Vitamin D Fails to Stave Off Statin-Related Muscle Symptoms

Vitamin D supplements do not prevent muscle symptoms in new statin users or affect the likelihood of discontinuing a statin due to muscle pain and discomfort, a substudy of the VITAL trial indicates.

Among more than 2000 randomized participants, statin-associated muscle symptoms (SAMS) were reported by 31% assigned to vitamin D and 31% assigned to placebo.

The two groups were also equally likely to stop taking a statin due to muscle symptoms, at 13%.

No significant difference was observed in SAMS (odds ratio [OR], 0.97; 95% CI, 0.80-1.18) or statin discontinuations (OR, 1.04; 95% CI, 0.80-1.35) after adjustment for baseline variables and other characteristics, namely age, sex, and African-American race, previously found to be associated with SAMS in VITAL.

“We actually thought when we started out that maybe we were going to show something, that maybe it was going to be that the people who got the vitamin D were least likely to have a problem with a statin than all those who didn’t get vitamin D, but that is not what we showed,” senior author Neil J. Stone, MD, Feinberg School of Medicine, Northwestern University, Chicago, told | Medscape Cardiology.

He noted that patients in the clinic with low levels of vitamin D often have muscle pain and discomfort and that previous unblinded studies suggested vitamin D might benefit patients with SAMS and reduce statin intolerance.

As previously reported, the double-blind VITAL trial showed no difference in the primary prevention of cardiovascular disease or cancer at 5 years among 25,871 middle-aged adults randomized to vitamin D3 at 2000 IU/d or placebo, regardless of their baseline vitamin D level.

Unlike previous studies showing a benefit with vitamin D on SAMS, importantly, VITAL participants were unaware of whether they were taking vitamin D or placebo and were not expecting any help with their muscle symptoms, first author Mark A. Hlatky, MD, Stanford University School of Medicine, California, pointed out in an interview.

As to how many statin users turn to the popular supplement for SAMS, he said that number couldn’t be pinned down, despite a lengthy search. “But I think it’s very common, because up to half of people stop taking their statins within a year and many of these do so because of statin-associated muscle symptoms, and we found it in about 30% of people who have them. I have them myself and was motivated to study it because I thought this was an interesting question.”

The results were published online November 23, 2022, in JAMA Cardiology.

SAMS by Baseline 25-OHD

The substudy included 2083 patients who initiated statin therapy after randomization and were surveyed in early 2016 about their statin use and muscle symptoms.

Two thirds, or 1397 patients, had 25-hydroxy vitamin D (25-OHD) measured at baseline, with 47% having levels < 30 ng/mL and 13% levels < 20 ng/mL.

Serum 25-OHD levels were virtually identical in the two treatment groups (mean, 30.4 ng/mL; median, 30.0 ng/mL). The frequency of SAMS also did not differ between those assigned to vitamin D or placebo (28% vs 31%).

The odds ratios for the association with vitamin D on SAMS were:

  • 0.86 in all respondents with 25-OHD measured (95% CI, 0.69-1.09)

  • 0.87 in those with levels ≥ 30 ng/mL (95% CI, 0.64-1.19)

  • 0.85 with levels of 20-30 ng/mL (95% CI, 0.56-1.28)

  • 0.93 with levels < 20 ng/mL (95% CI, 0.50-1.74).

The test for treatment effect modification by baseline serum 25-OHD level was not significant (P for interaction = .83).

In addition, the rate of muscle symptoms was similar between participants randomized to vitamin D and placebo when researchers used a cut-point to define low 25-OHD of < 30 ng/mL (27% vs 30%) or < 20 ng/mL (33% vs 35%).

“We didn’t find any evidence at all that the people who came into the study with low levels of vitamin D did better with the supplement in this case,” Hlatky said. “So that wasn’t the reason we didn’t see anything.”

Critics may suggest the trial didn’t use a high enough dose of vitamin D, but both Hlatky and Stone say that’s unlikely to be a factor in the results because 2000 IU/d is a substantial dose and well above the recommended adult daily dose of 600-800 IU.

They caution that the substudy wasn’t prespecified, was smaller than the parent trial, and did not have a protocol in place to detail SAMS. They also can’t rule out the possibility that vitamin D may have an effect in patients who have confirmed intolerance to multiple statins, especially after adjusting the statin type and dose.

“If you’re taking vitamin D to keep from having statin-associated muscle symptoms, this very carefully done substudy with the various caveats doesn’t support that and that’s not something I would give my patients,” Stone said.

“The most important thing from a negative study is that it allows you to focus your attention on things that may be much more productive rather than assuming that just giving everybody vitamin D will take care of the statin issue,” he added. “Maybe the answer is going to be somewhere else, and there’ll be a lot of people I’m sure who will offer their advice as what the answer is but, I would argue, we want to see more studies to pin it down. So people can get some science behind what they do to try to reduce statin-associated muscle symptoms.”

Paul D. Thompson, MD, chief of cardiology emeritus at Hartford Hospital, Connecticut, and a SAMS expert who was not involved with the research, said, “This is a useful publication, and it’s smart in that it took advantage of a study that was already done.”

He acknowledged being skeptical of a beneficial effect of vitamin D supplementation on SAMS, because some previous data have been retracted, but also said that potential treatments are best tested in patients with confirmed statin myalgia, as was the case in his team’s negative trial of CoQ10 supplementation.

That said, the present “study was able to at least give some of the best evidence so far that vitamin D doesn’t do anything to improve symptoms,” Thompson said. “So maybe it will cut down on so many vitamin D levels [being measured] and use of vitamin D when you don’t really need it.”

The study was sponsored by the Hyperlipidemia Research Fund at Northwestern University. The VITAL trial was supported by grants from the National Institutes of Health, and Quest Diagnostics performed the laboratory measurements at no additional costs. Hlatky reports no relevant financial relationships. Stone reports a grant from the Hyperlipidemia Research Fund at Northwestern and honorarium for educational activity for Knowledge to Practice. Thompson is on the executive committee for a study examining bempedoic acid in patients with statin-associated muscle symptoms.

JAMA Cardiol. Published online November 23, 2022. Abstract

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