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Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial
Open accessAbstract
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.
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“Three clinical trials consistently describe a slowed decline in motor function when using the short-acting GLP-1 receptor agonists exenatide and lixisenatide in people with Parkinson's disease; 102-104”
From GLP-1 receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits (2026) · cites this paper as [102]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Treatment with exenatide or lixisenatide for 1 year produced a modest but positive effect on Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III scores in people with recently diagnosed Parkinson’s disease (15, 53).”
From Antiinflammatory actions of glucagon-like peptide-1–based therapies beyond metabolic benefits (2025) · cites this paper as [15]
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In the citing paper
“This discrepancy may reflect differences in the neuroprotective mechanisms of semaglutide and tirzepatide vs earlier GLP-1RAs, such as exenatide, liraglutide, and lixisenatide, which have demonstrated favorable clinical benefits in early-stage Parkinson disease.33,50”
From Neurodegeneration and Stroke After Semaglutide and Tirzepatide in Patients With Diabetes and Obesity (2025) · cites this paper as [50]
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“In Parkinson's disease, phase II trials have shown that GLP-1 RAs such as exenatide and lixisenatide improve motor activity compared to placebo,53,54 and liraglutide has shown improvements in non-motor symptoms, mobility, and quality of life.55”
From The expanding role of GLP-1 receptor agonists: a narrative review of current evidence and future directions (2025) · cites this paper as [53]
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“There is increasing evidence from animal studies and clinical trials to suggest that GLP-1 receptor agonists could be beneficial in the treatment of PD, and one study using a prebiotic supplement that enhanced SCFA levels showed an increase GLP-1 levels in mouse models [141–144].”
From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [142]
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“Multiple GLP-1 medicines, including exenatide (15), liraglutide (16), semaglutide (17, 18), and tirzepatide (19), reduce plasma CRP levels in people living with T2D and/or obesity.”
From Antiinflammatory actions of glucagon-like peptide-1–based therapies beyond metabolic benefits (2025) · cites this paper as [15]
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“Moreover, GLP-1 receptors interact with various neurotransmitter systems such as serotonin, dopamine, and glutamate, which are essential for mood regulation and may contribute to the onset of depression and other psychological disorders [82].”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [82]
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“There is increasing evidence from animal studies and clinical trials to suggest that GLP-1 receptor agonists could be beneficial in the treatment of PD, and one study using a prebiotic supplement that enhanced SCFA levels showed an increase GLP-1 levels in mouse models [141–144].”
From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [142]
Experimental — accuracy not yet measuredIn the citing paper
“exenatide, administered at the dose approved for type 2 diabetes treatment, crosses the BBB in appreciable quantities and improves the motor and cognitive function of PD patients.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [616]
In the citing paper
“This study provides in vivo evidence that “beta-cell rest” can at least temporarily allow insulin secretory capacity recovery, and in vitro studies examining the effect of diazoxide on diabetic human islets produced similar findings.177”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [176]
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Schechter, M., Fishkin, A., Mosenzon, O., Sehtman-Shachar, D. R., Cukierman‐Yaffe, T., Leibowitz, G., & Aharon‐Hananel, G. (2025) · Cardiovascular Diabetology · doi:10.1186/s12933-025-02962-8 · Cited by 7
“A follow-up placebo-controlled trial found that exenatide mitigated the deterioration in the MDS-UPDRS part III off-medication score among 62 people with moderate Parkinson's disease [23].”
GLP-1 Signalling as a Therapeutic Avenue in Parkinson’s Disease: A Comprehensive Review
Orozco, M. P., Rivadeneira, V. V., & León-Rojas, J. E. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262412163 · Cited by 7
“Therefore, the response to GLP-1RAs likely varies between subgroups, and this biological variability calls attention to the need for precision medicine, dose adaptation, and the identification of subgroups that may benefit from its metabolic modulation [11,93].”
InfluentialEffects of glucagon-like peptide-1 receptor agonists on psychiatric disorders: a systematic review
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“To the best of our knowledge, this is the world’s first phase 2 RCT testing oral semaglutide tablets in patients with PD, addressing both mechanistic plausibility and unmet clinical needs.”
InfluentialAtar, A., & Şahin, İ. N. (2026) · Current Nutrition Reports · doi:10.1007/s13668-026-00743-7 · Cited by 5
“These findings support the perspective that Parkinson’s disease is not only a classical movement disorder but also a metabolically modifiable neu - rodegenerative process [7, 46].”
Cardiovascular outcomes in Parkinson’s disease patients from a retrospective cohort study
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“…Advancement of traditionally cardiovascular medicine such as glucagon-like peptide-1 (GLP-1) analogues in treatment of PD, for example, suggests that cardiovascular diseases and PD may share similar pathophysiologic aspects, enhancing the need to address CV risk factors in patients with PD 32,33 .”
