Effect of Statin Therapy on Muscle Symptoms

Were Clinicians Right All Along?

Whether or not statins can cause statin-associated muscle symptoms (SAMS) such as pain, weakness, and cramps without clinically important elevations in creatine kinase levels has been debated for years. Clinical trialists maintained that SAMS did not exist because there was no increase in SAMS in their best data — randomized controlled clinical trials (RCTs) — whereas clinicians maintained that SAMS did exist, at least in some of their individual patients. Well, here’s the news: the clinical trialists have just used individual patient data from their RCTs to suggest that the clinicians were right all along.

The Cholesterol Treatment Trialists’ Collaborative analyzed data from more than 150,000 patients enrolled in 23 RCTs to demonstrate that statins produced a 7% increase in SAMS (95% CI, 4%–10%) but an excess of only 11 complaints per 1000 patient-years (95% CI, 6–16). This increase only occurred during year 1. More intensive statin treatment produced an 8% increase (95% CI, 4%–13%) in year 1, with a 5% statistically insignificant (95% CI, –1% to +12%) increase after year 1.

These small absolute increases in SAMS are trivial compared with statins’ ability to decrease cardiovascular risk, but this report probably underestimates the incidence of SAMS. Participants in RCTs are different from our usual patients in ways too numerous to enumerate. The present analysis included some RCTs that used a statin run-in period to eliminate nonadherent subjects who might also have been statin-intolerant. The trialists’ data do not indicate that this affected the results, but one wonders. The methods used to detect SAMS varied among the studies, possibly leading to a “don’t ask and we won’t tell” underestimation of SAMS.

But this is an important report. It reaffirms that clinicians should encourage patients to remain on these life-saving drugs because true SAMS are rare, but it also confirms what clinicians have long suspected: some patients get SAMS. This report may also curtail the argument as to whether or not SAMS exist and encourage more research into what causes SAMS so that we can keep patients on these life-saving drugs.

Statins and muscle issues

The internet is full of commentaries about statins causing lots of muscle issues.  Sometimes these commentaries stop patients from getting the benefits of statin therapy.  Therefore it is important to investigate the connection between statins and muscle adverse effects.

This paper looked at 19 double-blind trials of statin versus placebo to see if there is an increase in muscle issues and to quantify that rate. From these trials, they analyzed individual participant data.  The median duration of follow-up was 4.3 years.

During the first year, the statin therapy group had a 7% relative increase in muscle pain or weakness (HR 1·07; 1·04–1·10) compared to placebo.  After the first year, there was no difference seen (HR 0·99; 0·96–1·02).  

They also looked at 4 double-blind trials of more intensive statin therapy versus a less intensive statin regimen.  Intensive was defined as atorvastatin 40–80 mg or rosuvastatin 20–40 mg.  Overall the duration of the trials, the higher intensity group did have a slightly higher rate of muscle complaints.  The high-intensity group had 8% compared to placebo (1·08 [1·04–1·13]) while the less intensive statin group had 3% (1·03 [1·00–1·05]) compared with placebo.  And for the higher intensity statin patients there was still a slight increase even after the first year of therapy (HR 1·05 [0·99–1·12]).

As for measurable parameters like creatine kinase which indicates muscle injury, there was a very small increase in the median creatine kinase.  It increased by 0·02 times the upper limit of normal and as the authors pointed out – this is not clinically significant.

So the bottom line is that a small number of patients will have adverse muscle effects, but the majority will not.  Therefore we need to acknowledge that muscle symptoms can occur in a small number of people but we need to emphasize the cardiovascular protection that statins provide.  And if you know your patients will google things then make sure that you are the reliable source that tells them about this issue as opposed to some random website they happen to find. 

Let us properly explain the risk and benefits of statin therapy to our patients.