Evidence Table 5Trials comparing LDL-c lowering and HDL-c raising abilities of fixed-dose combination products

Clinical TrialInclusion Criteria/ Patient PopulationExclusion criteriaInterventionResults (mean changes in lipoprotein levels)Safety/CommentsFunding Source
Ballantyne C, et al, 2005 (Vyva study)
R (1:1), DB, MC, AC, modified ITT

1,902 patients randomized (n= 951 atorva, 951 ez/simva)
6 weeks
Men and women, 18 to 79 years, LDL-C level at or above drug treatment thresholds established by NCEP ATP III; established CHD or CHD risk equivalent with an LDL-C ≥130 mg/dL; no established CHD or CHD risk equivalent, with ≥2 risk factors conferring a 10-year risk for CHD ≥10% and ≤20% with an LDL-C >130 mg/dL; no established CHD or CHD risk equivalent, with >2 risk factors conferring a 10-year risk for CHD <10% with an LDL-C ≥160 mg/dL; and no established CHD or CHD risk equivalent, with <2 risk factors, and with LDL-C z190 mg/dL; Fasting serum triglyceride (TG) level ≤350 mg/dL, alanine aminotransferase (ALT), aspartate aminotransferase (AST), or creatine kinase (CK) level ≤1.5 times the upper limit of normal, serum creatinine level V1.5 mg/dL, and hemoglobin A1C <9.0% in patients with diabetes.See inclusion criteria10 weeks, with 4-week placebo/diet run-in period followed by 6 weeks of active treatment (ezetimibe/simvastatin (10/10, 10/20, 10/40, and 10/80 mg) and atorvastatin (10, 20, 40, and 80 mg).)Efficacy analysis for 1850 patients.
LDL-c reduction % from baseline at week 6:
atorva 10 mg: 36.1
atorva 20 mg 43.7
atorva 40 mg 48.3
atorva 80 mg 52.9
All doses 45.3
ez/simva 10 mg 47.1
ez/simva 20 mg 50.6
ez/simva 40 mg 57.4
ez/simva 80 mg 58.6
All doses 53.4
Between differences at same dose and all p < 0.001
HDL-c increase % from baseline at week 6:
atorva 10 mg: 6.9
atorva 20 mg 5.1
atorva 40 mg 3.8
atorva 80 mg 1.4
All doses 4.3
ez/simva 10 mg 7.7
ez/simva 20 mg 7.2
ez/simva 40 mg 9.0
ez/simva 80 mg 7.6
All doses 7.9
Between differences at same dose for 40 and 80 mg levels and all p < 0.001, others were NS
ALT ≥3 ULN, presumed consecutive all atorva 10 (1.1) vs.. All ez/simva 0 (0.0) p = 0.002
AST ≥3 ULN, presumed consecutive all atorva 7 (0.7) vs.. All ez/simva 1 (0.1) p = 0.070
No other AEs reported.
Merck/Schering Plough
Pharmaceuticals
Barrios V, et al 2005
R (1:1), DB, MC, AC, modified ITT

435 patients randomized (EZE/SIMVA 10/20 mg (n = 221 eze/simva 10/20, 214 atv 20).
Men and women 18 years with documented hypercholesterolemia and atherosclerotic or CHD; serum LDL-C between 2.5 and 4.2 mmol/l (100 to 160 mg/dl) and triglycerides (TG) <4.0 mmol/l (350 mg/dl) while on a stable dose of ATV
10 mg for 6 weeks.
Congestive heart failure; MI, coronary artery bypass surgery or angioplasty within the past 3 months; poorly controlled or newly diagnosed (within 3 months) Type I or II diabetes; uncontrolled hypertension (systolic >160 mmHg or diastolic >100 mmHg); uncontrolled endocrine or metabolic disease known to influence serum lipids; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels >1.5 times the upper limit of normal (ULN) and creatine kinase (CK) levels >1.5 ULN.eze/simva 10/20 mg or atv 20 mg once daily for 6 weeks.LDL-c reduction % from baseline at week 6:
eze/simva −33
atv −20 (p < 0.001)
Non HDL-c reduction % from baseline at week 6:
eze/simva −28
atv −17 (p < 0.001)
HDL-c change % from baseline at week 6:
eze/simva +2
atv < −1 (p < 0.05)
One or more clinical AEs [44 (19.9%) EZE/SIMVA vs. 51 (23.8%) ATV]
Serious clinical AEs [5 (2.3%) EZE/SIMVA vs.2 (0.9%) ATV]
myalgia [6 (2.7%) EZE/SIMVA vs. 5 (2.3%) ATV] headache [3 (1.4%)
EZE/SIMVA vs. 8 (3.7%) ATV].
Merck/Schering-Plough
Pharmaceuticals
Constance C, et al 2007

