Vitamin D and Statin-Related Myalgia

Post on March 15, 2017 by André Broussard, D.C.

Philip J. Gregory, PharmD

March 10, 2017

Question

Do low vitamin D levels increase the risk for myalgia in patients who are taking statins?

About 1%-2% of patients who take hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins for hyperlipidemia develop muscle pain. This myalgia can feel like the aches and pains experienced with the flu. Muscles may feel sore or stiff and be sensitive to touch.[1] In some cases, statin-related myalgia can lead to poor adherence or discontinuation of the drug.[2]

The mechanism for statin-related myalgia is not fully understood, but vitamin D has been speculated to play a role.

Vitamin D deficiency itself is associated with symptoms of myalgia that resemble those caused by statins.[1,3] There has been speculation that statins themselves might affect vitamin D levels. Because low-density lipoprotein (LDL)-cholesterol is a vitamin D carrier and statins reduce LDL cholesterol, it has been proposed that statins could decrease vitamin D levels. On the other hand, both vitamin D and some statins are metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. Owing to competitive inhibition at CYP3A4, it has been proposed that statins could increase levels of vitamin D.

Clinical trials and observational studies have produced mixed results in terms of the actual effect of statins on vitamin D levels. Overall, a meta-analysis of clinical trials found increased vitamin D levels in statin users.[4]

Several retrospective studies have shown that low vitamin D levels (measured as 25-hydroxyvitamin D) are associated with a higher risk for statin-induced myalgia. In a study by Shantha and colleagues,[5]patients with vitamin D levels in the lowest quartile had a 1.21 times increased risk for statin-induced myalgia compared with those in the highest quartile. Levels of 15 ng/mL or lower positively predicted the development of myalgia in statin users.

In a cross-sectional study, statin-treated patients with vitamin D levels of less than 15 ng/mL had a 1.9 times increased odds of myalgia compared with non-statin users; however, statin users with higher vitamin D levels did not have an increased risk for myalgia compared with non-statin users.[6]

A retrospective chart review in veterans taking statins found that levels of vitamin D were approximately 10 ng/dL lower in those who experienced statin-induced myalgia compared with those who did not.[7]

A meta-analysis of seven observational studies found that vitamin D levels were significantly lower in statin-treated patients who had symptoms of myalgia compared with those who were asymptomatic. The mean difference in vitamin D levels between the groups was approximately 9.4 ng/mL.[2]

Not all studies have found an association between low vitamin D and myalgia, especially in studies evaluating patients with symptoms confirmed to be caused by statins.[8,9] The discrepancies in findings may be because of the nonspecific nature of muscle symptoms. Some evidence shows that up to 50% of self-reported symptoms of muscle pain in statin users may not be because of statins specifically. Therefore, low vitamin D levels may contribute to muscle pain symptoms more generally, including in patients with statin-induced myalgia or nonspecific myalgia.[9]

Assessing and treating low vitamin D levels may be worth considering before starting or restarting a statin in patients who develop muscle pain while taking a statin.

A retrospective chart review found that replenishing vitamin D before a statin rechallenge in previously intolerant patients increases statin tolerability and adherence.[10]

In uncontrolled studies, some authors have used vitamin D2 (ergocalciferol) supplements (from 50,000 units to 100,000 units per week) in statin-treated patients with muscle symptoms and low vitamin D levels and reported resolution of myalgia in about 90% of patients. In these studies, low vitamin D levels were considered to be less than 32 ng/mL.[11,12]

References

  1. Minissian M, Agarwal M, Schufelt C, et al. Do women with statin-related myalgias have low vitamin D levels? BMC Res Notes. 2015:8:449-453. Abstract
  2. Michalska-Kasiczak M, Sahebkar A, Mikhailidis DP, et al. Analysis of vitamin D levels in patients with and without statin-associated myalgia – a systematic review and meta-analysis of 7 studies with 2420 patients. Int J Cardiol. 2015;178:111-116. Abstract
  3. Lee P, Greenfield JR, Campbell LV. Vitamin D insufficiency – a novel mechanism of statin-induced myalgia. Clin Endocrinol. 2009;71:154-156.
  4. Mazidi M, Rezaie P, Vatanparast H, Kengne AP. Effect of statins on serum vitamin D concentrations: a systematic review and meta-analysis. Eur J Clin Invest. 2017;47:93-101. Abstract
  5. Shantha GPS, Ramos J, Thomas-Hemak L, Pancholy SB. Association of vitamin D and incident statin induced myalgia – a retrospective cohort study. PLoS One. 2014;9:e88877.
  6. Morioka T, Lee AJ, Bertisch S, Buettner C. Vitamin D status modifies the association between statin use and musculoskeletal pain: a population based study. Atherosclerosis. 2015;238:77-82. Abstract
  7. Mergenhagen K, Ott M, Heckman K, et al. Low vitamin D as a risk factor for development of myalgia in patients taking high-dose simvastatin: a retrospective review. Clin Ther. 2014;36:770-777. Abstract
  8. Eisen A, Lev E, Iakobishvilli Z, et al. Low plasma vitamin D levels and muscle-related adverse effects in statin users. Isr Med Assoc J. 2014;16:42-45. Abstract
  9. Taylor BA, Lorson L, White CM, Thompson PD. Low vitamin D does not predict statin associated muscle symptoms but is associated with transient increases in muscle damage and pain. Atherosclerosis. 2016.
  10. Kang JH, Nguyen QN, Mutka J, Le QA. Rechallenging statin therapy in veterans with statin-induced myopathy post vitamin D replenishment. J Pharm Pract. 2016 Oct 24. pii: 0897190016674407. [Epub ahead of print]
  11. Ahmed W, Khan N, Glueck CJ, et al. Low serum 25(OH) vitamin D levels (< 32 ng/mL) are associated wit

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