The Effect of Vitamin D Supplements on Statin-Associated Muscle Symptoms

Vitamin D supplementation does not prevent statin-associated muscle symptoms or reduce statin discontinuation among patients, investigators reported in JAMA Cardiology.

The substudy of the Vitamin D and Omega-3 trial (VITAL; ClinicalTrials.gov Identifier: NCT01169259) assessed whether vitamin D was associated with a significant decrease in statin-associated muscle symptoms among new statin users and if it would be more effective in those with low prerandomization levels of serum 25-hydroxy vitamin D (25-OHD).

VITAL included men aged 50 years or older and women aged 55 years or older without a history of cardiovascular disease or cancer other than nonmelanoma skin cancer. The participants were randomly assigned to receive vitamin D supplements, ω-3 fatty acid supplements, or placebo. Those who were randomized to vitamin D received 2000 international units of cholecalciferol per day. All participants completed study questionnaires during the follow-up.

The researchers mailed a survey to presumed new statin users in early 2016. The survey was in regards to their statin use and muscle symptoms. The participants confirmed statin initiation after enrolling in VITAL and answered questions about muscle symptoms. The primary endpoint was the development of muscle symptoms when taking a statin, and the secondary endpoint was discontinuing a statin owing to muscle symptoms.

A total of 25,871 participants (mean age, 67.1 [SD, 6.2] years; 51% women) were randomly assigned from November 2011 to March 2014. After a mean follow-up of 4.8 years, the substudy included 2083 survey respondents who confirmed statin initiation, and 1033 participants were randomly assigned to vitamin D and 1050 were randomly assigned to placebo.

Of the cohort, 31% of participants who received vitamin D and 31% of participants assigned to placebo reported muscle symptoms while taking a statin. The unadjusted odds ratio (OR) was 0.97 (95% CI, 0.81-1.17; P =.75), and the adjusted OR was 0.97 (95% CI, 0.80-1.18; P =.78).

Statin discontinuation resulting from muscle symptoms was not different between the 2 groups, 137 participants who received vitamin D vs 133 of those who received placebo stopped taking a statin. The unadjusted OR was 1.05 (95% CI, 0.81-1.36; P =.71), and the adjusted OR was 1.04 (95% CI, 0.80-1.35; P =.78).

Among participants with measured 25-OHD levels, muscle symptoms occurred in 194 of 699 who received vitamin D supplements and in 214 of 698 of those who received placebo. The test for treatment effect modification according to baseline serum 25-OHD level was not significant (P interaction =.83).

Similar findings were observed when different cut points were used to define low 25-OHD levels. For 25-OHD levels of less than 30 ng/mL, statin-associated muscle symptoms were reported by 88 of 330 patients who took vitamin D and by 96 of 323 participants who received placebo. For 25-OHD levels of less than 20 ng/mL, statin-associated muscle symptoms were reported by 28 of 85 patients who received vitamin D and by 33 of 95 of those who received placebo.

Among several limitations, statin therapy was initiated after random assignment by the participants’ personal physicians, and patients with statin-associated muscle symptoms were not evaluated or treated prospectively. Also, information is not available regarding the duration or dose of statins before statin-associated muscle symptoms or for any measures used to manage statin-associated muscle symptoms or reinstitute statin therapy. Furthermore, an effect of vitamin D cannot be excluded in treating patients with well-documented intolerance to multiple statins.

“Participants in the VITAL study who initiated statin therapy had a similar, high frequency of SAMS [statin-associated muscle symptoms] whether they were randomized to vitamin D or to placebo,” the investigators wrote. “This suggests that vitamin D lacks a clinically important effect in preventing SAMS.”

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.