R (1:1:1), DB, MC, AC, modified ITT

661 patients randomized
(n= 220 eze/simva 10/20, 222 eze/simva 10/40, 219 atv)
6 weeks
Men and women ≥18 years of age, diagnosed with T2D, HBA1C < 10%, alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels 1.5 times the upper limit of normal (ULN), and creatine kinase (CK) levels 1.5 times ULN, on ATV 10 mg for >6 weeks prior and complete a 4-week, open-label ATV 10 mg/day run-in.Congestive heart failure defined by NYA class III or IV; myocardial infarction, coronary artery bypass surgery or angioplasty within 3 months; uncontrolled hypertension (systolic >160 mm Hg or diastolic >100 mm Hg); uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins; impaired renal function (creatinine 177 mmol/l) or nephrotic syndrome; alcohol consumption >14 drinks per week and treatment with excluded concomitant medications, pregnancy4-week baseline period while continuing to receive open label
ATV 10 mg and counseling for a low cholesterol diet. EZE/SIMVA 10/20 mg, EZE/SIMVA 10/40 mg
or ATV 20 mg once-daily for 6 weeks.
LDL-C % change from baseline
eze/simva 10/20 −26.15 vs. atv −8.49 p < 0.001
eze/simva 10/20 −30.13 vs. atv −8.49 p < 0.001
HDL-C % change from baseline
eze/simva 10/20 2.37 vs. atv 1.25 p = 0.569
eze/simva 10/20 1.29 vs. atv 1.25 p = 0.795
Eze/simva 10/20 vs. eze/simva 10/40 vs. atv 20
Clinical AE 51 (23.2) vs.50 (22.5) vs. 42 (19.2)
Treatment-related clinical AE 13 (5.9) vs. 9 (4.1) vs. 11 (5.0)
Serious clinical AE 1 (0.5) vs.1 (0.5) vs.5 (2.3)
Discontinuations due to AE 3 (1.4) vs. 7 (3.2) vs. 2 (0.9)
Discontinuations due to treatment-related AE 3 (1.4) vs.4 (1.8) vs. 0
Allergic reaction/rash AE 4 (1.8) vs.0 vs. 3 (1.4)
Gallbladder-related AE 0 vs. 1 (0.5) vs. 1 (0.5)
Gastrointestinal-related AE 9 (4.1) vs. 10 (4.5) vs. 5 (2.3)
Laboratory AE 10 (4.5) vs.10 (4.5) vs.8 (3.7)
Treatment-related laboratory AE 5 (2.3) vs.4 (1.8) vs. 3 (1.4)
Merck/Schering-Plough Pharmaceuticals
Goldberg R, 2006 (Vital study)

R (1:1:1:1:1), DB, MC, AC, mITT

1229 patients randomized
(n= 245 atv 10, 247 eze/simva 10/20, 245 atv 20, 247 eze/simva 10/40, 245 atv 40)
6 weeks
type 2 diabetes (aged 18–80 years) with hemoglobin A1c levels of 8.5% or lessNRezetimibe/simvastatin, 10/20 mg/d, vs atorvastatin, 10 or 20 mg/d) or next highest (ezetimibe/simvastatin, 10/40 mg/d, vs atorvastatin, 40 mg/dEfficacy analysis for 1198 patients.
LDL-c reduction % from baseline at week 6:

