Recommended Topic Related To:

Niaspan

"What is the diabetes medication insulin and how does it work?

Insulin is a hormone that is produced by certain cells in the pancreas called beta cells. Insulin helps the body use blood glucose (a type of sugar) for energy. When we e"...

Niaspan

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism by which niacin alters lipid profiles has not been well defined. It may involve several actions including partial inhibition of release of free fatty acids from adipose tissue, and increased lipoprotein lipase activity, which may increase the rate of chylomicron triglyceride removal from plasma. Niacin decreases the rate of hepatic synthesis of VLDL and LDL, and does not appear to affect fecal excretion of fats, sterols, or bile acids.

Pharmacodynamics

Niacin functions in the body after conversion to nicotinamide adenine dinucleotide (NAD) in the NAD coenzyme system. Niacin (but not nicotinamide) in gram doses reduces total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and triglycerides (TG), and increases high-density lipoprotein cholesterol (HDL-C). The magnitude of individual lipid and lipoprotein responses may be influenced by the severity and type of underlying lipid abnormality. The increase in HDL-C is associated with an increase in apolipoprotein AI (Apo A-I) and a shift in the distribution of HDL subfractions. These shifts include an increase in the HDL2:HDL3 ratio, and an elevation in lipoprotein A-I (Lp A-I, an HDL-C particle containing only Apo A-I). Niacin treatment also decreases serum levels of apolipoprotein B-100 (Apo B), the major protein component of the very low-density lipoprotein (VLDL) and LDL fractions, and of Lp(a), a variant form of LDL independently associated with coronary risk. In addition, preliminary reports suggest that niacin causes favorable LDL particle size transformations, although the clinical relevance of this effect requires further investigation. The effect of niacin-induced changes in lipids/proteins on cardiovascular morbidity or mortality in individuals without preexisting coronary disease has not been established.

A variety of clinical studies have demonstrated that elevated levels of TC, LDL-C, and Apo B promote human atherosclerosis. Similarly, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiological investigations have established that cardiovascular morbidity and mortality vary directly with the level of Total-C and LDL-C, and inversely with the level of HDL-C.

Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate-density lipoprotein (IDL), and their remnants, can also promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease (CHD). As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Pharmacokinetics

Absorption

Due to extensive and saturable first-pass metabolism, niacin concentrations in the general circulation are dose dependent and highly variable. Time to reach the maximum niacin plasma concentrations was about 5 hours following NIASPAN. To reduce the risk of gastrointestinal (GI) upset, administration of NIASPAN with a low-fat meal or snack is recommended.

Single-dose bioavailability studies have demonstrated that the 500 mg and 1000 mg tablet strengths are dosage form equivalent but the 500 mg and 750 mg tablet strengths are not dosage form equivalent.

Metabolism

The pharmacokinetic profile of niacin is complicated due to extensive first-pass metabolism that is dose-rate specific and, at the doses used to treat dyslipidemia, saturable. In humans, one pathway is through a simple conjugation step with glycine to form nicotinuric acid (NUA). NUA is then excreted in the urine, although there may be a small amount of reversible metabolism back to niacin. The other pathway results in the formation of nicotinamide adenine dinucleotide (NAD). It is unclear whether nicotinamide is formed as a precursor to, or following the synthesis of, NAD. Nicotinamide is further metabolized to at least N-methylnicotinamide (MNA) and nicotinamide-N-oxide (NNO). MNA is further metabolized to two other compounds, N-methyl-2-pyridone5-carboxamide (2PY) and N-methyl-4-pyridone-5-carboxamide (4PY). The formation of 2PY appears to predominate over 4PY in humans. At the doses used to treat hyperlipidemia, these metabolic pathways are saturable, which explains the nonlinear relationship between niacin dose and plasma concentrations following multiple-dose NIASPAN administration.

Nicotinamide does not have hypolipidemic activity; the activity of the other metabolites is unknown.

Elimination

Following single and multiple doses, approximately 60 to 76% of the niacin dose administered as NIASPAN was recovered in urine as niacin and metabolites; up to 12% was recovered as unchanged niacin after multiple dosing. The ratio of metabolites recovered in the urine was dependent on the dose administered.

