Ezetimibe and Simvastatin (Page 9 of 11)

14 CLINICAL STUDIES

14.1 Primary Hyperlipidemia

Ezetimibe and Simvastatin Tablets

Ezetimibe and simvastatin tablets reduce total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C in patients with hyperlipidemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.

Ezetimibe and simvastatin tablets are effective in men and women with hyperlipidemia. Experience in non-Caucasians is limited and does not permit a precise estimate of the magnitude of the effects of ezetimibe and simvastatin tablets.

Five multicenter, double-blind studies conducted with either ezetimibe and simvastatin tablets or coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets in patients with primary hyperlipidemia are reported: two were comparisons with simvastatin, two were comparisons with atorvastatin, and one was a comparison with rosuvastatin.

In a multicenter, double-blind, placebo-controlled, 12 week trial, 1,528 hyperlipidemic patients were randomized to one of ten treatment groups: placebo, ezetimibe (10 mg), simvastatin (10 mg, 20 mg, 40 mg, or 80 mg), or ezetimibe and simvastatin tablets (10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg, or 10 mg/80 mg).

When patients receiving ezetimibe and simvastatin tablets were compared to those receiving all doses of simvastatin, ezetimibe and simvastatin tablets significantly lowered total-C, LDL-C, Apo B, TG, and non-HDL-C. The effects of ezetimibe and simvastatin tablets on HDL-C were similar to the effects seen with simvastatin. Further analysis showed ezetimibe and simvastatin tablets significantly increased HDL-C compared with placebo (see Table 7). The lipid response to ezetimibe and simvastatin tablets was similar in patients with TG levels greater than or less than 200 mg/dL.

Table 7: Response to Ezetimibe and Simvastatin Tablets in Patients with Primary Hyperlipidemia (Mean * % Change from Untreated Baseline2)
*
For triglycerides, median % change from baseline.
Ezetimibe and simvastatin tablet doses pooled (10 mg/10 mg to 10 mg/80 mg) significantly reduced total-C, LDL-C, Apo B, TG, and non-HDL-C compared to simvastatin and significantly increased HDL-C compared to placebo.

Treatment (Daily Dose)

N

Total-C

LDL-C

Apo B

HDL-C

TG

Non-HDL-C

Pooled data (All ezetimibe and simvastatin tablet doses)

609

-38

-53

-42

+7

-24

-49

Pooled data (All simvastatin doses)

622

-28

-39

-32

+7

-21

-36

Ezetimibe 10 mg

149

-13

-19

-15

+5

-11

-18

Placebo

148

-1

-2

0

0

-2

-2

Ezetimibe and simvastatin tablets by dose

10 mg/10 mg

152

-31

-45

-35

+8

-23

-41

10 mg/20 mg

156

-36

-52

-41

+10

-24

-47

10 mg/40 mg

147

-39

-55

-44

+6

-23

-51

10 mg/80 mg

154

-43

-60

-49

+6

-31

-56

Simvastatin by dose

10 mg

158

-23

-33

-26

+5

-17

-30

20 mg

150

-24

-34

-28

+7

-18

-32

40 mg

156

-29

-41

-33

+8

-21

-38

80 mg

158

-35

-49

-39

+7

-27

-45

In a multicenter, double-blind, controlled, 23 week study, 710 patients with known CHD or CHD risk equivalents, as defined by the NCEP ATP III guidelines, and an LDL-C ≥ 130 mg/dL were randomized to one of four treatment groups: coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets (10 mg/10 mg, 10 mg/20 mg, and 10 mg/40 mg) or simvastatin 20 mg. Patients not reaching an LDL-C < 100 mg/dL had their simvastatin dose titrated at 6 week intervals to a maximal dose of 80 mg.

At Week 5, the LDL-C reductions with ezetimibe and simvastatin tablets 10 mg/10 mg, 10 mg/20 mg, or 10 mg/40 mg were significantly larger than with simvastatin 20 mg (see Table 8).