BackgroundAshraf, T., Abunada, O., Kumar, A., Ahmed, S., Siddiqui, M. B. A., Memon, U. F., Dev, S., Meghjiani, A., Turesh, M., Khatri, G., et al. (2024) · Annals of Medicine and Surgery · doi:10.1097/ms9.0000000000002908 · Cited by 5
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Exercise Improves Spatial Learning and Memory Performance through the Central GLP-1 Receptors
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Nanocarriers to mediate the pathways from diabetes toward Parkinson's disease
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Incretin Mimetics as Potential Disease Modifying Treatment for Alzheimer’s Disease
Crook, H., & Edison, P. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-240730 · Cited by 5
“Otherclin-icaltrialsofexenatidehavefoundpositiveeffects ofthetreatmentonmotorfunctioninpatientswith PD,withtreatedpatientsimprovingintheirperfor-manceontheMovementDisordersSocietyUnified Parkinson’sDiseaseRatingScale(MDS-UPDRS) whileplacebo-treatedpatientsperformancewors-ened[111,112].”
Current clinical approaches in neurodegenerative diseases
Gago, M. F., Machado, Á. S., & Rocha, S. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-818084-6.00004-0 · Cited by 5
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“CCK and GLP1 are implicated in neuroprotection and neurite outgrowth within the central nervous sys-tem (CNS) [35,36], with GLP1R agonists offering therapeutic avenues for Alzheimer’s and Parkinson’s disease [37 – 39].”
BackgroundDisease‐modifying approaches for Parkinson disease
Lewis, S. J. G. (2018) · The Medical Journal of Australia · doi:10.5694/mja17.01135 · Cited by 8
Quantitative measurements of α-synuclein seeds in CSF inform diagnosis of synucleinopathies
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“Homogenization was done using the Precellys homogenization machine (Cryolys - Bertin) using their custom soft tissue homogenization CK14 tubes.”
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“For instance, a Phase II trial of exenatide (NCT01971242) showed improved UPDRS scores [140,141].”
Hölscher, C. (2026) · Journal of Alzheimer s Disease · doi:10.1177/13872877261458402 · Cited by 5
“Drugs that can enter the brain readily showed good effects in phase 2 clinical trials, 20,21 while a GLP-1 receptor agonist that does not enter the brain well did not show effects in a phase 2 trial.”
PAUL, S., & SARKAR, A. (2024) · Asian Journal of Pharmaceutical and Clinical Research · doi:10.22159/ajpcr.2024v17i8.51398 · Cited by 4
“…administering exenatide (2 mg) by self-injection (s.c. route) once weekly, showed that patients underwent such treatment were improved compared to the placebo arm with regard to their performance in part 3 of Movement Disorders Society-Unified Parkinson’s Disease Rating Scale motor subscale [17].”
MethodWhite, A. C., Krout, I. N., Mouhi, S., Blackmer‐Raynolds, L., Chang, J., Kelly, S. D., Caudle, W. M., & Sampson, T. R. (2025) · Toxicological Sciences · doi:10.1093/toxsci/kfaf076 · Cited by 4
“Clinical studies have recently demonstrated benefit of systemic GLP-1 agonists for PD symptoms (Athauda et al. 2017; Meissner et al. 2024).”
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Challenges and unfulfilled promises in Parkinson's disease
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“In agreement with this is the fact that the neuroprotective potential of a glucagon-like peptide-1 (GLP-1) receptor agonist, which significantly increased pathological α-synuclein load in an animal model of α-synucleinopathy [43], has recently been shown to be a possible disease-modifying treatment in PD patients [44].”
Genetic modifiers of synucleinopathies—lessons from experimental models
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“A single-center Phase 2 trial of exenatide on PD showed improvement of motor scores that was sustained beyond the period of exposure [278,279].”
BackgroundFountain of youth—Targeting autophagy in aging
Danics, L., Abbas, A. A., Kis, B., & Pircs, K. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1125739 · Cited by 4
“Other promising pharmacotherapeutic agents currently under clinical testing for PD which are used since decades for other indications such as bronchitis, chronic obstructive pulmonary disease (Ambroxol) or type II diabetes and metabolic syndrome (Exenatide) (Aviles-Olmos et al., 2014; Foltynie and Aviles-Olmos, 2014;…”
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“Interestingly, the improvement persisted for 12 weeks after the end of the administration period, suggesting that exenatide may have both a neuroprotective and an acute effect on motor symptoms [50].”
