GLP-1 Receptor Agonists: A Guide for Prescribers

GLP-1 receptor agonists (GLP-1s) have made headlines for several years, with equal focus on the weight loss they provide and their side effects, such as muscle loss and “Ozempic® face.” Although the media reporting and usage of this class of drugs massively increased fairly recently, the first GLP-1 receptor agonist, exenatide, was actually approved more than 20 years ago for treating type 2 diabetes. 

Since then, other GLP-1s have received FDA approval, including liraglutide, dulaglutide, semaglutide, and tirzepatide. These newer medications are generally more effective and have better side effect profiles. Eventually, they supplanted exenatide, leading to its discontinuation by AstraZeneca in late 2024. 

As a class of medications, GLP-1s are effective for many patient populations, as shown by nearly two decades of research and patient usage data. This post will provide prescribers with an overview of the different GLP-1s, including their indications and administration routes, as well as emerging indications and new drugs. 

FDA-Approved GLP-1 Indications

Since 2005, the indications for GLP-1s have expanded to include weight loss, as well as indications encompassing kidney disease and cardiovascular disease. These FDA-approved indications include:

• Treating type 2 diabetes (semaglutide, dulaglutide, liraglutide, tirzepatide, exenatide, lixisenatide)
• Weight loss in overweight or obese patients (semaglutide, liraglutide, tirzepatide)
• Reduction in cardiovascular risks (semaglutide, dulaglutide, liraglutide)
• Obstructive sleep apnea in adults with obesity (tirzepatide)
• Noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH)/fatty liver disease in adults with moderate-to-advanced fibrosis (semaglutide)
• Reducing the risk of worsening kidney disease and cardiovascular death in adults with type 2 diabetes and chronic kidney disease (semaglutide)

The FDA recently approved Wegovy® 25 mg for two indications in combination with a reduced-calorie diet and increased physical activity:

• Reducing the risk of major cardiovascular events such as death, non-fatal myocardial infarction, or non-fatal stroke in adults with established CV disease and either obesity or overweight.
• To reduce excess body weight and maintain long-term weight reductions in adults with obesity, or in adults with overweight in the presence of at least one weight-related comorbidity. 

Ozempic® made headlines due to its off-label use for weight loss. Additional off-label indications for GLP-1s include addiction treatment, such as for nicotine and opioids,¹ and reducing inflammation.² Some early studies have suggested it can also improve knee osteoarthritis in patients with obesity.³

Administration Routes and Dosing Frequency 

The information shared here is meant to support understanding and awareness, not to provide medical advice, dosing instructions, or clinical recommendations. Any references to administration routes or dosing frequency are drawn directly from manufacturer materials, such as package inserts and published product information. Because everyone’s body, health history, and needs are different, treatment decisions should always be made in partnership with a qualified healthcare provider who can offer individualized guidance.

GLP-1s are typically administered via subcutaneous injection either daily or weekly, and semaglutide is also available as oral tablets. 

Daily injections: Liraglutide (Victoza®, Saxenda® once daily)

Weekly injections: Dulaglutide (Trulicity®), semaglutide (Ozempic® for diabetes, Wegovy® for obesity), and tirzepatide (Mounjaro®/Zepbound®)

Oral tablets: Semaglutide tablets (Rybelsus® and Wegovy®) are taken once daily on an empty stomach

Wegovy® tablets are first given at a dose of 1.5 mg for the first 30 days and then titrated up to 25 mg per day after 90 days. Rybelsus® tablets will generally be prescribed at a starting dose of 3 mg for the first 30 days and then increased to 7 mg after 30 days. If additional blood sugar control is needed after 30 days on the 7 mg dose, further dose escalation to 14 mg is possible. 

Side Effects of GLP-1s

Large trials^4–6 have shown reduced major adverse cardiovascular events with liraglutide, semaglutide, and dulaglutide versus placebo in high-risk diabetics. This wealth of long-term data shows that GLP-1s are generally well-tolerated, but gastrointestinal side effects are common, especially during initiation or dose titration. 

The most common adverse events include nausea, vomiting, diarrhea, and reduced appetite, and occur in up to half of patients. They are typically mild-to-moderate in severity and tend to diminish over time or with slower titration, demonstrating the critical need for a strong prescriber-patient relationship. Other frequent adverse effects include dizziness, headache, and injection-site redness/itch. GLP-1s also have a low risk of mild hypoglycemia, which can become more serious if patients are taking other medications that lower blood sugar, such as sulfonylureas or insulin.⁷

Although some studies have associated GLP-1s with minor tachycardia, they have shown various cardiovascular benefits, including improvements in blood pressure, lipid profile, cardiovascular-related mortality, as well as non-fatal myocardial infarction and stroke.⁸

Tirzepatide Versus Semaglutide 

Clinical trials have shown that tirzepatide leads to more weight loss than semaglutide. One large trial showed that tirzepatide 10 mg and 15 mg led to greater weight loss (20.2%) than semaglutide 2.4 mg, which led to 13.7% weight loss.⁹ This was in part because tirzepatide acts on both GIP and GLP-1 receptors, compared with semaglutide’s single GLP-1 action. Both are weekly injections with similar GI side effects (nausea, diarrhea, and constipation). 

