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.
“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]
The Results (page unavailable) report that off-medication motor scores worsened with placebo but improved with once-weekly exenatide at 60 weeks. The Discussion (page unavailable) cautions that a lasting symptomatic effect cannot be distinguished from an effect on disease progression. This trial does not establish the claim about three trials or clinical motor outcomes with lixisenatide, and it tested a once-weekly exenatide formulation rather than a short-acting regimen. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTreatment with exenatide or lixisenatide for 1 year produced a modest but positive effect on MDS-UPDRS part III scores in people with recently diagnosed Parkinson's disease.
“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]
The Results and Discussion (pages not provided) report a modest improvement in off-medication MDS-UPDRS part III scores after 48 weeks of exenatide. This trial did not test lixisenatide, and it preferentially recruited patients with moderate disease rather than recently diagnosed or early-stage Parkinson’s disease. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe discrepancy between no significant Parkinson protection and prior animal model data may reflect differences in neuroprotective mechanisms of semaglutide and tirzepatide vs earlier GLP-1RAs.
“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]
The Results report a significant off-medication motor benefit for exenatide versus placebo at 60 weeks. But the Discussion says the trial recruited patients with moderate Parkinson’s disease preferentially over those with early-stage disease, so this source does not support the sentence’s early-stage qualifier. The proposed difference in mechanisms involving semaglutide and tirzepatide is the citing authors’ speculation, not a finding attributed to this trial. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn Parkinson's disease, phase II trials have shown that exenatide and lixisenatide improve motor activity compared to placebo.
“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]
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.
“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]
Multiple GLP-1 medicines, including exenatide, liraglutide, semaglutide, and tirzepatide, reduce plasma CRP levels in people living with T2D and/or obesity.
“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]
The Methods describe a trial in people with Parkinson’s disease that excluded diabetes. The Results and Discussion address exenatide’s clinical effects and adverse events, but the passages found when searching for CRP and C-reactive protein do not report plasma CRP changes in people with type 2 diabetes or obesity. (LLM, conf=0.76)
Experimental — accuracy not yet measuredGLP-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.
“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]
The Introduction discusses GLP-1 receptor activation and neuroprotective effects in Parkinson’s disease, not interactions with serotonin, dopamine, and glutamate in mood regulation. A search for those neurotransmitters and for depression found a depression-rating outcome in the Results, but no passage connecting GLP-1 receptors to the claimed mechanism or to the onset of psychological disorders. Page numbers were unavailable in our copy. (LLM, conf=0.73)
Experimental — accuracy not yet measuredOne study using a prebiotic supplement that enhanced SCFA levels showed an increase GLP-1 levels in mouse models.
“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]
The Introduction and Discussion (page numbers unavailable) address exenatide and GLP-1 receptor agonists in Parkinson’s disease, including rodent research. Searches for prebiotic supplementation and short-chain fatty acids found no passage reporting increased GLP-1 levels in mice. (LLM, conf=0.76)
Experimental — accuracy not yet measuredExenatide, administered at the dose approved for type 2 diabetes treatment, crosses the blood-brain barrier in appreciable quantities and improves the motor and cognitive function of PD patients.
“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]
Beta-cell rest can at least temporarily allow insulin secretory capacity recovery.
“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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BackgroundResultThe Therapeutic Potential of Metformin in Neurodegenerative Diseases
Rotermund, C., Machetanz, G., & Fitzgerald, J. C. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00400 · Cited by 310 · see citing works
“Very recently a randomized, double-blind, placebo-controlled trial for PD showed that a GLP-1 agonist had positive effects on motor symptoms in PD (237), generating a new potential mechanism for metformin action in neurodegeneration.”
