[The effects of the cholesterol synthesis inhibitor simvastatin in patients with hypercholesterolemia with and without diabetes mellitus]

[Article in Dutch]

Wolffenbuttel BH.

Afd. Inwendige Geneeskunde, Academisch Ziekenhuis, Maastricht.

We studied the short-term effects of simvastatin on lipid variables in 33 dyslipidemic patients without and 18 with diabetes mellitus who were on a lipid-lowering diet for at least 3 months. Six diabetic patients had type I, and 12 had type II diabetes mellitus, of whom 5 were using insulin. In the whole group total cholesterol decreased by 28%, from 9.35 (SD 2.10) mmol/l to 6.69 (SD 1.47) mmol/l after 3 months and 6.60 (SD 1.27) mmol/l after 6 months (mean daily dose of simvastatin 21 (SD 12) mg). Calculated LDL-cholesterol showed a decrease of 38%, HDL-cholesterol increased by 10% and plasma triglycerides decreased by 13%. In patients receiving 10, 20, or 40 mg simvastatin daily, the following changes were observed: total cholesterol -26, -31 and -34% and LDL-cholesterol -37, -38 and -39%, respectively. The effect of simvastatin in the diabetic patients was comparable with that in the non-diabetic individuals, although in the diabetics LDL-cholesterol before therapy was lower, as was the daily dose of simvastatin after 6 months (14 versus 24 mg). In the diabetic patients blood glucose control, measured as HbA1c, was not affected. One patient discontinued therapy because of stomach complaints. Our results show that a low daily dose (10 mg) of simvastatin effectively lowers plasma total and LDL-cholesterol and that the drug can be safely used in diabetic patients.

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[Evaluation of tolerance, efficacy and safety of 3-year simvastatin use in the treatment of primary hypercholesterolemia]

[Article in French]

Bercher L.

Policlinique medicale universitaire, Division d'hypertensiologie, CHUV, Lausanne.

Simvastatin (synvinolin MK-733) is a potent inhibitor of 3-HMG-CoA-reductase, the key enzyme for cholesterol biosynthesis. To investigate the efficiency and safety of this new drug on a long term basis, simvastatin was administered for 3 years to ten patients with type II hyperlipoproteinemia. Daily dosages were 20 or 40 mg. The drug therapy produced a significant reduction in serum levels of total cholesterol (19-34%), LDL-cholesterol (26-44%) and Apo B (19-33%). Triglycerides decreased moderately (2-23%) while HDL-cholesterol and Apo A1 changed only slightly (-3 to 6% and 5-13% respectively). Simvastatin was well tolerated. No consistent adverse clinical or biochemical effects were observed during the three-year therapy. The results indicate that simvastatin is a promising new therapy for high risk hypocholesterolemic patients.

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Simvastatin in the treatment of hypercholesterolemia in elderly patients.

Paciaroni E.

Cardiovascular Pathology Center, University of Ancona, Italy.

Twenty elderly (mean age, 69 years), hypercholesterolemic patients (low-density lipoprotein [LDL] levels greater than or equal to 160 mg/dl) were supplied a lipid-lowering diet for one month and then received 10 mg of simvastatin daily for 12 months. Total cholesterol levels fell significantly, from 304.6 mg/dl at baseline to 277.4 mg/dl after one month on the diet, to 245.9 mg/dl after one month of simvastatin, and to 216.1 mg/dl after two months of simvastatin; total cholesterol levels remained significantly lower (221.6 mg/dl at month 12). LDL levels decreased significantly, from 217.6 mg/dl at baseline to 130.4 mg/dl at month 12. High-density lipoprotein levels increased significantly only at months 2 and 3. Apolipoprotein (apo) A levels increased significantly, from 147.2 mg/dl at baseline to 217.9 mg/dl at month 12. There were no significant changes in triglyceride or apo B levels. No changes in blood pressure, heart rate, or body weight or in results of laboratory tests were noted. Few side effects were reported. It is concluded that simvastatin is safe and effective in the treatment of hypercholesterolemia in elderly patients.

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The effects of simvastatin on serum lipoproteins in severe hypercholesterolaemia.

Stalenhoef AF.

Department of Medicine, University Hospital, Nijmegen.

