Extended-Release Niacin and Statins in Mixed Dyslipidemia

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Selection from: Highlights of the American Heart Association (AHA) 2007 Scientific Sessions

Extended-Release Niacin and Statins in Mixed Dyslipidemia CME/CE

H. son, MD, FACC s, MSc Disclosures

In light of the failure of torcetrapib (Pfizer, New York, NY), a CETP inhibitor that markedly increases high-density lipoprotein cholesterol (HDL-C), to modify cardiovascular risk in the clinical endpoints ILLUMINATE trial, new interest has returned to the use of other agents for this indication. One such agent, niacin, is the most potent HDL-raising drug presently available, and it raises HDL irrespective of baseline triglyceride levels. Although this drug has been available in generic form for a long time, the new importance attached to its possible benefits has stimulated renewed interest and new clinical trials evaluating an investigational fixed-dose combination of extended-release (ER) niacin and simvastatin have shown initial promise. A second approach addresses the well-known side effect of niacin, flushing; a new investigational agent, lapropiprant, has shown promise in clinical studies when used in combination with niacin plus a statin.

SEACOAST (Safety and Efficacy of a Combination of Extended-Release Niacin and Simvastatin in Patients with Dyslipidemia)

At the American Heart Association (AHA) 2007 Scientific Sessions, the results of the SEACOAST (Safety and Efficacy of a Combination of Extended-Release Niacin and Simvastatin in Patients With Dyslipidemia) trial were presented by the study's lead investigator, Christie Ballantyne, MD (Baylor College of Medicine and Methodist DeBakey Heart Center, Houston, Texas). The results demonstrated that the fixed-dose combination of ER niacin/simvastatin met its primary endpoint of lowering non-HDL-C (ie, total cholesterol minus HDL-C), while demonstrating improvements in levels of low-density lipoprotein cholesterol (LDL-C), HDL-C, and triglycerides.[1]

The fixed-dose ER niacin/simvastatin formulation evaluated in SEACOAST is being developed by Abbott Laboratories (Abbott Park, Illinois), which markets prescription ER niacin (Niaspan). (Simvastatin, which was marketed by Merck, is now off patent and available generically in most countries.) Data from the first study to compare the long-term effects of the fixed-dose niacin plus simvastatin combination vs high-dose simvastatin were presented earlier in the year at the annual meeting of the American College of Cardiology.[2] This study showed that ER niacin/simvastatin was as effective as simvastatin 80 mg in lowering LDL-C and more effective in improving levels of apolipoprotein B (apo and HDL-C in patients with carotid atherosclerosis.

SEACOAST was an international phase III, randomized, double-blind clinical trial that was designed to evaluate the efficacy and safety of ER niacin/simvastatin combination compared with simvastatin alone in patients with elevated non-HDL-C (type II hyperlipidemia or mixed dyslipidemia) who had already been on simvastatin monotherapy. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) introduced non-HDL-C as a new secondary target of therapy in patients with elevated triglycerides (≥ 200 mg/dL) in 2002.[3,4] Non-HDL-C equates to very low-density-lipoprotein + LDL-C (which includes intermediate-density lipoprotein), and the NCEP non-HDL-C goal is set at 30 mg/dL higher than the LDL-C goal. Non-HDL-C was added as a secondary target of therapy to take into account the atherogenic potential associated with remnant lipoproteins in patients with hypertriglyceridemia. Statins lower LDL-C and non-HDL-C to a similar percentage, so clinical trials tended not to differentiate between LDL-C and non-HDL-C in regard to benefits in risk reduction.

Trial Design

All patients in SEACOAST who were not treatment-naïve entered a run-in phase during which they were treated with simvastatin (variable dose), they discontinued all other antidyslipidemic medications, and they began a standard cholesterol-lowering diet. Following this phase more than 600 patients were randomly assigned to either the low-dose (20 mg) or high-dose (40 mg) simvastatin arm.

Patients in the low-dose group (SEACOAST I) were randomized to:

ER niacin 1 g/simvastatin 20 mg;

ER niacin 2 g/simvastatin 20 mg; or

Simvastatin 20 mg.

Patients in the high-dose group (SEACOAST II) were randomized to:

ER niacin 2 g/simvastatin 40 mg;

ER niacin 1 g/simvastatin 40 mg; or

Simvastatin 80 mg.

Patients in the simvastatin control groups received a 50-mg dose of immediate-release niacin to maintain study blinding.

The primary endpoint of SEACOAST I and II was median percent change from baseline to Week 24 in non-HDL-C. However, SEACOAST I was aimed at demonstrating the superiority of ER niacin/simvastatin vs simvastatin monotherapy in patients already at NCEP III coronary heart disease risk-adjusted target LDL-C, while SEACOAST II was aimed at demonstrating the noninferiority of ER niacin/simvastatin vs simvastatin monotherapy in patients at NCEP-defined higher risk with any level of LDL-C.