BackgroundEmerging therapies in Parkinson disease — repurposed drugs and new approaches
Elkouzi, A., Vedam‐Mai, V., Eisinger, R. S., & Okun, M. S. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0155-7 · Cited by 304 · see citing works
α-Synuclein pathology in Parkinson’s disease and related α-synucleinopathies
Henderson, M. X., Trojanowski, J. Q., & Lee, V. M. ‐. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134316 · Cited by 291 · see citing works
Kopp, K. O., Glotfelty, E. J., Li, Y., & Greig, N. H. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106550 · Cited by 298 · see citing works
Self-citationTherapeutic strategies for Parkinson disease: beyond dopaminergic drugs
Charvin, D., Medori, R., Hauser, R. A., & Rascol, O. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.136 · Cited by 285 · see citing works
The Impact of Disease Comorbidities in Alzheimer’s Disease
Santiago, J. A., & Potashkin, J. A. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.631770 · Cited by 259 · see citing works
“Exendin-4 (exenatide), a GLP-1 receptor agonist, has been shown to improve motor symptoms in PD clinical trials (Aviles-Olmos et al., 2013; Athauda et al., 2017).”
BackgroundKlausen, M. K., Jensen, M. E., Møller, M., Le Dous, N., Jensen, A.-M. Ø., Zeeman, V. A., Johannsen, C.-F., Lee, A., Thomsen, G. K., Macoveanu, J., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.159863 · Cited by 262 · see citing works
“Importantly, exenatide crosses the bloodbrain barrier (20), and a similar dosing regimen, i.”
The role of glucagon‐like peptide 1 (GLP‐1) in addictive disorders
Klausen, M. K., Thomsen, M., Wortwein, G., & Fink‐Jensen, A. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15677 · Cited by 259 · see citing works
“with Parkinson's disease, where an effect on off-medication motor scores was reported, but no significant effect on DAT availability after 48 weeks of treatment (Athauda et al., 2017).”
BackgroundAthauda, D. S., Gulyani, S., Karnati, H. K., Li, Y., Tweedie, D., Mustapić, M., Chawla, S., Chowdhury, K., Skene, S. S., Greig, N. H., et al. (2019) · JAMA Neurology · doi:10.1001/jamaneurol.2018.4304 · Cited by 259 · see citing works
“Patients and Study Design TheExenatide-PD trial (a randomized, double-blind, placebocontrolled, single center, 60-week trial of exenatide once weekly for the treatment of moderate-severity PD(43)) (NCT01971242)wasperformed fromJune 18, 2014, to June 16, 2016, to assess the effects of exenatide ondiseaseprogression for…”
BackgroundResultSelf-citationHuman trials exploring anti-aging medicines
Guarente, L., Sinclair, D. A., & Kroemer, G. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.12.007 · Cited by 257 · see citing works
Medical, surgical, and physical treatments for Parkinson's disease.
Foltynie, T., Bruno, V., Fox, S. H., Kühn, A., Lindop, F., & Lees, A. (2024) · The Lancet · doi:10.1016/s0140-6736(23)01429-0 · Cited by 197 · see citing works
Self-citationReich, N., & Hölscher, C. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.970925 · Cited by 248 · see citing works
Hou, Y.-F., Shan, C., Zhuang, S.-Y., Zhuang, Q.-Q., Ghosh, A., Zhu, K.-C., Kong, X.-K., Wang, S.-M., Gong, Y.-L., Yang, Y.-Y., et al. (2021) · Microbiome · doi:10.1186/s40168-020-00988-6 · Cited by 231 · see citing works
Batista, A. F., Forny‐Germano, L., Clarke, J. R., Silva, N. M. L. E., Brito‐Moreira, J., Boehnke, S. E., Winterborn, A., Coe, B. C., Lablans, A., Vital, J. F. S., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5056 · Cited by 246 · see citing works
GLP-1-based therapies for diabetes, obesity and beyond
Drucker, D. J. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01183-8 · Cited by 270 · see citing works
“Positive results, principally the halting of disease progression, were reported in trials of exenatide twice daily 136 , exenatide once weekly 137 and lixisenatide once daily 138 .”
Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1
Hammoud, R., & Drucker, D. J. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00783-3 · Cited by 244 · see citing works
“…small, randomized trials examined the effects of twice daily or once weekly exenatide versus conventional therapy for 12 months in people with moderate Parkinson disease without T2DM and demonstrated improved motor activity scores that persisted following discontinuation of exenatide 160,161 .”