Pediatric Use

No pharmacokinetic studies have been performed in this population ( ≤ 16 years) [see Use In Specific Populations].

Geriatric Use

No pharmacokinetic studies have been performed in this population ( > 65 years) [see Use In Specific Populations].

Renal Impairment

No pharmacokinetic studies have been performed in this population. NIASPAN should be used with caution in patients with renal disease [see WARNINGS AND PRECAUTIONS].

Hepatic Impairment

No pharmacokinetic studies have been performed in this population. Active liver disease, unexplained transaminase elevations and significant or unexplained hepatic dysfunction are contraindications to the use of NIASPAN [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Gender

Steady-state plasma concentrations of niacin and metabolites after administration of NIASPAN are generally higher in women than in men, with the magnitude of the difference varying with dose and metabolite. This gender differences observed in plasma levels of niacin and its metabolites may be due to gender-specific differences in metabolic rate or volume of distribution. Recovery of niacin and metabolites in urine, however, is generally similar for men and women, indicating that absorption is similar for both genders [see Gender].

Drug interactions

Fluvastatin

Niacin did not affect fluvastatin pharmacokinetics [see DRUG INTERACTIONS].

Lovastatin

When NIASPAN 2000 mg and lovastatin 40 mg were co-administered, NIASPAN increased lovastatin Cmax and AUC by 2% and 14%, respectively, and decreased lovastatin acid Cmax and AUC by 22% and 2%, respectively. Lovastatin reduced NIASPAN bioavailability by 2-3% [see DRUG INTERACTIONS].

Simvastatin

When NIASPAN 2000 mg and simvastatin 40 mg were co-administered, NIASPAN increased simvastatin Cmax and AUC by 1% and 9%, respectively, and simvastatin acid Cmax and AUC by 2% and 18%, respectively. Simvastatin reduced NIASPAN bioavailability by 2% [see DRUG INTERACTIONS].

Bile Acid Sequestrants

An in vitro study was carried out investigating the niacin-binding capacity of colestipol and cholestyramine. About 98% of available niacin was bound to colestipol, with 10 to 30% binding to cholestyramine [see DRUG INTERACTIONS].

Clinical Studies

Niacin Clinical Studies

The role of LDL-C in atherogenesis is supported by pathological observations, clinical studies, and many animal experiments. Observational epidemiological studies have clearly established that high TC or LDL-C and low HDL-C are risk factors for CHD. Additionally, elevated levels of Lp(a) have been shown to be independently associated with CHD risk.

Niacin's ability to reduce mortality and the risk of definite, nonfatal myocardial infarction (MI) has been assessed in long-term studies. The Coronary Drug Project, completed in 1975, was designed to assess the safety and efficacy of niacin and other lipid-altering drugs in men 30 to 64 years old with a history of MI. Over an observation period of 5 years, niacin treatment was associated with a statistically significant reduction in nonfatal, recurrent MI. The incidence of definite, nonfatal MI was 8.9% for the 1,119 patients randomized to nicotinic acid versus 12.2% for the 2,789 patients who received placebo (p < 0.004). Total mortality was similar in the two groups at 5 years (24.4% with nicotinic acid versus 25.4% with placebo; p=N.S.). At the time of a 15year follow-up, there were 11% (69) fewer deaths in the niacin group compared to the placebo cohort (52.0% versus 58.2%; p=0.0004). However, mortality at 15 years was not an original endpoint of the Coronary Drug Project. In addition, patients had not received niacin for approximately 9 years, and confounding variables such as concomitant medication use and medical or surgical treatments were not controlled.

The Cholesterol-Lowering Atherosclerosis Study (CLAS) was a randomized, placebo-controlled, angiographic trial testing combined colestipol and niacin therapy in 162 non-smoking males with previous coronary bypass surgery. The primary, per-subject cardiac endpoint was global coronary artery change score. After 2 years, 61% of patients in the placebo cohort showed disease progression by global change score (n=82), compared with only 38.8% of drug-treated subjects (n=80), when both native arteries and grafts were considered (p < 0.005); disease regression also occurred more frequently in the drug-treated group (16.2% versus 2.4%; p=0.002). In a follow-up to this trial in a subgroup of 103 patients treated for 4 years, again, significantly fewer patients in the drug-treated group demonstrated progression than in the placebo cohort (48% versus 85%, respectively; p < 0.0001).