Table 8: Response to Ezetimibe and Simvastatin Tablets after 5 Weeks in Patients with CHD or CHD Risk Equivalents and an LDL-C ≥ 130 mg/dL

Simvastatin

Ezetimibe and Simvastatin Tablets,

Ezetimibe and Simvastatin Tablets,

Ezetimibe and Simvastatin Tablets,

20 mg

10 mg/10 mg

10 mg/20 mg

10 mg/40 mg

N

253

251

109

97

Mean baseline LDL-C

174

165

167

171

Percent change LDL-C

-38

-47

-53

-59

In a multicenter, double-blind, 6 week study, 1,902 patients with primary hyperlipidemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to one of eight treatment groups: ezetimibe and simvastatin tablets (10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg, or 10 mg/80 mg) or atorvastatin (10 mg, 20 mg, 40 mg, or 80 mg).

Across the dosage range, when patients receiving ezetimibe and simvastatin tablets were compared to those receiving milligram-equivalent statin doses of atorvastatin, ezetimibe and simvastatin tablets lowered total-C, LDL-C, Apo B, and non-HDL-C significantly more than atorvastatin. Only the 10 mg/40 mg and 10 mg/80 mg ezetimibe and simvastatin tablet doses increased HDL-C significantly more than the corresponding milligram-equivalent statin dose of atorvastatin. The effects of ezetimibe and simvastatin tablets on TG were similar to the effects seen with atorvastatin (see Table 9).

Table 9: Response to Ezetimibe and Simvastatin Tablets and Atorvastatin in Patients with Primary Hyperlipidemia (Mean * % Change from Untreated Baseline )
*
For triglycerides, median % change from baseline.
Baseline — on no lipid-lowering drug.
Ezetimibe and simvastatin tablet doses pooled (10 mg/10 mg to 10 mg/80 mg) provided significantly greater reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to atorvastatin doses pooled (10 mg to 80 mg).
§
p < 0.05 for difference with atorvastatin at equal mg doses of the simvastatin component.

Treatment (Daily Dose)

N

Total-C

LDL-C

Apo B

HDL-C

TG

Non-HDL-C

Ezetimibe and simvastatin tablets by dose

10 mg/10 mg

230

-34 §

-47

-37

+8

-26

-43

10 mg/20 mg

233

-37

-51

-40

+7

-25

-46

10 mg/40 mg

236

-41

-57

-46

+9

-27

-52

10 mg/80 mg

224

-43

-59

-48

+8

-31

-54

Atorvastatin by dose

10 mg

235

-27

-36

-31

+7

-21

-34

20 mg

230

-32

-44

-37

+5

-25

-41

40 mg

232

-36

-48

-40

+4

-24

-45

80 mg

230

-40

-53

-44

+1

-32

-50

In a multicenter, double-blind, 24 week, forced-titration study, 788 patients with primary hyperlipidemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to receive coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets (10 mg/10 mg and 10 mg/20 mg) or atorvastatin 10 mg. For all three treatment groups, the dose of the statin was titrated at 6 week intervals to 80 mg. At each pre-specified dose comparison, ezetimibe and simvastatin tablets lowered LDL-C to a greater degree than atorvastatin (see Table 10).

Table 10: Response to Ezetimibe and Simvastatin Tablets and Atorvastatin in Patients with Primary Hyperlipidemia (Mean * % Change from Untreated Baseline )
*
For triglycerides, median % change from baseline.
Baseline — on no lipid-lowering drug.
Atorvastatin: 10 mg start dose titrated to 20 mg, 40 mg, and 80 mg through Weeks 6, 12, 18, and 24.
§
Ezetimibe and simvastatin tablets: 10 mg/10 mg start dose titrated to 10 mg/20 mg, 10 mg/40 mg, and 10 mg/80 mg through Weeks 6, 12, 18, and 24.
p ≤ 0.05 for difference with atorvastatin in the specified week.
#
Ezetimibe and simvastatin tablets: 10 mg/20 mg start dose titrated to 10 mg/40 mg, 10 mg/40 mg, and 10 mg/80 mg through Weeks 6, 12, 18, and 24.
Þ
Data pooled for common doses of ezetimibe and simvastatin tablets at Weeks 18 and 24.

