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Dose-response of statins in short-term trials

 

Clinical bottom line

All statins show a dose response in trials of two to six weeks' duration.


Reference


MR Law et al. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003 326: 1423-1429.


Background


Statins to reduce total cholesterol and low density lipoprotein cholesterol have been available for a decade or more, and are now much used. Different statins are prescribed at different doses. The evidence here quantified the average reduction in LDL cholesterol in short term (2-6 week) trials.

Systematic review

Randomised trials of statins used in a fixed dose were chosen, including rosuvastatin but omitting cerivastatin. Several electronic databases were searched, including the Cochrane Library. All double blind studies were included, irrespective of age or disease states in patients. Excluded were trials without placebo groups, trials that lasted for less than two weeks, used dose titration, or which used cholesterol lowering drugs in combination. Also excluded were trials in patients with renal failure or after organ transplantation.

Results

There were 164 trials with 24,000 patients on statins and 14,000 on placebo. Participants in most trials were healthy with above average lipid concentrations, and in some trials they had high blood pressure, ischaemic heart disease or diabetes.

All the statins had a dose response (Figure 1) over the range of 5 mg to 80 mg daily. Rosuvastatin 5 mg/day, atorvastatin 10 mg/day, and lovastatin or simvastatin 40 mg/day reduced LDL cholesterol concentrations by about 35% (or about 1.8 mmol/L).

Figure 1: Dose response for statins - percentage reduction in LDL cholesterol in trials over 2-6 weeks

Atorvastatin and rosuvastatin were taken in the morning, and other statins in the evening. Three randomised trials reported an average greater reduction of 0.2 mmol/L (95% confidence interval 0.05 to 0.44 mmol/L) with evening dose.

There was an average increase in LDL cholesterol of 0.07 mmol/L (0.06 to 0.08 mmol/L).

Comment

First, this is a good paper, which needs to be read in full. It pulls together much information. The possible limitation of this part of it relating to dose-response is that it examines only studies over two to six weeks, when people taking statins should be taking it life long.

The implications are particularly interesting for making decisions about individuals. Foe example, the Joint British Societies coronary risk protection charts suggest that a man aged 55 to 64 years, a non-smoker, and with a systolic blood pressure of 120 mmHg would just creep in to a 15% risk with a total cholesterol of about 5.5 mmol/L and a HDL cholesterol of 0.85 mmol/L (TC:HDL of 6.6.5). Using an effective dose of statin would, on average, change the figures to 4.0 mmol/L and 0.92 mmol/L respectively, bringing the ratio down to 4.3, and a much lower risk.

When there are suggestions that statins may become available from pharmacists without prescription, this brings reduced risk even to people whose risk, at face value, is not high.