The Familial Atherosclerosis Treatment Study (FATS) in 146 men ages 62 and younger with Apo B levels ≥ 125 mg/dL, established coronary artery disease, and family histories of vascular disease, assessed change in severity of disease in the proximal coronary arteries by quantitative arteriography. Patients were given dietary counseling and randomized to treatment with either conventional therapy with double placebo (or placebo plus colestipol if the LDL-C was elevated); lovastatin plus colestipol; or niacin plus colestipol. In the conventional therapy group, 46% of patients had disease progression (and no regression) in at least one of nine proximal coronary segments; regression was the only change in 11%. In contrast, progression (as the only change) was seen in only 25% in the niacin plus colestipol group, while regression was observed in 39%. Though not an original endpoint of the trial, clinical events (death, MI, or revascularization for worsening angina) occurred in 10 of 52 patients who received conventional therapy, compared with 2 of 48 who received niacin plus colestipol.

The Harvard Atherosclerosis Reversibility Project (HARP) was a randomized placebo-controlled, 2.5-year study of the effect of a stepped-care antihyperlipidemic drug regimen on 91 patients (80 men and 11 women) with CHD and average baseline TC levels less than 250 mg/dL and ratios of TC to HDL-C greater than 4.0. Drug treatment consisted of an HMG-CoA reductase inhibitor administered alone as initial therapy followed by addition of varying dosages of either a slow-release nicotinic acid, cholestyramine, or gemfibrozil. Addition of nicotinic acid to the HMG-CoA reductase inhibitor resulted in further statistically significant mean reductions in TC, LDL-C, and TG, as well as a further increase in HDL-C in a majority of patients (40 of 44 patients). The ratios of TC to HDL-C and LDL-C to HDL-C were also significantly reduced by this combination drug regimen [see WARNINGS AND PRECAUTIONS].

NIASPAN Clinical Studies

Placebo-Controlled Clinical Studies in Patients with Primary Hyperlipidemia and Mixed Dyslipidemia: In two randomized, double-blind, parallel, multi-center, placebo-controlled trials, NIASPAN dosed at 1000, 1500 or 2000 mg daily at bedtime with a low-fat snack for 16 weeks (including 4 weeks of dose escalation) favorably altered lipid profiles compared to placebo (Table 3). Women appeared to have a greater response than men at each NIASPAN dose level (see Gender Effect, below).

Table 3. Lipid Response to NIASPAN Therapy

Treatment Mean Percent Change from Baseline to Week 16*
n TC LDL-C HDL-C TC/HDL-C TG Lp(a) Apo B Apo A-I
NIASPAN 1000 mg at bedtime 41 -3 -5 +18 -17 -21 -13 -6 +9
NIASPAN 2000 mg at bedtime 41 -10 -14 +22 -25 -28 -27 -16 +8
Placebo 40 0 -1 +4 -3 0 0 +1 +3
NIASPAN 1500 mg at bedtime 76 -8 -12 +20 -20 -13 -15 -12 +8
Placebo 73 +2 +1 +2 +1 +12 +2 +1 +2
n = number of patients at baseline;
* Mean percent change from baseline for all NIASPAN doses was significantly different (p < 0.05) from placebo for all lipid parameters shown except Apo A-I at 2000 mg.

In a double-blind, multi-center, forced dose-escalation study, monthly 500 mg increases in NIASPAN dose resulted in incremental reductions of approximately 5% in LDL-C and Apo B levels in the daily dose range of 500 mg through 2000 mg (Table 4). Women again tended to have a greater response to NIASPAN than men (see Gender Effect, below).

Table 4: Lipid Response in Dose-Escalation Study

Treatment Mean Percent Change from Baseline*
n TC LDL-C HDL-C TC/HDL-C TG Lp(a) Apo B Apo A-I
Placebo‡ 44 -2 -1 +5 -7 -6 -5 -2 +4
NIASPAN 87                
   500 mg at bedtime   -2 -3 +10 -10 -5 -3 -2 +5
   1000 mg at bedtime   -5 -9 +15 -17 -11 -12 -7 +8
   1500 mg at bedtime   -11 -14 +22 -26 -28 -20 -15 +10
   2000 mg at bedtime   -12 -17 +26 -29 -35 -24 -16 +12
n = number of patients enrolled;
‡ Placebo data shown are after 24 weeks of placebo treatment.
* For all NIASPAN doses except 500 mg, mean percent change from baseline was significantly different (p < 0.05) from placebo for all lipid parameters shown except Lp(a) and Apo A-I which were significantly different from placebo starting with 1500 mg and 2000 mg, respectively.

