Five Unexpected New Uses for GLP-1 Receptor Agonists

Medications are often used off label when they are found to have properties or effects that could potentially benefit a disease state or condition they were not originally intended for. Up to one-third of all prescriptions for common medications in the United States are used off label.¹ Glucagon-like peptide 1 (GLP-1) receptor agonists are a class of medications that were first approved in 2005 for type 2 diabetes (T2D).^2,3 However, since their original entry into the market, GLP-1 receptor agonists have gained FDA approval and have 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 other—somewhat unrelated—conditions.

History of the GLP-1 Receptor Agonist Development

GLP-1 is an incretin hormone that is released from the distal ileum in the small intestine and the colon within minutes of ingesting food. It has been shown to decrease glucagon secretion, increase glucose uptake and glycogen synthesis in the peripheral tissues, delay gastric emptying, and increase satiety.⁴

GLP-1 was first discovered in 1987 by Bernhard Kreymann and Stephen Robert Bloom, who were affiliated with the Royal Postgraduate Medical School Department of Medicine at Hammersmith Hospital in London, England.⁵ They established 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.^4,6 In 2005, the FDA approved the first subcutaneous GLP-1 receptor agonist, exenatide (Byetta; Amylin Pharmaceuticals, Inc/Eli Lilly and Company), for the treatment of T2D. In the following years, more subcutaneous GLP-1 receptor agonists were approved for this indication, including liraglutide (Victoza; Novo Nordisk) in 2010, dulaglutide (Trulicity; Eli Lilly and Company) in 2014, lixisenatide (Adlyxin; Sanofi) in 2016, exenatide (Bydureon BCise; AstraZeneca) in 2017, and semaglutide (Ozempic; Novo Nordisk) in 2017. Semaglutide (Rybelsus; Novo Nordisk) was also FDA approved in 2019 as the first oral GLP-1 receptor agonist for T2D. Additionally, liraglutide (Saxenda; Novo Nordisk) and semaglutide (Wegovy; Novo Nordisk) were FDA approved in 2014 and 2021, respectively, to treat obesity. Tirzepatide (Mounjaro; Eli Lilly and Company), a combination GIP and GLP-1 receptor agonist, was FDA approved in 2022 to treat T2D and in 2023 to treat obesity.³

GLP-1 receptor agonists are known to possess positive cardiovascular effects. GLP-1 receptors are expressed on cells found in the cardiovascular system, including monocytes/macrophages, smooth muscle cells, and endothelial cells. Specifically, GLP-1 receptors are mainly expressed in the macrophage enrichment region of the atherosclerotic plaques. GLP-1 receptor agonists can prevent and stabilize atherosclerotic vascular disease by reducing the lipid deposition and plaque volume on the aortic surface by regulating markers of plaque instability and inflammation. These markers of plaque instability and inflammation include those linked to plaque hemorrhage, matrix turnover, cholesterol metabolism, and leukocyte recruitment. They can also alleviate the vascular remodeling after induced vascular injury by suppressing vascular smooth muscle cell proliferation and migration via the cAMP/PKA pathway. In addition, GLP-1 receptor agonists can reduce monocyte/macrophage accumulation in the arterial wall by inhibiting the adhesion of monocytes to activated endothelium in the arteries. This means that GLP-1 receptor agonists can limit and stabilize the development of atherosclerotic plaques through anti-inflammatory mechanisms and by preventing vascular remodeling, which ultimately can provide protective effects against major adverse cardiac events (MACEs). GLP-1 receptor signaling helps to control blood pressure through the tonic actions on the proximal tube sodium/hydrogen-mediated sodium reabsorption and the intrarenal renin-angiotensin II system. Further, GLP-1 receptor agonist treatment mediates renal vasodilation and attenuates renal autoregulatory responses, which can lower a patient’s blood pressure. Thus, 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.⁷

As the benefits of the GLP-1 receptor agonists with T2D, obesity, and cardiovascular health are becoming widely known, research into using these agents to treat other conditions has accelerated. Through these studies, potential new opportunities have risen to utilize GLP-1 receptor agonists to treat nonalcoholic fatty liver disease (NAFLD), Parkinson disease, Alzheimer disease, osteoarthritis, and chemical dependency.