eze/simva 10/20 −53.6 vs. atv 10 −38.3 p < 0.001
atv 20 −44.6 vs. eze/simva 10/20 −53.6 p < 0.001
eze/simva 10/40 −57.6 vs. atv 40 −50.9 p < 0.001
HDL-c reduction % from baseline at week 6:
eze/simva 10/20 8.0 vs. atv 10 4.3 p < 0.001
atv 20 4.5 vs. eze/simva 10/20 8.0 p = 0.001
eze/simva 10/40 6.3 vs. atv 40 2.3 p < 0.001
Atv vs. eze/simva
CAEs ≥1 166 (22.7) 98 (19.8) p= 0.26
Drug related‡ 30 (4.1) 20 (4.0) p >.99
Serious 10 (1.4) vs.3 (0.6) p= 0.26
Serious drug related‡ 0 vs 0
Discontinuations 11 (1.5) vs. 4 (0.8) p= 0.43
Gastrointestinal 32 (4.4) 19 (3.8) 0.5 (−1.9 to 2.7) p= 0.77
Gallbladder related 0 (0.0) vs. 0 (0.0)
Allergic reaction or rash 5 (0.7) vs. 1 (0.2) p= 0.41
Hepatitis related 0 (0.0) vs. 0 (0.0)

ALT ≥3 times the ULN, consecutive 2 (0.3) vs. 0 (0.0) p=0.52
AST ≥3 times the ULN, consecutive 3 (0.4) vs. 0 (0.0) p=0.28
ALT and/or AST >3 times the ULN, consecutive 3 (0.4) vs. 0 (0.0) p=0.28
Merck/Schering-Plough Pharmaceuticals
Ezetimibe/Simvastatin (Vytorin) vs. Simvastatin
Bays H, et al 2004
R(1:1:1:1:1:1:1:1::1:1), DB, MC, PC, ITT

1,528 patients randomized
(n= 148 placebo, 149 eze, 622 pooled simva, 609 pooled eze/simva)
12 weeks
men and women aged 18 to 80 years; primary hypercholesterolemia defined as LDL-C concentrations ≥145 mg/dL but ≤150 mg/dL and triglycerides (TG) ≤350 mg/dL at visit 2; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations ≤1.5 times the upper limit of normal (ULN) with no active liver disease and creatine kinase (CK) concentrations ≥ 1.5 times ULN at visit 2.<50% of ideal body weight according to the 1983 Metropolitan Height and Weight tables (or body weight <100 lb), hypersensitivity to statins, or alcohol consumption >14 drinks per week; pregnant or lactating females.6- to 8 week washout period; 4-week, single-blind, placebo run in, randomized equally to 1 of 10 daily treatments for 12 weeks: EZE/SIMVA 10/10, 10/20, 10/40, or 10/80 rag; SIMVA 10, 20, 40, or 80 nag; EZE 10 rag; or placebo.LDL-c reduction % from baseline at week 12:
eze/simva 10/10 44.8* **
eze/simva10/20 51.9* **
eze/simva10/40 55.2* **
eze/simva10/80 60.2* **
pooled eze/simva 53.0
simva 10 32.7
simva 20 34.3
simva 40 40.6
simva 80 48.5
pooled simva 39.0
eze 18.9
placebo 2.2
*P < 0001 EZE/SIMVA versus same dose of SIMVA monotherapy
**P < 0001 EZE/SIMVA versus next highest dose of SIMVA monotherapy.
placebo vs. eze vs. pooled simva vs. pooled eze/simva
Treatment related AEs 54.1 vs.. 53 vs.. 53.4 vs. 57.5
Serious AEs 1.4 vs. 1.3 vs. 1.8 vs. 1.5
Serious treatment related AEs 0 vs. 0 vs. 0.2 vs. 0
Merck
Research Laboratories,
Ose L, et al 2007
R(1:1:1:1:1:1), DB, MC, AC, ITT

