GLP-1 Agonists Show Promise in Treatment of Neurodegenerative Disorders

The commonalities between type 2 diabetes (T2D) and neurodegenerative disorders have gained increasing attention in terms of treatment opportunities, explained Nigel H. Greig, PhD, a senior investigator in the Translational Gerontology Branch at the National Institute of Health, during a presentation at the 2024 Alzheimer’s Association International Conference (AAIC) in Philadelphia, Pennsylvania. Notably, commonalities in cell death pathways between these conditions suggest that treatments effective in one may also benefit the other, according to Greig.¹

Among the promising therapeutic candidates are glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, which have shown potential in reducing the risk of neurodegenerative diseases, such as Parkinson and Alzheimer disease.¹

The commonalities between type 2 diabetes and neurodegenerative disorders have gained increasing attention in terms of treatment opportunities. Image Credit: © Artur - stock.adobe.comNormal

Epidemiological Evidence and GLP-1 Receptor Distribution

Epidemiological studies have demonstrated a significant finding: Individuals with T2D treated with GLP-1 receptor agonists (incretin mimetics) or gliptins (DPP-4 inhibitors) are 36% to 60% less likely to develop Parkinson disease. These data show the potential of these drugs beyond their current use in diabetes management, Greig explained.¹

GLP-1 receptors are widely distributed in the brain and are present on various neurons, astrocytes, and microglial cells. The activation of these receptors, particularly in response to ischemia or neuroinflammation, increases their number on microglial cells. This response to activation suggests that GLP-1 receptor agonists may influence neuroprotective and anti-inflammatory pathways, offering a novel approach to treating neurodegenerative diseases.¹

Preclinical Studies and Mechanistic Insights

The journey of GLP-1 receptor agonists from preclinical research to clinical evaluation spans over 2 decades, according to Greig. Initial studies in 2002 demonstrated the neuroprotective potential of these agents, paving the way for extensive research across various neurodegenerative diseases.¹

GLP-1 receptor agonists have been shown to exert varying beneficial effects, including anti-inflammatory, neurotrophic, and neuroprotective actions. The pathways activated by these receptors encompass a broad spectrum, contributing to their therapeutic potential. Over the past 2 decades, studies have demonstrated consistent preservation of neuronal phenotypes and protection against neurotoxin-induced cell loss, Greig explained.¹

“There are certain pathways which are initiated through the GLP-1 receptor, but there are a plethora of pathways which have different effects, some leading to anti-inflammatory actions, some to neurotrophic actions, some to neuroprotective actions, and some to others still,” Greig said during the AAIC session.¹

Clinical Trials and Efficacy

In a study (NCT01174810) conducted at the University College London, investigators assessed the effects of the GLP-1 receptor agonist exenatide (Byetta; Amylin Pharmaceuticals), which is a synthetic version of exendin-4, in patients with moderately advanced Parkinson disease.^1,2 Using a single-blind trial design, investigators evaluated the progress of 45 patients with Parkinson disease who were randomly assigned to receive subcutaneous exenatide injection for 12 months or to act as controls. After overnight withdrawal of conventional Parkinson disease medication, patients’ disease was compared using blinded video assessment of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), together with several nonmotor tests, at baseline, 6 months, and 12 months, as well as after a further 2-month washout period.²

The analysis showed that exenatide was well tolerated, although weight loss was common and l-DOPA (Sinemet; Organon Pharma) dose failures occurred in a single patient. In the exenatide-treated group, investigators observed clinically relevant improvements in Parkinson disease across motor and cognitive measures compared with the control group.^1,2 Patients treated with exenatide had a mean improvement at 12 months on the MDS-UPDRS of 2.7 points, compared with a mean decline of 2.2 points among patients in the control arm (P = 0.037).²

The sustained effects observed in this trial suggest potential disease-modifying properties, Greig explained.¹ Additionally, a follow up study conducted with the trial cohorts showed that the improvements persisted 12 months after cessation of exenatide.³

The Promise of Dual and Triple Agonists

While single GLP-1 receptor agonists have shown promise, recent preclinical studies have shown that dual and triple agonists may offer enhanced therapeutic benefit when evaluated at a clinically translatable dose. These compounds simultaneously target multiple pathways, potentially amplifying their neuroprotective and anti-inflammatory effects, according to Greig. For example, in a mouse concussive traumatic brain injury (TBI) model, a 5-fold lower dose of dual agonist twincretin (Tirzepatide; Eli Lilly and Company) was required for similar efficacy vs a single dose of GLP-1 receptor agonist liraglutide (Victoza; Novo Nordisk).¹

Notably, the neurotrophic and neuroprotective actions of these multi-targeted agents have been consistently observed at lower doses, Grieg explained. However, Grieg noted these preclinical studies also showed that benefit from these drugs were dependent on brain uptake of the selected agonist, which remains important.¹

“In general, the dual and triple agonists have more anti-inflammatory action than the single agonists. So, we've looked at TBI, and, in general, the dual and triple agonists have more efficacy than the single agonists, or [they have] the same efficacy, but at lower doses,” Grieg said. “In each of these studies, what we'd use was a clinically translatable dose…which would be the dose that would translate to humans.”¹

Future Directions

The exploration of GLP-1 receptor agonists and related compounds in neurodegenerative diseases represents a promising frontier for the future of neurodegenerative disease treatment. The compelling epidemiological evidence, coupled with robust preclinical and clinical findings, supports the potential of these agents to modify disease progression and improve patient outcomes.¹

Ongoing research aims to further elucidate the mechanisms underlying the neuroprotective effects of GLP-1 receptor agonists and to optimize their therapeutic efficacy, Greig explained. Future studies will likely focus on the development and clinical evaluation of dual and triple agonists, leveraging their multi-faceted actions to combat neurodegenerative disorders.¹

“Multiple actions, as discussed, underpin the efficacy [of these drugs]: neurotrophic, neuroprotective, anti-inflammatory, re-sensitization of insulin, neurogenesis, etc, and they can all be mapped out pathways-wise. These agonists are [being looked at] in Parkinson disease and Alzheimer disease, and they look promising, and it's likely that we should look at other diseases as well,” Greig said. “The future, I think, is in dual and triple agonist drug combinations.”¹

REFERENCES

1. Greig NH. Elevating brain GLP-1 and GIP levels as a treatment strategy for neurodegenerative disorders. 2024 Alzheimer’s Association International Conference; Philadelphia, Pennsylvania; July 28-August 1, 2024.
2. Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Exenatide and the treatment of patients with Parkinson's disease. J Clin Invest. 2013;123(6):2730-2736. doi:10.1172/JCI68295
3. Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson's disease. J Parkinsons Dis. 2014;4(3):337-344. doi:10.3233/JPD-140364