PubMed · 2335666
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1990. Counterpoint.. https://doi.org/10.14219/jada.archive.1990.0090
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A detailed overview of the various forms of hyperlipidemia/dyslipidemia that constitute a major risk factor for coronary heart disease and a detailed discussion of the various types of cholesterol-lowering drugs are presented. The importance of identifying the type of dyslipidemia with respect to the choice of treatment is emphasized, as is the use of nonpharmacologic intervention, i.e., diet, exercise, and weight loss. The appropriate use and benefits of bile acid sequestrants, nicotinic acid, fibric acids, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, and probucol are individually discussed, whereas nonpharmacologic approaches used in conjunction with the drugs are recommended emphatically.
OBJECTIVE: To examine whether a small dose of bile acid sequestrant used in combination with a hydroxymethylglutaryl coenzyme A reductase inhibitor is more effective in reducing serum and low-density lipoprotein (LDL) cholesterol levels than inhibitor used alone. DESIGN: A randomised, double-blind study. SETTING: Subjects receiving tertiary care at a hospital lipid clinic. PATIENTS: Subjects with severe primary hypercholesterolaemia (types IIa and IIb), already stabilised on a cholesterol-lowering diet, with serum cholesterol levels of 7.0 mmol/L or more and triglyceride levels of 6.0 mmol/L or less. Sixty-four subjects were randomly assigned to the treatment groups; three withdrew before any outcome observations; 61 completed the trial and their results were analysed. INTERVENTIONS: Subjects were randomly assigned to receive either colestipol placebo or colestipol 5 g or 10 g each morning in fixed dosage for 18 weeks. They simultaneously received incremental doses of simvastatin: placebo for six weeks, then 20 mg/night for six weeks, then 40 mg/night for a final six weeks. MAIN OUTCOME MEASURES: Lipids, lipoproteins, and haematological and biochemical safety parameters were measured at the end of each treatment period. Adverse events were monitored. RESULTS: Respective maximum reductions (95% confidence intervals) in serum cholesterol, LDL cholesterol and apolipoprotein B (apo-B) values in subjects taking combination therapy were 41% (38%-45%), 50% (46%-53%) and 43% (39%-46%), compared with lesser reductions of 32% (26%-37%), 38% (31%-45%) and 37% (32%-41%) in those taking simvastatin monotherapy. The percentage changes in LDL cholesterol with combination therapy were independent of baseline cholesterol level or lipid phenotype. Combination therapy reduced serum triglyceride levels by up to 24% (15%-32%) and increased high-density lipoprotein (HDL) cholesterol levels by up to 9% (3%-15%). Three subjects withdrew within a few weeks because of severe gastrointestinal side effects related to colestipol; 19 experienced milder gastrointestinal side effects, 15 were taking combination therapy. CONCLUSIONS: A combination of low-dose colestipol and simvastatin was found to be more effective in reducing serum and LDL cholesterol than simvastatin used alone. Such combination therapy offers the possibility of improved cholesterol lowering without the need for full dosage of either drug.
The effect of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on human glioma cell growth was investigated. When incubated with simvastatin, cell proliferation decreased in a concentration-dependent fashion, as measured by cell number and [3H]-thymidine incorporation into DNA (concentration producing 50% inhibition, 60 nM). The effect was detectable 12 h after cells were exposed to the drug and persisted for 2 days. Addition of mevalonate to cells exposed effect of simvastatin in combination with beta-interferon and N,N'-bis(2-chloroethyl)-N-nitrosourea, both antitumoral drugs, was also evaluated by cell growth inhibition assay. The concentration producing 50% inhibition for each of these drugs was 650 units/ml and 50 nM, respectively. Subliminal concentrations of beta-interferon or N,N'-bis(2-chloroethyl)-N-nitrosourea were incubated together with 1 nM simvastatin. The data were analyzed with the aid of an isobologram using the concept of an envelope of additivity. Simultaneous cell exposure to simvastatin with either N,N'-bis(2-chloroethyl)-N-nitrosourea or beta-interferon produced a strong synergistic inhibitory effect on cell proliferation. These data provide in vitro support for the possibility that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, utilized as plasma cholesterol-lowering agents, could potentiate the effect of antiblastic drugs on tumor growth.