Medications are sometimes prescribed “off-label,” meaning for a condition not initially approved by regulatory agencies. This occurs when a drug demonstrates potential benefits for a different disease. Glucagon-like peptide 1 (GLP-1) receptor agonists, originally approved for type 2 diabetes (T2D), exemplify this phenomenon. Since 2005, their use has expanded to include cardiovascular disease, obesity, and kidney disease. Emerging research suggests even broader applications for these versatile medications.
A Brief History of GLP-1 Receptor Agonists
GLP-1, a hormone released after eating, plays crucial roles in glucose regulation and appetite control. Its discovery in 1987 paved the way for the development of GLP-1 receptor agonists. Exenatide, approved in 2005, was the first subcutaneous GLP-1 receptor agonist for T2D. Subsequently, several others received approval, including liraglutide, dulaglutide, lixisenatide, and semaglutide (Ozempic). In 2019, oral semaglutide (Rybelsus) became available. Liraglutide (Saxenda) and semaglutide (Wegovy) were also approved for obesity treatment. Tirzepatide, a dual GIP and GLP-1 receptor agonist, was approved for both T2D and obesity.
GLP-1 receptor agonists exert beneficial cardiovascular effects by interacting with receptors in the cardiovascular system. They contribute to plaque stabilization, offer protection against major adverse cardiac events, and can lower blood pressure. Given these established benefits, research is exploring the potential of GLP-1 receptor agonists in other conditions like nonalcoholic fatty liver disease (NAFLD), Parkinson’s disease, Alzheimer’s disease, osteoarthritis, and chemical dependency.
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GLP-1 Receptor Agonists and NAFLD
NAFLD, characterized by fat accumulation in the liver, affects a significant portion of the global population. While often asymptomatic initially, it can progress to more severe forms like nonalcoholic steatohepatitis (NASH) and cirrhosis. Given the link between NAFLD and insulin resistance, GLP-1 receptor agonists offer a promising treatment avenue. A 2023 meta-analysis demonstrated their effectiveness in improving liver function, with semaglutide showing particular promise in reducing liver enzymes and stiffness.
Figure 1: Pharmacology of GLP-1 Receptor Agonist Treatment in Patients With NAFLD. ER, endoplasmic reticulum; FA, fatty acid; GLP-1, glucagon-like peptide 1; HbA1c, hemoglobin A1c; NAFLD, nonalcoholic fatty liver disease; RA, receptor agonist.
Recent trials with survodutide, an investigational GLP-1 receptor agonist, showed impressive results in treating NASH. A significant percentage of participants experienced histological improvement, suggesting a potential breakthrough in NASH treatment.
Potential in Parkinson’s Disease
Parkinson’s disease, a neurodegenerative disorder affecting dopamine-producing neurons, leads to progressive motor impairment. GLP-1 receptor agonists, by binding to receptors on these neurons, may offer neuroprotection. A meta-analysis of clinical trials indicated that exenatide improved motor function in Parkinson’s patients, with benefits persisting even after treatment cessation.
Figure 2: Pharmacology of GLP-1 Receptor Activation in Patients With Parkinson Disease. CREB, cAMP/PKA response element-binding protein; GLP-1, glucagon-like peptide 1.
Exploring the Role in Alzheimer’s Disease
Alzheimer’s disease, the most prevalent form of dementia, involves progressive cognitive decline. Research suggests a link between insulin resistance in the brain (sometimes referred to as “type 3 diabetes”) and Alzheimer’s. GLP-1 receptor agonists may influence several pathways relevant to Alzheimer’s, including neuroinflammation and amyloid-beta deposition. A study using liraglutide showed potential in preventing the decline of cerebral glucose metabolism, a marker associated with cognitive decline.
Figure 3: Pharmacology of GLP-1 Receptor Agonist Treatment in Patients With Alzheimer Disease. Aß, amyloid-ß; AD, Alzheimer disease; BDNF, brain-derived neurotrophic factor; GLP-1, glucagon-like peptide 1; NFT, neurofibrillary tangle.
Promising Results in Osteoarthritis
Osteoarthritis, a degenerative joint disease, currently lacks disease-modifying treatments. Preclinical studies indicate that GLP-1 receptor agonists may exert anti-inflammatory and protective effects on joint tissues. Research with liraglutide in a rat model demonstrated reduced inflammation and improved markers associated with osteoarthritis.
Figure 4: Pharmacology of GLP-1 Receptor Agonist Treatment in Patients With Osteoarthritis. FA, fatty acid; GLP-1, glucagon-like peptide 1
Potential for Addressing Chemical Dependency
Addiction involves complex interactions within the brain’s reward system. Preclinical evidence suggests that GLP-1 receptor agonists might influence these pathways, potentially reducing alcohol intake and attenuating the effects of alcohol deprivation.
Figure 5: Pharmacology of GLP-1 Receptor Agonist Treatment in Patients With Chemical Dependency. GLP-1, glucagon-like peptide 1.
Conclusion
While initially developed for T2D and obesity, GLP-1 receptor agonists are demonstrating promise in a wider range of conditions. Although much of the research is still in early stages, these findings offer hope for new treatment options for debilitating diseases lacking effective cures. For personalized treatment plans, consult with a healthcare professional today.
