By Claire Henchcliffe, MD, PhD

Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College

Dr. Henchcliffe reports she is on the speakers bureau and advisory boards for Teva, IMPAX, and ACADIA; is on the advisory board for U.S. World Meds; and is a consultant for Cynapsus and Pfizer.

SYNOPSIS: In approximately 50,000 individuals with Parkinson’s disease and diabetes, identified from a National Health Insurance database in Taiwan, statin use was dose-dependently associated with lower risk of Parkinson’s disease. This strengthens the argument for a possible protective role for statins.

SOURCE: Lin KD, Yang CY, Lee MY, et al. Statin therapy prevents the onset of Parkinson’s disease in patients with diabetes. Ann Neurol 2016;80:532-540.

Recent studies have highlighted the importance of attention to overall patient health in Parkinson’s disease (PD). In particular, there is concern that modifiable cardiovascular risk factors may play a role in risk of PD. In this study, Lin et al randomly sampled 1 million patients from a reimbursement database of the National Health Insurance (NHI) program in Taiwan. ICD-9 codes were used to identify patients with diabetes, and inclusion in this group required at least three visits within a 30-day to one-year period. ICD-9 codes for PD and secondary parkinsonism, as well as anti-PD medication use, were used to define those with PD for the purposes of this study. Those presenting with dementia or malignancy before the index date (first visit for diabetes) were excluded. Statin dose and duration was determined, and statin users were compared with patients not taking statins. Of patients included in the study, average age was 59 ± 11 years, 48% were women, 76% had hypertension, 69% had hyperlipidemia, 39% had ischemic heart disease, and 28% had suffered a stroke. The crude hazard ratio of PD incidence of statin users vs. non-users was 0.60 (95% confidence interval [CI], 0.51-0.69) in men and 0.65 (95% CI, 0.57-0.74) in women. Relative risk (RR) was 0.70 (95% CI, 0.63-0.79). A Cox regression analysis demonstrated a significant trend for dose-dependence of this effect. However, when statins were examined individually, lovastatin did not seem to associate with lower risk of PD, in contrast to simvastatin, atorvastatin, and “other” (pravastatin plus fluvastatin). The incidence of PD was higher with increasing age, as expected, and also higher in patients with strokes, but lower in patients with hyperlipidemia. Of note, regardless of statin use, incidence of PD was actually higher in women than men in this study of individuals with diabetes, as seen previously in diabetics, but contrary to the usual male preponderance of this disorder.

COMMENTARY

Although multiple previous studies have attempted to pin down the relationship of statin use and PD, the true nature of the association has proved elusive. Statin prescription targets lowering low-density lipoprotein cholesterol, as a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. However, statins also may inhibit neuroinflammatory processes and reduce microglial activation, increase antioxidant pathways, and there is good evidence that they provide neuroprotection in animal models of disease as well as in cells in tissue culture. This study very comprehensively analyzed the association of statin use with PD incidence, specifically in individuals with diabetes. Using multiple regression analyses, the authors found that even after adjusting for a number of factors (including age, hypertension, hyperlipidemia, stroke, ischemic heart disease, Charlson comorbidity index), there was a “protective effect” against PD. A strength of the study is that this effect was dose-dependent. The NHI covers 98% of the Taiwanese population as of 2005 (although the study goes back to 2001), and the large number of patients included, the long-term follow-up data available, and finding of a dose relationship make this study highly compelling. Nonetheless, inherently it is a study of association, and not causation, and the article title states that statin therapy prevents PD in those with diabetes and, therefore, should not be misinterpreted. As the authors stated, more studies will be needed and an interventional study would provide critical data in this regard. The use of ICD-9 codes without the ability to verify diagnosis limits the study’s strength somewhat. But more importantly, the use of ICD-9 codes for secondary parkinsonism, in addition to PD, raises many questions about what is under examination precisely. This raises questions as to the mechanisms underlying the association described in this study. Finally, the study strongly suggests a pragmatic approach to curbing the effect of neurodegenerative disorders, including PD, in the near future, and it certainly emphasizes the importance of attention to general health issues in healthy aging.