The expanding incretin universe: from basic biology to clinical translation
Drucker, D. J., & Holst, J. J. (2023) · Diabetologia · doi:10.1007/s00125-023-05906-7 · Cited by 243 · see citing works
Diabetes mellitus and Parkinson disease
Pagano, G., Polychronis, S., Wilson, H., Giordano, B., Ferrara, N., Niccolini, F., & Politis, M. (2018) · Neurology · doi:10.1212/wnl.0000000000005475 · Cited by 243 · see citing works
“Most of our patients were only treated with dietary changes or metformin monotherapy, and we were unable to perform a comparison with the new antidiabetic drugs, such as the GLP-1 analog exenatide, which exerted beneficial effects on patients with PD in a 12-month, randomized, double-blind, placebo-controlled trial.(3…”
BackgroundResultAssociation between diabetes and subsequent Parkinson disease: A record-linkage cohort study
De Pablo-Fernandez, E., Goldacre, R., Pakpoor, J., Noyce, A. J., & Warner, T. T. (2018) · Neurology · doi:10.1212/wnl.0000000000005771 · Cited by 242 · see citing works
“A recent doubleblind trial involving 62 patients with PD randomly assigned to placebo or exenatide 2-mg weekly injections showed positive and persistent effects on motor symptoms measured by section 3 of the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale.(9)Whether the effect is secondary to sympto…”
BackgroundSelf-citationType 2 Diabetes as a Determinant of Parkinson's Disease Risk and Progression
Chohan, H., Senkevich, K., Patel, R. K., Bestwick, J. P., Jacobs, B. M., Bandres Ciga, S., Gan‐Or, Z., & Noyce, A. J. (2021) · Movement Disorders · doi:10.1002/mds.28551 · Cited by 228 · see citing works
“A double-blind, placebocontrolled trial showed that the GLP-1 analogue, Exenatide, may have an effect on reducing PD severity after a prolonged washout period, increasing the possibility of a disease-modifying effect.(64) A recent cohort study from the same group reported evidence that patients with T2DM taking certai…”
BackgroundDiabetes medications and risk of Parkinson’s disease: a cohort study of patients with diabetes
Brauer, R., Wei, L., Ma, T., Athauda, D., Girges, C., Vijiaratnam, N., Auld, G., Whittlesea, C., Wong, I., & Foltynie, T. (2020) · Brain · doi:10.1093/brain/awaa262 · Cited by 233 · see citing works
“The positive markers from this population study seem to be further supported by the findings of potential disease modifying effects of two single centre phase 2 interventional studies (Aviles-Olmos et al., 2014; Athauda et al., 2017).”
BackgroundResultSelf-citationThe Association Between Type 2 Diabetes Mellitus and Parkinson’s Disease
Cheong, J. L. Y., Pablo‐Fernández, E. D., Foltynie, T., & Noyce, A. J. (2020) · Journal of Parkinson s Disease · doi:10.3233/jpd-191900 · Cited by 230 · see citing works
“5 points less on the MDS-UPDRS than those not treated with exenatide, following a washout period to exclude a symptomatic effect [105].”
BackgroundSelf-citationGlucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases
Grieco, M., Giorgi, A., Gentile, M. C., d’Erme, M., Morano, S., Maras, B., & Filardi, T. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01112 · Cited by 218 · see citing works
Parkinson disease therapy: current strategies and future research priorities
Stocchi, F., Bravi, D., Emmi, A., & Antonini, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-01034-x · Cited by 211 · see citing works
“For example, glucagon-like peptide 1 receptor agonists that are used to treat diabetes have shown promise in patients with PD, highlighting a potential role for brain insulin signalling and insulin receptors in this condition 133,134 .”
Initiation of pharmacological therapy in Parkinson's disease: when, why, and how
de Bie, R. M. A., Clarke, C. E., Espay, A. J., Fox, S. H., & Lang, A. E. (2020) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30036-3 · Cited by 200 · see citing works
Glucose metabolic crosstalk and regulation in brain function and diseases
Zhang, S., Lachance, B. B., Mattson, M. P., & Jia, X. (2021) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2021.102089 · Cited by 205 · see citing works
Hölscher, C. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.01.040 · Cited by 201 · see citing works
“Importantly, GLP-1 mimetics can cross the BBB (Athauda et al., 2017; Christensen et al., 2015; Hunter and Holscher, 2012; Kastin and Akerstrom, 2003; Kastin et al., 2002; McClean et al., 2011b).”
