Effect of Vitamin D on Statin-Associated Muscle Symptoms Among New Statin Users

Do we need a randomized controlled clinical trial to prove that vitamin D does not prevent statin myopathy?

That title’s question was posed to me by a medical reporter reviewing Hlatky and colleagues' article that used the VITAL study to examine the effect of vitamin D supplementation (VitD) on statin-associated muscle symptoms (SAMS).¹ VITAL, or the Vitamin D and Omega-3 Trial, randomized middle-aged men and women to VitD (cholecalciferol 2000 IU daily), omega-3 fatty acids (1 g daily), or placebo in a 2x2 design.² VITAL’s  primary endpoints were the development of cancer or cardiovascular disease. Hlatky et al took advantage of VITAL’s randomized controlled clinical trial (RCCT) design to examine VitD’s effect on SAMS. About halfway through the VITAL study, participants, not taking statins at baseline but reporting statin use in at least one of the yearly follow-ups, were asked to complete questionnaires on muscle symptoms. Participants reported which statin they were using, if they had muscle discomfort on the statin, and if they had stopped the statin because of muscle symptoms.

At baseline 66% (16,981) of the 25,871 participants were not taking a statin. Of these 2835 subsequently reported new statin use. Of these new users 2083 (88%) returned the muscle survey, and they comprise the study population: 1050 on placebo; 1033 on VitD. Muscle symptoms were reported by 31% in both the placebo and VitD group, and 13% in each group stopped their statin because of SAMS. Baseline VitD levels were measured in about two-thirds of the SAMS study population, but VitD baseline values had no relationship to the incidence of SAMS.

This is a smartly designed study that used an ongoing trial to examine a frequently proposed treatment for SAMS.  Nevertheless, an RCCT is still needed to settle the VitD and SAMS issue. Medication use was measured yearly, so it is possible that some participants who started and stopped statins between medication assessments were undetected. Also, the study did not verify that the muscle symptoms were statin-associated using such techniques as a careful assessment of the symptoms or a statin cessation/re-challenge protocol. The rate of possible SAMS was high, making it unlikely that all these muscle complaints were SAMS. Nevertheless, this is the best study yet on the effect of VitD on SAMS, and its results make the possibility that VitD prevents or treats SAMS unlikely. It argues against the routine use of VitD to prevent or treat SAMS, but this opinion is not new. ³

References

1. Hlatky MA, Gonzalez PE, Manson JE, et al. Statin-Associated Muscle Symptoms Among New Statin Users Randomly Assigned to Vitamin D or Placebo. JAMA Cardiol. 2022 Nov 23. doi:10.1001/jamacardio.2022.4250. Online ahead of print. https://jamanetwork.com/journals/jamacardiology/article-abstract/2798958
2. Manson JE, Cook N, Lee I-M, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2019;380(1):33-44. https://www.nejm.org/doi/full/10.1056/nejmoa1809944
3. Gupta A, Thompson PD. The relationship of vitamin D deficiency to statin myopathy.  Atherosclerosis. 2011;215(1):23-29. https://www.atherosclerosis-journal.com/article/S0021-9150(10)00978-0/fulltext