Could an approved diabetes medication treat Parkinson’s disease? Perhaps, according to results published online May 20 in the Journal of Clinical Investigation. Scientists led by Thomas Foltynie, University College London, U.K., report that in a Phase 2 clinical trial, the drug exenatide improved motor and cognitive function in patients with moderate PD. The benefit persisted for two months after treatment stopped. The catch? Because of the expense, the researchers had no placebo control. Drug maker Amylin Pharmaceuticals, now owned by Bristol-Myers Squibb, wanted to run their own experiments before investing too much in a clinical trial, Foltynie told Alzforum. While this single-blind study cannot rule out a placebo effect, it provides a cost-efficient proof-of-concept that may convince funders to support a more rigorous double-blind, placebo-controlled trial, wrote the authors.

“This is the first clinical trial of any GLP-1 analogue that looks at neuroprotective and cognitive effects in humans,” said Konrad Talbot, University of Pennsylvania, Philadelphia. Even without a placebo group, the magnitude of the effect convinces him that the findings are real.

Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist that won FDA approval for treatment of type 2 diabetes in 2005. It stimulates the pancreas to secrete insulin, which moves sugar from the blood into tissues. GLP-1 receptors are expressed in the brain, and in-vitro evidence suggests that agonists that cross the blood-brain barrier protect neurons from toxic insults (see Perry et al., 2002). Scientists became interested in GLP-1 mimics for PD when studies of mouse models found that exenatide prevented and reversed dopaminergic neuron loss in the substantia nigra, improved motor function, and promoted adult neurogenesis (see Harkavyi et al., 2008, and Bertilsson et al., 2008). The authors further pointed out that exenatide may protect neurons by reducing microglial activation (see Kim et al., 2009).

For this study, lead author Iciar Aviles-Olmos and colleagues evaluated 44 patients with moderate PD, all of whom were taking L-dopa. The trial minimized bias by using an established protocol to score videotaped tests rather than having clinicians directly interact with patients. Half the patients injected themselves twice daily with exenatide for 12 months, while the other half only took L-dopa. Clinicians were blind to patients’ treatment status. At baseline, six months, 12 months, and 14 months, the researchers evaluated participants’ motor function with the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and cognitive abilities with the Mattis Dementia Rating Scale-2 (Mattis DRS-2).

Patients tolerated the exenatide therapy, though many experienced weight loss. They appeared to experience clear benefits over controls. By 12 months, the exenatide group improved relative to baseline by an average of 2.7 points on the MDS-UPDRS, while controls declined by 2.2 points. Differences persisted two months after treatments stopped, with an average 1.6-point over baseline in the treated group versus a 2.8-point drop in controls. Cognitive scores improved, too. Over 14 months, the Mattis DRS-2 score rose in treated people by an average of 2.8 points, while control scores fell by 3.5 points.

The researchers acknowledge they cannot conclude anything without a placebo control. That improvements extended beyond treatment by at least two months suggests that exenatide’s influence was not due solely to placebo effects, said Christian Holscher, University of Ulster, Coleraine, U.K. For the same reason, the authors argue that exenatide might have a disease-modifying effect even though this trial has not formally demonstrated that. While PD treatments such as L-dopa or deep-brain stimulation might have larger effects, they lose efficacy after some years and do not stop disease progression, Foltynie said.

Holscher is co-leading a Phase 2 clinical trial of a related GLP-1 agonist, liraglutide, made by Novo Nordisk, in patients with mild Alzheimer’s disease (AD). He was encouraged by the improvement on the Mattis DRS-2. “That demonstrates that activating the GLP-1 receptor has protective effects on cognition,” he told Alzforum. Another Phase 2 clinical trial at the National Institute on Aging, Baltimore, Maryland, will evaluate exenatide’s safety and efficacy for patients with early-stage AD or mild cognitive impairment. Both trials are double-blinded with a placebo control, though neither drug company is paying for the trials. That may be because these companies focus on diabetes, not neuroscience, said Holscher. Novo Nordisk provided both drug and placebo control. Foltynie said that Amylin has been sufficiently convinced by the current data to supply placebo injections for the next project.