Results

SEACOAST I patients receiving combination treatment achieved 14% (1 g/20 mg) and 23% (2 g/20 mg) reductions in non-HDL-C vs a 7% reduction with simvastatin 20 mg alone (Table 1). Combination treatment also resulted in significant improvements in HDL-C and triglycerides compared with simvastatin monotherapy.

Table 1. SEACOAST I: Median Percent Change in Lipids From Baseline at 24 Weeks

Lipid

Simvastatin 20 mg

ER Niacin 1 g/ Simvastatin 20 mg

ER Niacin 2 g/ Simvastatin 20 mg

Non-HDL-C

-7.4%

-13.9%*

-22.5%**

LDL-C

-7.1%

-13.1%

-14.2%

HDL-C

6.7%

18.3%**

24.9%**

TC:HDL-C

-10.3%

-21.0%**

-31.3%**

Lp(a)

-7.6%

-16.7%*

-25.0%**

Triglycerides

-15.3%

-26.5%*

-38.0%**

*P < .01; **P < .001 vs simvastatin monotherapy; HDL-C = high-density lipoprotein cholesterol; Lp(a) = lipoprotein (a); LDL-C = low-density lipoprotein cholesterol; TC:HDL-C = ratio of total cholesterol and HDL-C

More patients on combination treatment achieved their lipid goals (HDL-C ≥ 40 mg/dL, triglycerides < 150 mg/dL, and NCEP cardiovascular risk factor adjusted goals for non-HDL-C and LDL-C) and a significantly greater percentage of patients on ER niacin 2 g/simvastatin 20 mg compared with patients on simvastatin 20 mg achieved LDL-C, HDL-C, and triglyceride goals.

The combination of ER niacin/simvastatin was well tolerated with no unanticipated adverse events. The proportion of patients who experienced flushing was similar in all 3 treatment groups (Table 2), but over 90% of the flushing episodes were mild or moderate in intensity. The overall discontinuation rate for ER niacin/simvastatin was 7.5%. About 28% of patients who reported flushing with combination treatment within the first 12 weeks of the study did not report it during Weeks 13-24.

Table 2. SEACOAST I: Incidence of Treatment-related Flushing

Flushing

Simvastatin 20 mg

ER Niacin 1 g/ Simvastatin 20 mg

ER Niacin 2 g/ Simvastatin 20 mg

Flushing

49 (43.0%)

64 (52.0%)

39 (60.9%)

Discontinuation due to flushing

0 (0.0)

8 (6.5%)*

6 (9.4%)*

*P < .05

In SEACOAST II, combination therapy showed non-inferiority in reducing non-HDL-C, with decreases of about 11% (1 g/40 mg) and 17% (2 g/40 mg) compared with a 10% reduction with simvastatin 80 mg alone (Table 3). Both combination treatment doses were associated with significant improvements in other lipid parameters, including (HDL-C, triglycerides, lipoprotein (a) (Lp[a]), and apolipoprotein A-1 (apo A-1). Three times more patients on ER niacin 2 g/simvastatin 40 mg achieved their lipid goals than patients on simvastatin 80 mg monotherapy.

Table 3. SEACOAST II: Median Percent Change in Lipids From Baseline at 24 Weeks

Lipid

Simvastatin 80 mg

ER Niacin 1 g/ Simvastatin 40 mg

ER Niacin 2 g/ Simvastatin 40 mg

Non-HDL-C

-10.1%

-11.3%

-17.1%

LDL-C

-12.7%

-8.6%

-11.6%

HDL-C

-1.0%

14.8%*

21.9%*

TC:HDL-C

-5.1%

-16.2%

-24.5%*

Triglycerides

0.3%

-22.8%*

-31.8%*

Lp(a)

0.0

-16.7%*

-21.0%**

Apo B

-8.8%

-10.1%

-14.1%

Apo A-1

1.4%

5.4%*

8.7**

*P < .001. **P < .0001 vs simvastatin monotherapy; Apo A-1 = apolipoprotein A-1; Apo B = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol; Lp(a) = lipoprotein (a); LDL-C = low-density lipoprotein cholesterol; TC:HDL-C = ratio of total cholesterol to HDL-C

The combination of ER niacin/simvastatin was also well tolerated in SEACOAST II. A similar proportion of patients in each group experienced flushing (Table 4), but over 90% of the flushing episodes were mild or moderate in intensity. Overall discontinuation rates for ER niacin/simvastatin were 4.6%. Almost 50% of patients who reported flushing with combination treatment within the first 12 weeks of the study did not report it during Weeks 13-24.

