A Phase II, Randomized, Double-Blinded, Placebo-Controlled Trial of Liraglutide in Parkinson's Disease

Background: Metabolic disorders such as insulin resistance and diabetes are associated with Parkinson's disease (PD). Therefore, the identification and repurposing of drugs already used to treat insulin resistance, like glucagon-like peptide-1 (GLP-1) agonists, is a promising treatment strategy for PD. Liraglutide is a powerful GLP-1 agonist, used in diabetes and obesity treatment.Methods: In a single-center, randomized, double-blind, placebo-controlled trial, PD patients self-administered liraglutide injections once-daily (1.2 or 1.8 mg, as tolerated) or placebo in a 2:1 study design for 52 weeks after titration. Primary outcomes included adjusted difference in the OFF-state Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) part III, non-motor symptom scale (NMSS) and Mattis Dementia Rating Scale (MDRS-2) at week 54. Secondary outcomes included global MDS-UPDRS scores and subscores, quality of life scores (Parkinson Disease Questionnaire, PDQ-39) and other neuropsychological tests. Efficacy analyses were based on an intention-to-treat and per-protocol design for patients completing post-randomization follow-up assessments.Findings: Sixty-three subjects were enrolled and randomized to liraglutide (n=42) or placebo (n=21). There were 12 early withdrawals (9 liraglutide, 3 placebo), 4 of whom completed week 28 endpoint assessments. At 54 weeks, NMSS scores had improved by 6.6 points in the liraglutide group and worsened by 6.5 points in the placebo group, a 13.1 point adjusted mean difference (p<0.05). MDS-UPDRS part III and MDRS-2 score changes did not significantly differ between liraglutide and placebo. Secondary outcome analyses revealed a significant improvement of MDS-UPDRS part II (p=0.001), PDQ-39 (p<0.001), and Parkinson's Anxiety Scale Avoidance Behavior scores (p<0.05) in the treatment group. MDRS-2 sub-scores did not further differentiate study groups, while Delis-Kaplan Executive Function System letter fluency scores favored placebo group (p<0.05). Injection site reactions and gastrointestinal symptoms were common adverse events (AEs). Eleven serious AEs (9 liraglutide, 2 placebo) were reported, none related to the trial intervention.Interpretation: Treatment with liraglutide is safe and improves critical features of PD, including non-motor symptoms, overall mobility, activities of daily living, and quality of life. These results validate similar outcomes reported with other GLP-1 agonists and offer new strategies to comprehensively treat a larger variety of PD symptoms.Trial Registration: Our trial is registered with ClinicalTrials.gov, NCT02953665Funding: Cure Parkinson'sDeclaration of Interest: MT has received honoraria from Abbott, Acorda, Allergan, Boston Scientific and Medtronic. ET reports consulting fees from Abbvie. JW privately owns stocks in Novo Nordisk, the study drug manufacturer. All other authors declare no competing interests.Ethical Approval: Cedars-Sinai Institutional Review Board (CSMC IRB) approved this study, IRB approval number, (Pro#0044598) dated 8/8/2016.