Beyond Anti-Obesity: Glucagon-Like Peptide-1 Benefits

Researchers examined clinical data on the benefits of glucagon-like peptide-1 (GLP-1) medications beyond glycemic and weight control in a recent Science paper.

Overview

GLP-1 drugs, which are mostly used to treat diabetes and obesity, decrease inflammation both directly through T cell activation and indirectly through weight loss and neural GLP-1 receptor (GLP-1R) activation.

Hepatocytes and renal cells include glucagon receptors, which may offer additional benefits such as a potential reduction in the occurrence of metabolic liver disorders and diabetic kidney disease.

They are being studied for neurological and psychiatric conditions, and if they prove effective in clinical trials, the list of therapeutic reasons for which GLP-1 therapy is useful may grow.

Benefits of GLP-1 medications for the liver, kidneys, and heart
Beyond managing weight and blood sugar levels, GLP-1 medications—mostly acylated peptides like semaglutide and liraglutide—have pleiotropic benefits that include preventing heart and kidney disease. Their ability to reduce systemic inflammation has significant ramifications for the development of new medications and clinical uses.

Semaglutide reduces cardiovascular mortality and kidney illnesses in patients with type 2 diabetes by 24%. GLP-1 receptor signaling can be increased or decreased to improve or worsen renal function in animal models of renal injury.

Nevertheless, our present knowledge of the activities of glucagon-like peptide-1 in renal pathways is insufficient. GLP-1 receptors are found in vascular smooth muscles in the kidneys of rodents and humans, not in the glomerular epithelium or tubules.

Therefore, it is unknown what processes underlie the effects of glucagon-like peptide-1 drugs on the kidneys.

GLP-1 drug use is supported by animal studies and clinical trials in the treatment of metabolic liver disease. Clinical trials for semaglutide are currently in phase 3. GLP-1R does not, however, express in hepatocytes, which makes it challenging to recognize its benefits for liver health.

Preclinical research suggests that the therapeutic advantages are partly attributed to rare populations of intrahepatic GLP-1R-expressing cells, particularly T cells and endothelial cells.

GLP-1 inhibitors benefit the cardiovascular system in nonmetabolic ways, such as avoiding myocardial ischemia and preserving heart function after injury. Reduction of weight and glucose regulation have little effect on these activities.

In people with type 2 diabetes and obesity, long-acting GLP-1 agonists can reduce nonfatal stroke, myocardial infarction, atherosclerosis, and cardiovascular mortality.

Patients with heart failure can also benefit from semaglutide. Lower blood pressure, fewer atherogenic lipoproteins, better blood glucose control, and weight loss are examples of indirect advantages.

Peripheral artery disease patients are undergoing clinical studies, however it’s unclear how GLP-1R activation, atherosclerotic reduction, and improved blood flow work together.

Glucagon-like peptide-1 medications: other uses
In the aftermath of brain trauma, stroke, or neurodegenerative illnesses, GLP-1 receptor signaling plays a critical role in neuroinflammation and neurodegeneration.

Inconsistent results have been found in clinical trials investigating the exenatide GLP-1 drug’s therapeutic efficacy in Parkinson’s disease. GLP-1 agonists, such semaglutide and tirzepatide, have been linked to decreased rates of cognitive impairment in those who are obese or have type 2 diabetes.

Concerns have been raised by the increasing usage of these drugs about their potential to affect the outcomes of central nervous system (CNS) illnesses, such as depression, compulsive behaviors, excessive drug and alcohol use, and suicidal ideation.

Comparing semaglutide medication to other weight-loss and glucose-lowering medications, research show that it lessens suicidal thoughts.

Comparing non-glucagon-like peptide-1 type weight-loss or glucose-lowering drugs to patients with type 2 diabetes, obesity, or overweight, TriNetx medical data demonstrate lower odds of acute or recurrent marijuana use problems.

Randomized trials are inconclusive despite anecdotal indications of reduced alcohol consumption with glucagon-like peptide-1 medicines. People taking dulaglutide consumed less alcohol overall, but people with alcohol use disorders who were randomly assigned to receive exenatide once a week for 26 weeks did not experience a decrease in excessive drinking.

The results led to the initiation of other randomized controlled trials to examine the potential therapeutic benefits of glucagon-like peptide-1 drugs for a range of diseases.

In response to infection or tissue injury, enteroendocrine L cells secrete a substance called GLP-1R agonism, which reduces inflammation in the small and large intestines.

It is primarily seen in the immune system’s worn-out T cells and intestinal intraepithelial lymphocytes (IELs). For both local and systemic anti-inflammatory effects, IEL-GLP-1R is necessary.

According to the results, GLP-1 drugs may help the kidneys and cardiovascular system in addition to encouraging glycemic control, weight loss, gut health, liver inflammation, alcohol use, and suicidal thoughts.

Additionally, the medications may lessen the symptoms of myocardial infarction, atherosclerosis, metabolic liver disease, diabetic kidney disease, Parkinson’s, substance misuse issues, obsessive behavior, and Alzheimer’s.

These drugs may work better when used alongside GIPR antagonists, glucagon receptor agonists, GLP-2R agonists, or amylin receptor agonists.

For more information: The benefits of GLP-1 drugs beyond obesity Glucagon-like peptide-based medicines have weight-loss-independent actions, Science, https://doi.org/10.1126/science.adn4128