PubMed · 8167517
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G Davey Smith, M Egger. 1994-04-16. Statistical problems.. https://doi.org/10.1136/bmj.308.6935.1025
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PURPOSE: To develop an optimal treatment strategy that reduces low-density lipoprotein (LDL) cholesterol levels and improves adherence to therapy by reviewing clinical trials that define the dose-response characteristics for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), bile acid sequestrants, and niacin. DATA SOURCES: Data were obtained from a MEDLINE search of the English-language literature published from 1975 through November 1995 and from an extensive bibliography review. STUDY SELECTION: Controlled, clinical trials were reviewed if they evaluated 1) the effectiveness and toxicity of one LDL cholesterol-lowering agent (statins, bile acid sequestrants, or niacin, at two or more doses) or 2) monotherapy with two LDL cholesterol-lowering agents at defined doses used alone and in combination. Studies that had fewer than 10 patients in a treatment group or that selected patients on the basis of previous response to therapy were not included. DATA EXTRACTION: Trials were reviewed for overall methodology, inclusion and exclusion criteria, sources of bias, and outcomes. DATA SYNTHESIS: Dose-response relations for bile acid sequestrants and statins are nonlinear, and most of their LDL cholesterol-lowering effects can be obtained with lower doses. The few dose-response studies of niacin that have been done suggest that most of niacin's high-density lipoprotein cholesterol-increasing effect can also be achieved with relatively low doses, but higher doses are needed to substantially reduce LDL cholesterol levels. If bile acid sequestrants or niacin are added to statin therapy, the effect of combined therapy on LDL cholesterol levels is additive. CONCLUSION: The nonlinear dose-response relation of statins, bile acid sequestrants, and niacin and their additive LDL cholesterol-lowering effect when used together suggest a strategy for treating hypercholesterolemia that may optimize effectiveness while minimizing adverse effects and cost.
The effects of 2 months treatment with simvastatin (40 mg, 20 mg p.o. daily) or placebo on erythrocyte membrane cholesterol content and acyl chain composition have been studied in 36 patients with a clinical history of atherosclerosis enrolled in the Oxford Cholesterol Study. All patients received advice corresponding to a standard phase 1 cholesterol-lowering diet. As expected the mean serum total cholesterol fell substantially (-26.5%, 20 mg simvastatin, P < 0.05; -32.7%, 40 mg simvastatin, P < 0.05) compared to placebo (-6.3%, ns). However, mean erythrocyte cholesterol content did not change significantly in any group (2 months therapy: 20 mg simvastatin, -0.62%; 40 mg simvastatin, +2.2%; placebo, -4.2%). Erythrocyte cholesterol was also unaltered after 5 months of therapy. Erythrocyte osmotic fragility was unchanged in the treatment and placebo groups. In the placebo group dietary advice alone was associated with a significant increase in the linoleic acid content of erythrocytes from 9.4 mole% of total acyl chains to 11.8 mole% (P < 0.05). Treatment with simvastatin was associated with an increase in the arachidonic acid content of the erythrocyte membrane from 12.2 to 15.3 mole% (P < 0.05). Treatment with simvastatin does not alter erythrocyte cholesterol content, but does alter acyl chain distribution. These results suggest that the chemical potential of cholesterol in serum is not markedly altered by HMG-CoA reductase inhibition.
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