Treatment

N

Total-C

LDL-C

Apo B

HDL-C

TG

Non-HDL-C

Week 6

Atorvastatin 10 mg

262

-28

-37

-32

+5

-23

-35

Ezetimibe and simvastatin tablets, 10 mg/10 mg §

263

-34

-46

-38

+8

-26

-43

Ezetimibe and simvastatin tablets, 10 mg/20 mg #

263

-36

-50

-41

+10

-25

-46

Week 12

Atorvastatin 20 mg

246

-33

-44

-38

+7

-28

-42

Ezetimibe and simvastatin tablets, 10 mg/20 mg

250

-37

-50

-41

+9

-28

-46

Ezetimibe and simvastatin tablets, 10 mg/40 mg

252

-39

-54

-45

+12

-31

-50

Week 18

Atorvastatin 40 mg

237

-37

-49

-42

+8

-31

-47

Ezetimibe and simvastatin tablets, 10 mg/40 mg Þ

482

-40

-56

-45

+11

-32

-52

Week 24

Atorvastatin 80 mg

228

-40

-53

-45

+6

-35

-50

Ezetimibe and simvastatin tablets, 10 mg/80 mg

459

-43

-59

-49

+12

-35

-55

In a multicenter, double-blind, 6 week study, 2959 patients with primary hyperlipidemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to one of six treatment groups: ezetimibe and simvastatin tablets (10 mg/20 mg, 10 mg/40 mg, or 10 mg/80 mg) or rosuvastatin (10 mg, 20 mg, or 40 mg).

The effects of ezetimibe and simvastatin tablets and rosuvastatin on total-C, LDL-C, Apo B, TG, non-HDL-C and HDL-C are shown in Table 11.

Table 11: Response to Ezetimibe and Simvastatin Tablets and Rosuvastatin in Patients with Primary Hyperlipidemia (Mean * % Change from Untreated Baseline )
*
For triglycerides, median % change from baseline.
Baseline — on no lipid-lowering drug.
Ezetimibe and simvastatin tablet doses pooled (10 mg/20 mg to 10 mg/80 mg) provided significantly greater reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to rosuvastatin doses pooled (10 mg to 40 mg).
§
p < 0.05 vs. rosuvastatin 10 mg.
p < 0.05 vs. rosuvastatin 20 mg.
#
p < 0.05 vs. rosuvastatin 40 mg.

Treatment (Daily Dose)

N

Total-C

LDL-C

Apo B

HDL-C

TG

Non-HDL-C

Ezetimibe and simvastatin tablets by dose

10 mg/20 mg

476

-37 §

-52

-42

+7

-23

-47

10 mg/40 mg

477

-39

-55

-44

+8

-27

-50

10 mg/80 mg

474

-44 #

-61

-50

+8

-30

-56

Rosuvastatin by dose

10 mg

475

-32

-46

-37

+7

-20

-42

20 mg

478

-37

-52

-43

+8

-26

-48

40 mg

475

-41

-57

-47

+8

-28

-52

In a multicenter, double-blind, 24 week trial, 214 patients with type 2 diabetes mellitus treated with thiazolidinediones (rosiglitazone or pioglitazone) for a minimum of 3 months and simvastatin 20 mg for a minimum of 6 weeks were randomized to receive either simvastatin 40 mg or the coadministered active ingredients equivalent to ezetimibe and simvastatin tablets, 10 mg/20 mg. The median LDL-C and HbA1c levels at baseline were 89 mg/dL and 7.1%, respectively.

Ezetimibe and simvastatin tablets, 10 mg/20 mg were significantly more effective than doubling the dose of simvastatin to 40 mg. The median percent changes from baseline for ezetimibe and simvastatin tablets vs. simvastatin were: LDL-C -25% and -5%; total-C -16% and -5%; Apo B -19% and -5%; and non-HDL-C -23% and -5%. Results for HDL-C and TG between the two treatment groups were not significantly different.

Ezetimibe

In two multicenter, double-blind, placebo-controlled, 12 week studies in 1,719 patients with primary hyperlipidemia, ezetimibe significantly lowered total-C (-13%), LDL-C (-19%), Apo B (-14%), and TG (-8%), and increased HDL-C (+3%) compared to placebo. Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.

Simvastatin

In two large, placebo-controlled clinical trials, the Scandinavian Simvastatin Survival Study (N = 4,444 patients) and the Heart Protection Study (N = 20,536 patients), the effects of treatment with simvastatin were assessed in patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease. Simvastatin was proven to reduce: the risk of total mortality by reducing CHD deaths; the risk of non-fatal myocardial infarction and stroke; and the need for coronary and non-coronary revascularization procedures.

No incremental benefit of ezetimibe and simvastatin tablets on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

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