BackgroundInfluentialKia, D. A., Zhang, D., Guelfi, S., Manzoni, C., Hubbard, L., Reynolds, R. H., Botía, J. A., Ryten, M., Ferrari, R., Lewis, P. A., et al. (2021) · JAMA Neurology · doi:10.1001/jamaneurol.2020.5257 · Cited by 199 · see citing works
“This finding issupportedbyrecentwork indicating an association between bodymass index and PD, and a randomized clinical trial of exenatide, a glucagon-like peptide 1 receptor agonist, as adisease-modifyingagent forPD.(30,31) Furthermore, a role forCD38 in regulatingneuroinflammation, especially in glial cells, has bee…”
ResultSelf-citationSalameh, T. S., Rhea, E. M., Talbot, K., & Banks, W. A. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114187 · Cited by 188 · see citing works
“The single IRAs thus far demonstrating the greatest promise as AD and/or PD therapeutics are the FDA approved GLP-1 receptor agonists (GLP-1RAs) exendin-4 (Byetta®) [42, 43, 56-58, 65-67, 84], liraglutide (Victoza®) [36-41, 43, 48-50, 53, 85], lixisenatide (Adlyxin® in the U.”
BackgroundThe Antidepressant Effects of GLP-1 Receptor Agonists: A Systematic Review and Meta-Analysis
Chen, X., Zhao, P., Wang, W., Guo, L., & Pan, Q. (2024) · The American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2023.08.010 · Cited by 185 · see citing works
Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease
Nowell, J., Blunt, E., Gupta, D., & Edison, P. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101979 · Cited by 179 · see citing works
“In two meta-analyses (Mulvaney et al., 2020; Wang et al., 2020b) of GLP-1 receptor agonists, only the two previously discussed trials met the inclusion criteria (Athauda et al., 2017; Aviles-Olmos et al., 2013).”
Sorrentino, Z. A., Giasson, B. I., & Chakrabarty, P. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-01977-2 · Cited by 177 · see citing works
“1 3 double-blind trial of the GLP1R agonist exenatide appeared to improve motor and cognitive function in PD patients [10, 11].”
Brain insulin resistance: role in neurodegenerative disease and potential for targeting
Hölscher, C. (2020) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2020.1738383 · Cited by 180 · see citing works
“Growth factors such as insulin, GLP-1 and GIP can cross the BBB and offer a promising treatment strategy [87, 91, 92, 197].”
BackgroundCopas, A. N. M., McComish, S. F., Fletcher, J. M., & Caldwell, M. A. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.666737 · Cited by 175 · see citing works
Timper, K., del Río-Martín, A., Cremer, A. L., Bremser, S., Alber, J., Giavalisco, P., Varela, L., Heilinger, C., Nolte, H., Trifunovic, A., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.05.001 · Cited by 170 · see citing works
The multifaceted pyruvate metabolism: role of the mitochondrial pyruvate carrier
Zangari, J., Petrelli, F., Maillot, B., & Martinou, J.-C. (2020) · Biomolecules · doi:10.3390/biom10071068 · Cited by 172 · see citing works
Vijiaratnam, N., Girges, C., Auld, G., McComish, R., King, A., Skene, S. S., Hibbert, S., Wong, A., Melander, S., Gibson, R., et al. (2025) · The Lancet · doi:10.1016/s0140-6736(24)02808-3 · Cited by 181 · see citing works
Self-citationRecent developments in the treatment of Parkinson's Disease
Stoker, T. B., & Barker, R. A. (2020) · F1000Research · doi:10.12688/f1000research.25634.1 · Cited by 168 · see citing works
A Pilot Study of Exenatide Actions in Alzheimer’s Disease
Mullins, R. J., Mustapić, M., Chia, C. W., Carlson, O. D., Gulyani, S., Tran, J., Li, Y., Mattson, M. P., Resnick, S. M., Egan, J. M., et al. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190913155950 · Cited by 160 · see citing works
Self-citationTrapp, S., & Brierley, D. I. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15638 · Cited by 154 · see citing works
“…GLP-1 receptor agonists seem to have beneficial effects on other organs including the brain, with potential neuroprotective effects, even in Alzheimer's and in Parkinson's disease (Athauda et al., 2017; During et al., 2003; Foltynie & Athauda, 2020; Gault & Holscher, 2008; McClean et al., 2011).”
