Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease

Stevens, Kara; Creanor, Siobhan; Jeffery, Alison; Whone, Alan; Zajicek, John; Foggo, Andy; Jones, Ben; Chapman, Rebecca; Cocking, Laura; Wilks, Jonny; Webb, Doug; Carroll, Camille; Inches, Jemma; Underwood, Donna; Frost, J. A.; James, Ali; Schofield, Christine; James, Rob S.; O’Reilly, Claire; Sheridan, Ray; Statton, Sarah; Goff, Anita; Russell, Tamlyn; Whitcher, Alison; Craw, Sarah; Lewis, Alison; Sophia, Rani; Amar, Khaled; Hernandez, Rochelle; Pitcher, Alison; Carvey, Samantha; Hamlin, Ruth; Lyell, Veronica; Aubry, Louisa; Carey, Gillian; Coebergh, Jan; Mojela, Idah; Molloy, Sophie; Bergaz, Yolanda Berceruelo; Camera, Bintou; Campbell, Philip; Morris, Huw; Samakomva, Tinashe; Schrag, Anette; Fuller, Sarah; Misbahuddin, Anjum; Parker, Laura C.; Visentin, Elisa; Gallehawk, Stephanie; Rudd, Jacqueline; Singh, Sudhir Kumar; Wilson, Sarsha; Creven, Julie; Croucher, Yvonne; Tluk, Susan; Watts, Paul; Hargreaves, Simone; Johnson, Danielle; Worboys, Lucy; Worth, Paul; Brooke, Judith; Kobylecki, Christopher; Johnson, Linda L.; Joseph, Rosane; Melville, Julie; Raw, Jason; Birt, Janice; Hare, Marianne; Shaik, Saifuddin; Alty, Jane; Cosgrove, Jeremy; Burn, David; Green, Angela; McNichol, Ann P.; Pavese, Nicola; Pilkington, Helen; Price, Maria; Walker, Kathryn; Chaudhuri, Ray; Podlewska, Aleksandra; Reddy, Prashanth; Trivedi, Dhaval; Bandmann, Oliver; Clegg, R. T.; Cole, Grace; Emery, Anna; Dostál, Václav; Graham, Jodie; Keshet-Price, Jocelyn; Mamutse, Godwin; Miller-Fik, Alex; Wiltshire, Alison; Wright, C.; Dixon, Kathryn; Abdelhafiz, Ahmed H.; Rose, Joanne

doi:10.1001/jamaneurol.2022.3718

Cited by 14 publications

(9 citation statements)

References 30 publications

(47 reference statements)

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“…Thus, simvastatin was ineffective as a disease‐modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial. 66 These observations may explain the duration‐dependent effect of statins in the progression of PD.…”

Section: Harmful Role Of Statins In Pdmentioning

confidence: 95%

“… 65 An updated clinical trial demonstrated that simvastatin has a potential role in the progression of PD. 66 A total of 216 patients progressed to the 80‐mg dose, the primary outcome analysis showed that the simvastatin group had an additional deterioration in motor symptoms while not taking medication at 24 months compared with the placebo group ( p = .006). Thus, simvastatin was ineffective as a disease‐modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial.…”

Section: Harmful Role Of Statins In Pdmentioning

confidence: 99%

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Pros and cons for statins use and risk of Parkinson's disease: An updated perspective

Al-Kuraishy¹,

Al-Gareeb²,

Αλεξίου³

et al. 2023

Pharmacology Res & Perspec

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Parkinson's disease (PD) is the second most frequent neurodegenerative brain disease (NBD) after Alzheimer's disease (AD). Statins are the most common lipid‐lowering agents used in the management of dyslipidemia and the prevention of primary and secondary cardiovascular diseases (CVD) events. In addition, there is a controversial point regarding the role of serum lipids in the pathogenesis of PD. In this bargain, as statins reduce serum cholesterol so they affect the PD neuropathology in bidirectional ways either protective or harmful. Statins are not used in the management of PD, but they are frequently used in the cardiovascular disorders commonly associated with PD in the elderly population. Therefore, the use of statins in that population may affect PD outcomes. Concerning the potential role of statins on PD neuropathology, there are conflicts and controversies either protective against the development of PD or harmful by increasing the risk for the development of PD. Therefore, this review aimed to clarify the precise role of statins in PD regarding the pros and cons from published studies. Many studies suggest a protective role of statins against PD risk through the modulation of inflammatory and lysosomal signaling pathways. Nevertheless, other observations suggest that statin therapy may increase PD risk by diverse mechanisms including reduction of CoQ10. In conclusion, there are strong controversies regarding the protective role of statins in PD neuropathology. Therefore, retrospective and prospective studies are necessary in this regard.

