Skip navigation

Statins: when should you take the tablet?

 

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 than in the morning.


Background

Most manufacturers of statins recommend that they are taken at night because physiological studies show that most cholesterol is synthesised when dietary intake is low. Bandolier 88 (June 2001) 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 now have two studies that make things a little clearer.

Reference


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: 784-786.
2 A Wallace et al. Taking simvastatin in the morning compared with in the evening: randomised controlled trial. BMJ 2003 327: 788.


Study1

The first study [1] enrolled 25 patients with coronary artery disease (mean age 66 years) who were stable on 10-40 mg 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 to 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.

Table 1: 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)
<0.001
HDL-cholesterol
1.4 (0.3)
1.4 (0.3)
-0.04 (-0.12 to 0.05)
NS
Triglycerides
1.4 (1.0)
1.4 (0.9)
0.01 (-0.16 to 0.18)
NS

 

Study 2

The second study [2] enrolled 60 patients (mean age 66 years) who were stable on 10 or 20 mg 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-, 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 to the evening. Levels of alanine transferase were also measured and were not affected by time of dosing.

Table 2: Levels of lipids at baseline and difference in change after morning versus evening dosing of simvastatin (n=60)

mmol/L
Baseline (SD)
Change (95% CI)
p value
Total cholesterol
4.4 (0.8)
0.38 (0.17 to 0.59)
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

 

Comment

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% 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.