Vitamin D supplementation did not relieve muscle symptoms in statin users in the randomized VITAL trial, a sub-study showed.
Over a 4.8-year follow-up, 31% of statin users assigned vitamin D reported muscle pain or discomfort for several days, which was the same percentage as those assigned placebo, with 13% of both groups discontinuing their statin due to muscle symptoms, reported Mark Hlatky, MD, of Stanford University School of Medicine in California, and colleagues.
“These null results in a large, contemporary randomized clinical trial suggest that vitamin D has little or no association with the occurrence of SAMS. [statin-associated muscle symptoms]’ they concluded JAMA Cardiology.
Statins are important preventive drugs widely blamed for muscle pain in patients. Observational studies have linked low levels of vitamin D to the development of statin-associated muscle symptoms, with mechanisms proposed related to altered enzyme activity and the indirect increased toxicity of some statins.
Now, however, the benefits of vitamin D supplementation for muscle symptoms have not come to fruition in a more rigorous study. Indeed, there is strong evidence that such complaints actually stem from a nocebo effect due to negative expectations of statin users from the start.
“We had high expectations that vitamin D would be effective because in our clinic and across the country, statin-associated muscle symptoms were a major reason so many patients stopped taking their statin medications,” said study co-author Neil Stone, MD, of Northwestern University Feinberg School of Medicine in Chicago, in a press release.
“So it was very disappointing that vitamin D didn’t pass rigorous testing. Nevertheless, it’s important to avoid ineffective treatments and instead focus on research that can provide an answer,” he added.
Stone suggested that in clinical practice any observed statin intolerance should be investigated by analyzing other medications used by patients, determining whether patients have associated metabolic or inflammatory conditions, advising patients on adequate hydration and discussing pill anxiety.
VITAL was a 2×2 factorial, double-blind study in which the participating men and women were free of cancer and cardiovascular disease at baseline.
Hlatky and colleagues conducted a substudy in participants who reported starting statin therapy after randomization to daily cholecalciferol (n=1,033) or placebo (n=1,050). The mean age was 66.8 years and approximately half of the cohort consisted of women.
The response rate to the study survey on statin-associated muscle symptoms was high at 88%.
Vitamin D null results were consistent across pretreatment 25-hydroxy vitamin D levels. In patients with levels less than 20 ng/ml, muscle symptoms were reported by 33% of the vitamin D group and 35% of those assigned to placebo; for those with levels less than 30 ng/mL, muscle symptoms were reported by 27% and 30%, respectively.
Hlatky and team acknowledged that statin therapy was initiated after randomization in the study, at the discretion of the participants’ personal physicians, and that statin-associated muscle symptoms had not been evaluated or prospectively treated.
The main finding of VITAL was that supplementation with vitamin D and omega-3 fatty acids prevent cardiovascular disease and cancer in women aged 55 and older and men aged 50 and older. Subsequent VITAL analyzes also showed that vitamin D does not help prevent bone fractures or frailty, although there was a signal that the supplements tested were associated with reductions in autoimmune disorders.
The study was supported by Northwestern University’s Hyperlipidemia Research Fund. The VITAL study was funded by NIH grants and supported by Quest Diagnostics.
Hlatky had no disclosures.