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NEWS FROM THE AAN ANNUAL MEETING: Is Vitamin D Deficiency in People Taking Statins a Possible Risk Factor for Muscle-Related Complications?

Talan, Jamie

doi: 10.1097/01.NT.0000430531.27988.7e
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Investigators reported at the AAN annual meeting that they found a significant relationship between vitamin D and elevated creatine kinase levels and myalgia in patients taking statins.

Scientists trying to identify the risk factors that put people taking statin drugs at risk for muscle pain and weakness have evidence that vitamin D deficiency may be linked to the common complication.

Nicholas Silvestri, MD, an assistant professor of clinical neurology at the State University of New York, Buffalo, and his colleagues were interested in exploring the role of vitamin D because of past associated research on multiple sclerosis (MS). Senior resident Atul Mangla, MD, now a stroke fellow at Columbia University College of Physicians and Surgeons, and Dr. Silvestri teamed up to look at the vitamin's putative role in statin-related elevations in creatine kinase (CK) levels and myalgia. (CK — a surrogate marker for muscle cell damage — is a molecule inside muscle fibers that can leak into the blood if the integrity of the muscle is disrupted.)

Dr. Silvestri and colleagues reviewed data from 1089 records of people taking statins between 2001 and 2011 to see whether there was an association between statin-induced myalgia and vitamin D deficiency. In Buffalo, where winters are long, vitamin D deficiency is fairly prevalent. They separated patients into two groups — those with normal vitamin D levels and those deficient in the vitamin; vitamin D deficiency was defined as levels below 30 ng/dL. They only studied patient records that included those who also had a baseline vitamin D level. Those with high serum CK secondary to other conditions were excluded from the study.

Then, they looked at those with complications such as an elevation in CK levels and myalgia and those without complications and asked the simple question: were people with elevated CK levels or myalgia more likely to have low levels of vitamin D than people with normal levels of the vitamin?

Indeed, they reported at the AAN annual meeting that they found a significant relationship between vitamin D and elevated CK levels and myalgia in the patients taking statins.

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Dr. Silvestri and his colleagues found 244 patients in the elevated CK/myalgia group and 845 patients in the control group who were comparable for age and statin dose but with significant difference in vitamin D level (p<0.05) and serum CK levels (p<0.05). Among 244 patients in the myopathy group 207(84.8 percent) had low vitamin D (OR 3.176; 95% CI 2.17 – 4.63). Patients who were younger than 60 years, male, or African-American showed a trend towards a higher incidence of complications but the numbers were not significant (p>0.05). By multivariate analysis, low vitamin D level was the only independent predictor of statin-induced complications, Dr. Silvestri said.

“Myalgia in statin-treated patients may reflect a reversible interaction between vitamin D deficiency and statins,” he explained. “This study suggests that screening for and treating vitamin D insufficiency may reduce the development of myopathic complications in patients placed on statins.”

“As a general rule, correlation does not mean causation,” added Dr. Silvestri. “The next step is to see whether supplementing vitamin D in those who are deficient would improve symptoms of myopathy. We haven't tried that yet.”

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There are some estimates that 2- to 10-percent of people who take statins may experience some muscle problems, according to Andrew Mammen, MD, an associate professor of neurology and medicine at Johns Hopkins School of Medicine who studies statin-induced muscle problems. Although the mechanism of statin toxicity is not known, a single nucleotide polymorphism has been identified that puts statin users at risk.



With all the attention to the risk of muscle problems among statin users, though, no one has figured out what the drug does to increase the risk for muscle pain and/or weakness. Dr. Mammen said that there are several theories and some evidence for each one of them. One theory is that statins deplete cholesterol from muscles and it damages the fibers. Another theory is that cholesterol byproducts — isoprenoids — are depleted and this can lead to apoptosis of muscle cells. Or another downstream byproduct — NADH:ubiquinone oxidoreductase (complex I) — is disrupted and causing mitochondrial dysfunction.

Vitamin D seems to be important in maintaining healthy muscles, Dr. Mammen said, but he noted vitamin D deficiency does not normally cause significant myopathy, “and one would not think that vitamin D levels alone would cause an increase in CK levels.”

While the association is intriguing, he added, it is not clear from the findings presented in the abstract whether they measured vitamin D when the statin was started or down the road. “It is possible the test was ordered because there was muscle pain,” Dr. Mammen said. “It is hard to get this kind of information from a retrospective study.”

“If the association is real, and it remains to be seen, treating patients with vitamin D supplements may reduce the risk for myopathy,” he continued. “But that has not been shown in this study. One would like to see a prospective study where you measure vitamin D before statins are started and then follow [the participants] over time to see who goes on to develop muscle problems.”

“A lot more research needs to be done to prove the relationship,” added Matthew P. Wicklund, MD, professor of neurology and pediatrics at Pennsylvania State Hershey Medical Center, who is a neuromuscular specialist. He pointed out that while some investigators have made a case for vitamin D deficiencies among statin-users who develop muscle pain and weakness, others have compared vitamin D levels among statin users and have not found a link; for the latter perspective, he cited a 2012 paper in the journal Clinical Endocrinology.

“While I find the study findings intriguing, it is premature to consider treating myopathy with vitamin D supplementation,” he said. “I am not sure it would have a benefit.”

Paresh Dandona, MD, PhD, an endocrinologist at SUNY Buffalo who studies vascular disease, said he was not surprised by the latest preliminary findings. “Since there is an interaction with statins and myopathy, there may well be an amplifying influence of low vitamin D levels,” said Dr. Dandona, who published a paper in the Archives of Internal Medicine in 2000 on severe myopathy associated with vitamin D deficiency. He described five diabetic patients with such severe myopathy that they required wheelchairs. He treated them with vitamin D supplements and the muscle weakness abated.

“This retrospective report confirms our stronger prospective data,” said Charles J. Glueck, MD, director of the Jewish Hospital Cholesterol and Metabolism Center in Cincinnati, OH. “Vitamin D deficiency interacts with statins to produce myalgia-myositis, and can be reversed by the simple expedient of providing vitamin D (usually 50,000 to 100,000 units of D3 per week) to raise vitamin D into the normal range, and then maintaining it there. Once the vitamin D is normalized, we have shown that more than 90 percent of previously vitamin D-deficient, statin-intolerant patients, can now tolerate statins without problems, achieving LDL cholesterol lowering goals.”

A clinical trial treating vitamin D deficiency to resolve statin-induced muscular symptoms is now under way at Cedars-Sinai Medical Center.

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Bianca Weinstock-Guttman, MD, professor of neurology at SUNY University of Buffalo and the director of the Baird MS Center and Pediatric MS Center of Excellence at the Jacobs Neurological Institute, studies the link between vitamin D deficiency and MS. Her group showed that low levels of vitamin D were associated with an increased risk of MS, as well as more rapid disease progression. She said that vitamin D deficiency has also been linked to an increased risk for stroke, cancer, and autoimmune diseases.

Her group suspects that vitamin D has anti-inflammatory properties. “Vitamin D has a clear influence on the immune system, increasing the resistance to infection and decreasing pro-inflammatory markers considered to be beneficial in autoimmune diseases like MS,” she said. In looking at the latest finding from Dr. Silvestri's team, she added: “The large sample size supporting the negative effect of low vitamin D during statin therapy raises the consideration [that clinicians should] check vitamin D and CK levels.”

—Jamie Talan





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