GLP-1 Receptor Agonists: Current Roles in Medicine

In recent years, the popularity of glucagon-like peptide 1 receptor agonists (GLP-1RAs) has skyrocketed, along with interest in clinical applications beyond diabetes and weight management. Here, we present a brief review of GLP-1RAs, including a history, a look at the mechanism of action, pivotal results in diabetes trials, pivotal results in weight management studies, current indications, and potential future indications.

In the 1980s, the Habener lab first identified GLP-1 as a target for the treatment of diabetes, through use of cloned recombinant complementary DNA (cDNA) copies of messenger RNAs (mRNA) with anglerfish genes. Later, others utilized proglucagon sequences from various mammalian sequences; mammalian pre-proglucagons were found to encode not only glucagon but two glucagon-related peptides (GLP-1 and GLP-2).¹ In 1987, Drucker et al published their findings on the role of GLP-1 in stimulating glucose-dependent insulin synthesis and secretion.² Subsequent studies found that GLP-1 also suppresses glucagon release and acts on other organ groups, including delay of gastric emptying, hepatic decrease in gluconeogenesis, and hypothalamic action leading to hunger reduction.^1,3 These findings did not translate into an FDA-approved therapy until 2 decades later.⁴

Diabetes Trials and Drug Development

The early GLP-1RAs have a relatively short half-life, which require twice-daily injection and were studied exclusively for Type 2 diabetes mellitus (T2DM) management.3 Exenatide was the first GLP-1RA approved for management of T2DM, following 2005 phase 3 results in a randomized, placebo-controlled clinical trial.⁴ In this trial, patients with T2DM were randomized to receive metformin in combination with twice-daily exenatide subcutaneous injections at differing doses (5-μg or 10-μg) or metformin monotherapy. The primary endpoint was comparing change in hemoglobin A1c (HbA1c) after 30 weeks, with a set of secondary endpoints that included bodyweight. At week 30, both treatment arms achieved significant HbA1c reduction (5-μg: -0.4%; 10-μg: -0.8%), compared to placebo (+0.1%) along with significant body weight reduction (5-μg: -1.6 kg; 10-μg: -2.8 kg; placebo -0.3 kg).⁴

Exenatide is a 39-amino acid synthetic peptide based on exendin-4, a hormone from the saliva of the Gila monster. Exendin-4 shares significant sequence homology with human GLP-1, with similar binding affinity to the human GLP-1 receptor.³ Liraglutide is a modified version of human GLP-1 with a 31-amino acid peptide chain and two major substitutions: a palmitic acid attached to lysine at position 26 and a substitution of lysine with arginine at position 34. These modifications led to less frequent dosing (due to the conjugated palmitic acid allowing binding to albumin in the blood), and liraglutide was approved in 2014 for the treatment of T2DM as a daily administration.5 Semaglutide is also a modified version of human GLP-1 with a 31-amino acid peptide chain and two differing major substitutions: a substitution of alanine with α-aminoisobutyric acid (Aib) at position 8 and a longer fatty acid chain attached to lysine at position 26. These modifications further enhanced albumin binding, extending the drug’s half-life, and semaglutide was approved in 2017 for the treatment of T2DM as a weekly administration.⁶

The SUSTAIN-1 trial, published in 2017, was a phase 3 randomized, placebo-controlled clinical trial that compared once-weekly semaglutide to placebo in patients with T2DM. Patients were randomized to receive semaglutide (0.5 mg or 1.0 mg) or placebo. Mean baseline HbA1c was 8.05%, with significant reduction at 30 weeks in both treatment arms (0.5 mg: 1.45%; 1.0 mg: 1.55%) compared to placebo (0.02%). Mean bodyweight reduction was similarly significant in both treatment arms (0.5 mg: -3.73 kg; 1.0 mg: -4.53 kg), without a similar effect observed in the placebo group (-0.98 kg).⁶

The PIONEER-1 trial, published in 2019, evaluated the first oral GLP-1RA, oral semaglutide. In this phase 3, randomized, placebo-controlled trial, once-daily oral semaglutide was compared to placebo in patients with T2DM. Patients were randomized to receive oral semaglutide (3 mg, 7 mg or 14mg) or placebo. Mean baseline HbA1c was 8.0% with significant reduction in all three treatment arms with placebo-adjusted treatment differences of -0.7% (3 mg), -1.2% (7 mg) and -1.4% (14 mg).⁷

The SURPASS-1 trial, published in 2021, evaluated a novel dual GLP-1RA and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, tirzepatide. In this phase 3, randomized, placebo-controlled trial, once-weekly tirzepatide was compared to placebo in patients with T2DM. Patients were randomized to receive tirzepatide (5 mg, 10 mg or 15 mg) or placebo. Mean baseline HbA1c was 7.9%, with significant reduction in all three treatment arms (5 mg: -1.87%; 10 mg: -1.89%; 15 mg: -2.07%) compared to placebo (+0.04%), along with dose-dependent body weight loss of 7.0-9.5 kg.⁸

Weight Loss and Other Indications

Three GLP-1RAs have gone on to receive FDA approval for weight loss in patients with obesity, including liraglutide (2014), semaglutide (2021), and tirzepatide (2023).^9-11

The SCALE trial, published in 2015, was a phase 3 randomized, placebo-controlled clinical trial that compared once-daily subcutaneous injections of liraglutide 3.0 mg vs placebo in patients with obesity without T2DM. Mean baseline body weight was 106.2 kg, with a significant average weight reduction at Week 56 in the treatment arm (-8.4 kg), in comparison to placebo (-2.8 kg).⁹