Tirzepatide 5 mg, 10 mg, and 15 mg versus injectable semaglutide 0.5 mg were studied as second-line treatments for adults with type 2 diabetes mellitus, after metformin monotherapy. Glycated hemoglobin and weight reductions were greater for all tirzepatide doses versus semaglutide 0.5 mg, with similar adverse events for both medications.¹⁰ 

Other GLP-1s include:

• Liraglutide, which is a daily injection that provides weight loss of 5-10%, as well as cardiovascular benefits. Although it is generally less potent than semaglutide or tirzepatide, some studies have shown that it has lower rates of gastrointestinal side effects than semaglutide.
• Dulaglutide is a weekly injection that lowers A1c and has cardiovascular benefits. Although it is not FDA-approved for weight loss, patients typically see modest weight loss.¹¹

Emerging GLP-1 Receptor Agonists and Indications

The FDA-approved indications of GLP-1s are rapidly expanding, with 2025 seeing an expansion in the indications for existing medications. New administration routes have also been approved, with Novo Nordisk’s oral semaglutide tablets approved for obesity in late 2025, joining early approvals for Ozempic® for kidney disease in January and Wegovy® for MASH/fatty liver disease.

Retatrutide is being developed by Eli Lilly and Company and showed 24.2% weight loss at its highest dose as a once-weekly subcutaneous injection in a 48-week Phase 2 trial.12 Its side effects were mainly dose‐dependent GI symptoms (mitigated by slow titration). Retatrutide is now in Phase 3 trials for obesity, and the results of a Phase 2a sub-study suggested it may help treat metabolic dysfunction-associated steatotic liver disease (MASLD), i.e., nonalcoholic fatty liver disease.13

Oral GLP-1 pills like Rybelsus® are already approved for treating diabetes, and other pills such as orforglipron are in late-stage development for treating obesity. Lilly submitted orforglipron to the FDA with a priority voucher after positive Phase 3 maintenance data, and a decision is expected in 2026. 

Combination Therapies

Cagrilintide and semaglutide induce weight loss when administered separately, and CagriSema (2.4 mg of both cagrilintide and semaglutide) was submitted for FDA approval in December 2025 for weight management in adults with type 2 diabetes.¹⁴ The combination has also shown clinically relevant reductions in blood pressure.¹⁵ 

Despite how promising GLP-1s are overall, not every GLP-1 is a success story, with Pfizer discontinuing the development of its GLP-1 danuglipron because a single asymptomatic participant in a dose-optimization study experienced drug-induced liver injury.

Conclusion

GLP-1s are a powerful weapon for fighting diabetes, obesity, and cardiovascular disease. Prescribers should choose the right medication, dose, and administration route for each patient by considering each individual’s goals (weight loss versus primarily glucose control), preference (pill or injection; daily versus weekly), and tolerance of gastrointestinal side effects. 

References

1. Xie Y, Choi T, Al-Aly Z. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nat Med. 2025;31(3):951-962. doi:10.1038/s41591-024-03412-w
2. Mehdi SF, Pusapati S, Anwar MS, et al. Glucagon-like peptide-1: a multi-faceted anti-inflammatory agent. Front Immunol. 2023;14:1148209. doi:10.3389/fimmu.2023.1148209
3. 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
4. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes | New England Journal of Medicine. Accessed January 9, 2026. https://www.nejm.org/doi/full/10.1056/NEJMoa1603827
5. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes | New England Journal of Medicine. Accessed January 9, 2026. https://www.nejm.org/doi/full/10.1056/NEJMoa1607141
6. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial – The Lancet. Accessed January 9, 2026. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31149-3/abstract
7. Filippatos TD, Panagiotopoulou TV, Elisaf MS. Adverse Effects of GLP-1 Receptor Agonists. Rev Diabet Stud RDS. 2014;11(3):202-230. doi:10.1900/RDS.2014.11.202
8. Bramante CT, Raatz S, Bomberg EM, Oberle MM, Ryder JR. Cardiovascular Risks and Benefits of Medications Used for Weight Loss. Front Endocrinol. 2020;10. doi:10.3389/fendo.2019.00883
9. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity | New England Journal of Medicine. Accessed January 16, 2026. https://www.nejm.org/doi/10.1056/NEJMoa2416394
10. Osumili B, Fan L, Paik JS, et al. Tirzepatide 5, 10 and 15 mg versus injectable semaglutide 0.5 mg for the treatment of type 2 diabetes: An adjusted indirect treatment comparison. Diabetes Res Clin Pract. 2024;212. doi:10.1016/j.diabres.2024.111717
11. Bonora E, Frias JP, Tinahones FJ, et al. Effect of dulaglutide 3.0 and 4.5 mg on weight in patients with type 2 diabetes: Exploratory analyses of AWARD‐11. Diabetes Obes Metab. 2021;23(10):2242-2250. doi:10.1111/dom.14465
12. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial | New England Journal of Medicine. Accessed January 9, 2026. https://www.nejm.org/doi/10.1056/NEJMoa2301972?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
13. Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024;30(7):2037-2048. doi:10.1038/s41591-024-03018-2
14. Davies MJ, Bajaj HS, Broholm C, et al. Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. N Engl J Med. 2025;393(7):648-659. doi:10.1056/NEJMoa2502082
15. Verma S, Böttcher M, Brown P, et al. CagriSema Reduces Blood Pressure in Adults With Overweight or Obesity: REDEFINE 1. Hypertension. 0(0). doi:10.1161/HYPERTENSIONAHA.125.26055

 

 

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