Statin Benefit in Multiple Sclerosis Not Due to Cholesterol-Lowering Effects

A new study found that statins may have the potential to treat patients with secondary progressive multiple sclerosis (SPMS) for reasons unrelated to lowering cholesterol.

The study, which was published in the Proceedings of the National Academy of Sciences, analyzed data on the effects of simvastatin use in individuals with SPMS over a 2-year period. Using data from the MS-STAT trial, the researchers modelled hypothesized causal association by which simvastatin affects brain atrophy, clinical, and cognitive outcome measures. To do this, they used 2 computational models: a cholesterol-mediated model and a cholesterol-independent model.

The phase 2 MS-STAT clinical trial included 140 patients with SPMS who received either a high dose of simvastatin (80 mg per day) or a placebo for 2 years. According to the data, patients who received simvastatin had a brain volume loss of 43% less compared with those who took a placebo.

The study also demonstrated smaller but significant effects on 2 of the disability measures: a slower change in disability levels and improved scores on a questionnaire that measures the impact of MS on daily life. Overall, the findings indicated that simvastatin had a positive effect on delaying disability progression and slowing brain atrophy, although it was not certain what the cause of this benefit was.

For this study, the researchers aimed to determine the causal relationship between the underlying mechanisms of simvastatin’s cholesterol-lowering ability and its benefit in MS. In previous studies, it has been reported that elevated peripheral cholesterol levels are associated with adverse MS outcomes. The researchers noted that this suggests that a reduction in serum cholesterol levels through statin treatment may confer a benefit. However, the study found that these effects were actually independent of lower serum cholesterol.

“My study tells us that statins help patients with MS for reasons different from how they help people lower their cholesterol,” lead author Arman Eshaghi, MD, from UCL Queen Square Institute of Neurology, said in a press release about the findings. “For example, statins can modulate other elements that are produced in the pathways before cholesterol but have indirect effects on immune system.”

According to the models, 31% of the reduction in the rate of disability worsening was explained by the treatment effects on brain atrophy and 69% by a separate direct treatment effects, all of which were independent of the change in cholesterol levels.

“Since we have observed positive effects of simvastatin on brain atrophy and disability, it is unlikely that they are due to its possible effect on central cholesterol,” the study authors wrote. “Our results suggest that future research should focus on changes in levels of the upstream metabolites of the cholesterol synthesis pathway, rather than the potential anti-comorbidity effects of statin in progressive MS.”

References

Eshaghi A, Kievit R, Prados F, et al. Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis. PNAS. 2019. Doi: https://doi.org/10.1073/pnas.1818978116

Statins’ potential to treat MS unrelated to lowering cholesterol [news release]. UCL. https://www.ucl.ac.uk/news/2019/may/statins-potential-treat-ms-unrelated-lowering-cholesterol. Accessed May 13, 2019.