The STEP-1 trial, published in 2021, was a phase 3 randomized, placebo-controlled trial that compared once-weekly subcutaneous injections of semaglutide at 2.4 mg vs placebo in patients with obesity without T2DM. A significant reduction in body weight at Week 68 was seen in the treatment arm (-15.3 kg) vs placebo (-2.6 kg).¹⁰

The SURMOUNT-1 trial, published in 2022, was a phase 3 randomized, placebo-controlled trial that compared once-weekly subcutaneous injections of tirzepatide at 5 mg, 10 mg, and 15 mg vs placebo in patients with obesity without T2DM. Mean baseline body weight was 104.8 kg, with a significant average weight reduction of -15.0% (5 mg), -19.5% (10 mg), and -20.9% (15 mg) in the three treatment arms in comparison to -3.1% in the placebo group.¹¹

A recent phase 3, open-label, controlled clinical trial compared once-weekly tirzepatide (10 mg or 15 mg) to semaglutide (1.7 mg or 2.4 mg) in patients with obesity without T2DM. At Week 72, patients receiving tirzepatide had significantly greater reduction in least-squares mean percent change in weight (-20.2%) compared to those receiving semaglutide (-13.7%).¹²

Other Potential Roles

Apart from T2DM and weight management, current FDA-approved indications for GLP-1RAs include obstructive sleep apnea and metabolic dysfunction-associated steatohepatitis (MASH) for tirzepatide and semaglutide, respectively.^13,14

Trials for other types of diabetes are being considered, including type 1 diabetes mellitus, gestational diabetes, steroid-induced diabetes, maturity-onset diabetes in the young (MODY), and diabetes related to cystic fibrosis. In further extension of the curiosity surrounding metabolic management, conditions related to both diabetes and obesity are being investigated, including coronary heart disease, heart failure with preserved ejection fraction, chronic kidney disease, knee osteoarthritis, polycystic ovarian syndrome (PCOS), and obesity-related asthma.¹⁵

The role of GLP-1RAs in the treatment of addiction, owing to its action in several brain regions involved in reward processing, is a particularly interesting area of investigation. At this moment, trials are ongoing for the role of GLP-1RA in the treatment of alcohol use disorder, opioid use disorder, methamphetamine use disorder, and nicotine use disorder.^15,16

Conditions not related to diabetes or obesity under investigation for the role of GLP-1RAs in management include idiopathic intracranial hypertension, open-angle glaucoma, Parkinson’s disease, and Alzheimer’s disease. Inflammatory conditions with concomitant obesity, including psoriasis/psoriatic arthritis treated with ixekizumab and inflammatory bowel disease treated with biologics, are of interest as well.¹⁵

Further implications will be discussed in a subsequent article. 

1. Drucker DJ, Habener JF, Holst JJ. Discovery, characterization, and clinical development of the glucagon-like peptides. J Clin Invest. 2017;127(12):4217-4227. https://doi.org/10.1172/JCI97233

2. Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF. Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci U S A. 1987;84(10):3434-3438. https://doi.org/10.1073/pnas.84.10.3434

3. Cornell S. A review of GLP-1 receptor agonists in type 2 diabetes: a focus on the mechanism of action of once-weekly agents. J Clin Pharm Ther. 2020;45(Suppl 1):17-27. https://doi.org/10.1111/jcpt.13230

4. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28(5):1092-1100. https://doi.org/10.2337/diacare.28.5.1092

5. Marre M, Shaw J, Brändle M, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med. 2009;26(3):268-278. https://doi.org/10.1111/j.1464-5491.2009.02666.x

6. Sorli C, Harashima SI, Tsoukas GM, et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017;5(4):251-260. https://doi.org/10.1016/S2213-8587(17)30013-X

7. Aroda VR, Rosenstock J, Terauchi Y, et al. PIONEER 1: randomized clinical trial of the efficacy and safety of oral semaglutide monotherapy in comparison with placebo in patients with type 2 diabetes. Diabetes Care. 2019;42(9):1724-1732. https://doi.org/10.2337/dc19-0749

8. Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-155. https://doi.org/10.1016/S0140-6736(21)01324-6

9. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11-22. https://doi.org/10.1056/NEJMoa1411892

10. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. https://doi.org/10.1056/NEJMoa2032183

11. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216. https://doi.org/10.1056/NEJMoa2206038

12. Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as compared with semaglutide for the treatment of obesity. N Engl J Med. 2025;393(1):26-36. https://doi.org/10.1056/NEJMoa2416394

13. Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the treatment of obstructive sleep apnea and obesity. N Engl J Med. 2024;391(13):1193-1205. https://doi.org/10.1056/NEJMoa2404881

14. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. https://doi.org/10.1056/NEJMoa2413258

15. ClinicalTrials.gov. https://clinicaltrials.gov/search?intr=GLP-1. Published 2025. Accessed September 1, 2025.

16. Klausen MK, Thomsen M, Wortwein G, Fink-Jensen A. The role of glucagon-like peptide 1 (GLP-1) in addictive disorders. Br J Pharmacol. 2022;179(4):625-641. https://doi.org/10.1111/bph.15677

Corey L. Snyder, MD

• Dermatology resident
• Dell Medical School, The University of Texas at Austin, Austin, TX

Youssef Abdullah, MD, MBA

• Resident physician, Dell Medical School
• Co-founder, Le Chateau
  Austin, TX

Olayemi Olubowale, MD, MA

• Obesity medicine fellow
• Massachusetts General Hospital
  Boston, MA

Ted Lain, MD

• Austin Institute for Clinical Research, Austin, TX