Pooled results for major lipids from these three placebo-controlled studies are shown below (Table 5).

Table 5: Selected Lipid Response to NIASPAN in Placebo-Controlled Clinical Studies*

NIASPAN Dose Mean Baseline and Median Percent Change from Baseline (25th, 75th Percentiles)
n LDL-C HDL-C TG
1000 mg at bedtime 104
Baseline (mg/dL) 218 45 172
Percent Change -7 (-15, 0) +14 (+7, +23) -16 (-34, +3)
1500 mg at bedtime 120
Baseline (mg/dL) 212 46 171
Percent Change -13 (-21, -4) +19 (+9, +31) -25 (-45, -2)
2000 mg at bedtime 85
Baseline (mg/dL) 220 44 160
Percent Change -16 (-26, -7) +22 (+15, +34) -38 (-52, -14)
* Represents pooled analyses of results; minimum duration on therapy at each dose was 4 weeks.

Gender Effect: Combined data from the three placebo-controlled NIASPAN studies in patients with primary hyperlipidemia and mixed dyslipidemia suggest that, at each NIASPAN dose level studied, changes in lipid concentrations are greater for women than for men (Table 6).

Table 6: Effect of Gender on NIASPAN Dose Response

NIASPAN n Mean Percent Change from Baseline
LDL-C HDL-C TG Apo B
Dose (M/F) M F M F M F M F
500 mg at bedtime 50/37 -2 -5 +11 +8 -3 -9 -1 -5
1000 mg at bedtime 76/52 -6* -11* +14 +20 -10 -20 -5* -10*
1500 mg at bedtime 104/59 -12 -16 +19 +24 -17 -28 -13 -15
2000 mg at bedtime 75/53 -15 -18 +23 +26 -30 -36 -16 -16
n = number of male/female patients enrolled.
* Percent change significantly different between genders (p < 0.05).

Other Patient Populations: In a double-blind, multi-center, 19-week study the lipid-altering effects of NIASPAN (forced titration to 2000 mg at bedtime) were compared to baseline in patients whose primary lipid abnormality was a low level of HDL-C (HDL-C ≤ 40 mg/dL, TG ≤ 400 mg/dL, and LDL-C ≤ 160, or < 130 mg/dL in the presence of CHD). Results are shown below (Table 7).

Table 7: Lipid Response to NIASPAN in Patients with Low HDL-C

  Mean Baseline and Mean Percent Change from Baseline*
n TC LDL-C HDL-C TC/HDL-C TG Lp(a)† Apo B† Apo A-I† Lp A-I††
Baseline (mg/dL) 88 190 120 31 6 194 8 106 105 32
Week 19 (% Change) 71 -3 0 +26 -22 -30 -20 -9 +11 +20
n = number of patients
* Mean percent change from baseline was significantly different (p < 0.05) for all lipid parameters shown except LDL-C.
† n = 72 at baseline and 69 at week 19.
†† n = 30 at baseline and week 19.

At NIASPAN 2000 mg/day, median changes from baseline (25th, 75th percentiles) for LDL-C, HDL-C, and TG were -3% (-14, +12%), +27% (+13, +38%), and -33% (-50, -19%), respectively.

