Not Sure If the Patient Tolerates Statins? Consider an N-of-1 Trial

Summary and Comment |
March 19, 2014

Not Sure If the Patient Tolerates Statins? Consider an N-of-1 Trial

  1. Joel M. Gore, MD

Data from n-of-1 trials in eight patients with apparent statin-related myalgia suggest that such trials may be the best available option for assessing statin tolerance.

  1. Joel M. Gore, MD

Diagnosing statin-related myalgia depends largely on patients' and physicians' perceptions of what's causing muscle symptoms during open-label therapy. In N-of-1 trials, each patient serves as his or her own control, thus allowing a randomized, multiple-crossover, blinded comparison of active treatment and placebo. Researchers have now conducted n-of-1 trials in eight patients (mean age, 66) who met criteria for statin-related myalgia and had high-risk Framingham scores. At baseline, the participants had a mean LDL level of 128 mg/dL, had tried a median of three statins, and still had mild myalgia symptoms 3 months after discontinuing all statins.

During the 3-week active-treatment phases, overall adherence to a rechallenge with the previously tried statin (mostly atorvastatin, pravastatin, or rosuvastatin) was 92%. Seven of eight patients showed neither a clinically nor a statistically greater level of myalgia symptoms with statin treatment than with placebo; one patient's on-statin symptoms reached clinical but not statistical significance.

In a combined analysis of the eight trials, patients' myalgia symptoms and their symptom-specific and pain-interference scores did not differ significantly between the statin-use and placebo-use periods. Compared with placebo, statin treatment was associated with greater pain severity that reached statistical but not clinical significance. Of seven patients whose end-of-trial LDL levels warranted statin use, five resumed and continued to receive statin therapy for a median of 10 months.


In most of these n-of-1 trials, differences in myalgia pain levels between statin treatment and placebo use were not clinically significant. N-of-1 trials are useful for assessing statin-related myalgia, given that we lack a biologic marker or test that accurately distinguishes statin-related myalgia from other sources of muscle pain. Although many institutions currently lack the resources to conduct large n-of-1 trials, advances in information technology might permit more of this type of research in the future.

To join a discussion of these findings, read Andrew Kates's blog on CardioExchange, an online community hosted by the New England Journal of Medicine and NEJM Journal Watch, and dedicated to improving cardiac patient care. Membership is free for medical professionals.

Editor Disclosures at Time of Publication

  • Disclosures for Joel M. Gore, MD at time of publication Grant / research support NIH; NIH-NHLBI; NSF


Reader Comments (7)

Barbara Dyble, MD, CCFP, FCFP Physician, Family Medicine/General Practice, University of Victoria Health Services

Since all statins inhibit HMCoAReductase, they will all reduce the body's ability to produce Coenzyme Q10 - essential for mitochondrial funciton. I am dismayed that we do not routinely supplement with this vital component of ATP production every time we put a patient on a statin, regardless of whether there is myalgia or not. And lets reduce our use of statins in populations where there is evidence of more harm than good from them (such as women who have not had an MI - who have a significantly increased risk of Type 2 DM from statin treatment.) I believe thiese approaches would be in ine with our Hippocratic oath of "first do no harm."

Tom Hight, MD Internal Medicine, Woodstock, GA

SLCO1b1 is a genetic test, which I've found to be extremely useful in patients who have statin induced myopathy, as it reveals whether a patient has genetically altered statin metabolism. Homozygous positive patients have an 8x risk for statin-induced myopathy. Heterozygous positive patients have a 4x risk. And, as Dr Hansen pointed out, some patients do have prolonged statin clearance due to CYP3A4 effects of calcium blockers, benzos, caffeine and other 3A4 drugs. Beta blockers can prolong Crestor metabolism by 2C9 pathways. Pravastatin may be a 2C9 drug, but there some authors disagree. Livalo is not hepatically cleared.

Dr. A. M. Jha, MD.\, PhD Physician, Internal Medicine, Hospital

As the challenge did not bring favourable outcome on discontinuation, atient counselling with regular monitoring should be attempted.

Stephen Hansen,MD Physician, Internal Medicine, hospital

2 recent patients with myalgia,cramps and CK's of 2000+ had been on diltiazem when 20 mg./d. Zocor was added--this CYP3A simva metabolism inhibition interaction may be underappreciated.

Monica Carsky, PhD Other Healthcare Professional, Psychiatry, medical school faculty; private practice

One of my well informed physicians suggested I take a supplement, Swanson brand Ubiquinol, for severe new onset myalgia with statin use, and this has taken care of the pain. If it's placebo I don't enables me to work out again.

Paul April,MD Physician, Internal Medicine, retired

A useless study in which patients continued to have mild pain after stoppimg statins 3 months earlier and return to a statin did not increase pain.

kdkaraiskos md,endocr Physician, Endocrinology, priv off,primary national health net

i thing that changing lipid soluble versus water soluble statin,
pose myalgic patients tto smaller risk

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