The effects of simvastatin, an inhibitor of cholesterol synthesis, on serum lipids, lipoprotein composition and apolipoproteins were evaluated in a total of 50 patients with hypercholesterolaemia. In the first study, 24 patients (mean serum cholesterol 10.74 +/- 1.59 mmol/l) were treated with simvastatin 40 mg daily for 24 wk. Serum cholesterol and low density lipoprotein (LDL) cholesterol decreased to average values 29-36% and 35-42% below the basal value, respectively. Serum triglycerides decreased by 16-28%, and high density lipoprotein (HDL) cholesterol increased by 6-11%. Apolipoprotein A-I concentration increased 6-8% and that of apolipoprotein B decreased 29-33%. The composition of LDL remained unchanged whereas the very low density lipoproteins became enriched in triglycerides. Lipoprotein Lp(a) was not affected. In the second study 26 patients (mean serum cholesterol 12.35 +/- 2.05 mmol/l) were treated with simvastatin 40 mg daily as monotherapy or combined with a bile acid binding resin for 2 yr. Serum cholesterol levels decreased to values which remained stable throughout the entire study period; after 2 yr this decrease amounted to 43%. Compared to monotherapy, combination therapy yielded a further 12% decrease of cholesterol. In the entire group, triglycerides decreased by 16% and HDL cholesterol increased by 9%. Side effects were limited to slight increases in alanine aminotransferase and creatine phosphokinase in some patients. Simvastatin appears to be an important asset in the treatment of hypercholesterolaemia.

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Influence of apo E polymorphism on the response to simvastatin treatment in patients with heterozygous familial hypercholesterolemia.

Havekes LM.

Gaubius Institute TNO, Leiden, The Netherlands.

In a group of 120 patients with heterozygous familial hypercholesterolemia (FH) the influence of the apolipoprotein E (apoE) polymorphism on pre-treatment plasma lipid levels and on the response to treatment with simvastatin was studied. The apoE phenotype distribution did not differ significantly between the FH group and a sample group of the Dutch population. Differences in pre-treatment lipid levels were not related to the apoE polymorphism in this FH population. After 12 weeks use of a daily dose of 40 mg simvastatin, the plasma total cholesterol, low density lipoprotein (LDL)-cholesterol and plasma triglyceride levels were reduced on average by 33%, 38% and 19%, respectively. At the same time high density lipoprotein (HDL)-cholesterol concentration increased on average by 7%. In the combined FH patient group (males and females) a considerable interindividual variation in response to simvastatin was observed, but was not related to the apoE polymorphism. However, considering males and females separately, we found that female FH patients with the apoE3E3 phenotype responded better on simvastatin treatment with respect to LDL-cholesterol than male FH patients with the apoE3E3 phenotype.

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Simvastatin reduces platelet thromboxane formation and restores normal platelet sensitivity against prostacyclin in type IIa hypercholesterolemia.

Steinhagen-Thiessen E.

Institut fur Pharmakologie, Heinrich-Heine-Universitat Dusseldorf, Federal Republic of Germany.

The effect of lowering total serum cholesterol and low-density lipoprotein (LDL) cholesterol on platelet function, thromboxane formation and platelet sensitivity against PGI2 was studied in platelet-rich plasma ex vivo. Additionally, PGI2 receptors were determined in membrane preparations of these platelets. Twelve patients suffering from familial hyperlipoproteinemia type IIa (FH) were treated for 8 months with simvastatin (20-40 mg/day) and compared with 10 untreated FH patients and 10 untreated normocholesterolemic subjects. Compared with those of healthy controls, platelets of untreated FH patients were hyperreactive, as shown by an enhanced aggregation response and release of ATP and thromboxane after stimulation by collagen (0.3-5 micrograms/ml) and ADP (0.3-10 micrograms/ml). Simvastatin reduced the total and LDL serum cholesterol towards control levels while HDL cholesterol remained unchanged. This was accompanied by a significant decrease of platelet aggregation, thromboxane formation and ATP secretion being no more different from normocholesterolemic controls. In addition, the reduced platelet sensitivity against prostacyclin (aggregation, stimulation of cAMP formation) in untreated FH patients was improved to normal values by simvastatin. This was associated with a significant elevation of the reduced prostacyclin binding sites and might be explained by an improved access of prostacyclin to its receptors at platelet membranes. These data demonstrate that the reduction of total and LDL serum cholesterol by simvastatin results in a normalization of platelet function by (i) reduction of platelet hyperreactivity and (ii) improvement of the sensitivity against prostacyclin towards normal via enhanced PGI2-binding sites.

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