2959 patients randomized-2855 MITT
(n= 1427 eze/simva and 1428 rosuvastatin)
14 weeks
See Bays 2004See Bays 2004Protocol-compliant patients who completed the 12-week base study were eligible to enter a randomized, double-blind, 14-week extension study and were administered 1 of 8 daily treatments: EZE/SIMVA 10/10-, 10/20-, 10/40- or 10/80-mg, or SIMVA 10-, 20-, 40- or 80-mg.LDL-c reduction % from baseline at week 14:
simva 10 31.4 vs. eze/simva 10/10 47.2 (p< 0.001)
simva 20 34.3 vs. eze/simva10/20 51.3 (p< 0.001)
simva 40 41.3 vs. eze/simva10/40 55.5 (p< 0.001)
simva 80 48.5 vs. eze/simva10/80 60.8 (p< 0.001)
pooled simva 38.8 vs. pooled eze/simva 53.3 (p< 0.001)
HDL-c increase % from baseline at week 14:
simva 10 4.0 vs. eze/simva 10/10 6.0
simva 20 6.1 vs. eze/simva10/20 6.1
simva 40 6.6 vs. eze/simva10/40 7.9
simva 80 5.6 vs. eze/simva10/80 4.8
pooled simva 5.6 vs. pooled eze/simva 6.4 (p= 0.30)
Pooled simva vs. pooled eze/simva
Number of patients with AEs 34.5% (193) vs. 34.9% (190)
Drug-related AEs 5.5% (31) vs. 7.4% (40)
Serious AEs 2.3% (13) vs. 2.0% (11)
Discontinuations because of AEs 2.1% (12) vs. 2.0% (11)
Discontinuations because of drug-related AEs
1.3% (7) vs. 0.9% (5)
Discontinuations because of serious AEs 0.2% (1) vs.0.2% (1)
Consecutive ALT and/or AST elevations ≥ 3 x ULN
1.3% (7/559) vs. 1.5% (8/540)
CK elevations ≥ 10 x ULN 0.2% (1/559) vs. 0.2% (1/540)
Merck/Schering-Plough Pharmaceuticals
Shankar, et al 2007
R(1:1), DB, MC, AC, ITT

230 patients randomized
(n= 116 simva, 609 114 eze/simva)
12 weeks
Male and female 18 years or more; LDL-C > 135 for naïve and >120 otherwise.Unstable angina w/in 3 months; uncontrolled diabetes; hypertension, active hepatitis or hepatic dysfunction, renal failure, hypothyroidism, hypersensitivity to statins, pregnant or lactating.4 week diet run in, eze/simva or simva for 12 weeks.LDL-c reduction % from baseline at week 12:
simva −26.3 vs.. Eze/simva −33.7 (p < 0.05)
HDL-c increase % from baseline at week 12:
simva 3.3 vs.. Eze/simva 6.0 (p=ns)
Simva vs. eze/simva
Adverse events 34% vs. 35%
Drug related AEs 26% vs. 29%
GI complaints 16% vs. 18%
HeteroDrugs Unlimited
Ezetimibe/Simvastatin (Vytorin) vs. Rosuvastatin
Catapano A, et al 2006

R(1:1:1:1:1:1), DB, MC, AC, ITT

2959 patients randomized- 2855 MITT (n= 1427 eze/simva and 1428 rosuvastatin)
6 weeks
Men and women 18–81 years with LDL–C ≥ 145 mg/dL (3.7 mmol/L) and ≤ 250 mg/dL (6.5 mmol/L), fasting serum triglyceride (TG) level ≤ 350 mg/dL (4.0 mmol/L), alanine aminotransferase (ALT), aspartate aminotransferase (AST), or creatine kinase (CK) level ≤ 1.5 times the upper limit of normal (ULN), serum creatinine level ≤ 1.5 mg/dL (133 mmol/L), and HBA1c < 9.0% in patients with diabetes.None reported10 weeks, 4 weeks placebo/diet run-in followed by 6 weeks active treatment of eve/simva vs. ros.LDL-C % change from baseline
ros 10 −45.8 vs. eze/simva 20 −51.5***
ros 20 −52.3 vs. eze/simva 40 −54.8**
ros 40 −56.7 vs. eze/simva 80 −61.0***
all ros −51.6 vs all eze/simva −55.8***
** p=0.001 *** p < 0.001
HDL-C % change from baseline
ros 10 6.9 vs. eze/simva 20 7.0
ros 20 8.1 vs. eze/simva 40 8.3
ros 40 8.1 vs. eze/simva 80 7.6
all ros 7.6 vs. all eze/simva 7.6
P=NS
** p=0.001
*** p < 0.001
Pooled eze/simva vs., pooled ros
One or clinical adverse events 29.2% vs. 31.1
Drug related adverse events 8.1% vs. 7.4%
Serious adverse events 1.2% vs. 1.1%
Merck-Scering Plough Pharmaceuticals
Ezetimibe/Simvastatin (Vytorin) vs. Doubling of Statin dose
Reckless J, 2008 (INFORCE)
R(1:1), open label, blinded endpoint, MC, AC, ITT