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Section: Harmful Role Of Statins In Pdmentioning

confidence: 95%

Section: Harmful Role Of Statins In Pdmentioning

confidence: 99%

Pros and cons for statins use and risk of Parkinson's disease: An updated perspective

Al-Kuraishy¹,

Al-Gareeb²,

Αλεξίου³

et al. 2023

Pharmacology Res & Perspec

View full text Add to dashboard Cite

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“…Due to our MAMS trial requiring large sample sizes, the potential for Part II to be administered remotely was considered particularly advantageous. Nevertheless, only limited data are available on performance of Parts II and III over two or more years in disease‐modifying trials, 9,10 when nonmotor features may gain relevance 11–13 …”

Section: Resultsmentioning

confidence: 99%

Embedding Patient Input in Outcome Measures for Long‐Term Disease‐Modifying Parkinson Disease Trials

Gonzalez‐Robles,

Bartlett,

Burnell

et al. 2023

Movement Disorders

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BackgroundClinical trials of disease‐modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients.ObjectivesThe objective is to select a patient‐centered primary outcome measure for disease‐modification trials over three or more years.MethodsExperts in Parkinson's disease (PD), statistics, and health economics and patient and public involvement and engagement (PPIE) representatives reviewed and discussed potential outcome measures. A larger PPIE group provided input on their key considerations for such an endpoint. Feasibility, clinimetric properties, and relevance to patients were assessed and synthesized.ResultsAlthough initial considerations favored the Movement Disorder Society‐sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) Part III in Off, feasibility, PPIE input, and clinimetric properties supported the MDS‐UPDRS Part II. However, PPIE input also highlighted the importance of nonmotor symptoms, especially in the longer term, leading to the selection of the MDS‐UPDRS Parts I + II sum score.ConclusionsThe MDS‐UPDRS Parts I + II sum score was chosen as the primary outcome for large 3‐year disease‐modification trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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“…Moreover, recently published results of a randomized clinical trial of simvastatin (C10AA01) demonstrated no effect on moderate PD. 29…”

Section: Discussionmentioning

confidence: 99%

Association Between Use of Any of the Drugs Prescribed in Norway and the Subsequent Risk of Parkinson Disease

Romanowska,

Bjornevik,

Cortese

et al. 2023

Neurology

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Background and objectives: The incidence rate of Parkinson’s disease (PD) has been increasing rapidly during the last years. Yet, no treatments exist to prevent or slow the progression of the disease. Moreover, we are unable to detect early disease stages during which intervention with disease-modifying therapies is most likely to succeed. The objective of this study was to perform an agnostic drug-wide association study (DWAS) estimating the association between use of any of the drugs prescribed in Norway and the subsequent risk of PD. Methods: This registry-based cohort study use data from the entire Norwegian population between 2004–2019 linked to the Norwegian Prescription Registry, with more than 600 million individual prescriptions. Drug classes were screened according to ATC codes at level 2, corresponding to therapeutic subgroups. We used Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) for the associations between drug classes and PD risk. All p-values were corrected for multiple testing using the false discovery rate. Additionally, we conducted sensitivity analyses of exposure definition, as well as time-lag and dose-response analyses. Results: The study population comprised 3,223,672 individuals, 15,849 of whom developed PD during the follow-up. We identified thirty-one drug classes that were statistically significantly associated with PD risk in Norway during the follow-up. Drugs acting on the renin-angiotensin system (HR = 0.92, 95% CI: 0.89–0.95), corticosteroids for systemic use (0.88, 95% CI: 0.84–0.93), and vaccines (0.89, 95% CI: 0.82–0.96) were associated with a decreased risk of PD even up to 10 years prior to PD onset. Drug classes used to treat symptoms related to prodromal signs of PD such as constipation, urological issues, and depression were associated with an increased risk of subsequent diagnosis of PD with HRs of 1.6 (95% CI: 1.49–1.73), 1.48 (1.42–1.53), and 1.94 (1.87–2.01), respectively. Discussion: This drug-wide study identified thirty-one drug classes that were associated with the PD risk change. It reveals links of renin-angiotensin system medications, vaccines, and corticosteroids with PD risk and suggests that monitoring drug usage using pharmacoepidemiology may allow identifying individuals with prodromal PD.

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Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease

Cited by 14 publications

References 30 publications

Pros and cons for statins use and risk of Parkinson's disease: An updated perspective

Pros and cons for statins use and risk of Parkinson's disease: An updated perspective

Embedding Patient Input in Outcome Measures for Long‐Term Disease‐Modifying Parkinson Disease Trials

Association Between Use of Any of the Drugs Prescribed in Norway and the Subsequent Risk of Parkinson Disease

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