MK-0524A. MK-0524A is also being studied in a combination tablet with simvastatin.

  1. McKenney JM, Jones PH, Bays HE, et al. Comparative lipid effects of combination therapy with a statin and extended-release niacin versus statin plus ezetimibe versus a statin alone. Atherosclerosis. 2006;7(suppl):174. Abstract Tu-W27:4.

  2. Brown G, Zha X-Q, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592. Abstract

  3. Coronary Drug Project report on clofibrate and niacin. Atherosclerosis. 1978;30:239-240. Abstract

  4. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245-1255. Abstract


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