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“Calcium release from the ER mediates neurotransmitter exocytosis at the pre-synapse whilst potentiating gene transcription and modulating membrane excitability and dendritic spine structure for post-synaptic plasticity [14–16].”
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“Moreover, a recent phase II clinical trial of GLP-1 receptor agonist in PD patients was therapeutically promising [41].”
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“109 110 – 113 Theories fueling possible neuroprotective rationale for targeting GLP-1 receptors in neurodegenerative diseases are many, 114 but current clinical trial data offer limited to no clarity on this question.”
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The Effect of GLP-1RA on the Motor Function of Patients With Parkinson Disease
Costa, G. V. L., Cavalcante, L. F. F., Battistuta, S. M., Makabe, P. F., Bueno, I. S. F., Yuamoto, B., Vilela, F., Meloni, L. G. G., de Faria, D. D., Anghinah, R., et al. (2025) · Neurology Clinical Practice · doi:10.1212/cpj.0000000000200548 · Cited by 3
M14 substitutions in exanatide modulate alpha‐synuclein aggregation
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“A randomized, placebo-controlled trial of exenatide in PD reported significant improvement in the exenatide group on the primary outcome of change and suggested a disease-modifying effect of exenatide in PD [24].”
Engström, A., Svanström, H., Hviid, A. P., Eliasson, B., Guðbjörnsdóttir, S., Wintzell, V., Hveem, K., Jonasson, C., Melbye, M., Ueda, P., et al. (2026) · Diabetes Obesity and Metabolism · doi:10.1111/dom.70760 · Cited by 6
“A randomized controlled trial evaluating exenatide versus placebo in patients with moderately severe Parkinson's disease demonstrated significantly decreased motor symptoms [10].”
InfluentialRecent Developments in the Drug Treatment of Parkinson’s Disease
Leiter, S., Mahlknecht, P., & Poewe, W. H. (2026) · Drugs · doi:10.1007/s40265-026-02327-9 · Cited by 3
“…following phase 2 placebo-controlled trial of exenatide included 60 patients with moderately advanced PD and found significantly less worsening of motor symptoms as assessed by MDS-UPDRS part III scores in the practically defined OFF-condition (− 3.5 points difference vs placebo) at week 48 [185].”
InfluentialYang, M., & Liang, Z. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1839620 · Cited by 3
“From a clinical perspective, GLP-1R expression in the hippocampus and cerebral cortex provides an anatomical framework for the reported effects of GLP-1RAs on cognitive function in preclinical models and early-stage clinical studies of Alzheimer ’ s disease and other dementias (18, 19).”
Xiang, M., Cao, S.-Y., Sun, X.-H., Hu, J.-W., Lv, M., Li, J., & Li, W. (2026) · Translational Neurodegeneration · doi:10.1186/s40035-026-00573-1 · Cited by 3
“Exenatide has shown modest improvements in motor function in PD patients, with larger confirmatory trials ongoing [184].”
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The long road to neuroprotection for Parkinson's disease
Trenkwalder, C., & Mollenhauer, B. (2023) · The Lancet Neurology · doi:10.1016/s1474-4422(23)00462-3 · Cited by 3
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“27 Although this may seem contradictory initially, it makes sense if we consider that patient-rated motor symptoms could be suitable for predicting long-term PD progression, whereas clinician-rated motor symptoms are more appropriate for quantifying the current state or short-term changes in the…”
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“Also, in contrast to the open-label trial, in the double-blind trial, exenatide has no effect on cognition measured on the Mattis scale [13].”
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“Some of them such as ambroxol (traditionally used as a mucolytic agent) and exenatide (antidiabetic drug) have shown promising results warranting further studies (Athauda et al. 2017).”
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“Furthermore, therapeutic effects of exendin-4 have also been evaluated in randomized controlled trials with PD patients [121,122].”
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Modern Pharmacological Treatment of Parkinson's Disease : Reviving Known Drugs and New Perspectives
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“Also, a recent clinical trial showed that exenatide, which crosses the blood–brain barrier [9], significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients, as determined by body mass index (BMI) > 30 kg/m2 [4].”
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“Although exenatide has shown much promise in Parkinsons (Athauda et al. 2017), we found no effect linking peripheral GLP1R and Parkinson’s risk, age at onset or progression.”
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“Other drugs that are being repurposed for use in PD treatment and/or modification include exenatide [106] and terazosin [107].”
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“[2] In this context, new randomized controlled trials (RCTs) are being designed to assess the efficacy and safety of poten - tial disease-modifying treatments in PD, highlighting GLP-1 receptor agonists (GLP-1RA), as exenatide [ 3–5].”
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“2 In addition, both APM trials will allow for a precision medicine approach by conducting detailed genotyping in all participants.”
