5 Uses of the GLP-1’s beyond Weight Loss and Diabetes

Many medications are often used off-label when they are found to have effects that could positively impact a disease or condition they were not initially intended for. Almost one-third of all medications in the United States are used off-label. Glucagon-like peptide 1 (GLP-1) receptor agonists are a class of medications that were first approved in 2005 for type 2 diabetes (T2D) and in 2019 for weight loss.

However, since their origination, GLP-1 receptor agonists have gained FDA approval and established significant roles in therapy for cardiovascular disease, obesity, and kidney disease. Interestingly, emerging data suggest that this class of medications may have roles in many other conditions that could be very promising in the future. Through these studies, potential new opportunities have risen to utilize GLP-1 receptor agonists to treat nonalcoholic fatty liver disease (NAFLD), Parkinson’s disease, Alzheimer’s disease, osteoarthritis, and chemical dependency.

How were the GLP-1’s Discovered

GLP-1 is an incretin hormone released from the lower ileum in the small intestine and the colon within minutes of ingesting food. GLP-1 has been shown to decrease glucagon secretion, increase glucose uptake and glycogen synthesis, delay gastric emptying, and increase a feeling of fullness. This subjective feeling of fullness can vary from person to person.

GLP-1 was first discovered in 1987, Bernhard Kreymann and Stephen Robert Bloom, in London, England.  These researchers could see the insulinotropic actions of GLP-1 in humans and found that they were more effective than the glucose-dependent insulinotropic polypeptide (GIP) in stimulating insulin and reducing peak plasma glucose concentrations. In 2005, the FDA approved the first subcutaneous GLP-1 receptor agonist, exenatide (Eli Lilly), for treating type 2 diabetes. The GLP-1 receptor agonist Liraglutide (Novo Nordisk) was approved months later.  Tirzepatide (Mounjaro; Eli Lilly and Company), a combination GIP and GLP-1 receptor agonist, was FDA-approved in 2022 to treat type 2 diabetes and in 2023 to treat obesity.  Eli Lilly and Novo Nordisk are working on a future generation of the med, which looks even more promising.

GLP-1 receptor agonists are known to possess positive cardiovascular effects. GLP-1 receptors are expressed on cells found in the cardiovascular system, smooth muscle cells, and endothelial cells. GLP-1 receptor agonists have been shown to prevent and stabilize atherosclerotic vascular disease by reducing the lipid deposition and plaque volume on the aortic surface by regulating plaque instability and inflammation markers.  GLP-1s can also decrease cardiovascular inflammation via myriad of pathways.

Overall,  GLP-1 receptor agonists can stabilize the atherosclerotic plaques, provide protection against MACEs, and lower blood pressure, which all produce beneficial cardiovascular effects for the patient.

Nonalcoholic Fatty Liver Disease and GLP-1 receptor agonists (Semaglutide – Tirzepatide)

NAFLD is a condition that is characterized by the buildup of lipids or fat within liver cells. This form of liver disease impacts more than 30% of people worldwide. NAFLD is not often noticed in the early stages, and symptoms often do not appear until the disease has progressed.  NAFLD can progress to NASH and also cirrhosis. NASH and cirrhosis cause inflammation and scarring of the liver, which ultimately leads to permanent damage and reduced functional capacity of the liver. It is currently believed that NAFLD is closely linked to insulin resistance, which can lead to increased hepatic production and storage of fat.

In a 24-week study, significant improvements in NASH were seen in 83.0% of patients in the GLP-1 group compared with 18.2% of patients in the placebo group.

Parkinson’s Disease and GLP-1 receptor agonists (Semaglutide – Tirzepatide)

Parkinson’s disease is a neurodegenerative disorder that impacts the dopamine-producing neurons and causes tremors, muscle rigidity, and other movement-related symptoms that become more debilitating with time. GLP-1 receptor agonists can bind to the GLP-1 receptors located on the membrane of the midbrain’s dopaminergic neurons and reduce inflammation, oxidative stress, apoptosis, and a-synuclein deposition. Cell proliferation will also restore insulin signaling to improve neuronal function and neuroprotection.

