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Simvastatin Ineffective as Disease-Modifying Therapy for Intermediate Parkinson Disease


Patients with intermediate and mild Parkinson disease, defined by a Hoehn & Yahr stage of 3 or less, experienced an additional deterioration in motor function with simvastatin compared with placebo while not taking medication at 24 months.

Simvastatin was futile as a disease-modifying therapy in patients with intermediate Parkinson disease (PD), according to study findings published recently in JAMA Neurology.

An estimated 6.2 million people are affected by PD, which is the fastest growing neurological condition worldwide. Although current treatments manage symptoms of the neurological disease, no known treatment is available that slows disease progression.

Researchers note that preclinical studies suggest that statins, widely used to treat hypercholesterolemia, may have disease-modifying effects relevant to the pathogenesis of PD unrelated to cholesterol lowering.

“Much of this evidence relates to simvastatin, which is one of the most lipophilic statins and able to cross the bloodbrain barrier,” they said. “Epidemiological studies support a potential protective effect of statins on PD, with meta-analyses demonstrating statin use may be associated with a relative risk reduction in PD incidence.”

The study authors conducted a randomized, double-blind, parallel-group, placebo-controlled futility trial to assess the potential disease-modifying effects of 24 months’ exposure to simvastatin in patients with intermediate PD, defined by a Hoehn & Yahr (H&Y) stage of 3 or less, and to determine if simvastatin is clearly ineffective (futile) in preventing the clinical decline of PD.

Data on patients aged 40 to 90 years with a diagnosis of idiopathic PD were collected between March 2016 and May 2020 from 23 National Health Service Trusts in England. Participants who were taking medication and taking dopaminergic medication with wearing-off phenomenon were included. Data were analyzed from May 2020 to September 2020, with additional analysis in February 2021.

The analysis randomized patients 1:1 to receive simvastatin or matched placebo via a computer-generated random sequence, stratified by site and H&Y stage (either stage 2.0 or less or stage 2.5 to 3.0). Participants of the simvastatin arm entered a 1-month low-dose phase of simvastatin, 40 mg daily, followed by 23 months of high-dose simvastatin, 80 mg daily, before a 2-month washout period.

The prespecified primary outcome was 24-month change in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III score measured while not taking medication (high scores indicate worse outcome). The primary futility analysis included participants who commenced the 80-mg phase and had valid primary outcome data. The safety analysis included all participants who commenced trial treatment and is reported by dose at time of event.

A total of 332 patients were assessed for eligibility, in which 32 declined and 65 were ineligible. Of the 235 recruited participants, 97 (41%) were female, 233 (99%) were White, and the mean (SD) age was 65.4 (9.4) years. From the recruited cohort, 216 patients progressed to the 80-mg dose at one month and 178 of these patients (82.2%) remained in the study after 24 months.

Findings from the primary outcome analysis exploring the fully adjusted between-group difference (simvastatin minus placebo) in the 24-month change of MDS-UPDRS part III score showed that participants in the simvastatin group had worsened, on average, by an additional 1.52 points (2-sided 80% CI, −0.77 to 3.80) while not taking medication compared with the placebo group. Moreover, the test of the futility hypothesis indicated that simvastatin was futile as a treatment for PD (1-sided futility test, P = .006)

As there was no evidence that simvastatin was nonfutile, a disease-modifying analysis, including the 26-month data, was not performed. A total of 37 serious adverse events (AEs), including 3 deaths and 171 AEs were reported among patients not taking any active treatment (ie, 0 mg of simvastatin or placebo), of which 8 were after simvastatin discontinuation of at least 8 days. A total of 37 serious AEs and 150 AEs were reported for participants taking 40 mg or 80 mg of simvastatin, and 4 participants withdrew from the trial because of an AE.

The proportion of related AEs associated with known adverse effects increased as the dose of simvastatin increased (0 mg, 93 of 171 [54.4%]; 40 mg, 48 of 66 [72.7%]; 80 mg, 68 of 80 [85.0%])

“The relationship between PD and cardiovascular risk factors, including cholesterol level, is complicated,” concluded the study authors.

“A better understanding of the interplay between the potential protective effect of statins, the potential negative effect of low cholesterol level, the stage of disease, and relevant comorbidities might inform whether, when, and in whom statins merit further investigation as disease-modifying therapy in PD.”


Stevens KN, Creanor S, Jeffrey A, et al. Evaluation of simvastatin as a disease-modifying treatment for patients with Parkinson disease: a randomized clinical trial. Published online October 31, 2022. doi:10.1001/jamaneurol.2022.3718

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