Beyond Ozempic: Understanding the Rapid Evolution of GLP-1 based Therapies

Glucagon – like peptide – 1 (GLP-1) receptor agonists have recently captured public interest in a way that hardly any other areas of medicine have. While these drugs were initially developed for blood glucose and weight control, we now know that GLP-1 receptors are widely distributed through the body including the brain, pancreas, gastrointestinal tract, cardiovascular system and several other organs. This extensive distribution explains the multitude of benefits we now know GLP-1 medications confer, that go far beyond weight loss.

The Rise of GLP-1 Medications:

GLP-1 is a naturally occurring hormone made in the intestines in response to consuming a meal. It helps regulate:

• Appetite and fullness
• Blood sugar levels
• Insulin release
• Stomach emptying

Weight Loss and so Much More:

GLP-1 receptor medications have now shown benefit in several conditions including:

• Chronic kidney disease
• Cardiovascular disease
• Metabolic dysfunction associated liver disease (MASLD)
• Osteoarthritis
• Obstructive sleep apnea
• Peripheral vascular disease
• Biomarkers of inflammation

In addition to the above, ongoing trials are exploring the use of GLP-1 medicines in people with substance use disorders, psychiatric disorders and neurodegenerative disorders.

What GLP-1 medications are currently FDA approved and available for use?

While there are a number of new drugs in the pipeline, there are currently 3 in this category that have been approved for the management of obesity.

Wegovy (Semaglutide):

• Available both as a pill and as a once weekly injection.

• Average weight loss: 19% body weight loss from baseline with both oral and injectable formulations.

• Key features: oral formulation must be taken on an empty stomach.

Foundayo (Orforglipron):

• GLP -1 receptor agonist to enter the market.

• Available as a once daily pill.

• Average weight loss: 11% body weight loss from baseline.

• Key features: can be taken at any time of the day.

Zepbound (Tirzepatide): A Dual Hormone Approach

• Activates both GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) receptors

• In addition to appetite suppression, GIP increases the breakdown of stored fat resulting in greater weight loss than earlier medications.

• Average weight loss approaching 20% or more i

• Once weekly injection

Triple-Hormone Therapies on the Horizon: Retatrutide

Medications are currently being studied that activate three hormone pathways simultaneously. These include GLP-1, GIP and glucagon receptors. These therapies aim to:

• Further reduce appetite
• Increase energy expenditure
• Improve metabolic health
• Potentially achieve even greater weight loss

Initial studies show weight loss approaching 25 - 30% with Retatrutide.

Frequently asked questions:

Can I stop taking my GLP-1 based medication once I have achieved my goal weight?

Obesity is a chronic condition and therefore these medications are recommended for long term use. Short term use and discontinuation of these medications have been shown in studies to lead to weight regain.

How do I know if I meet criteria to start one of these medications?

At the present time criteria for use in weight management are:

1. Obesity – defined as a body mass index > 30 Kg/m2
2. Overweight – BMI > 27 - 29.99 Kg/m2 with a weight related medical condition such as HTN, DMT2, Hyperlipidemia etc

What options do I have if my insurance does not cover any of these medications?

On July 1^st, Centers for Medicare & Medicaid Services will be launching the ‘Medicare GLP-1 Bridge short-term demonstration’ – a pilot program that will provide eligible Medicare Part D beneficiaries with access to certain GLP-1 drugs.

In addition, several self-pay options offered by the manufacturers of these drugs are now available.

Clinical Trials:

At Chase Medical Research we have several trials that are currently enrolling overweight and obese patients with and without diabetes. These trials are investigating GLP-1 or similar medications to gain a better understanding of the many benefits outlined above. If you are interested in learning more about these trials, please contact us at (203)419-4404.

References:

Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity Authors: Sean Wharton, M.D., Ildiko Lingvay, M.D., Pawel Bogdanski, M.D., Ruben Duque doVale, M.D., Stephan Jacob, M.D., Tobias Karlsson, M.D., Chaithra Shaji, M.Sc., Domenica Rubino, M.D., and W. Timothy Garvey, M.D., for the OASIS 4 Study Group

Published September 17, 2025 N Engl J Med 2025;393:1077-1087 DOI: 10.1056/NEJMoa2500969

Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment Authors: Sean Wharton, M.D., Louis J. Aronne, M.D., Adam Stefanski, M.D., Ph.D., Nasreen F. Alfaris, M.D., M.P.H., Andreea Ciudin, M.D., Ph.D., Koutaro Yokote, M.D., Ph.D., Bruno Halpern, M.D., Ph.D., Alpana P. Shukla, M.D., Chunmei Zhou, M.S., Lisa Macpherson, M.S.P.H., Sheryl E. Allen, M.D., Nadia N. Ahmad, M.D., M.P.H., and Suzanne R. Klise, B.S., for the ATTAIN-1 Trial Investigators^* -6

Published September 16, 2025 N Engl J Med 2025;393:1796-1806 DOI: 10.1056/NEJMoa2511774

Tirzepatide Once Weekly for the Treatment of Obesity

Authors: Ania M. Jastreboff, M.D., Ph.D., Louis J. Aronne, M.D., Nadia N. Ahmad, M.D., M.P.H., Sean Wharton, M.D., Pharm.D., Lisa Connery, M.D., Breno Alves, M.D., Arihiro Kiyosue, M.D., Ph.D., Shuyu Zhang, M.S., Bing Liu, Ph.D., Mathijs C. Bunck, M.D., Ph.D., and Adam Stefanski, M.D., Ph.D., for the SURMOUNT-1 Investigators Published June 4, 2022 N Engl J Med 2022;387:205-216 DOI: 10.1056/NEJMoa2206038

Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 TrialAuthors: Ania M. Jastreboff, M.D., Ph.D., Lee M. Kaplan, M.D., Ph.D., Juan P. Frías, M.D., Qiwei Wu, Ph.D., Yu Du, Ph.D., Sirel Gurbuz, M.D., Tamer Coskun, M.D., Ph.D., Axel Haupt, M.D., Ph.D., Zvonko Milicevic, M.D., and Mark L. Hartman, M.D., for the Retatrutide Phase 2 Obesity Trial Investigators Published June 26, 2023 N Engl J Med 2023;389:514-526 DOI: 10.1056/NEJMoa2301972