424 patients randomized (n= 213 eze/simva and 211 doubling of statin)
12 weeks
Men and women (≥18 years) hospitalized for investigation of a coronary event and taking a stable daily dose of one of the following statin medications for > 6 weeks prior, atorvastatin ; fluvastatin ; lovastatin; pravastatin; rosuvastatin or SimvaCongestive heart failure defined by NYA Class III or IV; poorly controlled (HBA1c > 9.0%) or newly diagnosed (within 3 months) type I or II diabetes; uncontrolled hypertension (systolic > 160 mmHg or diastolic > 100 mmHg); uncontrolled endocrine or metabolic disease known to influence serum lipids and lipoproteins; impaired renal function (creatinine ≥ 177 mmol/l) or nephrotic syndrome; alcohol consumption > 14 drinks per week; cancer diagnosis within the past 5 years (except for clinically cured cases with normal life expectancy); any medical condition that the investigator determined could limit a patient’s evaluation or participation in the study; and treatment with excluded concomitant medications.Doubling of the statin dose (n = 211) or Eze/Simva 10/40 mg (n = 213) for 12 weeksLDL-c reduction % from baseline at week 12:
eze/simva 27% vs.. doubling 4.2% (p < 0.001)
Eze/simva vs. doubling
One or more clinical AEs 89.2% vs. 85.3%
One or more lab AEs 4.9% vs. 6.4%
Allergic reaction 6.6% vs. 6.6%
Gallbladder related 0 vs. 0
Gastrointestinal AEs 7.0% vs. 11.8%
Merck/Schering-Plough Pharmaceuticals
Roeters van Lennep H, 2008 (EASEGO)
R(1:1), open-label, MC, AC, ITT

367 patients randomized (n= 178 eze/simva and 189 doubling statin)
12 weeks
Men and women > 18 years of age with controlled stable DM2 (> 3 months) and/or established CHD. stable medical condition; stable daily statin dose of either atorvastatin 10 mg or simvastatin 20 mg for at least 4 weeks. LDL–C ≥ 2.5 mmol/L and < 5.0 mmol/L, TG ≤ 4.0 mmol/L and TC ≤ 7.0 mmol/L.Cholesterol-lowering medication regime changed in the previous 4 weeks; any other investigational drug within 3 months; pregnant or lactating and any condition or situation which, might pose a risk to the patient or interfere with participation in the study; congestive heart failure NYHA class III or IV, uncontrolled hypertension with systolic blood pressure > 160 mmHg or diastolic > 100 mmHg; poorly controlled diabetes mellitus (HbA1c > 10.0%) or newly diagnosed diabetes mellitus (within 3 months) or a change in antidiabetic pharmacotherapy within 3 months; uncontrolled endocrine or metabolic disease ; impaired renal function (creatinine ≥ 177 μmol/L) or nephrotic syndrome; disorders of the hematologic, digestive or central nervous system, including CVD and degenerative disease that would limit study evaluation or participation; history of mental instability and/or drug/alcohol abuse within the past 5 years.(1) doubling the statin dose or (2) switching to the ezetimibe/simvastatin 10/20 mg tablet in CHD/DM2 patients on the recommended starting doses of simvastatin 20 mg or atorvastatin 10 mgLDL-c reduction % from baseline at week 12:
eze/simva 29.1 vs. doubling 11.5 (p< 0.001)
HDL-c increase % from baseline at week 12:
eze/simva −2.6 vs. doubling 1.0 (p< 0.001)
Doubling vs. eze/simva
All adverse events 66 (35%) vs. 64 (36%)
Serious adverse events 7 (4%) vs. 9 (5%)
Treatment-related adverse events 19 (10%) vs. 24 (13%)
Gastrointestinal adverse events 10 (5%) vs. 10 (6%)
Musculoskeletal adverse events 13 (7%) vs. 17 (10%)
Laboratory adverse event 1 (1%) vs. 2 (1%)
Merck Sharp and Dohme and Schering Plough
Ezetimibe/Simvastatin (Vytorin) vs. Misc
Farnier M, et al 2007
R (3:3:3:1), DB, MC, P/AC, ITT

