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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 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:

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.