NIASPAN and Lovastatin Clinical Studies

Combination NIASPAN and Lovastatin Study: In a multi-center, randomized, double-blind, parallel, 28-week study, a combination tablet of NIASPAN and lovastatin was compared to each individual component in patients with Type IIa and IIb hyperlipidemia. Using a forced dose-escalation study design, patients received each dose for at least 4 weeks. Patients randomized to treatment with the combination tablet of NIASPAN and lovastatin initially received 500 mg/20 mg (expressed as mg of niacin/mg of lovastatin) once daily before bedtime. The dose was increased by 500 mg at 4-week intervals (based on the NIASPAN component) to a maximum dose of 1000 mg/20 mg in one-half of the patients and 2000 mg/40 mg in the other half. The NIASPAN monotherapy group underwent a similar titration from 500 mg to 2000 mg. The patients randomized to lovastatin monotherapy received 20 mg for 12 weeks titrated to 40 mg for up to 16 weeks. Up to a third of the patients randomized to the combination tablet of NIASPAN and lovastatin or NIASPAN monotherapy discontinued prior to Week 28. Results from this study showed that combination therapy decreased LDL-C, TG and Lp(a), and increased HDL-C in a dose-dependent fashion (Tables 8, 9, 10, and 11). Results from this study for LDL-C mean percent change from baseline (the primary efficacy variable) showed that:

  1. LDL-lowering with the combination tablet of NIASPAN and lovastatin was significantly greater than that achieved with lovastatin 40 mg only after 28 weeks of titration to a dose of 2000 mg/40 mg (p < 0.0001)
  2. The combination tablet of NIASPAN and lovastatin at doses of 1000 mg/20 mg or higher achieved greater LDL-lowering than NIASPAN (p < 0.0001)

The LDL-C results are summarized in Table 8.

Table 8: LDL-C mean percent change from baseline

Week Combination Tablet of NIASPAN and Lovastatin NIASPAN Lovastatin
n* Dose (mg/mg) LDL n* Dose (mg) LDL n* Dose (mg) LDL
Baseline 57 - 190.9 mg/dL 61 - 189.7 mg/dL 61 - 185.6 mg/dL
12 47 1000/20 -30% 46 1000 -3% 56 20 -29%
16 45 1000/40 -36% 44 1000 -6% 56 40 -31%
20 42 1500/40 -37% 43 1500 -12% 54 40 -34%
28 42 2000/40 -42% 41 2000 -14% 53 40 -32%
* n = number of patients remaining in trial at each time point

Combination therapy achieved significantly greater HDL-raising compared to lovastatin and NIASPAN monotherapy at all doses (Table 9).

Table 9: HDL-C mean percent change from baseline

Week Combination Tablet of NIASPAN and Lovastatin NIASPAN Lovastatin
n* Dose (mg/mg) HDL n* Dose (mg) HDL n* Dose (mg) HDL
Baseline 57 - 45 mg/dL 61 - 47 mg/dL 61 - 43 mg/dL
12 47 1000/20 +20% 46 1000 +14% 56 20 +3%
16 45 1000/40 +20% 44 1000 +15% 56 40 +5%
20 42 1500/40 +27% 43 1500 +22% 54 40 +6%
28 42 2000/40 +30% 41 2000 +24% 53 40 +6%
* n = number of patients remaining in trial at each time point

In addition, combination therapy achieved significantly greater TG lowering at doses of 1000 mg/20mg or greater compared to lovastatin and NIASPAN monotherapy (Table 10).

Table 10: TG median percent change from baseline

Week Combination Tablet of NIASPAN and Lovastatin NIASPAN Lovastatin
n* Dose (mg/mg) TG n* Dose (mg) TG n* Dose (mg) TG
Baseline 57 - 174 mg/dL 61 - 186 mg/dL 61 - 171 mg/dL
12 47 1000/20 -32% 46 1000 -22% 56 20 -20%
16 45 1000/40 -39% 44 1000 -23% 56 40 -17%
20 42 1500/40 -44% 43 1500 -31% 54 40 -21%
28 42 2000/40 -44% 41 2000 -31% 53 40 -20%
* n = number of patients remaining in trial at each time point

The Lp(a)-lowering effects of combination therapy and NIASPAN monotherapy were similar, and both were superior to lovastatin (Table 11). The independent effect of lowering Lp(a) with NIASPAN or combination therapy on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Table 11: Lp(a) median percent change from baseline

Week Combination Tablet of NIASPAN and Lovastatin NIASPAN Lovastatin
n* Dose (mg/mg) Lp(a) n* Dose (mg) Lp(a) n* Dose (mg) Lp(a)
Baseline 57 - 34 mg/dL 61 - 41 mg/dL 60 - 42 mg/dL
12 47 1000/20 -9% 46 1000 -8% 55 20 +8%
16 45 1000/40 -9% 44 1000 -12% 55 40 +8%
20 42 1500/40 -17% 43 1500 -22% 53 40 +6%
28 42 2000/40 -22% 41 2000 -32% 52 40 0%
* n = number of patients remaining in trial at each time point

