Simvastatin Study

Pedersen TR, Kjekshus J, Pyorala K, et al. Effect of Simvastatin on Ischemic Signs and Symptoms in the Scandanavian Simvastatin Study Study. Am J Cardiol 1998 81 333-335. 

In rodent stroke models, statin pretreatment has been shown to reduce infarct volumes and improve outcomes. Similarly, several clinical studies have shown that prior statin use reduced the severity of acute ischemic stroke and myocardial infarction. Recent studies indicate that beneftt can be achieved even when treatment is initiated after the onset of symptoms. In rodents, atorvastatin and simvastatin have been shown to reduce the growth of ischemic lesions, enhance functional outcome, and induce brain plasticity when administered after stroke onset. A retrospective analysis of the population-based Northern Manhattan Stroke Study (NOMASS) showed that patients using lipid-lowering agents at the time of ischemic stroke have a lower incidence of in-hospital stroke progression and reduced 90-day mortality rates. Retrospective analysis of data of the phase III citicoline trial showed... 

Corti R, Fayad ZA, Fuster V, Worthley SG, Helft G, Chesebro J, Mercuri M, Badimon JJ. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation 2001 104(3) 249. 

Over the last decade, several studies in tens of thousands of patients have revealed that lowering cholesterol, specifically lowering LDL cholesterol with statins, is effective for both primary and secondary prevention of IHD-related events. Statins shown to decrease morbidity and mortality associated with IHD include lovastatin, simvastatin, pravastatin, and atorvas-tatin.22,23 A recent meta-analysis showed that the risk of major adverse cardiac events is reduced by 21% with the use of statins in patients at high risk for IHD-related events.23... 

In an elegant paper, Gerdes et al. [59] examined whether the risk of death or a major coronary event in survivors of myocardial infarction (MI) was related to the apo E genotype and whether risk reduction brought about by simvastatin was different between genotypes. They analyzed 5.5 years of follow-up data of 966 Danish and Finish myocardial infarction survivors enrolled in the Scandinavian Simvastatin Survival Study and found that MI survivors with the apo E4 allele have a nearly 2-fold increased risk of death, and that treatment with simvastatin abolished excess mortality. They concluded that the effect of apo E4 may involve mechanisms unrelated to serum lipoproteins because... 

Gerdes LU, Gerdes C, Kervinen K, Sa-volainen M, Klausen IC, Hansen PS, et al. The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction a substudy of the Scandinavian simvastatin survival study. Circulation 2000 101 1366-1371. 

There is interest in the use of lipid-lowering agents, especially the 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors, to prevent AD. Pravastatin and lovastatin, but not simvastatin, were associated with a lower prevalence of AD. Further study is needed before these agents can be recommended for this use. 

As indicated in Table 1, statins, which block cholesterol biosynthesis by inhibition of hepatic HMGCoA reductase, have been used extensively to reduce LDL-C levels. At most therapeutic doses, statins marginally increase HDL levels by 5-10% [3,16]. The HDL elevation observed with statins has been highly variable and not easily extrapolated from the effects on LDL. A recent study (STELLAR) demonstrated increased HDL elevation with the use of rosuvastatin compared to simvastatin, pravastatin or atorvastatin (10% vs. 2-6%) [16,24], Although the mechanism of HDL elevation by statins is not clearly understood, it is proposed that statins enhance hepatic apoA-I synthesis [25] and decrease apoB-containing lipoproteins [26]. A number of clinical trials have demonstrated that statins reduce the risk of major coronary events. However, it is not clear if the statin-induced rise in HDL levels is an independent contributor to the reduced risk of coronary events. The observed small increase in HDL and adverse side effect profile related to liver function abnormalities and muscle toxicity limits the use of statins as monotherapy for HDL elevation [27],... 

Eleart Protection Study Collaborative Group. (2002) MRC/BHF Heart Protection study of cholesterol lowering with simvastatin in 20,506 high-risk individuals a randomized placebo-controlled trial. Lancet, 360, 7-22. 

For clinical studies demonstrating that statins are effective in the various populations mentioned, see Scandinavian Simvastatin Survival Study T. R. Pedersen A. G Olsson,... 

Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004 363 757-67. 

Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease ... 