Table 4. SEACOAST II: Incidence of Treatment-related Flushing

Simvastatin 80 mg

ER Niacin 1 g/Simvastatin 40 mg

ER Niacin 2 g/Simvastatin 40 mg

Flushing

60 (50.4%)

65 (56.0%)

67 (67.0%)

Discontinuation due to flushing

1 (0.8)

5 (4.3%)

5 (5.0%)

There was no evidence for increased risk of hepatotoxicity or myopathy with the combination. Only 1 patient in both studies combined had elevations 3 times the upper limit of normal of aspartate aminotransferase and alanine aminotransferase, on 1 visit only (the last).

The SEACOAST results demonstrated that reductions in non-HDL with the ER niacin/simvastatin combination were greater than those achieved with the same or even a larger dose of simvastatin alone. Regarding the principal side effect of niacin, 6% of the patients on the combination treatment discontinued therapy due to flushing, compared with 0.8% with simvastatin alone.

Commenting on the results, Dr. Ballantyne emphasized the important of controlling HDL-C and triglycerides levels as well as LDL-C. "With the SEACOAST study, ER niacin/simvastatin provided comparable LDL-C lowering to simvastatin with significant benefit in raising good cholesterol and lowering triglycerides. This type of combination approach could be an important tool in treating patients with complex lipid disorders," he commented.

Current Status and Further Studies -- AIM-HIGH

The fixed-dose combination is also currently being investigated in the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes). This study will determine whether the fixed dose combination is superior to simvastatin alone, at comparable levels of on-treatment LDL-C, for delaying the time to a first major cardiovascular disease outcome over a 4-year median follow-up in 3300 patients with atherogenic dyslipidemia. The study is needed to confirm whether statin-niacin combination therapy, designed to target a wider spectrum of dyslipidemic factors in addition to LDL-C, will provide a more substantial reduction (> 50%) of cardiovascular events. This trial is sponsored by the National Heart, Lung, and Blood Institute with supplemental funding from Abbott.

Abbott has said that it expects to launch the ER niacin/simvastatin fixed combination, as Simcor, early 2008.[5] A New Drug Application (NDA) for Simcor was submitted to the US Food and Drug Administration (FDA) in April 2007. The submission was based on data from 2 large clinical studies, including the SEACOAST trial that evaluated the safety and efficacy of the combination of ER niacin/simvastatin in over 1150 patients with mixed dyslipidemia. The NDA seeks an indication to target multiple lipid parameters in a single pill on the basis of improved patient convenience and outcomes. In the United States it will be co-marketed by Abbott and Solvay Pharmaceuticals.

A fixed-dose combination of ER niacin and a statin is already available in the United States. Like Simcor, Advicor, a fixed-dose combination of ER niacin plus lovastatin, was developed by Kos Pharmaceuticals, and acquired along with the company by Abbott. Advicor is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone have been inadequate. Advicor is indicated for the treatment of primary hypercholesterolemia and mixed dyslipidemia in patients who are taking: lovastatin who require additional triglyceride-lowering or HDL-C raising, who may benefit from having niacin added to their therapy, or niacin who require further LDL-C lowering who may benefit from having lovastatin added to their therapy.

Extended-release Niacin Plus Laropiprant (MK-0524A) Combined With Simvastatin

A fixed combination of ER niacin and laropiprant coadministered with simvastatin has significant additive effects on LDL-C, HDL-C, and triglycerides in patients with primary hypercholesterolemia or mixed dyslipidemia, according to the results of a phase III study presented at the 2007 AHA meeting by Gilbert Gleim, PhD (Merck Research Laboratories, Rahway, New Jersey).[6] Laropiprant is a selective antagonist of the prostaglandin D(2) receptor subtype 1 (DP1), which appears to mediate niacin-induced vasodilation in the skin, causing the flushing symptoms associated with the drug in some patients. This flushing side effect has been a barrier to many patients reaching the maximum 2 g dose of niacin.

In an earlier study reported at the 2007 annual congress of the European Society of Cardiology, combination of ER niacin 1 or 2 g plus laropiprant 20 mg given alone or with a statin produced significant, durable improvements in LDL-C, non-HDL-C, HDL-C, triglycerides, apo B, and apo A-1 compared with placebo in patients with dyslipidemia, with significantly less flushing compared with those patients treated with ER niacin alone.[7]

At the AHA meeting, Dr. Gleim presented the results of a double-blind, parallel, factorial 12-week study with 7 treatment arms in 1398 patients (44% male), 74.8% of whom had primary hypercholesterolemia and 25.2% had mixed hyperlipidemia.

