The Expanding Landscape of GLP-1 Receptor Agonists

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) originally entered the market for the treatment of type 2 diabetes (T2D) in 2005 with the approval of exenatide (Byetta; Bristol Myers Squibb).In the past 20 years, GLP-1 RAs have gained additional indications too include weight loss, cardiovascular disease (CVD) risk reduction, and obstructive sleep apnea (OSA), among others. As additional clinical trials demonstrate efficacy and multi-faceted benefit, the indications for GLP-1 RAs have expanded.

This cycle has already led to considerable growth and an evolving definition of how GLP-1 RAs are utilized across various indications. Current studies are exploring GLP-1 RA benefits in cardiometabolic conditions such as heart failure,metabolic-associated steatohepatitis (MASH),and polycystic ovary syndrome (PCOS). Furthermore, research is expanding into arthritic and neurological disease states, such as osteoarthritis, Alzheimer disease (AD), Parkinson disease, and more.

SURMOUNT-OSA (NCT05412004)

Published in June 2024, SURMOUNT-OSA was a randomized, placebo-controlled, 52-week phase 3 trial that investigated the efficacy and safety of tirzepatide (Mounjaro, Zepbound; Eli Lilly) for the treatment of moderate to severe OSA. Tirzepatide is a long-acting, glucose-dependent insulinotropic polypeptide (GIP)-GLP-1 receptor dual agonist that has shown remarkable efficacy in both diabetes and weight management.¹ OSA, if untreated, can lead to serious long-term complications. Weight loss remains the standard treatment proposal for OSA.¹

In SURMOUNT-OSA, participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy

## The Expanding Universe of GLP-1 Receptor Agonists

Gastrointestinal (GI) physiology has long been recognized for it’s role beyond digestion, and the incretin system is a prime example. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were initially developed to treat type 2 diabetes (T2D) by mimicking the effects of endogenous GLP-1, stimulating insulin secretion, suppressing glucagon, and slowing gastric emptying. However, the benefits of GLP-1 ras extend far beyond glycemic control, leading to thier increasing use in obesity management and exploration in a wide range of other conditions.

### Cardiometabolic Benefits

The cardiovascular (CV) benefits of GLP-1 RAs have been demonstrated in several landmark trials. Semaglutide, for example, showed a 26% reduction in major adverse cardiovascular events (MACE) in the SELECT trial, encompassing individuals with obesity and established CV disease but without T2D.¹ This trial expanded the therapeutic landscape, demonstrating CV protection independent of glycemic control.Beyond MACE reduction, GLP-1 RAs have shown promise in managing heart failure (HF) and chronic kidney disease (CKD). The FLOW trial demonstrated that semaglutide reduced the risk of CV death, nonfatal myocardial infarction, nonfatal stroke, or HF hospitalization in patients with T2D and established CV disease but without HF at baseline.² Similarly, the AMPLIFY-TOP trial showed that semaglutide slowed the progression of renal impairment in patients with T2D and CKD.³

Current guidelines reflect these findings, recommending GLP-1 RAs as first-line therapy for patients with T2D and established CV disease or CKD.⁴ For patients without these conditions, GLP-1 RAs are considered for those with obesity and additional cardiometabolic risk factors. Notably,currently approved therapies directed at nonalcoholic steatohepatitis (NASH),now termed metabolic dysfunction-associated steatohepatitis (MASH),only include sodium-glucose cotransporter-2 inhibitors,aldosterone antagonists,and angiotensin receptor-neprilysin inhibitors.⁵

### ESSENCE (NCT04822181)

MASH is a liver disorder characterized by damage and inflammation that manifests in patients with preexisting fatty liver disease.⁶ The best course of treatment for patients with MASH involves weight loss, and patients may need to lose up to 7% to 10% of their body weight to reduce liver inflammation and fibrosis.⁶

In the first part of the randomized, double-blind ESSENCE trial, semaglutide was compared with placebo over 72 weeks in 1197 patients with biopsy-defined steatohepatitis.⁷ Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the semaglutide group and 34.3% of the placebo group.⁷