BackgroundZhang, L., Zhang, L., Li, L., & Hölscher, C. (2019) · Journal of Parkinson's Disease · doi:10.3233/jpd-181503 · Cited by 173 · see citing works
“Importantly, a phase II clinical trial showed protective effects in PD patients even 3 months after treatment had been discontinued [24].”
Zhang, L., Zhang, L., Li, L., & Hölscher, C. (2018) · Neuropeptides · doi:10.1016/j.npep.2018.07.003 · Cited by 151 · see citing works
McGarry, A., Rosanbalm, S., Leinonen, M., Olanow, C. W., To, D., Bell, A., Lee, D., Chang, J., Dubow, J., Dhall, R., et al. (2024) · The Lancet Neurology · doi:10.1016/s1474-4422(23)00378-2 · Cited by 153 · see citing works
Diet in Parkinson’s Disease: Critical Role for the Microbiome
Jackson, A., Forsyth, C. B., Shaikh, M., Voigt, R. M., Engen, P. A., Ramirez, V., & Keshavarzian, A. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01245 · Cited by 145 · see citing works
Protective properties of GLP‐1 and associated peptide hormones in neurodegenerative disorders
Hölscher, C. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15508 · Cited by 147 · see citing works
“Unfortunately, there are few studies that measure levels of such drugs in the CSF in humans to estimate the BBB penetrations.”
BackgroundMethodInfluentialManagement of hypoglycemia in older adults with type 2 diabetes
Freeman, J. S. (2019) · Postgraduate Medicine · doi:10.1080/00325481.2019.1578590 · Cited by 148 · see citing works
“Improvements in motor and cognitive assessments have been demonstrated in a clinical trial of exenatide in patients with Parkinson’s disease [70], and other trials assessing exenatide and liraglutide in both disease states are currently ongoing.”
BackgroundMoiz, A., Filion, K. B., Tsoukas, M. A., Yu, O. H. Y., Peters, T. M., & Eisenberg, M. J. (2025) · EClinicalMedicine · doi:10.1016/j.eclinm.2025.103363 · Cited by 157 · see citing works
“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.”
Parkinson’s Disease Drug Therapies in the Clinical Trial Pipeline: 2020
McFarthing, K., Buff, S., Rafaloff, G., Dominey, T., Wyse, R. K. H., & Stott, S. (2020) · Journal of Parkinson s Disease · doi:10.3233/jpd-202128 · Cited by 138 · see citing works
Kim, D. S., Choi, H.-I., Wang, Y., Luo, Y., Hoffer, B. J., & Greig, N. H. (2017) · Cell Transplantation · doi:10.1177/0963689717721234 · Cited by 136 · see citing works
“”(99) This suggests disease-modifying effects of exenatide, and the results are encouraging enough that a subsequent doubleblind clinical study (NCT01971242) was initiated by the same investigators using a sustained release formulation of exenatide (Bydureon: 2 mg administered subcutaneously once weekly) to evaluate i…”
BackgroundMethodResultInfluentialSelf-citationHong, C.-T., Chen, K.-Y., Wang, W., Chiu, J.-Y., Wu, D., Chao, T.-Y., Hu, C.-J., Chau, K.-Y., & Bamodu, O. (2020) · Cells · doi:10.3390/cells9030740 · Cited by 133 · see citing works
“Furthermore, several anti-glycemic agents, including exenatide, a glucagon-like peptide analogue, have exerted a disease-modifying effect on PD; exenatide is presently in phase III clinical trial as a neuroprotective drug for patients with PD [18,19].”
BackgroundWong, C. K., Yusta, B., Koehler, J. A., Baggio, L. L., McLean, B. A., Matthews, D., Seeley, R. J., & Drucker, D. J. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.08.003 · Cited by 138 · see citing works
Incretin and insulin signaling as novel therapeutic targets for Alzheimer’s and Parkinson’s disease
Nowell, J., Blunt, E., & Edison, P. (2023) · Molecular Psychiatry · doi:10.1038/s41380-022-01792-4 · Cited by 136 · see citing works
“Exenatide was also safe and well-tolerated, with no patients in the exenatide-treated group withdrawn due to excessive weight loss and weight loss reversed following drug cessation, within the latest trial [87].”