611 patients randomized (Placebo (n = 60) eze/simva (n = 184) feno (n = 184) eze/simva + feno (n = 183))
12 weeks
Men and women 18 through 79 years of age with mixed hyperlipidemia and no coronary heart disease (CHD) or CHD-risk equivalent disease (except for type 2 diabetes), or 10-year CHD risk >20%homozygous familial hypercholesterolemia; type I or V hyperlipidemia; treatment with LDL apheresis; congestive heart failure ; uncontrolled cardiac arrhythmia; unstable hypertension; pancreatitis; inadequately controlled diabetes (HbA1c >8.5% or newly diagnosed within 3 months of screening); gallbladder, renal (serum creatinine N1.5 mg/dL), or active liver disease; uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins; pregnancy or lactation; contraindicated medicationsWash out, run in and one of 4 daily treatments for 12 weeks: EZE/SIMVA 10/20 mg + FENO 160 mg (EZE/SIMVA + FENO), FENO
160 mg, EZE/SIMVA 10/20 mg, or placebo.
LDL-c reduction % from baseline at week 12:
Placebo 3.5
eze/simva 47.1
feno 15.7
eze/simva + feno 45.8
HDL-c increase % from baseline at week 12:
Placebo 1.1
eze/simva 9.3
feno 18.2
eze/simva + feno 18.7
Placebo vs eze/simva vs. feno vs. eze/simva + feno
Number (%) of patients with-
One or more AEs 18 (30.0) vs. 65 (35.3) vs. 87 (47.3) vs. 72 (39.3)
Drug-related AEs 4 (6.7) vs. 13 (7.1) vs. 23 (12.5) vs. 16 (8.7)
SAEs 2 (3.3) vs. 1 (0.5) vs. 3 (1.6) vs. 0
Drug-related SAEs 0 vs. 0 vs. 1 (0.5) vs. 0
ALT and/or AST ≥3 ULN (consecutive), 0 vs. 0 vs. 6 (3.3) vs. 5 (2.8)
CK z10 ULN, 0 vs. 0 vs. 2 (1.1) vs. 0
Myopathy 0 vs. 0 vs. 0 vs. 0
Merck/Schering-Plough Pharmaceuticals
Guyton J, et al 2008
R(2:2:5), DB, MC, AC, ITT

1220 patients randomized-1112 MITT (n= 272 niacin, 272 eze/simva and 676 eze/simva+niacin)
24 weeks
Men and women aged 18 years to 79 years with LDL-C levels (130 to 190 mg/dl), triglyceride levels ( 500 mg/dl), and metabolic and clinical stabilityNReze/simva (10/20 mg) or niacin (titrated to 2 g), eze/simva (10/20 mg) + niacin (titrated to 2 g) for 24 weeksLDL-c reduction % from baseline at week 24:
eze/simva −53.2
niacin −17.0
eze/simva+niacin −56.8 vs.. niacin (p< 0.001) vs. eze/simva
(p=0.007)
HDL-c increase % from baseline at week 24:
eze/simva 7.3
niacin 22.6
eze/simva+niacin 25.1 vs.. niacin (p> 0.05) vs. eze/simva
(p<0.001)

From on-line appendix
Eze/simva vs. niacin vs eze/simva + niacin
One or more AE 62.9% vs.. 82.4% vs. 75.2%
Drug related AE 18.4% vs. 59.9% vs. 54.2%
Serious AE 2.6% vs. 2.6% vs. 2.1%
Serious drug related AE 0.4 vs. 0 vs. 0
Death 0.4% vs. 0 vs. 0
Discontinuations 25% vs. 9.6% vs. 23.3%
New onset diabetes 0.9% vs. 2.2% vs 4.4%
Eze/simva+niacin vs eze/simva (p = 0.009)
Lab AEs 7.4% vs. 7.0% vs. 5.1%
Merck/Schering-Plough Pharmaceuticals
Lovastatin/Niacin-ER (Advicor) vs Statin.
Bays H, et al 2003