NIASPAN and Simvastatin Clinical Studies

In a double-blind, randomized, multicenter, multi-national, active-controlled, 24-week study, the lipid effects of a combination tablet of NIASPAN and simvastatin were compared to simvastatin 20 mg and 80 mg in 641 patients with type II hyperlipidemia or mixed dyslipidemia. Following a lipid qualification phase, patients were eligible to enter one of two treatment groups. In Group A, patients on simvastatin 20 mg monotherapy, with elevated non-HDL levels and LDL-C levels at goal per the NCEP guidelines, were randomized to one of three treatment arms: combination tablet of NIASPAN and simvastatin 1000/20 mg, combination tablet of NIASPAN and simvastatin 2000/20 mg, or simvastatin 20 mg. In Group B, patients on simvastatin 40 mg monotherapy, with elevated non-HDL levels per the NCEP guidelines regardless of attainment of LDL-C goals, were randomized to one of three treatment arms: combination tablet of NIASPAN and simvastatin 1000/40 mg, combination tablet of NIASPAN and simvastatin 2000/40 mg, or simvastatin 80 mg. Therapy was initiated at the 500 mg dose of combination tablet of NIASPAN and simvastatin and increased by 500 mg every four weeks. Thus patients were titrated to the 1000 mg dose of combination tablet of NIASPAN and simvastatin after four weeks and to the 2000 mg dose of combination tablet of NIASPAN and simvastatin after 12 weeks. All patients randomized to simvastatin monotherapy received 50 mg immediate-release niacin daily in an attempt to keep the study from becoming unblinded due to flushing in the combination tablet of NIASPAN and simvastatin groups. Patients were instructed to take one 325 mg aspirin or 200 mg ibuprofen 30 minutes prior to taking the double-blind medication to help minimize flushing effects.

In Group A, the primary efficacy analysis was a comparison of the mean percent change in non-HDL levels between the combination tablet of NIASPAN and simvastatin 2000/20 mg and simvastatin 20 mg groups, and if statistically significant, then a comparison was conducted between the combination tablet of NIASPAN and simvastatin 1000/20 mg and simvastatin 20 mg groups. In Group B, the primary efficacy analysis was a determination of whether the mean percent change in non-HDL in the combination tablet of NIASPAN and simvastatin 2000/40 mg group was non-inferior to the mean percent change in the simvastatin 80 mg group, and if so, whether the mean percent change in non-HDL in the combination tablet of NIASPAN and simvastatin 1000/40 mg group was non-inferior to the mean percent change in the simvastatin 80 mg group.

In Group A, the non-HDL-C lowering with combination tablet of NIASPAN and simvastatin 2000/20 and combination tablet of NIASPAN and simvastatin 1000/20 was statistically significantly greater than that achieved with simvastatin 20 mg after 24 weeks (p < 0.05; Table 12). The completion rate after 24 weeks was 72% for the combination tablet of NIASPAN and simvastatin arms and 88% for the simvastatin 20 mg arm. In Group B, the non-HDL-C lowering with combination tablet of NIASPAN and simvastatin 2000/40 and combination tablet of NIASPAN and simvastatin 1000/40 was non-inferior to that achieved with simvastatin 80 mg after 24 weeks (Table 13). The completion rate after 24 weeks was 78% for the combination tablet of NIASPAN and simvastatin arms and 80% for the simvastatin 80 mg arm.

The combination tablet of NIASPAN and simvastatin was not superior to simvastatin in lowering LDL-C in either Group A or Group B. However, the combination tablet of NIASPAN and simvastatin was superior to simvastatin in both groups in lowering TG and raising HDL (Tables 14 and 15).