Nonalcoholic Fatty Liver Disease

NAFLD is a condition that is characterized by the buildup of lipids within hepatic cells.⁸ Affecting more than 30% of people worldwide, this condition does not have any symptoms or negative effects in earlier stages but may progress into more severe forms of liver disease if not counteracted, such as nonalcoholic steatohepatitis (NASH) or 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 then lead to increased hepatic production and storageof fatty acids. Some of the most common risk factors for the development of NAFLD are obesity, T2D, and hyperlipidemia.⁹

GLP-1 receptor agonists have emerged in recent years as a promising treatment option to halt or even reverse the effects of NAFLD. This is largely due to the GLP-1 receptor agonists’ effects on weight loss and insulin secretion (Figure 1), which affect the conditions most often responsible for the development of NAFLD.8 However, there is increasing evidence that GLP-1 receptor agonists may have more direct effects on the liver and benefits in the treatment of NAFLD. In a meta-analysis from 2023, 5 sodium-glucose cotransporter protein-2 (SGLT2) inhibitors (dapagliflozin [Farxiga; AstraZeneca/Bristol Myers Squibb], ipragliflozin [Suglat; Astellas Pharma Inc/Kotobuki Pharmaceutical Co, Ltd], luseogliflozin [Lusefi; Taisho Pharmaceutical Co, Ltd], tofogliflozin [Apleway; Sanofi], and empagliflozin [Jardiance; Boehringer Ingelheim]) and 4 GLP-1 receptor agonists (exenatide, liraglutide, semaglutide, and dulaglutide) were evaluated based on improvements in liver enzymes and liver fat parameters in patients with NAFLD. The results showed that although both SGLT2 inhibitors and GLP-1 receptor agonists generated improvements in liver function over the placebo, the GLP-1 receptor agonists were noted to have been generally more effective than SGLT2 inhibitors at producing these improvements.¹⁰ In particular, semaglutide was most successful at reducing alanine transaminase (mean difference, −14.70 U/L), aspartate transaminase (mean difference, −9.32 U/L), g-glutamyl transferase (mean difference, −16.56 U/L), and liver stif fness measurement (mean difference, −3.08 kPa) compared with the other medications studied, whereas liraglutide demonstrated efficacy in reducing subcutaneous adipose tissue (mean difference, −30.27 cm²) and liver fat fraction (mean difference, −5.16%).¹⁰ Overall, this study presents us with promising evidence regarding the efficacy of GLP-1 receptor agonists in the treatment of NAFLD.

A phase 3 clinical trial was conducted more recently with survodutide, an investigational new GLP-1 receptor agonist, which evaluated this medication’s ability to combat NASH, one of the complications that may result from NAFLD.¹¹ The primary end point of this study was the percentage of participants achieving histological improvement of NASH without worsening of fibrosis after 48 weeks of treatment, with histological improvement of NASH being defined as a decrease of 2 or more points on the NAFLD activity score. Survodutide dosing consisted of dose escalation to 2.4-mg, 4.8-mg, or 6.0-mg treatment groups for up to 24 weeks, with dose maintenance for 24 weeks. Significant improvements in NASH were seen in 83.0% of patients in the survodutide group compared with 18.2% of patients in the placebo group. Although the findings of this trial have not yet been formally published in their entirety, this study suggests the possibility of a promising new treatment for NASH from among the GLP-1 receptor agonist class, warranting further investigations into the potential benefits of survodutide in this condition.