R (1:1:1:1), Open label, MC, AC, modified ITT

315 patients randomized (niacin extended-release/lovastatin fixed-dose combination (1000/40 or 2000/40) (n=79 and 78) vs. atorvastatin (n=82) or simvastatin (n=76))
Women and men, 18 to 70 years old, with 2 consecutive baseline low-density lipoprotein (LDL) cholesterol blood levels ≥160 mg/dl without coronary artery disease, or ≥130 mg/dl if coronary artery disease was present. Other lipid inclusion criteria included triglycerides <300 mg/dl and high-density lipoprotein (HDL) cholesterol <45 mg/dl in men and <50 mg/dl in women.Known prior allergy or intolerability to any of the study drugs, history of substance abuse or dependence within 12 months, >14 alcoholic drinks/week, uncontrolled psychiatric disease, participation in another investigational study within 30 days, or probucol administration within the previous year history of; active gallbladder disease; uncontrolled hypertension; renal insufficiency (serum creatinine 1.5 mg/dl); hepatic dysfunction ; fasting glucose 115 mg/dl; New York Heart Association class III/IV congestive heart failure; active gout symptoms or uric acid 1.3 times the upper limit of normal; active peptic ulcer disease; type 1 or 2 diabetes; fibromyalgia; cancer within the previous 5 years (except for basal cell carcinoma); unstable angina, myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or stroke within prior 6 months; or any condition or laboratory abnormality.Niacin extended-release/lovastatin fixed-dose combination(1000/40 or 2000/40) vs. Atorvastatin (10–40) or simvastatin (10–40).LDL-c reduction % from baseline at week 16:
Niacin ER/Lovastatin 1000/40 39
Niacin ER/Lovastatin 2000/40 42
atorvastatin 49
simvastatin 39
niacin ER/lovastatin 2,000/40 mg vs. simvastatin (p =ns) or
atorvastatin (p<0.001).
HDL-c increase % from baseline at week 16:
Niacin ER/Lovastatin 1000/40 17
Niacin ER/Lovastatin 2000/40 32
atorvastatin 6
simvastatin 7

Niacin ER/lovastatin vs. Atorvastatin or simvastatin at all compared doses (p <0.001)
One study subject receiving atorvastatin withdrew due to myalgias. Otherwise, no significant differences were seen in the incidence of rash, hyperglycemia, hyperuricemia, or gastrointestinal complaints between treatment groups.Kos Pharmaceuticals
Lin, et al 2006
R (1:1), DB, SC (Taiwan), AC, modified ITT

70 patients randomized (modified ITT 61) (niacin extended-release/lovastatin fixed-dose combination (n=36 (31)) vs. or simvastatin (n=34(30)))
≥ 20 years of age; failure to control LDL-C level under the 4-week therapeutic lifestyle changes (TLC); hyperlipidemia, CHD and CHD risk equivalents, receiving concomitant treatment other than lipid- control treatment that was known to affect lipid level and dose maintained unchanged throughout the study; male/female subject with reproductive potential is under appropriate contraception; compliance and geographic proximity to the study site and willing to participate.TG > 500 mg/dL; breast feeding in female subject; pregnancy or not exercising appropriate birth control during course of study; type I diabetes; uncontrolled type II diabetes requiring insulin treatment; uncontrolled hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg); uncontrolled hypothyroidism; acute myocardial infarction within the proceeding 3 months; insufficient renal function (serum creatinine > 2.0 mg/dL); insufficient liver function (aspartate aminotransferase, AST/alanine aminotransferase, ALT > 2 times normal); severe peptic ulcer disease; not able to stop concomitant lipid-control treatment during the study; history of hypersensitivity to product being investigated; drug or alcohol abuse.5-week wash out, 16-week drug treatment, and 4-week follow-up periodLDL-c reduction % from baseline at week 16:
Niacin ER/Lovastatin 30.5 vs. simvastatin 36 (p=0.159)

HDL-c increase % from baseline at week 16:
Niacin ER/Lovastatin 10.4 vs. simvastatin 2.2 (p=0.029)
Niacin ER/Lovastatin 30 vs. simvastatin
Arrhythmia 3 (8.6%) vs. 1 (3.0%)
Arteriosclerosis 4 (11.4%) 2 (6.1%)
Cardiovascular disorder 9 (25.7%) vs 12 (36.4%)
Myocardial ischemia 3 (8.6%) vs. 2 (6.1%)
Palpitation 6 (17.1%) vs. 2 (6.1%)
Pericardial effusion 1 (2.9%) vs. 3 (9.1%)
Vascular disorder 5 (14.3%) vs. 1 (3.0%)
Dyspepsia 2 (5.7%) vs. 5 (15.2%)
Flatulence 2 (5.7%) vs. 3 (9.1%)
Nausea 1 (2.9%) vs.3 (9.1%)
Edema/cramp/pain 8 (22.9%) vs.2 (6.1%)
Dizziness 8 (22.9%) vs 11 (33.3%)
Insomnia 4 (11.4%) vs. 2 (6.1%)
Cough and sputum 3 (8.6%) vs. 8 (24.2%)
Pharyngitis 3 (8.6%) vs. 4 (12.1%)
Pruritus or rash 2 (5.7%) vs. 4 (12.1%)
Lotus pharmaceutical
Simvastatin/Niacin-ER (Simcor) vs. Statin
Ballantyne C, et al 2008
(SEACOAST I study)
R (2:2:1), DB, MC, AC, modified ITT (completers analysis)