Since the completion of the first part of the ESSENCE trial, the FDA has granted an approval for semaglutide in the treatment of MASH.⁸ The proven efficacy of semaglutide in weight loss has seemingly provided a way for patients to achieve the necessary weight loss targets to improve their outcomes associated with MASH.Part 2 of the ESSENCE trial is designed to continue for an additional 240 weeks and evaluate the difference in clinically significant events between the 2 groups.### A Look at the Horizon

Beyond the cardiometabolic realm, the neuroprotective benefits of GLP-1 RAs are still being researched. one recent study that made waves in the media was a target trial in 2024 that used emulation of electronic health records to determine whether semaglutide reduced the risk of AD diagnosis in patients with T2D.⁹ Using 7 different target trials,all comparing semaglutide with other antidiabetic medications,it was found that semaglutide displayed significant preclinical risk reduction in AD diagnosis.⁹ based on the results of the 7 target trials, semaglutide was associated with 40% to 70% reduced risks of first‐time AD diagnosis in T2D patients compared to other antidiabetic medications.⁹ Although these results are promising, there is a lack of real-world clinical evidence proving benefit at this moment, but future clinical trials may continue to explore neuroprotective benefits of the GLP-1 RAs.

There are clinical trials across the United states and globally evaluating the efficacy of GLP1 RA use in a litany of different disease states. In the past 2 years alone, GLP-1 therapies have seen 3 new FDA-approved indications. Ongoing trials are investigating both the direct and indirect benefits of GLP-1 RAs in other conditions, such as PCOS, osteoarthritic joint pain, and even neurodegenerative disorders, including Parkinson disease and AD.¹⁰

Semaglutide Approved for Treatment of MASH, Offering New Hope for Liver Disease

November 27, 2025 – In a landmark decision, the Food and Drug Governance (FDA) has approved semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). This approval marks the second medication specifically indicated for MASH, a severe form of nonalcoholic fatty liver disease (NAFLD), and represents a significant advancement in addressing a condition with limited treatment options. [1]

MASH, previously known as nonalcoholic steatohepatitis (NASH), affects millions worldwide and can lead to cirrhosis, liver failure, and liver cancer. It is often linked to obesity, type 2 diabetes, and metabolic syndrome. currently,the primary treatment strategies for MASH involve lifestyle modifications,such as diet and exercise,with limited pharmacological interventions available until recently. [6]

The approval is based on the positive results of the Phase 3 ESSENCE trial, which demonstrated that semaglutide considerably improved liver fibrosis and NASH resolution in adults with MASH and moderate to severe fibrosis, with no evidence of cirrhosis. [2] Specifically, the trial showed a statistically significant betterment in liver fibrosis by at least one stage without worsening of NASH, and a notable rate of NASH resolution.

Semaglutide’s mechanism of action extends beyond its well-established role in glucose control.It is indeed believed to exert beneficial effects on the liver by reducing inflammation and fat accumulation. The FDA’s decision acknowledges the substantial unmet need for effective MASH therapies and provides a new avenue for clinicians to address this growing health concern. [1]

While semaglutide offers a promising treatment option, it is significant to note that it is not a cure for MASH. Lifestyle interventions remain crucial for managing the condition and preventing its progression. Further research is ongoing to explore the long-term effects of semaglutide and its potential benefits in different patient populations. [1]

References:

[1] FDA approves treatment for serious liver disease known as ‘MASH’. News release. FDA. Updated August 15, 2025. Accessed November 25,2025. https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-serious-liver-disease-known-mash
[2] Phase 3 ESSENCE trial: semaglutide in metabolic dysfunction-associated steatohepatitis. Hepatol Gastroenterol (NY). 2024;20(12 Suppl 11):6-7.
[6] Nonalcoholic fatty liver disease (NAFLD) and NASH. National Institute of Diabetes and Digestive and Kidney Disease. April 2021. Accessed November 25, 2025. https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash