Simvastatin clinical trials

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],... 

Clinical trials with lovastatin (Mevacor), simvastatin (Zocor) and pravastatin (Pravachol) provided much of the evidence supporting the observation that lowering... 

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). 

Recent reports on clinical trials of pravastatin and simvastatin have shown a significant reduction in patient mortality rates for both hypercholesterolemic patients without known coronary heart disease and for those with existing coronary heart disease [7,8], These trials have established cholesterol-lowering agents as an effective treatment for coronary disease and have stimulated the search for new cholesterol-lowering agents with other mechanisms of action. 

Based on clinical trial evidence and cost, generic simvastatin 20 mg or 40 mg daily would seem a reasonable first-line choice. In the largest statin trial to date, the Heart Protection Study (2002), which included people with and without existing coronary heart disease (CHD), simvastatin 40 mg was associated with a significant 27% reduction in major coronary events (CHD death plus non-fatal myocardial infarction), equating to an NNT (number needed to treat) of 32 over 5 years. 

Based on clinical trial evidence, atorvastatin 10 mg daily would be a reasonable alternative to simvastatin. However, branded atorvastatin 10 mg is over four times more expensive than generic simvastatin 40 mg. 

A comparison of simvastatin and atorvastatin up to maximal recommended doses in a large multicenter randomized clinical trial. Curr Med Res Opin 2001 17(1) 43-50. 

Multiple well-controlled clinical trials have documented the efficacy and safety of simvastatin, pravastatin, lovastatin, and atorvastatin in reducing fatal and nonfatal CHD events, strokes, and total mortality. Rates of adverse events in statin trials were the same in the placebo groups and in the groups receiving the drug. This was true with regard to noncardiac illness and the two laboratory tests, hepatic transaminases and creatine kinase (CK), that are commonly monitored in patients taking statins. 

No clinically relevant adverse interactions appear to have been reported between the statins and the sulphonylureas. One study reported an increased incidence of adverse effects with repaglinide and simvastatin, the clinical relevance of which is unclear. Most studies have shown no pharmacokinetic interaction or increased incidence of adverse effects when pioglitazone or rosiglitazone were used with atorvastatin or simvastatin. Subcutaneous exenatide modestly decreased the AUC of lovastatin, but no clear pattern of altered efficacy of statins was noted in exenatide clinical trials. 

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... 

Ezetimibe is the first member of a group of drugs that inhibit intestinal absorption of phytosterols and cholesterol. Its primary clinical effect is reduction of LDL levels. In one trial, patients receiving ezetimibe in combination with simvastatin had marginal, but not statistically significant, increases in carotid intimal-medial thickness (IMT) compared with those... 

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