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Patients want continuity not masses of choices

How convincing is the evidence suggesting it makes any difference? Bandolier editors

Dr Andrew Moore and Professor Henry McQuay assess the most recent studies

Most manufacturers of statins recommend they are taken at night because physiological studies show that most cholesterol is synthesised when dietary intake is low.

Back in 2001 we looked for clinical evidence to support taking statins in the evening, and found one small trial that was not terribly convincing in terms of credibility or clinical relevance.

We asked for a large study demonstrating that normal doses of evening statin produced convincingly lower cholesterol levels than normal doses of morning statin, and will now look at two such studies (below left).

Is it worth getting patients to

change time they take statin?

These studies support the recommendation that simvastatin should be taken in the evening to maximise lipid-lowering effects.

It is not clear whether time of dosing influences other effects of statins, such as endothelial function and plaque stability, but the first study suggests that it does not influence effects on the immune system mediated by C-reactive protein.

The size of the change is probably of clinical relevance, but only if evening dosing is reliable. There is an inverse relationship between patient compliance and both number of drugs and number of doses per day, and there can be further loss in compliance when medication regimens are changed.

What is really important is that the patient takes the drug reliably, and if that is easier with morning dosing, the extra10 to 13 per cent reduction in LDL-cholesterol potentially achieved with evening dosing is probably worth foregoing. An evening dose is more easily forgotten.

Finally, these studies have looked at simvastatin, and may not apply to other statins.

One trial using atorvastatin found no differences with morning and evening dosing, which may be explained by its longer half-life.

Clinical bottom line

For simvastatin, the evidence is that marginally better lowering of total and LDL cholesterol comes from taking the tablets in the evening rather than in the morning.

Andrew Moore is honorary professor of health sciences at University College Swansea and editor-in-chief of Bandolier

Henry McQuay is professor of pain relief at the Oxford pain relief unit and co-editor of Bandolier

Study 1

The first study1 enrolled 25 patients with coronary artery disease (mean age 66 years) who were stable on 10-40mg simvastatin daily. Patients were randomised to receive their usual dose either in the morning or in the evening for six weeks, followed by the alternate regimen. Blood samples were taken after an overnight fast at baseline and at six and 12 weeks, after each treatment period, for determination of total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides.

The study found a statistically significant increase in total and LDL-cholesterol when simvastatin was taken in the morning compared with the evening, but no changes in HDL-cholesterol or triglycerides. Levels at baseline did not differ from levels for the corresponding time of dosing during the study, and no period effects or treatment-period interactions were found. The investigators also measured high, sensitive C-reactive protein as a marker of effects on the immune system, and found that levels were not influenced by time of dosing.

Lipid levels at baseline and after morning or evening dosing of simvastatin (n=25)

Mmol/L Evening intake (SD) Morning intake (SD) Change (95% CI) p value

Total cholesterol 4.5 (0.9) 4.8 (1.1) 0.34 (0.14 to 0.52) 0.002

LDL-cholesterol 2.5 (0.7) 2.8 (0.9) 0.39 (0.24 to 0.54) <>

HDL-cholesterol 1.4 (0.3) 1.4 (0.3) -0.04 (-0.12 to 0.5) NS

Triglycerides 1.4 (1.0) 1.4 (0.9) 0.01 (-0.16 to 0.18) NS

Study 2

The second study2 enrolled 60 patients (mean age 66 years) who were stable on 10 or 20mg simvastatin daily, taken in the evening. Patients were randomised to receive their usual dose in the morning or the evening for eight weeks, and fasting blood samples were taken at baseline and at eight weeks to determine total, LDL-cholesterol, and HDL-cholesterol and triglycerides.

Again, the study found a statistically significant increase in total and LDL-cholesterol, but not HDL-cholesterol or triglycerides, when simvastatin was taken in the morning compared with the evening. Levels of alanine transferase were also measured and were not affected by time of dosing.

What happened to lipids baseline when patients switched taking evening statin to morning

Mmol/L Baseline (SD) Change (95% CI) p value

Total cholesterol 4.4 (0.8) 0.38 (0.17 to 0.49) 0.001

LDL cholesterol 2.4 (0.6) 0.25 (0.06 to 0.44) 0.012

HDL cholesterol 1.3 (0.3) 0.02 (-0.03 to 0.08) 0.43

Triglycerides 1.6 (0.8) 0.09 (-0.31 to 0.48) 0.67

References

1 TM Lund et al. Effect of morning versus evening intake of simvastatin on the serum cholesterol level in patients with coronary heart disease. Am J Cardiol 2002;90:784-6

2 A Wallace et al. Taking simvastatin in the morning compared with in the evening: randomised controlled trial. BMJ 2003;327:788

Bandolier(www.ebandolier.com)

is an independent monthly journal on evidence-based health care. Subscription costs £36 for 12 issues and subscribers receive the print journal three months before articles are available on the website.

A subscription form is available on the website or from: maura.moore@pru.ox.ac.uk

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