After a 6- to 8-week washout and 4-week diet/placebo run-in, patients were randomized equally to ER niacin 1 g/laropiprant 20 mg, simvastatin 10 mg, 20 mg, or 40 mg, or ER niacin 1 g/laropiprant 20 mg plus simvastatin 10 mg, 20 mg, or 40 mg. From Week 5 through Week 12, all doses of ER niacin and simvastatin were doubled except simvastatin 40 mg, which remained unchanged.

Results

Over the 12 weeks of the study, ER niacin/laropiprant plus simvastatin (pooled across doses) significantly improved all lipid parameters compared with ER niacin/laropiprant alone and pooled simvastatin alone (Table 5). ER niacin 2 g/laropiprant 20 mg plus simvastatin 20-40 mg reduced LDL-C, the primary endpoint of the study, by about 48%. With regard to secondary endpoints, the combination of ER niacin/laropiprant plus simvastatin increased HDL-C and reduced triglycerides (by 33%), non-HDL-C (18%), and apo B (by -17%).

All of the comparative lipid efficacy results were statistically significant (P < .001) for each dose of ER niacin/laropiprant vs the corresponding simvastatin dose. Percent changes in LDL-C, HDL-C, and triglycerides were comparable by gender, age (< 65/> 65 years), race, region (United States/ex United States), type of hyperlipidemia, baseline LDL-C, baseline HDL-C, and baseline triglyceride levels.

Table 5. Percent Change in Lipids From Baseline to Week 12 (least squares mean %)

Lipid

ER Niacin/Laropiprant 2 g

Pooled Simvastatin

Pooled ER Niacin/Laropiprant 2 g + Simvastatin

LDL-C

-17%

-37%

-47.9%

HDL-C

27.5%

6.0%

27.5%

Triglycerides

-21.6%

-14.7%

-33.3%

Total cholesterol

-9%

-25%

-30%

Non-HDL-C

-18%

-33%

-46%

Apo B

-17%

-29%

-41%

Apo A-I

8%

2%

9%

LDL-C:HDL-C

-31%

-40%

-57%

TC:HDL-C

-25%

-28%

-43%

Lp(a) (median)

-25%

0%

-20%

Apo A-1 = apolipoprotein A-1; Apo B = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol; Lp(a) = lipoprotein (a); LDL-C = low-density lipoprotein cholesterol; TC:HDL-C = ratio of total cholesterol to HDL-C

The safety profile of ER niacin/laropiprant plus simvastatin was similar to that of ER niacin/laropiprant and simvastatin alone (Table 6). The incidence of serious clinical adverse events was low and comparable among treatment groups. There was no potentiation of statin effects on the liver or in muscle. All elevations were asymptomatic and resolved with discontinuation of treatment. There were no cases of myopathy, rhabdomyolysis, or drug-related hepatitis. Discontinuations due to flushing were 4.8% in the group treated with ER niacin/laropiprant coadministered with simvastatin, 8.7% with ER niacin/laropiprant alone, and 0.3% with simvastatin alone.

Table 6. Adverse Events

Adverse Event

ER Niacin/Laropiprant 2 g

Pooled Simvastatin

Pooled ER Niacin/Laropiprant 2 g + Simvastatin

Discontinuations due to flushing

8.7%

0.3%

4.8%

Drug-related hepatitis

0

0

0

ALT/AST elevation ≥ 3 × ULN

0.5%

1.0%

0.3%

Myopathy or rhabdomyolysis

0

0

0

CK elevation ≥ 10 × ULN

0.5%

0.3%

0

Increase in fasting blood glucose (median)

4.0 mg/dL

1.0 mg/dL

4.0 mg/dL

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatine kinase; ULN = upper limit of normal

Regulatory Status

Currently, a fixed-dose combination of ER niacin/laropiprant is under review by the FDA and if the review is positive, Merck is anticipating marketing the combination in the United States as Cordaptive, possibly as early as the second quarter of 2008.[8] The company is also moving forward with regulatory submissions in countries outside the United States. Researchers at Merck believe that these results presented at the AHA support the development of ER niacin/laropiprant coadministered with simvastatin. The company plans to file an NDA in the United States for this combination, currently known as MK-0524B, in 2008.[9] The scheduled date for filing was delayed after Merck reported formulation issues with the fixed-dose combination in 2006.[10]

Niacin's well-known side effect, flushing, remains an issue for long-term compliance, and niacin plus a DPI antagonist (laropiprant) appears to improve the severity of flushing episodes. Hopefully, this will translate into improved compliance and outcomes.

This activity is supported by an educational grant from Takeda and an independent educational grant from Forest Pharmaceuticals.

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