319 patients randomized Simvastatin (20 mg/d) (n =121) vs.. NER/S (1,000/20 mg/d) (n = 127) vs.NER/S (2,000/20 mg/d) (n = 66)
6 weeks
Increased ATP III risk-adjusted non–HDL cholesterol at screening; men and women aged 21 years; Women could not be pregnant or breast-feeding or planning to conceive or breast-feed during the study. Patients had to comply reasonably with a standard cholesterol-lowering diet for at least 4 weeks and be willing to comply with this diet for the duration of the study.Aspartate aminotransferase or alanine aminotransferase ≥ 1.3 times the upper limit of normal, calculated creatinine clearance < 30 ml/min, creatine kinase ≥ 3 times the upper limit of normal, hemoglobin A1c ≥ 9%, and active gout symptoms and/or uric acid level > 1.3 times the upper limit of normal.A screening phase, an open-label simvastatin run-in phase, a lipid qualification phase, and a double-blind treatment phase of 6 weeks.Median % change in Non-HDL Cholesterol
Simvastatin −7.4
NER/S (1000/20) −13.9 p < 0.01 compared with simvastatin 20 mg/day
NER/S (2000/20) −22.5 p < 0.001 compared with simvastatin
Median % change in LDL Cholesterol
Simvastatin −7.1
NER/S (1000/20) −13.1
NER/S (2000/20) −14.2
Median % change in HDL Cholesterol
Simvastatin 6.7
NER/S (1000/20) 18.3 p < 0.001 compared with simvastatin
NER/S (2000/20) 24.9 p < 0.001 compared with simvastatin
Simvastatin (20 mg/d) vs.. NER/S (1,000/20 mg/d) vs.NER/S (2,000/20 mg/d)
Any adverse events
20 (17.5%) vs.31 (25.2%) vs. 23 (35.9%) P < 0.05 vs. Sim
Serious adverse events 0 (0.0%) vs.1 (0.8%) vs. 0 (0.0%)
Discontinuation due to adverse events†
6 (5.3%) vs.15 (12.2%) vs.10 (15.6%)
Discontinuation due to flushing
0 (0.0%) vs.8 (6.5%) vs. 6 (9.4%)
Deaths 0 (0.0%) vs. 0 (0.0%) vs. 0 (0.0%)
Flushing‡ 0 (0.0%) vs.9 (7.3%) P < 0.05 vs. Sim vs.7 (10.9%) P < 0.05 vs. Sim
Headache 1 (0.9%) vs. 3 (2.4%) vs.3 (4.7%)
Hyperglycemia 0 (0.0%) 2 (1.6%) 2 (3.1%)
Vomiting 1 (0.9%) vs. 0 (0.0%) vs. 2 (3.1%) P < 0.05 vs.. NER/S (1,000/20 mg/d)
Gastritis 2 (1.8%) vs.0 (0.0%) vs. 2 (3.1%)
Hypertension 3 (2.6%) vs. 0 (0.0%) 1 (1.6%)
Abdominal pain (upper)
3 (2.6%) vs.1 (0.8%) vs. 0 (0.0%)
Nausea 1 (0.9%) vs. 3 (2.4%) vs. 1 (1.6%)
Abbott

From: Evidence Tables

Cover of Drug Class Review: HMG-CoA Reductase Inhibitors (Statins) and Fixed-dose Combination Products Containing a Statin
Drug Class Review: HMG-CoA Reductase Inhibitors (Statins) and Fixed-dose Combination Products Containing a Statin: Final Report Update 5 [Internet].
Smith MEB, Lee NJ, Haney E, et al.
Portland (OR): Oregon Health & Science University; 2009 Nov.
Copyright © 2009, Oregon Health & Science University, Portland, Oregon.

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