Despite their drawbacks, could single-blind trials become more common as precursors to larger studies? “Preliminary data are useful to prevent wasted time and effort on behalf of patients, funders, and investigators,” wrote Foltynie to Alzforum in an e-mail. Talbot guessed that such studies might become the norm as a growing number of proposed trials are vying for shrinking funds. “There is incredible competition for funding at NIH,” said Talbot, especially as some drug companies are pulling out of neuroscience. Funds allowing, researchers should aim to do the most rigorous studies possible, said Holscher. “It is always best to run a double-blind, placebo-controlled trial,” he told Alzforum.

Exenatide may be ready for a Phase 3, pivotal trial, suggests an accompanying editorial by Patrik Brunden, Van Andel Institute, Grand Rapids, Michigan, and colleagues. Foltynie is awaiting an announcement from a major PD funder about an application to perform a double-blind, placebo-controlled trial.—Gwyneth Dickey Zakaib.

Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, Whitton P, Wyse R, Isaacs T, Lees A, Limousin P, Foltynie T. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest. 2013 May 20.

Barker RA, Stacy M, Brundin P. A new approach to disease-modifying drug trials in Parkinson’s disease. J Clin Invest. 2013 May 20.


  1. I view this study of exenatide as very exciting, albeit an "open" clinical trial (without placebo). This caveat is well described by the authors and in the accompanying commentary. Open clinical trials clearly have pluses (reduced expense, thereby allowing early translational studies focused towards a hypothesis) and minuses (the lack of a blind placebo group as a valuable comparator). Despite this, the duration of the study (12 months) and the breadth of the reported measures, together with the washout period of two months, allow for a high level of enthusiasm. Indeed, high enough to support these authors' plans to initiate double-blind, placebo-controlled studies along the same lines, and to consider the study of PD subjects with milder forms of disease. This likely is the authors' aim, but gaining funding to support such studies is critical. The current study provides very high quality preliminary data.

    Numerous neuroscience research groups have now taken an interest in the GLP-1 receptor as a target for neurologic and, in particular, neurodegenerative disorders. Their studies not only support our initial publications of the neurotrophic and neuroprotective properties of GLP-1 receptor agonists published in 2002, but importantly, each other. Different groups have effectively studied slightly different but complementary animal and cellular models of neurological disorders, and these, as found in PD animal models, are suggestive of activity at therapeutically relevant doses. This work has spurred clinical interest, and GLP-1 receptor agonists are being assessed in a number of neurological disorders where effective treatments are wanting—Parkinson's disease and Alzheimer's disease. We will have to await further clinical trials to define the true role of incretin mimetics for neurological disorders. Certainly this drug class has proved of huge value in both the treatment and understanding of type 2 diabetes, and the pioneers in this area, likewise, must be delighted that their research endeavors may be impacting neurological disorders.

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Paper Citations

  1. . Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther. 2002 Sep;302(3):881-8. PubMed.
  2. . Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease. J Neuroinflammation. 2008;5:19. PubMed.
  3. . Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson's disease. J Neurosci Res. 2008 Feb 1;86(2):326-38. PubMed.
  4. . Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson's disease. J Endocrinol. 2009 Sep;202(3):431-9. PubMed.

External Citations

  1. Phase 2 clinical trial
  2. Phase 2 clinical trial
  3. Phase 2 clinical trial

Further Reading


  1. . Parkinson's disease, insulin resistance and novel agents of neuroprotection. Brain. 2012 Feb 17; PubMed.
  2. . An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers. J Clin Invest. 2012 Apr 2;122(4):1339-53. PubMed.
  3. . Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. J Neurosci Res. 2011 Apr;89(4):481-9. PubMed.
  4. . Incretin analogues that have been developed to treat type 2 diabetes hold promise as a novel treatment strategy for Alzheimer's disease. Recent Pat CNS Drug Discov. 2010 Jun;5(2):109-17. PubMed.
  5. . Parkinson's disease: an update on pathogenesis and treatment. J Neurol. 2013 May;260(5):1433-40. PubMed.