Alzheimer's and Parkinson's disease are two CNS diseases with a large unmet need for disease-modifying therapies. Recently, two phase 3 clinical trials testing the GLP-1 analogue Semaglutide (Wegovy, Ozempic) in patients with Alzheimer's disease did not show improvements. This failure should not have been a surprise, since it has been known for many years that Semaglutide does not cross the blood-brain barrier (BBB) and enters the brain only in very small amounts. It is designed to stay in the blood stream and has a very long half-life in the blood (168 h). The GLP-1 analogue Liraglutide (Victoza), in contrast, has a much shorter half-life (13 h), and a phase 2 clinical trial showed improvements in cognitive tests after 1 year of treatment. GLP-1 receptor agonists have been tested in clinical trials in Parkinson's patients, and a similar picture emerged. Drugs that can cross the BBB well (exenatide, lixisenatide) show good protection, while a drug that cannot cross the BBB showed no effects (NLY01). Clearly, when treating CNS diseases, it is of importance to get the drug into the brain to ensure target engagement. This review will look at the clinical trials that have been conducted in more detail, describe the mode of action as derived from preclinical trials, and discuss novel strategies for getting GLP-1 receptor agonists into the brain to successfully treat CNS diseases.
