Beyond the anti-obesity benefits of glucagon-like peptide-1 drugs

In a recent article published in Science, researchers reviewed clinical studies on the advantages of glucagon-like peptide-1 (GLP-1) medicines beyond glycemic and weight control.

Introduction

GLP-1 medications, used to treat primarily obesity and diabetes, reduce inflammation indirectly through weight reduction, neuronal GLP-1 receptor (GLP-1R) activation, and directly through T cell activation.

Glucagon receptors, found in hepatocytes and renal cells, may provide further advantages, perhaps lowering the incidence of metabolic liver diseases and diabetic kidney disease.

They are under investigation for neurological and psychiatric illnesses, and their efficacy in clinical trials could broaden the range of therapeutic indications that benefit from GLP-1 therapy.

About the article

In the present article, researchers discuss potential non-weight-lowering applications of GLP-1 drugs.

Cardiovascular, hepatic, and renal benefits of GLP-1 medicines

GLP-1 medicines, mostly acylated peptides like semaglutide and liraglutide, have pleiotropic effects beyond weight and glycemic management, including renal and heart disease prevention. Their actions in lowering systemic inflammation have important implications for future clinical applications and medication development.

Semaglutide lowers renal diseases and cardiovascular mortality by 24% among type 2 diabetes patients. In animal models of renal damage, increasing or decreasing GLP-1 receptor signaling enhances or deteriorates renal function.

However, the current understanding of glucagon-like peptide-1 actions in renal pathways is inadequate. In rodent and human kidneys, GLP-1 receptors are present in vascular smooth muscles rather than glomerular epithelium or tubules.

As a result, the mechanisms underlying the impact of glucagon-like peptide-1 medications on the kidneys are unknown.

Clinical trials and animal research support GLP-1 medication usage to treat metabolic liver disease. Semaglutide is now in phase 3 clinical trials. However, hepatocytes do not express GLP-1R, making it difficult to appreciate its liver health advantages.

Preclinical studies indicate that uncommon populations of intrahepatic GLP-1R-expressing cells, especially endothelial cells and T cells, contribute to the therapeutic benefits.

GLP-1 medications provide nonmetabolic advantages to the cardiovascular system, such as preventing ischemic myocardium and maintaining heart function following damage. These activities are unaffected by glucose regulation or weight reduction.

Long-acting GLP-1 agonists can decrease nonfatal stroke, myocardial infarction, atherosclerosis, and cardiovascular mortality in adults with type 2 diabetes and obesity.

Semaglutide can also assist heart failure patients. Indirect benefits include lower blood pressure, reduced atherogenic lipoproteins, improved blood glucose management, and weight loss.

Clinical trials are underway in individuals with peripheral artery disease; however, the processes involving GLP-1R activation, atherosclerotic reduction, and enhanced blood flow are unclear.

Other uses of glucagon-like peptide-1 drugs

GLP-1 receptor signaling is crucial in neuroinflammation and neurodegeneration after brain injuries, stroke, or neurodegenerative diseases.

Clinical studies have explored the therapeutic effectiveness of the exenatide GLP-1 drug in Parkinson's disease, with inconsistent findings. GLP-1 agonists, such as tirzepatide and semaglutide, have been associated with lower rates of cognitive impairment among individuals with type 2 diabetes or obesity.

The growing use of these medications has prompted concerns regarding their ability to influence central nervous system (CNS) illness outcomes, including those of depression, excessive drug use and alcohol consumption, compulsive behaviors, and suicidal thoughts.

According to studies, semaglutide medication reduces suicidal thoughts when compared to other weight-loss and glucose-lowering drugs.

Furthermore, TriNetx medical records show decreased rates of incident or recurrent marijuana use disorders in individuals with type 2 diabetes, overweight, or adiposity compared to non-glucagon-like peptide-1-type weight-loss or glucose-lowering medications.

Despite anecdotal evidence of decreased alcohol usage with glucagon-like peptide-1 medications, randomized studies are unclear. Dulaglutide-treated individuals exhibited lower alcohol consumption; however, those with alcohol usage disorders randomized to receive exenatide once weekly over 26 weeks showed no reduction in heavy drinking.

The findings resulted in the launch of several randomized controlled studies to investigate the therapeutic usefulness of glucagon-like peptide-1 medications in various illnesses. GLP-1R agonism decreases inflammation in the small and large intestines by secreting it when enteroendocrine L cells respond to infection or tissue damage.

It is predominant in intestinal intraepithelial lymphocytes (IELs) and exhausted T cells in the immune system. IEL-GLP-1R is essential for both local and systemic anti-inflammatory activity.

Based on the findings, GLP-1 medications may benefit the cardiovascular and renal systems while also promoting weight loss, glycemic management, neurocognition, gut function, liver inflammation, alcohol use, and suicidal ideation.

The drugs may also improve Alzheimer's, Parkinson's, drug abuse problems, compulsive behavior, lower myocardial infarction, atherosclerosis, metabolic liver disease, and diabetic kidney disease.

Combining these medications with GIPR antagonist medications, glucagon receptor agonists, GLP-2R agonists, or agonists of amylin receptors might enhance their benefits.

• Daniel J. Drucker et al., (2024) The benefits of GLP-1 drugs beyond obesity Glucagon-like peptide-based medicines have weight-loss-independent actions. Science., doi: 10.1126/science.ado5019. https://www.science.org/doi/10.1126/science.adn4128