Table 12: Non-HDL Treatment Response Following 24-Week Treatment Mean Percent Change from Simvastatin 20-mg Treated Baseline

Group A Combination Tablet of NIASPAN and Simvastatin 2000/20 Combination Tablet of NIASPAN and Simvastatin 1000/20 Simvastatin 20
Week na Dose (mg/mg) Non-HDLb na Dose (mg/mg) Non-HDLb na Dose (mg/mg) Non- HDLb
Baseline 56 - 163.1mg/dL 108 - 164.8mg/dL 102 - 163.7mg/dL
4 52 500/20 -12.9% 86 500/20 -12.8% 91 20 -8.3%
8 46 1000/20 -17.5% 91 1000/20 -15.5% 95 20 -8.3%
12 46 1500/20 -18.9% 90 1000/20 -14.8% 96 20 -6.4%
24 40 2000/20 -19.5%t 78 1000/20 -13.6%t 90 20 -5.0%
Dropouts by 28.6% 27.8% 11.8%
an=number of subjects with values in the analysis window at each timepoint
bThe percent change from baseline is the model-based mean from a repeated measures mixed model with no imputation for missing data from study dropouts.
† significant vs. simvastatin 20 mg at the primary endpoint (Week 24), p < 0.05

Table 13: Non-HDL Treatment Response Following 24-Week Treatment Mean Percent Change from Simvastatin 40-mg Treated Baseline

Group B Combination Tablet of NIASPAN and Simvastatin 2000/40 Combination Tablet of NIASPAN and Simvastatin 1000/40 Simvastatin 80
Week na Dose (mg/mg) Non- HDLb na Dose (mg/mg) Non- HDLb na Dose (mg/mg) Non- HDLb
Baseline 98 - 144.4 mg/dL 111 - 141.2 mg/dL 113 - 134.5 mg/dL
4 96 500/40 -6.0% 108 500/40 -5.9% 110 80 -11.3%
8 93 1000/40 -15.5% 100 1000/40 -16.2% 104 80 -13.7%
12 90 1500/40 -18.4% 97 1000/40 -12.6% 100 80 -9.5%
24 80 2000/40 -7.6%c 82 1000/40 -6.7%d 90 80 -6.0%
Dropouts by week 24: 18.4% 26.1% 20.4%
an=number of subjects with values in the analysis window at each timepoint
bThe percent change from baseline is the model-based mean from a repeated measures mixed model with no imputation for missing data from study dropouts.
cnon-inferior to simvastatin 80 arm; 95% confidence interval of mean difference in non-HDL for the combination tablet of NIASPAN and simvastatin 2000/40 vs. simvastatin 80 is (-7.7%, 4.5%)
dnon-inferior to simvastatin 80 arm; 95% confidence interval of mean difference in non-HDL for combination tablet of NIASPAN and simvastatin 1000/40 vs. combination tablet of NIASPAN and simvastatin 80 is (-6.6%, 5.3%)

Table 14: Mean Percent Change from Baseline to Week 24 in Lipoprotein Lipid Levels

TREATMENT Treatment Group A
N LDL-C Total-C HDL-C TGa Apo B
Baseline (mg/dL)* 266 120 207 43 209 102
Simvastatin 20 mg 102 -6.7% -4.5% 7.8% -15.3% -5.6%
Combination Tablet of NIASPAN and Simvastatin 1000/20 108 -11.9% -8.8% 20.7% -26.5% -13.2%
Combination Tablet of NIASPAN and Simvastatin 2000/20 56 -14.3% -11.1% 29.0% -38.0% -18.5%
*either treatment na´ve or after receiving simvastatin 20 mg
amedians are reported for TG

Table 15: Mean Percent Change from Baseline to Week 24 in Lipoprotein Lipid Levels

TREATMENT Treatment Group B
N LDL-C Total-C HDL-C TGa Apo B
Baseline (mg/dL)* 322 108 187 47 145 93
Simvastatin 80 mg 113 -11.4% -6.2% 0.1% 0.3% -7.5%
Combination Tablet of NIASPAN and Simvastatin 1000/40 111 -7.1% -3.1% 15.4% -22.8% -7.7%
Combination Tablet of NIASPAN and Simvastatin 2000/40 98 -5.1 -1.6% 24.4% -31.8% -10.5%
*after receiving simvastatin 40 mg
amedians are reported for TG

Last reviewed on RxList: 3/12/2013
This monograph has been modified to include the generic and brand name in many instances.

A A A

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Cholesterol Management

Tips to keep it under control.