GLP-1 receptor agonists and/or DPP4 inhibitors: Drugs may lower the risk of Parkinson’s disease

Parkinson’s disease, the most common neurodegenerative movement disorder has growing prevalence with the age. Due to increasing life expectancy and the world’s aging population, Parkinson’s disease is growing so rapidly in prevalence, disability, and death.¹

According to Global Burden of Disease data, nearly 6.2 million people live with Parkinson’s disease and estimated to be doubled by 2040.² Men are at greater risk for Parkinson’s disease; however, the female gender is associated with rapid disease progression and increased risk of mortality.³

Emerging evidence suggests that type 2 diabetes (T2DM) may be an independent risk factor for Parkinson’s disease.⁴ Insulin resistance, the major feature of diabetes plays a critical role in the pathogenesis of neurodegeneration in Parkinson’s disease.⁵

The growing links between insulin resistance, metabolic syndrome, and Parkinson’s disease suggest that anti-hyperglycemic agents may attenuate the risk of Parkinson’s disease in patients with diabetes. According to a new study led by UCL researchers, dipeptidyl peptidase-4 (DPP-4) inhibitors and/or glucagon-like peptide-1 (GLP-1) mimetics are associated with a lower risk of Parkinson’s disease.⁶

Type 2 Diabetes and Parkinson’s Disease

Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s. The prevalence of the disease varies across the countries. Nearly 60,000 Americans are diagnosed with Parkinson’s every year and predicted to affect more than 1 million people in the US by 2030.⁷ In Europe, the prevalence of Parkinson’s disease is estimated approximately 108-257/100,000.⁸

Many studies support the association between diabetes and Parkinson’s disease, indicates that hyperglycemia plays a pivotal role in promoting neurodegeneration. Diabetes and Parkinson’s disease share similar dysregulated pathways,⁹ and both age-related diseases are characterized by abnormal protein aggregation, impaired lysosomal and mitochondrial function.⁵ Diabetes may be associated with postural instability and gait difficulty, a clinical feature of Parkinson’s disease.¹⁰ A recent study finds that T2DM can also accelerate the progression of motor symptoms in Parkinson’s disease.⁵

Glucagon-like peptide-1 receptor agonists and Dipeptidyl peptidase-4 inhibitors

Glucagon-like peptide-1 (GLP-1) receptor agonists or incretin mimetics are a class of drugs approved for the treatment of type 2 diabetes. GLP-1 receptor agonists stimulate glucose-dependent insulin secretion, suppress glucagon secretion and this, in turn, reduces blood glucose levels. GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), resulting in a short plasma half-life of GLP-1. GLP-1 mimetics with prolonged half-life or DPP-4 inhibitors that prolong the half-life of GLP-1¹¹ increase the insulin levels and lower the blood glucose and HbA1c levels. GLP-1 mimetics have shown neuroprotective effects in animal models- crosses the blood-brain barrier, protects against oxidative brain injury,¹² reduces hyperglycemia-induced neuronal inflammation by improving insulin signaling.⁶

GLP-1 mimetics have shown beneficial effects on Parkinson’s disease. In a recent open-label trial, the GLP-1 mimetic exenatide improved motor scores in Parkinson’s disease.¹³

Mounting evidence of the potential neuroprotective effects of GLP-1 mimetics in Parkinson’s disease led to the investigation of the potential neuroprotective association of the GLP-1 mimetics and DPP-4 inhibitors, the incretin-based therapies on the risk of Parkinson’s disease.

In a large population-based cohort study, researchers analyzed The Health Improvement Network (THIN) database, UK to compare the risk of Parkinson’s disease in individuals treated with glitazone or GLP-1 receptor agonists and/or DPP4 inhibitors with other glucose-lowering agents.⁶ The study involved >100 000 patients diagnosed with diabetes, prescribed at least two or more antidiabetic drugs between January 2006 and January 2019.

The results showed a significant disparity in the incidence rate of Parkinson’s disease in patients with diabetes, depending on the type of drug prescribed. The findings suggest the users of GLP-1 agonists such as exenatide and DPP4 inhibitors are 36-60% less likely to develop Parkinson’s disease than the users of other oral antidiabetic agents.

The study provided strong evidence for the protective effect of GLP-1 receptor agonists and DPP4 inhibitors on the risk of Parkinson’s disease in patients with diabetes.

The results provided further verifications for a multicenter phase 3 clinical trial of exenatide, the ongoing study that exploring the disease-modifying effect of exenatide in Parkinson’s disease.¹⁴ The exenatide has shown beneficial effects on nerve cells in the laboratory setting and a recent trial showed encouraging effects on motor and non-motor symptoms of Parkinson’s disease. A double-blind placebo-controlled trial has suggested that exenatide can be a neuroprotective drug. The study raises the possibility of new treatment options for patients with Parkinson’s disease.