CNS effects of Wegovy (semaglutide)


There is considerable discussion in the media (social and otherwise) about semaglutide (Wegovy), one of a class of drugs now approved for the treatment of obesity. Of further interest is the potential usefulness of these agents in a range of neurodegenerative disorders, including MS, Alzheimer’s disease and Parkinson disease.

Semaglutide is a long-acting agonist of glucagon-like peptide (GLP-1), an incretin hormone primarily secreted by enteroendocrine cells in the distal intestine and pancreatic alpha cells. Other GLP-1 agonists include exenatide (Byetta), liraglutide (Saxenda), dulaglutide (Trulicity), and tirzepatide (Mounjaro).

In the CNS, GLP-1 acts as a neurotransmitter and is synthesized in the hindbrain (nucleus of the solitary tract), with innervation to the hypothalamus and amygdala (Sandoval D. Physiol Behav 2008;94:670-674). GLP-1 receptors are also expressed in the hippocampus, neocortex, spinal cord and cerebellum (Muscogiuri et al. Trends Endocrinol Metab 2017;28:88-103). A key role of GLP-1 is energy homeostasis through activation of glucose-sensing GLP-1 receptors in the hypothalamus, which in turn can regulate insulin release by the pancreas (Huang et al. Sci Adv 2022;8:eabn5345).

In addition to its effects on brain glucose levels, GLP-1 may reduce neuroinflammation through modulation of PI3/Akt (phosphatidylinositol 3-kinase/Akt), a signal transduction pathway that regulates cell proliferation and survival (Bhalla et al. Neurosci Biobehav Rev 2022;142:104896). Preclinical studies have reported that GLP-1 promotes synaptic formation and neuronal plasticity; conversely, GLP-1 deficiency is associated with impaired cell signalling that contributes to neurodegeneration.

Semaglutide has been studied extensively in the STEP series (Semaglutide Treatment Effect in People with Obesity) of clinical trials. In STEP 1 and 3, mean weight loss was 10-12% at 68 weeks with semaglutide 2.4 mg/wk SC in conjunction with calorie restriction and exercise (Wilding and colleagues. N Engl J Med 2021;384:989-1002. Wadden and colleagues. JAMA 2021;325:1403-1413). Weight loss was attributed to drug effects on appetite, food cravings and food preferences (reduced liking for high-fat foods) that resulted in a lower caloric intake (Blundell et al. Diabetes Obes Metab 2017;19:1242-1251).

Preclinical and clinical studies have demonstrated potential neuroprotective effects in a range of neurodegenerative conditions:

Alzheimer disease: Semaglutide enhanced autophagy of cells damaged by beta-amyloid and inhibited apoptosis of cells involved in beta-amyloid clearance in an AD cell line (Chang et al. J Clin Neurosci 2020;81:234-239). Liraglutide reduced memory impairment and prevented neuronal loss in the hippocampus in an AD mouse model (McClean et al. J Neurosci 2011;31:6587-6594). Similarly, liraglutide reduced beta-amyloid-induced memory impairment in rats (Han et al. Neurobiol Aging 2013;34:576-588).

A 6-month study reported that liraglutide prevented a decline in brain glucose metabolism associated with cognitive impairment (Geil et al. Front Aging Neurosci 2016;8:108). More recently, an analysis of patients with Type 2 diabetes enrolled in three cardiovascular trials and a Danish registry found that GLP-1 agonist exposure was associated with a lower rate of dementia (hazard ratio 0.47) (Norgaard et al. Alzheimers Dement 2022;8:e12268). Preliminary results from the ELAD study showed improved cognitive function and greater cortical volume on MRI with liraglutide (Edison et al. Alzheimer’s Dement 2021;17(suppl.9):e057848).

Parkinson disease: Liraglutide and semaglutide prevented MPTP-induced motor impairment, reduced the accumulation of alpha-synuclein, improved chronic neuroinflammation and promoted the growth of dopaminergic neurons in the substantia nigra in a mouse model of PD (Liu et al. Neuroscience 2015;303:42-50. Zhang et al. J Parkinsons Dis 2019;9:157-171).

A phase II trial of exenatide in Parkinson disease reported promising results in improving off-medication motor scores (Athauda et al. Lancet 2017;390:1664-1675). Other phase II studies are planned/running in the U.S. and Europe and a phase III trial is underway in the UK.

Stroke: Liraglutide reduced infarct volume and improved neurological deficits in an animal model of stroke, an effect that was partially mediated by improving mitochondrial function (Zhu et al. Sci Rep 2016;6:26859).

In an exploratory analysis of the REWIND diabetes trial, dulaglutide significantly reduced the incidence of ischemic (HR 0.75) but not hemorrhagic stroke (HR 1.05) or stroke severity (Gerstein et al. Lancet Diabetes Endocrinol 2020;8:106-114).

Studies in other areas are more preliminary.

Epilepsy: Semaglutide reduced the brain inflammatory response, seizure severity and cognitive dysfunction in a chronic epilepsy mouse model (Wang et al. Int J Mol Med 2021;48:219).

Multiple sclerosis: A recent study reported that semaglutide administered intraperitoneally reduced motor and cognitive impairments in an EAE model (Sadek et al. Int Immunopharmacol 2023;115:109647). Autopsy studies showed a reduction in hippocampal damage and demyelination in the corpus callosum. The effect was attributed to PI3K/Akt activation and a reduction of oxidative stress.

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