Fluvastatin, launched in 1994, was the first S5mthetic HMG-CoA reductase inhibitor to be approved for the treatment of hypercholesterolemia. This statin was developed by Novartis (Sandoz), and it is marketed as a racemate under the trade name Lescol (Asberg and Holdaas, 2004). In laboratory studies, fluvastatin was shown to potently inhibit HMG-CoA reductase (IC50 = 8 nM) and effectively block cholesterol biosynthesis in hepatoc5de cells (IC50 = 52 nM) (Parker et al., 1990). Clinically, fluvastatin is prescribed less frequently than simvastatin, atorvastatin, or rosuvastatin, but it nevertheless remains an important medication for the treatment of hypercholesterolemia moreover, as the first completely S5mthetic statin to be approved, it offers a compelling synthetic story (Repic et al., 2001). 

Sugimoto et al. examined the effect of St. John s wort administration (300 mg three times a day for 14 days) on the disposition of simvastatin and pravastatin in 16 healthy male Japanese subjects in a double-blind crossover study (104). The administration of St. John s wort significantly... 

Note that the warnings in the labeling about interactions with lovastatin, atorvastatin, and pimozide are based on extrapolation from clinical studies with simvastatin and cisapride. 

Dart A, Jerums G, Nicholson G, d Emden M, Hamilton-Craig I, Tallis G, Best J, West M, Sullivan D, Braes P, Black D. A multicenter, double-blind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients with hypercholesterolemia. Am J Cardiol 1997 80(l) 39-44. 

Leiter LA, Hanna K. Efficacy and safety of cerivastatin in primary hypercholesterolemia a long term comparative titration study with simvastatin. Can J Cardiol 1999 15(5) 545-55. 

Ezetimibe is a selective potent inhibitor of the intestinal absorption of dietary and biliary cholesterol. A total of 432 patients were included in a pooled analysis of two phase-II studies, both lasting for 12 weeks ezetimibe was well tolerated, with an adverse events profile similar to that of placebo (1). In 668 patients who took ezetimibe with simvastatin, the adverse effects were similar to those with simvastatin alone (2). 

In a multicenter, open, phase III study in 104 Korean patients there were eight adverse drug reactions in six patients taking pitavastatin and 19 adverse drug reactions in 12 patients taking simvastatin (4). However, there were no reports of serious reactions in either group. 

Some studies have shown increased risks of violent death and depression in subjects with reduced serum cholesterol concentrations. Serum and membrane cholesterol concentrations, the microviscosity of erythrocyte membranes, and platelet serotonin uptake have been determined in 17 patients with hypercholesterolemia (21). There was a significant increase in serotonin transporter activity only during the first month of simvastatin therapy. This suggests that within this period some patients could be vulnerable to depression, violence, or suicide. This is an important paper, in that it explains why mood disorders are not regularly seen in clinical trials with statins, as has been summarized in a recent review (3). 

HMG CoA reductase inhibitors can be associated with small rises in alanine transaminase activity, but have not been definitely associated with severe morbidity involving altered hepatic function. The results of randomized trials do not suggest that statins in standard doses are hepato-toxic. In none of the large randomized studies in which standard doses were assessed (atorvastatin 10 mg/day, fluvastatin 40-80 mg/day, pravastatin 40 mg/day, simvastatin 20-40 mg/day) was there any clear excess risk of hepatitis or any other serious liver-related adverse events. Long-term large randomized trials have confirmed an excess of persistent rises in transaminases with atorvastatin 80 mg/day compared with lower doses or placebo, and similarly some excess with simvastatin 80 mg/day, but hepatitis and liver failure were not reported (4). 

In one series, the frequency of liver toxicity was similar in patients taking pravastatin or simvastatin (30), while in another study there was a difference 6 months after the start of the study when the simvastatin group showed increases in liver enzymes (SEDA-13,1327 31). 

Physicians should check for lipid-lowering drugs before treating elderly individuals with itraconazole (73). Susceptibility to this interaction varies from statin to statin, in that simvastatin is more affected than pravastatin (74). Concomitant use of simvastatin with itraconazole should be avoided, and the same holds true for atorvastatin (75). In another study, the blood concentration of fluvastatin was not significantly increased, whereas that of lovastatin was (76). 

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