As GLP-1 receptor agonists are understood to have neuroprotective properties, multiple randomized controlled trials that compared GLP-1 receptor agonists with Parkinson treatment, placebo, or no treatment in adult patients with all stages of Parkinson disease was conducted. The first double-blind study evaluated a GLP-1 vs placebo for 48 weeks in 62 randomly assigned participants and found evidence that GLP-1’s improvesmotor impairment. All studies found that GLP-1’s were well tolerated and did improve motor impairment, as improvement continued following cessation of the medication. The use of GLP-1 receptor agonists to treat Parkinson disease is promising as an option to improve motor impairment, even after the stopping the medication.

Alzheimer’s Disease and GLP-1 receptor agonists (Semaglutide – Tirzepatide)

Alzheimer’s disease is the most common cause of dementia and is an irreversible, slowly progressing condition associated with cognitive decline, memory impairment, personality changes, and difficulty with motor skills and verbal communication.  We understand that the primary causes of neurological disorders include insulin desensitization, demyelination, oxidative stress, neuroinflammation, amyloid-b deposits, and tau protein formation. Deficiencies in insulin receptor activation, insulin availability, and insulin receptor–related mechanisms may contribute to neurodegenerative conditions such as Alzheimer disease.Alzheimer’s has also been coined “type 3 diabetes.”  Insulin resistance increases amyloid-b deposition and tau protein hyperphosphorylation in the brain. As insulin resistance plays a role in the Alzheimer disease pathogenic pathway, GLP-1 receptor agonists can be used to increase neurogenesis and synaptic plasticity and decrease neuroinflammation and protein aggregations. Specifically, they reduce neuronal apoptosis, endoplasmic reticulum stress, oxidative stress, amyloid-b depositions, and phosphorylation.

Although the GLP-1’s were not shown to improve all aspects of Alzheimer disease, the use of this agent to improve the CMRglc and slow the progression of the disease could lead to better patient outcomes and quality of life.

Osteoarthritis and GLP-1 receptor agonists (Semaglutide – Tirzepatide)

Osteoarthritis is a degenerative joint disease in which chondrocytes, synovial cells, and other joint cells become activated when exposed to an abnormal environment caused by mechanical stress, inflammatory cytokines, or disorganization of the matrix proteins. The FDA has classified osteoarthritis as a serious disease with no disease-modifying treatments available. However,  preclinical data is beginning to demonstrate the potential benefits of using GLP-1 agonists for osteoarthritis. GLP-1 receptor agonists may counteract osteoarthritis that occurs in the cartilage, synovial membrane and bone tissue. The binding of GLP-1 receptor agonists to the GLP-1 receptors can lead to a decrease in inflammation and a reduction in oxidative stress, prodegradative mediator secretion, phenotype modification, and impairment/destruction of joint cells.

Although the use of GLP-1 receptor agonists for the treatment of osteoarthritis is not currently the standard of care, the properties of these agents and their effects on the joint tissues and cells may lead to improved treatment options for patients living with osteoarthritis, which is the most common degenerative joint condition.

Chemical Dependency and GLP-1 receptor agonists (Semaglutide – Tirzepatide)

Addiction is related to the reward-related dopamine levels that are present in the nervous system. Alcohol consumption acts on these reward-related areas in the nucleus accumbens and in the ventral tegmental area, causing an increase in the release of dopamine. GLP-1 receptor agonists act on these areas in the mesolimbic system, which can cause a decrease in the compulsion of alcohol consumption and other addictive tendencies by inhibiting the dopamine release.

The studies have revealed that GLP-1’s significantly reduced alcohol intake  compared with the placebo group.

At The Natural Path, we have created a wonderful wellness and weight loss program using Semaglutide and Tirzepatide which has had incredible results in our patient population in the past 3 years.

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