Do N-of-1 Studies Prove Statin Muscle Complaints are Bogus?

Paul Thompson, MD

StatinWISE is to my knowledge the third “N-of-1” study to examine statin-associated muscle symptoms (SAMS).¹“N-of-1” studies use an individual subject as his/her own control and treat these subjects with multiple periods of treatment or placebo. The first statin n-of-1 randomized 8 patients with possible SAMS to 3 x 3-week, randomized, double-blind trials of treatment with their offending statin or placebo separated by 3-week washout phases.² All patients had developed myalgia within 3 weeks of starting their statin, justifying the brief treatment periods. The second trial randomized 60 patients to 1-month trials of atorvastatin 20, placebo, or no pill for a year.³ All patients had previously developed SAMS within 2 weeks of starting statin therapy. Compared to no pill at all, symptom intensity was 15.4 during placebo pill treatment and 16.3 during statin treatment. This trial demonstrated that taking a pill, even a placebo, caused more symptoms than no pill at all and that treatment with the statin or placebo pill were similar.StatinWISE (Statin Web-based Investigations of Side Effects) is the third trial and randomized 200 participants to 6 x 2-month treatments with atorvastatin 20 mg or placebo.¹ Withdrawal secondary to intolerable muscle symptoms occurred in 9% of the statin and 7% of the placebo subjects, a non-significant difference, but only 151 of the randomized subjects completed at least one pair of statin/placebo trials. All 3 trials failed to confirm SAMS during statin therapy.

We imagine science as Lady Justice equally balancing the scales, but most studies find what they are designed to find. These n-of-1 trials were designed to show that most SAMS complaints are not related to the statins. These trials are useful because they encourage clinicians and patients to use these life-saving drugs. But these trials’ results should not be used to deny the existence of SAMS. That’s because these patients complained of SAMS, but obviously did not have SAMS. In genetics, you cannot get the genotype right without a consistent phenotype. The same is true with SAMS. How can you prove an intervention works for SAMS if you are not sure you are studying SAMS?

We have advocated verifying the presence of SAMS in SAMS studies. In our NIH-funded study of Co-Enzyme Q10 in treating SAMS, we randomized 120 of my patients, whom I thought had SAMS, to 2-month preliminary trials of simvastatin 20 or placebo separated by a 4-week washout⁴. Statin first subjects got placebo second and vice versa. Remarkably only 35.8% of the subjects got pain only on the statin, 17.5% got pain on both treatments, 29.2% only on placebo, and 17.5% had no pain. Only the subjects with verified SAMS were entered into the CoQ10 Trial, which by the way, did not work. The GAUSS-3 Trial used our design to determine if 491 patients had verifiable SAMS before assigning subjects to injections with the PCSK-9 inhibitor, evolocumab, or placebo⁵. GAUSS-3 found results similar to our:42.6% had verified myalgia, 9.8% had pain on both, 26.5% had pain on placebo, and 17.3% had no pain. What is striking in GAUSS-3 is that 42.6% had pain on atorvastatin only vs. 26.5% on placebo, a highly significant difference. Our CoQ10 study and GAUSS-3 were designed to evaluate specific therapies for SAMS. Both studies showed that many SAMS complaints are not SAMS, and GAUSS-3 confirmed that muscle symptoms are much more likely on a statin than on placebo.

So, these n-of-1 studies are useful in encouraging statin use, but they have to get the phenotype right before they can conclude that SAMS does not exist or are not real for some patients.

1. Herrett E, Williamson E, Beaumont D, et al. Study protocol for statin web-based investigation of side effects (StatinWISE): A series of randomised controlled N-of-1 trials comparing atorvastatin and placebo in UK primary care. BMJ Open. 2017;7(12):e016604-2017-016604. doi: 10.1136/bmjopen-2017-016604 [doi].

2. Joy TR, Monjed A, Zou GY, Hegele RA, McDonald CG, Mahon JL. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;160(5):301-310. doi: 10.7326/M13-1921 [doi].

3. Wood FA, Howard JP, Finegold JA, et al. N-of-1 trial of a statin, placebo, or no treatment to assess side effects. N Engl J Med. 2020;383(22):2182-2184. doi: 10.1056/NEJMc2031173 [doi].

4. Taylor BA, Lorson L, White CM, Thompson PD. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis. 2015;238(2):329-335. doi: 10.1016/j.atherosclerosis.2014.12.016 [doi].

5. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA. 2016;315(15):1580-1590.