BackgroundInfluentialTargeting Mitochondrial Impairment in Parkinson's Disease: Challenges and Opportunities
Prasuhn, J., Davis, R. L., & Kumar, K. R. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.615461 · Cited by 134 · see citing works
“Moreover, the drug exenatide has been shown to improve motor scores in PD and may have beneficial effects on mitochondrial biogenesis (Fan et al., 2010; Athauda et al., 2017).”
BackgroundTai, J., Liu, W., Li, Y., Li, L., & Hölscher, C. (2017) · Brain Research · doi:10.1016/j.brainres.2017.10.012 · Cited by 133 · see citing works
“In contrast, the placebo group deteriorated over time as would be expected in this disease (Athauda et al., 2017).”
Self-citationConnecting Alzheimer's disease to diabetes: Underlying mechanisms and potential therapeutic targets
Vieira, M. N. N., Lima‐Filho, R. A. S., & Felice, F. G. D. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.11.014 · Cited by 131 · see citing works
“Clinical trials aimed at testing the efficacy of insulin and GLP-1 analogues in Alzheimer's and Parkinson's disease and in mood disorders have shown some beneficial effects (Athauda et al., 2017; Claxton et al., 2015; Craft et al., 2012; Gejl et al., 2016; Mansur et al., 2017; Reger et al., 2008).”
The heterogeneity of Parkinson’s disease
Wüllner, U., Borghammer, P., Choe, C., Csóti, I., Falkenburger, B. H., Gasser, T., Lingor, P., & Riederer, P. F. (2023) · Journal of Neural Transmission · doi:10.1007/s00702-023-02635-4 · Cited by 132 · see citing works
“Among approved GLP-1 agonists, exenatide has emerged as a promising disease-modifying drug in PD (Athauda et al. 2017).”
Emerging Treatment Approaches for Parkinson’s Disease
Stoker, T. B., Torsney, K., & Barker, R. A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00693 · Cited by 128 · see citing works
GLP-1’s role in neuroprotection: a systematic review
Erbil, D., Eren, C. Y., Demirel, Ç., Küçüker, M. U., Solaroğlu, İ., & Eser, H. Y. (2019) · Brain Injury · doi:10.1080/02699052.2019.1587000 · Cited by 128 · see citing works
Zhao, L., Li, Z., Vong, J. S. L., Chen, X., Lai, H. M., Yan, L. Y. C., Huang, J., Sy, S. K. H., Tian, X. Y., Huang, Y., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18249-3 · Cited by 119 · see citing works
Parkinson’s disease determinants, prediction and gene–environment interactions in the UK Biobank
Jacobs, B. M., Belete, D., Bestwick, J. P., Blauwendraat, C., Bandrés‐Ciga, S., Heilbron, K., Dobson, R., Nalls, M. A., Singleton, A., Hardy, J., et al. (2020) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2020-323646 · Cited by 122 · see citing works
Self-citationInsulin Signaling Impairment in the Brain as a Risk Factor in Alzheimer’s Disease
Hölscher, C. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00088 · Cited by 105 · see citing works
“In a doubleblind, placebo-controlled phase II clinical trial in PD patients, the GLP-1 receptor agonist exendin-4 showed good protective effects compared to placebo, even after 3 months of wash-out of the drug (Athauda et al., 2017).”
BackgroundUnderstanding the Links Between Cardiovascular Disease and Parkinson's Disease
Potashkin, J., Huang, X., Becker, C., Chen, H., Foltynie, T., & Marras, C. (2019) · Movement Disorders · doi:10.1002/mds.27836 · Cited by 117 · see citing works
“In a 1-year phase II trial of 60 patients randomized to self-inject exenatide or placebo, PD patients using exenatide had smaller increase in theMovement Disorders Society Unified PD Rating Scale part 3 motor scores when assessed in the off medication state.(156) Despite the washout design of this trial (the primary o…”
MethodSelf-citationFeng, P., Zhang, X., Li, D., Ji, C., Yuan, Z., Wang, R., Xue, G., Li, G., & Hölscher, C. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.02.012 · Cited by 117 · see citing works
“CSF analysis confirmed that exendin-4 had crossed the BBB, and that there was no drug present after wash-out (Athauda et al., 2017).”
