Simvastatin and cognition in multiple sclerosis

Few treatment options are available for patients with progressive multiple sclerosis,1Ontaneda D Thompson AJ Fox RJ Cohen JA Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function.Lancet. 2017; 389: 1357-1366Summary Full Text Full Text PDF PubMed Scopus (187) Google Scholar in whom anti-inflammatory drugs have little effect and for whom clinical manifestations, such as cognitive impairment and neuropsychiatric dysfunction, have a dramatic effect on quality of life. Preservation of functional and social independence are perhaps the main therapeutic goals in these patients. Statins are widely used for the treatment of vascular diseases, and have an excellent safety profile and low cost. In addition to their beneficial effect on hypercholesterolaemia, statins exert immunomodulatory and neurotrophic effects.2Pihl-Jensen G Tsakiri A Frederiksen JL Statin treatment in multiple sclerosis: a systematic review and meta-analysis.CNS Drugs. 2015; 29: 277-291Crossref PubMed Scopus (63) Google Scholar Studies in patients with relapsing-remitting multiple sclerosis found no clear beneficial effects of statins,2Pihl-Jensen G Tsakiri A Frederiksen JL Statin treatment in multiple sclerosis: a systematic review and meta-analysis.CNS Drugs. 2015; 29: 277-291Crossref PubMed Scopus (63) Google Scholar, 3Sorensen PS Lycke J Eralinna JP et al.Simvastatin as add-on therapy to interferon beta-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial.Lancet Neurol. 2011; 10: 691-701Summary Full Text Full Text PDF PubMed Scopus (92) Google Scholar either as monotherapy or as add-on to interferon beta, at reducing clinical and MRI disease activity; however, in a 2-year double-blind controlled trial4Chataway J Schuerer N Alsanousi A et al.Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial.Lancet. 2014; 383: 2213-2221Summary Full Text Full Text PDF PubMed Scopus (292) Google Scholar of 140 patients with secondary progressive multiple sclerosis (SPMS; MS-STAT), a 43% reduction in annualised brain atrophy rate was reported in patients treated with high-dose simvastatin (n=70) compared with placebo (n=70). Simvastatin-treated patients also experienced a less pronounced accumulation of disability and worsening on the Multiple Sclerosis Impact Scale and, as might be expected, a significant reduction in serum cholesterol concentrations over the trial period. No effect on measures of disease activity (new MRI lesions or clinical relapses) was detected. In The Lancet Neurology, Dennis Chan and colleagues5Chan D Binks S Nicholas JM et al.Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial.Lancet Neurol. 2017; (published online June 6)http://dx.doi.org/10.1016/S1474-4422(17)30113-8PubMed Google Scholar report findings from a cognitive substudy of the previous trial,4Chataway J Schuerer N Alsanousi A et al.Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial.Lancet. 2014; 383: 2213-2221Summary Full Text Full Text PDF PubMed Scopus (292) Google Scholar providing data to further our understanding of the effect of simvastatin in patients with SPMS. At the end of the 2-year period, compared with placebo, simvastatin-treated patients showed better performance in some frontal lobe tests (difference in Frontal Assessment Battery score 1·2 points, 95% CI 0·2–2·3) and improved physical quality of life (difference in physical component summary of the Short-Form 36 2·5 points, 95% CI 0·3–4·8; p=0·028); these differences were not associated with frontal lobe volume changes, which were similar in the two study groups (difference in mean rate 0·0 mL/year, 95% CI −0·7 to 0·7; p=0·97). The discrepancy between the regional and global assessments of brain atrophy in the two analyses were discussed briefly by the investigators. Findings from several volumetric studies have shown that different patterns of regional involvement are associated with cognitive deficits in patients with multiple sclerosis, with a more distributed pattern of atrophy in patients with SPMS than in those with relapsing-remitting multiple sclerosis.6Rocca MA Amato MP De Stefano N et al.Clinical and imaging assessment of cognitive dysfunction in multiple sclerosis.Lancet Neurol. 2015; 14: 302-317Summary Full Text Full Text PDF PubMed Scopus (365) Google Scholar As a consequence, one may be tempted to speculate that region-specific involvement might be important in explaining cognitive, and clinical, deficits early in the course of the disease, whereas later on, the global burden of the disease, as reflected by whole brain atrophy, might become more clinically relevant. Disappointingly, since Chan and colleagues'5Chan D Binks S Nicholas JM et al.Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial.Lancet Neurol. 2017; (published online June 6)http://dx.doi.org/10.1016/S1474-4422(17)30113-8PubMed Google Scholar substudy was planned and focused particularly on frontal lobe assessment, the possible association between patients' functional improvement and global volume changes was not investigated. This is one of the main limitations of this study. Although adherence to pre-planned statistical analysis is a major requirement for confirmatory trials aimed at providing firm evidence of efficacy or safety of a drug, exploratory trials, and trial substudies, warrant a more flexible approach, particularly when peculiar aspects or groups of well-characterised patients are under investigation, as is the case in Chan and colleagues'5Chan D Binks S Nicholas JM et al.Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial.Lancet Neurol. 2017; (published online June 6)http://dx.doi.org/10.1016/S1474-4422(17)30113-8PubMed Google Scholar substudy. From this perspective, despite the limitations, Chan and colleagues' work offers several important take-home messages, which might affect the planning of future clinical trials as well as clinical practice in SPMS. First, treatment trials in patients with SPMS should include not only disability as the clinical outcome measure, but also cognition and quality of life measures. Second, investigating and controlling for comorbidities and their risk factors might help minimise the devastating clinical effect of the disease. Even though the exact mechanism of action of simvastatin has not been established, it is thought to work on vascular function and cell protection.2Pihl-Jensen G Tsakiri A Frederiksen JL Statin treatment in multiple sclerosis: a systematic review and meta-analysis.CNS Drugs. 2015; 29: 277-291Crossref PubMed Scopus (63) Google Scholar Consistent with the effects of comorbidity in other chronic diseases, vascular comorbidity adversely affected disability in multiple sclerosis,7Marrie RA Rudick R Horwitz R et al.Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis.Neurology. 2010; 74: 1041-1047Crossref PubMed Scopus (295) Google Scholar justifying the investigation of the effect of treatment of vascular comorbidities on disease progression. Unfortunately, assessment of comorbidities was not done in the MS-STAT trial, and so establishing whether simvastatin might have a different effect depending on their presence was not possible. Chan and colleagues' work has further merit in that it extensively characterises the pattern of cognitive dysfunction, including neuropsychiatric symptoms, and its progression over 2 years in a large cohort of patients with SPMS, assessed with a standardised battery of neuropsychological tests. Even though the data need confirmation in other groups of patients, as acknowledged by the investigators, these assessments could be used to inform the selection of patients with SPMS in future studies in which cognition is one of the outcomes and in studies aimed at treating cognitive impairment. MF is Editor-in-Chief of the Journal of Neurology; serves on a scientific advisory board for Teva Pharmaceutical Industries; has received compensation for consulting services or speaking activities, or both, from Biogen Idec, Merk-Serono, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer's Drug Discovery Foundation, the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA). MAR has received speaker honoraria from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva, and Merk Serono; and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trialTo our knowledge, this SPMS cohort is the largest studied to date with comprehensive longitudinal cognitive, neuropsychiatric, and HRQoL assessments. We found evidence of a positive effect of simvastatin on frontal lobe function and a physical quality-of-life measure. Although we found no effect of simvastatin on the other outcome measures, these potential effects warrant confirmation and underline the importance of fully assessing cognition and quality of life in progressive multiple sclerosis treatment trials. Full-Text PDF Open Access