Redefining the Role of GLP-1 Therapies: The Clinical Trials Behind the Expanding Indications

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 to 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 substantial 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 exceptional efficacy in both diabetes and weight management.¹ OSA, if untreated, can lead to serious long-term complications. Weight loss remains the standard treatment recommendation 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 at baseline were enrolled in trial 2.¹ The primary end point was the change in the apnea–hypopnea index.¹ When compared to placebo, tirzepatide showed an estimated treatment difference of −20.0 and -23.8 events per hour for trials 1 and 2, respectively.¹ Based on these significant results, tirzepatide was FDA-approved for the treatment of OSA in December of 2024.²

FLOW (NCT03819153)

The FLOW trial, a phase 3, randomized, placebo-controlled trial, evaluated the efficacy of semaglutide (Ozempic; Novo Nordisk) in the progression of renal impairment in chronic kidney disease.³ A total of 3533 participants underwent randomization, with the primary outcome being a composite of different adverse renal events.³ The composite included onset of kidney failure, a sustained 50% or greater reduction in estimated glomerular filtration rate (eGFR) from baseline, or death from kidney-related or cardiovascular causes.³

The risk of a primary outcome event was 24% lower in the semaglutide group than in the placebo group.³ Additionally, the mean annual slope of eGFR was significantly less steep (indicating a slower decrease) in the semaglutide group than in the placebo group (−2.19 vs. −3.36 ml/min per year).³ Based on these outcomes, semaglutide displayed efficacy in both reducing the risk of major adverse events and preserving kidney function.³

The FLOW trial was originally planned to last for 3.4 years but, because of the displayed benefit, was ended more than a year early by the FDA.³ In January 2025, semaglutide was approved for risk reduction in adults with chronic kidney disease (CKD) and T2D.³

STEP-HFpEF (NCT04916470)

With new indications for OSA and CKD approved in the past year, a potential new indication for risk reduction in heart failure with preserved ejection fraction (HFpEF) is expected soon. The STEP-HFpEF trial, completed in 2023, was a randomized controlled trial that evaluated the benefits of semaglutide in patients living with HFpEF and obesity.⁴

The trial had dual primary end points: the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and the change in body weight.⁴ The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo (with higher scores indicating better status), and the mean percentage change in body weight was -13.3% with semaglutide and -2.6% with placebo.⁴ Because of the significant improvement in functional capacity and weight loss, the FDA is currently evaluating semaglutide for an HFpEF indication. This is a potentially huge shift in future treatment strategies for HFpEF, as current guideline-directed therapies 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 Overall, 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.^10-12

Currently, it is uncertain whether these trials will lead to new FDA indications and shifts in guidelines. However, in the past decade, the GLP-1 drug class has reshaped the landscape of pharmacological treatment in cardiometabolic conditions. With ongoing trials and new indications on the horizon, the therapeutic landscape continues to rapidly evolve. Staying informed on the emerging evidence will be crucial for health care professionals to ensure GLP-1 therapies are used safely and effectively in the populations that stand to benefit.

REFERENCES

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2. FDA approves first medication for obstructive sleep apnea. News release. FDA. Updated December 20, 2024. Accessed November 25, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-medication-obstructive-sleep-apnea

3. Perkovic V, Tuttle KR, Rossing P, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024;391(2):109-121. doi:10.1056/NEJMoa2403347

4. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med. 2023;389(12):1069-1084. doi:10.1056/NEJMoa2306963

5. Kittleson MM, Panjrath GS, Amancherla K, et al. 2023 ACC expert consensus decision pathway on management of heart failure with preserved ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. JACC. 2023;81(18).

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

7. Phase 3 ESSENCE trial: semaglutide in metabolic dysfunction-associated steatohepatitis. Gastroenterol Hepatol (NY). 2024;20(12 Suppl 11):6-7.

8. 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/drugs/news-events-human-drugs/fda-approves-treatment-serious-liver-disease-known-mash

9. Wang W, Wang QQ, Qi X, et al. Associations of semaglutide with first-time diagnosis of Alzheimer’s disease in patients with type 2 diabetes: target trial emulating using nationwide real-world data in the US. Alzheimers Dement. 2024;20(12):8661-8672. doi:10.1002/alz.14313. doi:10.1002/alz.14313

10. Lin S, Deng Y, Huang J, et al. Efficacy and safety of GLP-1 receptor agonists on weight management and metabolic parameters in PCOS women: a meta-analysis of randomized controlled trials. Sci Rep. 2025;15(1):16512. doi:10.1038/s41598-025-99622-4

11. Bliddal H, Bays H, Czernichow S, et al. Once-weekly semaglutide in persons with obesity and knee osteoarthritis. N Engl J Med. 2024;391(17):1573-1583. doi:10.1056/NEJMoa2403664

12. Messak M, Abdelmageed A, Senbel AA, et al. Efficacy and safety of GLP-1 agonists in Parkinson’s disease: a systematic review and meta-analysis of randomized controlled trials. Naunyn Schmiedebergs Arch Pharmacol. 2025;398(8):9721-9736. doi:10.1007/s00210-025-03932-3