You don’t notice it at first but you find yourself tripping over and falling a lot more – you can’t ever remember being that clumsy. Everything seems to take that much longer because your muscles don’t do what you want them to, and you hurt all over from your muscles always being stiff and rigid, like they are stuck in cement. The tremor in your hands certainly doesn’t help, nor does that constant brain fog where you feel like you are scattered and your brain just won’t cooperate.
It is estimated that more than 10 million people worldwide live with Parkinson’s disease, a progressive neurodegenerative disorder due to loss of dopamine signaling, and relative cholinergic excess in the brain. Its incidence increases with age, though approximately 4% of people are diagnosed before 50 years of age. Parkinson’s disease, slowly robs people of their independence, which can have a devastating impact on patients and their family. There is no cure for Parkinson’s disease, and no medicine has been proven to slow its progression. The best patients can hope is for medicines to help control or manage their symptoms. Deep brain stimulation surgery may also be considered as an option for some patients with severe symptoms who do not respond to medicines.
Symptomatic management of Parkinson’s disease focuses on replenishing dopaminergic signaling, or reducing the cholinergic excess in the brain. Levodopa and dopamine agonists are preferred for initial treatment of Parkinson’s disease. Levodopa is the precursor to dopamine, and is converted to dopamine in the brain and the periphery. It is sometimes administered with a peripheral dopa decarboxylase inhibitor (carbidopa or benserazide), to reduce the amount of dopamine being converted in the periphery. All of the oral dopamine agonists (e.g. bromocriptine, cabergoline [ergot derivatives]; and pramipexole [non-ergot derivative]) appear broadly similar in terms of efficacy and safety.
They are often also used in combination with levodopa, to allow the levodopa dose to be reduced. Rotigotine is a transdermal dopamine agonist, used as monotherapy or with levodopa, but long-term safety and efficacy data are lacking. Other classes of medicines used include the monoamine oxidase type B inhibitors (rasagiline; selegiline; reduce dopamine breakdown and might also block dopamine reuptake), and the infrequently used anticholinergic drugs (benzatropine, biperiden, trihexyphenidyl [benzhexol]). Other medicines available include amantadine, which increases dopamine release and blocks cholinergic receptors; and entacapone, which inhibits catechol-O‐methyltransferase (COMT) mainly in peripheral tissues, so more levodopa is available to the brain.
Unfortunately, currently available drug options become less effective with long-term use and have dose-limiting side effects and/or poor efficacy. As such, there is still a need for options to better help manage symptoms. Ideally, the medication would also target the underlying cause of Parkinson’s disease. A growing body of research suggests neurodegenerative conditions like Parkinson’s disease are due to neurons becoming unresponsive to insulin, akin to the pancreas and type 2 diabetes. This negatively impacts upon the way neurons produce energy, leading to inflammation. As such, exenatide* (glucagon-like peptide-1 analogue; increases glucose-dependent insulin secretion, suppresses inappropriate glucagon secretion, and delays gastric emptying), which is used for type 2 diabetes, may be helpful in conditions such as Parkinson’s disease.
*Exenatide is a synthetic form of exendin-4, a 39-amino acid peptide isolated from the venom of the Gila monster lizard (Heloderma suspectum, Helodermatidae).
Exenatide has shown promise of neuroprotective effects in preclinical models of Parkinson’s disease, prompting more research, including a single-centre, randomised, double-blind, placebo-controlled trial in patients with moderate Parkinson’s disease. A total of 62 patients were randomly assigned to either exenatide (2 mg, subcutaneous injection once weekly) or a placebo for 48 weeks in addition to their standard medicines, followed by a 12-week washout period. After 60 weeks, the patients assigned to exenatide improved by 1.0 points, while the placebo group worsened by 2.1 points on the Movement Disorders Society Unified Parkinson’s disease Rating Scale (MDS-UPDRS), motor subscale (part 3), which was measured as the primary outcome – in the “off medication” state. This was equivalent to an adjusted mean difference of -3.5 points (95% confidence interval -6.7 to -0.3; p = 0.0318). Unfortunately, no significant differences were noted between the groups on other parts of the MDS-UPDRS during the “on medication” state, or in other secondary assessments relating to e.g. cognition, mood, non-motor symptoms, and quality of life.
More research is definitely required to better understand the role of GLP-1 receptor agonists in Parkinson’s disease, including risks vs benefits, how it may affect underlying pathology, or whether it provides any neuroprotective effects.
Nevertheless, this research provides hope that an already commercially available medicine may play a role in the management of Parkinson’s disease. This may be important for unlocking more management options for not only people living with Parkinson’s disease, but also those living with other neurodegenerative conditions.
Exenatide dosing information
|Type 2 diabetes (with metformin and/ or sulfonylurea; or metformin and basal insulin)||Byetta®, SC, initially 5 micrograms twice daily increasing to 10 micrograms twice daily if initial dose is tolerated for one month Bydureon®, SC, 2 mg once a week|
|Parkinson’s disease*||SC, 2 mg once a week|
*Exenatide does not have an indication for this condition – dose provided is indicative only
DR ESTHER LAU MPS School of Clinical Sciences, Queensland University of Technology, Brisbane PROF LISA NISSEN FPS School of Clinical Sciences, Queensland University of Technology, Brisbane
- Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet; 2017 doi: 10.1016/S0140-6736(17)31585-4.
- Foltynie T, Aviles-Olmos I. Exenatide as a potential treatment for patients with Parkinson’s disease: first steps into the clinic. Alzheimers Dement 2014;10(1 Suppl):S38–46.