Parkinson Disease

Parkinson disease is a neurodegenerative disorder that predominantly affects the dopamine-producing neurons in the substantia nigra and causes tremors, muscle rigidity, and other movement-related symptoms that become progressively more debilitating with time.¹² GLP-1 receptor agonists can bind to the GLP-1 receptors that are located on the membrane of the midbrain’s dopaminergic neurons. This binding can activate the cells against degeneration due to mitochondrial dysfunction that leads to a reduction of dopamine transmission, the deposition of a-synuclein, and the presence of oxidative stress (Figure 2).¹³ Thus, the signaling pathway that is activated through the binding of the GLP-1 receptor agonists to the GLP-1 receptors can reduce inflammation, oxidative stress, apoptosis, and a-synuclein deposition. Cell proliferation will also restore insulin signaling to improve neuronal functions and provide neuroprotection.¹³

As GLP-1 receptor agonists are understood to have neuroprotective properties, a meta-analysis with 2 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 meta-analysis reported data from the individual trials. The first double-blind study evaluated exenatide vs placebo for 48 weeks in 62 randomly assigned participants and found low-certainty evidence that exenatide improves motor impairment assessed by the Movement Disorder Society-Unified Parkinson’s Disease Rating (MDS-UPDRS) Part III off medication (mean difference, –3.10; 95% CI, –6.11 to –0.09). The second was a single-blind study that examined exenatide vs no additional treatment for 12 months in 45 participants, finding that at the 14-month follow-up, there was low-certainty evidence that suggests exenatide improves motor impairment as assessed by the MDS-UPDRS Part III off medication (mean difference, –4.50; 95% CI, –8.64 to –0.36). Both studies found that exenatide was well tolerated. Overall, the meta-analysis showed that exenatide did improve motor impairment, as improvement continued following cessation of the medication. However, it was unclear whether exenatide truly improved health-related quality of life, nonmotor outcomes, activities of daily living, and psychological outcomes.¹⁴

The use of GLP-1 receptor agonists to treat Parkinson disease is promising as an option to improve motor impairment, even after the cessation of the medication. Ultimately, more research will be necessary to provide definitive evidence.

Alzheimer Disease

Alzheimer disease is the most common cause of dementia and is an irreversible, slowly progressive condition that is often associated with cognitive decline, memory impairment, personality changes, and difficulty with motor skills and verbal communication.^15,16 Although Alzheimer disease can be multifactorial, primary causes of neurological disorders include insulin desensitization, demyelination, oxidative stress, neuroinflammation, amyloid-b deposits, and tau protein formation.¹⁵ Deficiencies in insulin receptor activation, insulin availability, and insulin receptor–related mechanisms may contribute to neurodegenerative conditions such as Alzheimer disease.¹⁷ In 2008, chronic insulin resistance plus insulin deficiency that is confined to the brain but can overlap with T2D was labeled as type 3 diabetes mellitus by Suzanne De La Monte, MD, MPH, of Brown University in Providence, Rhode Island. She proposed that type 3 diabetes is a major pathogenic mechanism in Alzheimer neurodegeneration.18 Insulin production in the central nervous system decreases in patients with Alzheimer disease, with insulin expression and insulin protein levels in the frontal cortex, hippocampus, and hypothalamus also being reduced.¹⁶ 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, tau protein hyperphosphorylation, cellular toxicity, and synaptic loss (Figure 3).¹⁹ The GLP-1 receptor agonists will also amplify the insulin signaling in the cells of the brain, which will increase insulin sensitivity in the neurons.¹³

A 26-week, randomized, placebo-controlled, double-blinded intervention in 38 patients with Alzheimer dementia in central Denmark found that subcutaneous liraglutide at 0.6 mg daily for 1 week, 1.2 mg daily for 1 week, and then 1.8 mg daily thereafter prevented the expected decline of cerebral metabolic rate of glucose (CMRglc), which correlates with cognitive decline. In the liraglutide group, CMRglc had a nonsignificant increase from baseline at 6 months in the cingulate cortex and frontal, temporal, and occipital lobes, along with the cerebellum and the cerebral cortex (data not provided; P > .49 reported for all end points). There were no differences between the groups treated with liraglutide vs placebo, with respect to amyloid deposition or cognition, implying that liraglutide can prevent the decline of CMRglc that correlates to cognitive impairment, synaptic dysfunction, and disease progression in patients with Alzheimer dementia.²⁰

Although liraglutide was 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. Although the use of GLP-1 receptor agonists to treat Alzheimer disease is promising, more research will be necessary to provide definitive evidence on the matter.

