Simvastatin is ineffective as a disease-modifying therapy for intermediate Parkinson’s disease


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

An estimated 6.2 million people are affected by PD, which is the fastest growing neurological disease in the world. Although current treatments manage the symptoms of the neurological disease, there are no known treatments available to slow the progression of the disease.

The 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 blood-brain barrier,” they said. “Epidemiological studies support a potential protective effect of statins on PD, with meta-analyses demonstrating that statin use may be associated with a relative reduction in the risk of PD incidence.”

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

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

The analysis randomized patients 1:1 to receive simvastatin or matching 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 in the simvastatin arm entered a phase of 1 month on low-dose simvastatin, 40 mg daily, followed by 23 months on high-dose simvastatin, 80 mg daily, before a 2-month washout period.

The prespecified primary endpoint was change over 24 months in the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III score, measured without taking medication (scores high indicates a worse result). The primary futility analysis included participants who started the 80 mg phase and had valid primary outcome data. The safety analysis included all participants who started the trial treatment and is reported by dose at time of event.

A total of 332 patients were assessed for eligibility, of whom 32 refused and 65 were ineligible. Of the 235 participants recruited, 97 (41%) were female, 233 (99%) were Caucasian, 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.

Results from the primary outcome analysis exploring the difference between the fully adjusted (simvastatin minus placebo) groups in 24-month change in MDS-UPDRS Part III score showed that participants in the simvastatin group worsened, on average , by 1.52 additional points (two-sided 80% CI, -0.77 to 3.80) without taking medication compared to the placebo group. In addition, testing of the futility hypothesis indicated that simvastatin was futile as a treatment for PD (one-sided futility test, P = .006)

As there was no evidence that simvastatin was non-futile, a disease modification analysis, including data at 26 months, was not performed. A total of 37 serious adverse events (AEs), including 3 deaths and 171 AEs, were reported in patients not taking any active treatment (i.e. simvastatin 0 mg or placebo), including 8 after stop simvastatin for at least 8 days. A total of 37 serious AEs and 150 AEs were reported in participants taking simvastatin 40 mg or 80 mg, and 4 participants withdrew from the trial due to an AE.

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

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

“A better understanding of the interplay between the potential protective effect of statins, the potential negative effect of low cholesterol, disease stage, and relevant comorbidities could indicate whether, when, and in whom statins are worth further investigation as a disease-modifying treatment in PD.


Stevens KN, Creanor S, Jeffrey A, et al. Evaluation of simvastatin as a disease-modifying therapy in patients with Parkinson’s disease: a randomized clinical trial. Posted October 31, 2022. doi:10.1001/jamaneurol.2022.3718


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