Statins and muscle

Clinical bottom line

Statins are associated with a range of muscle problems, but they are not common, and are nearly always reversible on withdrawal. In randomised controlled trials the frequency and severity of these problems did not differ between treated and placebo groups. As a rough guide we can say that for every 100,000 patients treated for one year, four will suffer from rhabdomyolysis, and 33 will suffer from myositis, but these rates do not differ significantly from those observed in the placebo group.

Reference

PD Thompson et al. Statin-associated myopathy. JAMA 2003 289: 1681-90.

Statins are known to be associated with muscle complaints, but the extent of the problem in terms of both severity and frequency is not well known, and the mechanism is unclear. A recent review in JAMA tries to address these points.

The review was thorough, including reports to the FDA and data from clinical trials, review articles, clinical guidelines, and case series, together with articles on the possible biochemical mechanisms involved.

The authors found a lack of clear definitions of reported muscle complaints, and chose to divide them into syndromes as follows:

Clinically important myositis and rhabdomyolysis : muscle pain with creatinine kinase (CK) levels more than ten times the upper limit of normal (ULN). Rhabdomyolysis occurs when the damage results in the release of cellular contents into the systemic circulation. Treatment is supportive and death can result from hyperkalaemia, cardiac arrythmia, renal failure and disseminated intravascular coagulation.
Mild CK elevations : raised CK levels that do not exceed ten times ULN. Patients may be asymptomatic.
Myalgia : muscle pain. It can affect patients’ quality of life and compliance with medication.
Muscle weakness: This is frequently reported in association with clinically important myositis and rhabdomyolysis, but can also occur in patients without significant CK elevation.
Muscle cramps : These are not reported frequently.
Persistent myalgia/CK elevations after statin withdrawal : There are rare reports of these problems occurring during statin therapy and continuing after withdrawal. These patients may have other clinical conditions that have been unmasked by statin therapy.

Clinically important muscle complaints

There were 3,339 cases of statin-associated rhabdomyolysis identified in the Qscan FDA database from January 1990 and March 2002 [1]. Details are shown in Table 1. These data are compiled from voluntary physician reporting, which is well known to under report, but give some idea of the severity of the problem. Overall 7.8% of patients died.

Table 1. Reports of rhabdomyolysis to the FDA, January 1st 1990 to March 31st 2002

			Age%*		Outcomes %*
Drug	Number of reports	Reports of rhabdomyolysis due to drug %	up to 50 years	greater than 50 years	Death, disability or hospitalisation	Life threatening
Cerivastatin	1869	57	5.8	68	67	8.2
Simvastatin	612	18	9.9	78	67	14
Atorvastatin	383	12	13	63	57	9.7
Pravastatin	243	7.3	8.6	63	72	10
Lovastatin	147	4.4	7.5	67	68	14
Fluvastatin	55	1.6	1.8	75	61	14
Total	3339	100	7.9	68	66	10
*percentages do not sum to 100 because of missing data

Spontaneous reporting gives no indication of rate, since we do not know how many patients were treated but did not have an event. The rate of fatal rhabdomyolysis with statins has been estimated as 0.15 per million prescriptions in the USA. Rates for individual statins are shown in Table 2.

Table 2. Incidence of fatal rhabdomyolysis with different statins, using prescription data

Drug	Incidence (per 1 million prescriptions)
Cerivastatin	3.16
Lovastatin	0.19
Simvastatin	0.12
Pravastatin	0.04
Atorvastatin	0.04
Fluvastatin	0

Once again, the data rely on voluntary reporting, so are likely to underestimate the problem. In addition the denominator is number of prescriptions not number of patients treated.

Randomised placebo-controlled trials support a low incidence of muscle problems, and may provide us with background and on-treatment event rates. Of 30 such trials identified by this review, 20 reported on rhabdomyolysis, and 18 on myositis. In no trial was there a significant difference between statin and placebo groups for either outcome, with only 12 cases reported in total. The included trials had mean or median durations ranging from 0.2 and 6 years, but were heavily dominated by the larger trials lasting five years. Numbers of patients treated and numbers of events are shown in Table 3, and estimates of rates are shown in Table 4.

Table 3. Rhabdomyolysis and myositis reported in randomised controlled trials

		Number of patients		Number with event
Event	Number of trials reporting	Statin	Placebo	Statin	Placebo	Relative risk (95% CI)
Rhabdomyolysis	20	35406	35503	7	5	1.4 (0.45-4.4)
Myositis	18	29440	29568	49	44	1.1 (0.74-1.7)

Table 4. Incidence of rhabdomyolysis and myositis reported in randomised controlled trials

Event	Rate per 100,000 patients treated for five years
	Statin	Placebo
Rhabdomyolysis	20	14
Myositis	170	150

As a rough guide we can say that for every 100,000 patients treated for one year, four will suffer from rhabdomyolysis, and 33 will suffer from myositis, but these rates do not differ significantly from those observed in the placebo group.

Reporting of other less severe muscle problems in the trials was very incomplete, but showed no differences between statin and placebo groups.

Can the results of carefully controlled clinical trials of statin monotherapy be generalised to unselected patients in normal clinical practice? Muscle problems increase with serum concentration of statin, and many factors can potentially affect this concentration. These include body size and sex (volume of distribution), renal and hepatic function, age, hypothyroidism, debilitation, diabetes, concomitant medications and genetic factors (drug metabolism and catabolism).

Concomitant medication

Many of the patients for whom statins are prescribed will suffer from other medical problems requiring medication. More than half of the reports of statin-induced rhabdomyolysis identified in the Qscan FDA database in this study were associated with concomitant medications affecting statin metabolism, and of these more than one third were associated with fibrates, and gemfibrozil in particular. Other concomitant medicines that might increase risk of statin-associated myopathy include amiodarone, azole antifungals, macrolide antibiotics or even grapefruit juice.

The mechanisms by which statins produce their effects on muscle are not well understood and are likely to be complex. A number of theories have been proposed and are discussed in the review. Briefly they include:

destabilisation of cell membranes;
reduction in production of small regulatory proteins important for myocyte maintenance, resulting in increased cytotoxicity;
a shift towards anaerobic metabolism causing mitochondrial dysfunction.

Comment

Statins are associated with a range of muscle problems, but they are not common, and are nearly always reversible on withdrawal. In randomised controlled trials the frequency and severity of these problems did not differ between treated and placebo groups. A number of factors that are commonly present in patients who need to take statins can increase the likelihood of muscle effects.