Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial

Abstract

Summary Background Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson’s disease. We investigated whether these effects would be apparent in a clinical trial. Methods In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson’s disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25–75 years, had idiopathic Parkinson’s disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed. Findings Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI −2·6 to 0·7) in the exenatide group and worsened by 2·1 points (−0·6 to 4·8) in the placebo group, an adjusted mean difference of −3·5 points (−6·7 to −0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions. Interpretation Exenatide had positive effects on practically defined off-medication motor scores in Parkinson’s disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson’s disease, and effects on everyday symptoms should be examined in longer-term trials. Funding Michael J Fox Foundation for Parkinson’s Research.

Semaglutide seems to be more effective the other GLP-1Ras

“…However, studies in humans have not supported the use of GLP-1 RA in cerebral diseases (19), except for one clinical trial of 48 weeks, which suggested that exenatide once weekly had positive effects in Parkinson's disease, which were sustained beyond the period of exposure (20). Whether the exenatide therapy affects the underlying disease pathophysiology or the result simply is secondary to long-lasting metabolic improvements is uncertain.…”

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“…GLP-1 receptor agonists increase insulin sensitivity and are neuroprotective in animal models of AD, PD, and stroke (Li et al, 2009, 2010; Liu et al, 2015b). A recent clinical trial revealed a therapeutic benefit of the GLP-1 analog exanatide in PD patients (Athauda et al, 2017). Metformin, which has been prescribed for diabetes for decades, inhibits liver glucose production, but also activates multiple cellular pathways that counteract aging processes, including activation of AMPK and inhibition of mTOR and inflammatory pathways (Barzilai et al, 2016).…”

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“…Currently, multiple GLP-1R agonists are indicated for the treatment of T2D, and liraglutide is also approved for obesity; however, indications such as nonalcoholic steatohepatitis, Parkinson's disease, and Alzheimer's disease are being explored. Indeed, several randomized controlled clinical trials have demonstrated significant clinical improvement in human subjects with Parkinson's disease (93). Despite the appeal of current GLP-1R agonists for the treatment of T2D, market penetration for many GLP-1R agonists remains disappointing, raising questions about the potential clinical classes used for treatment of T2D, the GLP-1R agonists and SGLT-2 inhibitors, produce weight loss, effective reduction of A1c, a low incidence of hypoglycemia, and reductions in rates of major adverse cardiovascular events and cardiovascular death (75,87).…”