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Cytoprotective effects of Gymnemic Acid 1 in cellular models of neurodegeneration
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The challenges of experimental pharmacology in identifying novel treatments for Parkinson's disease
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“More recently, the LixiPark phase 2 trial reported that lixisenatide significantly slowed the progression of motor disability compared with placebo in patients with early PD over 12 months (Athauda et al., 2017).”
Postprandial Hypotension—Methods for the Evaluation and Management
Ishikawa, J., Toba, A., Futami, S., & Harada, K. (2026) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/ggi.70456 · Cited by 2
“Recent studies have shown that exenatide improves off-medication motor scores in PD [57] and that lix-isenatide reduces motor disability progression at 12 months in early PD [58].”
The Gut-Brain Axis: A Critical Link between Type 2 Diabetes and Parkinson’s disease
Almohmadi, N. H., Al‐kuraishy, H. M., Hussein, K. S., Turkistani, A., Yousef, F. M., Al-Gareeb, A. I., Abdelaziz, A. M., Elewa, Y. H. A., & Batiha, G. E. (2026) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-026-11014-w · Cited by 2
“This bidirectional communication establishes a feed-forward loop, where peripheral metabolic inflammation [150– 153] discussed in this review, including human interventional and longitudinal studies [56, 57, 77, 95, 137, 142].”
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GLP-1 and Parkinson’s Disease: A Comprehensive Review of Biology, Mechanisms and Efficacy
Mezabrovschi, R., Gegg, M. E., & Schapira, A. H. V. (2026) · Cells · doi:10.3390/cells15090804 · Cited by 2
“Subsequently, a randomised, placebo-controlled trial in 62 patients with moderate PD demonstrated that exenatide treatment attenuated deterioration in the MDS-UPDRS part III off-medication motor score relative to placebos [167].”
Dahshan, A., Khalil, M. I. M., El-Jaafary, S. I., & Yamani, A. (2026) · Clinical Parkinsonism & Related Disorders · doi:10.1016/j.prdoa.2026.100461 · Cited by 2
“In 2017, Athauda and colleagues demonstrated a significant positive effect of exenatide once-weekly on motor scores in the off-medication state at 48 weeks, with a possible disease-modifying signal that persisted one-year post-treatment [17].”
Li, Y., Glotfelty, E. J., Parekh, P., Batsaikhan, B., Luo, W., Jackson, S. N., Harvey, B. K., & Greig, N. H. (2026) · Cells · doi:10.3390/cells15141301 · Cited by 2
“Data on brain uptake in humans is largely lacking, but the GLP-1R peptide agonist exenatide has a reported CSF/plasma concentration ratio of 1–2% [70,71], and has demonstrated both positive actions and a lack of action in human neurodegenerative disorders [70,72–77].”
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Striatal DAT availability does not change after supraphysiological glucose loading dose in humans
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The biological basis of Parkinson's disease: A comprehensive review
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First phase 3 trial of GLP-1 receptor agonist for neurodegeneration
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Molecular Function of Midnolin and Its Relevance to Parkinson’s Disease
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Treatment of Parkinson’s Disease: Early, Late, and Combined
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Metadata
- Authors
- Athauda, D., Maclagan, K., Skene, S. S., Bajwa-Joseph, M., Letchford, D., Chowdhury, K., Hibbert, S., Budnik, N., Zampedri, L., Dickson, J., Li, Y., Aviles-Olmos, I., Warner, T. T., Limousin, P., Lees, A. J., Greig, N. H., Tebbs, S., & Foltynie, T.
- Affiliations
- National Hospital for Neurology and Neurosurgery (GB)
- University College London (GB)
- National Institute on Aging (US)
- Corresponding author
- Foltynie, Thomas
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 390
- Issue
- 10103
- Pages
- 1664-1675
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC5831666
- OpenAlex
- W2744843428
- Cited by
- 889
- References
- 38
- Citations by year
- 2026: 114 · 2025: 136 · 2024: 114 · 2023: 73 · 2022: 85 · 2021: 93 · 2020: 98 · 2019: 77 · 2018: 77 · 2017: 20
- FWCI
- 51.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Open Research (University of Surrey) (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
- Funders
- National Institutes of Health (Z99 AG999999)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, exenatide, GLP-1 receptor agonists, neuroprotection, motor symptoms, off-medication state, dopaminergic therapy, neurodegeneration, adverse events, injection site reactions, gastrointestinal symptoms, drug repurposing, disease-modifying therapy
- MeSH terms
- Exenatide, Adult, Aged, Double-Blind Method, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Neurologic Examination, Parkinson Disease, Peptides, Venoms, Treatment Outcome
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