Osteoarthritis

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, pharmacological and preclinical data are 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, Hoffa fat pad, and bone tissue through the interaction between the GLP-1 receptor agonists and the GLP-1 receptors expressed in joint cells, such as chondrocytes, as well as in macrophages, in adipocytes, and on the osteocyte surface (Figure 4).²¹ 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. GLP-1 receptor agonists can also induce anabolic mechanisms, which include cell proliferation, cell differentiation, mineralization, and healing.²¹

Que et al evaluated a subcutaneous injection of liraglutide (50 μg/kg/day) for 28 days to treat knee osteoarthritis in a rat model by decreasing inflammation through the activation of the cAMP/PKA response element-binding protein (CREB). The results showed that treatment with liraglutide increased the expression of PKA (P < .0001), phospho-PKA (P < .0001), CREB (P < .0001), and p-CREB (P < .0001), and decreased the expression of inflammation-related proteins, such as tumor necrosis factor-a (P < .0001), IL-6 (P < .0001), and IL-1b (P < .0001), in the cartilage tissues of the osteoarthritis-affected knees vs treatment with saline. It is important to note that only P values were included as results in this study and the actual data were not provided. Based on these results, the study concluded that the anti-inflammatory effects of the GLP-1 receptor activation induced by liraglutide was through the PKA/CREB pathway, and that it provided promising targets for the development of potential efficacious treatments for osteoarthritis.22

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. The use of GLP-1 receptor agonists to treat osteoarthritisin clinical practice is promising, but more research in humans will be necessary to provide definitive evidence on the matter.

Chemical Dependency

The development of an 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 by inhibiting the dopamine release (Figure 5).¹³

The results of a preclinical study evaluating the ability of subcutaneous liraglutide at 0.1 mg/kg to decrease the accumbal dopamine release in mice showed that administration of liraglutide 60 minutes before the second alcohol injection of 1.75 g/kg significantly attenuated the alcohol-induced accumbal dopamine release in the liraglutide group vs the saline group, at 200 minutes (P < .05) and 240 to 280 minutes (P < .01), respectively. The authors also evaluated the effects of 0.1 mg/kg of subcutaneous liraglutide treatment on alcohol intake in rats and found that liraglutide significantly reduced alcohol intake in rats compared with saline (P < .01), as well as alcohol preference (P < .05) and food intake (P < .001), with no significant difference in the 24-hour baseline consumption.

Post hoc analysis of the third evaluation conducted by the authors revealed a significant alcohol deprivation effect in the saline-treated (P < .05) rats but not in the liraglutide-treated (P > .05) rats, and alcohol intake was higher in those who were treated with saline compared with those treated with liraglutide (P < .001). The post hoc analysis also revealed that liraglutide significantly reduced alcohol intake (g/kg; saline 2.6 + 0.4; liraglutide 0.6 + 0.1; P < .01) and alcohol preference (saline 41 + 7; liraglutide 12 + 3; P < .01) compared with the saline group, but no effect on food intake was observed. It is important to note that only P values were included as results in this study and the actual data were not provided.²³

Based on these results, GLP-1 receptor agonists may potentially suppress alcohol-induced accumbal dopamine release, prevent effects of alcohol deprivation, and reduce alcohol intake, which can attenuate the impact of alcohol withdrawal and reduce relapse in human patients living with an alcohol addiction.¹³ However, more research will be necessary to provide definitive evidence on the matter.

Conclusion

In recent years, the focus of scientific research on GLP-1 receptor agonists has primarily been on their role in therapy to treat patients with T2D and obesity. However, as the mechanisms and benefits of GLP-1 receptor agonists have become more understood, potential new opportunities have risen to use these agents to treat additional disease states and conditions. Although GLP-1 receptor agonists are still in the early stages of discovery and research, they could be beneficial in the treatment of many different conditions. As most of these disease states are degenerative in nature and lack curative therapy, the introduction of new and effective treatment options could provide patients and family members with hope, encouragement, and improved quality of life.

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