Simvastatin (Page 9 of 11)


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D.R. Taves, Minimization: a new method of assigning patients to treatment and control groups. Clin. Pharmacol. Ther. 15 (1974), pp. 443-453

Simvastatin
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Angiographic Studies

In the Multicenter Anti-Atheroma Study, the effect of simvastatin on atherosclerosis was assessed by quantitative coronary angiography in hypercholesterolemic patients with CHD. In this randomized, double-blind, controlled study, patients were treated with simvastatin 20 mg/day or placebo. Angiograms were evaluated at baseline, two and four years. The co-primary study endpoints were mean change per-patient in minimum and mean lumen diameters, indicating focal and diffuse disease, respectively. Simvastatin tablets significantly slowed the progression of lesions as measured in the Year 4 angiogram by both parameters, as well as by change in percent diameter stenosis. In addition, simvastatin significantly decreased the proportion of patients with new lesions and with new total occlusions.

Modifications of Lipid Profiles

Primary Hyperlipidemia (Fredrickson type lla and llb)

Simvastatin tablets have been shown to be effective in reducing total-C and LDL-C in heterozygous familial and non-familial forms of hyperlipidemia and in mixed hyperlipidemia. Maximal to near maximal response is generally achieved within 4 to 6 weeks and maintained during chronic therapy. Simvastatin tablets significantly decreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio; simvastatin tablets also decreased TG and increased HDL-C ( see Table 5).

Table 5: Mean Response in Patients with Primary Hyperlipidemia and Combined (mixed) Hyperlipidemia (Mean Percent Change from Baseline After 6 to 24 Weeks)

TREATMENT

N

TOTAL-C

LDL-C

HDL-C

TG *

*
median percent change
mean baseline LDL-C 244 mg/dL and median baseline TG 168 mg/dL
mean baseline LDL-C 188 mg/dL and median baseline TG 128 mg/dL
§
mean baseline LDL-C 226 mg/dL and median baseline TG 156 mg/dL
21% and 36% median reduction in TG in patients with TG ≤ 200 mg/dL and TG > 200 mg/dL, respectively. Patients with TG > 350 mg/dL were excluded
#
mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL.
Lower Dose Comparative Study(Mean % Change at Week 6)
Simvastatin Tablets 5 mg q.p.m. 109-19-2610-12
Simvastatin Tablets 10 mg q.p.m. 110-23-3012-15
Scandinavian Simvastatin Survival Study(Mean % Change at Week 6)
Placebo2223-1-10-2
Simvastatin Tablets 20 mg q.p.m. 2221-28-388-19
Upper Dose Comparative Study§(Mean % Change Averaged at Weeks 18 and 24)
Simvastatin Tablets 40 mg q.p.m. 433-31-419-18

Simvastatin Tablets 80 mg q.p.m.

664-36-478-24

Multi-Center Combined Hyperlipidemia Study#(Mean % Change at Week 6)

Placebo

125

1

2

3

-4

Simvastatin Tablets 40 mg q.p.m.

123-25-2913-28
Simvastatin Tablets 80 mg q.p.m. 124-31-3616-33

Hypertriglyceridemia (Fredrickson type IV)

The results of a subgroup analysis in 74 patients with type lV hyperlipidemia from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 6.

Table 6: Six-week, Lipid-lowering Effects of Simvastatin in Type lV Hyperlipidemia Median Percent Change (25 th and 75 th percentile) from Baseline *
TREATMENT N Total-C LDL-C HDL-C TG VLDL-C Non-HDL-C
*
The median baseline values (mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215
Placebo74

+2

(-7, +7)

+1

(-8, +14)

+3

(-3, +10)

-9

(-25, +13)

-7

(-25, +11)

+1

(-9, +8)

Simvastatin Tablets 40 mg/day 74

-25

(-34, -19)

-28

(-40, -17)

+11

(+5, +23)

-29

(-43, -16)

-37

(-54, -23)

-32

(-42, -23)

Simvastatin Tablets 80 mg/day 74

-32

(-38, -24)

-37

(-46, -26)

+15

(+5, +23)

-34

(-45, -18)

-41

(-57, -28)

-38

(-49, -32)

Dysbetalipoproteinemia (Fredrickson type lll)

The results of a subgroup analysis in 7 patients with type lll hyperlipidemia (dysbetalipoproteinemia) (apo E2/2) (VLDL-C/TG>0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 7.

Table 7: Six-week, Lipid-lowering Effects of Simvastatin in Type lll Hyperlipidemia Median Percent Change (min, max) from Baseline *
TREATMENT N Total-C LDL-C + IDL HDL-C TG VLDL-C+IDL Non-HDL-C
*
The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291.
Placebo7

-8

-8

-2

+4

-4

-8

Simvastatin Tablets 40 mg/day 7

-50

-50

+7

-41

-58

-57

Simvastatin Tablets 80 mg/day 7

-52

-51

+7

-38

-60

-59

(-61, -46)

Homozygous Familial Hypercholesterolemia

In a controlled clinical study, 12 patients 15 to 39 years of age with homozygous familial hypercholesterolemia received simvastatin 40 mg/day in a single dose or in 3 divided doses, or 80 mg/day in 3 divided doses. In 11 patients with reductions in LDL-C, the mean LDL-C changes for the 40- and 80-mg doses were 14% (range 8% to 23%, median 12%) and 30% (range 14% to 46%, median 29%), respectively. One patient had an increase of 15% in LDL-C. Another patient with absent LDL-C receptor function had an LDL-C reduction of 41% with the 80-mg dose.

Endocrine Function

In clinical studies, simvastatin did not impair adrenal reserve or significantly reduce basal plasma cortisol concentration. Small reductions from baseline in basal plasma testosterone in men were observed in clinical studies with simvastatin, an effect also observed with other statins and the bile acid sequestrant cholestyramine. There was no effect on plasma gonadotropin levels. In a placebo-controlled, 12-week study there was no significant effect of simvastatin 80 mg on the plasma testosterone response to human chorionic gonadotropin. In another 24-week study, simvastatin 20 to 40 mg had no detectable effect on spermatogenesis. In 4S, in which 4,444 patients were randomized to simvastatin 20 to 40 mg/day or placebo for a median duration of 5.4 years, the incidence of male sexual adverse events in the two treatment groups was not significantly different. Because of these factors, the small changes in plasma testosterone are unlikely to be clinically significant. The effects, if any, on the pituitary-gonadal axis in pre-menopausal women are unknown.

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