Emerging neuroprotective effect of metformin in Parkinson’s disease: A molecular crosstalk
Paudel, Y. N., Angelopoulou, E., Piperi, C., Shaikh, M. F., & Othman, I. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104593 · Cited by 113 · see citing works
Pharmacological Treatment of Parkinson’s Disease
Zahoor, I., Shafi, A., & Haq, E. (2018) · Codon Publications eBooks · doi:10.15586/codonpublications.parkinsonsdisease.2018.ch7 · Cited by 120 · see citing works
“Thereafter, it was taken forward to a single-center, randomized, double-blind, placebo-controlled Phase 2 clinical trial in which a weekly dosage of 2 mg was administered to patients subcutaneously (85).”
MethodRhee, S. Y., Han, K.-D., Kwon, H., Park, S.-E., Park, Y.-G., Kim, Y.-H., Yoo, S.-J., Rhee, E.-J., & Lee, W.-Y. (2020) · Diabetes Care · doi:10.2337/dc19-0760 · Cited by 109 · see citing works
“Recently, a double-blind, randomized, controlled study on the effects of glucagon-like peptide 1 agonists in PD subjects showed a positive effect in the intervention group (34).”
BackgroundThe Relevance of Insulin Action in the Dopaminergic System
Fiory, F., Perruolo, G., Cimmino, I., Cabaro, S., Pignalosa, F. C., Miele, C., Bèguinot, F., Formisano, P., & Oriente, F. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00868 · Cited by 114 · see citing works
The Non‐Motor Symptoms Scale in Parkinson’s disease: Validation and use
van Wamelen, D. J., Martínez‐Martín, P., Weintraub, D. A., Schrag, A. E., Antonini, A., Falup‐Pecurariu, C., Odin, P., Chaudhuri, К. R., & International Parkinson and Movement Disorder Society Parkinson's Disease Non‐Motor Study Group (2020) · Acta Neurologica Scandinavica · doi:10.1111/ane.13336 · Cited by 114 · see citing works
Song, S., Guo, R., Mehmood, A., Zhang, L., Yin, B., Yuan, C., Zhang, H., Guo, L., & Li, B. (2022) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13791 · Cited by 111 · see citing works
Protective role of IGF-1 and GLP-1 signaling activation in neurological dysfunctions
Bhalla, S., Mehan, S., Khan, A., & Rehman, M. U. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104896 · Cited by 108 · see citing works
Novel targeted therapies for Parkinson’s disease
Ntetsika, T., Papathoma, P.-E., & Markaki, I. (2021) · Molecular Medicine · doi:10.1186/s10020-021-00279-2 · Cited by 112 · see citing works
“In a phase 2 study of the GLP-1 RA exenatide for 12 months in 60 PD patients, the treatment showed efficacy in motor symptoms, and a good safety profile (Athauda et al. 2017).”
BackgroundRecent Advances in Drug Therapy for Parkinson's Disease
Murakami, H., Shiraishi, T., Umehara, T., Omoto, S., & Iguchi, Y. (2022) · Internal Medicine · doi:10.2169/internalmedicine.8940-21 · Cited by 114 · see citing works
“A phase 2 study of exenatide, a GLP-1 receptor agonist, showed efficacy for motor symptoms and a reduced rate of decline in nigrostriatal dopaminergic neurons using DAT imaging (40).”
GLP-1 Receptor Agonists: A New Treatment in Parkinson’s Disease
Kalinderi, K., Papaliagkas, V. T., & Fidani, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25073812 · Cited by 109 · see citing works
“Due to these positive results, a randomized, double-blind, placebo-controlled phase II clinical study (NCT01971242) [69], was conducted by the same research team with subcutaneous administration of exendin-4, one injection/week for 48 weeks in 60 PD patients with moderate disease.”
BackgroundParkinson’s progression prediction using machine learning and serum cytokines
Rastegar, D. A., Ho, N., Halliday, G. M., & Dzamko, N. L. (2019) · npj Parkinson s Disease · doi:10.1038/s41531-019-0086-4 · Cited by 107 · see citing works
- 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 › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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