Diabetes Dialogue: Celebrating 2025 as The Year of the Incretin Therapy

Welcome back to Diabetes Dialogue: Technology, Therapeutics, & Real-World Perspectives!

The rise of GLP-1 receptor agonists across a multitude of specialties and into the public consciousness has been meteoric and while many specialties now marvel at the effects of the class, endocrinology has been bearing witness to this ascent for years.

In 2025, several regulatory decisions and clinical trials have been nothing short of practice-changing, emphasizing the broad applicability of this medication across diabetes, obesity, chronic kidney disease, heart failure, and a variety of other conditions. Additionally, key approvals from the US Food and Drug Administration have positioned GLP-1 agents as critical components in the ongoing effort to lastingly and effectively treat obesity.

In this special edition of Diabetes Dialogue recorded for HCPLive’s This Year in Medicine series, cohosts Diana Isaacs, PharmD, an endocrine clinical pharmacist, director of Education and Training in Diabetes Technology, and co-director of Endocrine Disorders in Pregnancy at the Cleveland Clinic, and Natalie Bellini, DNP, program director of Diabetes Technology at University Hospitals Diabetes and Metabolic Care Center, review an unprecedented year of advances in incretin-based therapies in 2025.

January: FLOW and Semaglutide in CKD

Isaacs and Bellini open this episode by highlighting a landmark milestone from January 2025: the FDA’s approval of semaglutide for patients with type 2 diabetes and CKD, based on the FLOW trial. Bellini emphasizes how FLOW reshaped treatment algorithms by definitively establishing renal protection as a primary, not incidental, benefit of semaglutide. With clear evidence that GLP-1 receptor agonists can slow progression to advanced CKD—even when SGLT2 inhibitors are not tolerated—the hosts note this represents a genuine paradigm shift toward confident combination therapy.

February: FDA Ends the Semaglutide Shortage

Isaacs and Bellini also highlighted the end of the global semaglutide shortage in February 2025. During the shortage, clinicians were often forced to switch patients between multiple medications to achieve similar treatment with a limited supply. Oftentimes, as Bellini notes, patients using a 2 mg dose were moved to 1 mg when the former ran out, and then to an 0.5 mg dose when the 1 mg dose ran out. Novo Nordisk’s ultimate decision to ramp up production of semaglutide significantly alleviated the pressures of the shortage, and since then, the field has seen a substantial decrease in usage of compounding pharmacies.

March: STRIDE and Semaglutide in Peripheral Artery Disease

Conversation turns to March and the STRIDE trial, where semaglutide significantly improved pain-free walking distance in patients with peripheral artery disease. Isaacs and Bellini underscore how this data reinforces GLP-1 agents as cardiometabolic therapies with broad vascular relevance, particularly given the accessibility of walking as a functional endpoint. Additionally, the trial highlighted the cardiovascular aspect of diabetes, as it substantially increases heart attack and stroke risk – making diabetes the ideal crosspoint for adopting GLP-1 agents into cardiovascular care.

June: The American Diabetes Association Scientific Sessions

June’s ADA Scientific Sessions brought an “explosive” volume of incretin data. They spotlight the monthly GLP-1 candidate MariTide, producing ~16% weight loss in early studies; the oral GLP-1 orforglipron, which delivered strong A1c and weight reductions without dosing-timing constraints; and the dual amylin/GLP-1 combination Cagri-Sema (semaglutide and cagrilintide) in the REDEFINE program, with weight-loss results surpassing 20% in people without diabetes and nearly 14% in those with type 2 diabetes. They also discuss STEP UP, where a higher 7.2-mg semaglutide dose achieved a 21% weight reduction with acceptable tolerability, and the SLIMMER trial’s glucagon/GLP-1 dual-agonist ecnoglutide, which delivered more than 13% mean weight loss. The hosts emphasize that, taken together, these studies signal a future defined by combination incretin pharmacology and diversified receptor targeting.

July: SURPASS-CVOT and Tirzepatide in Cardiovascular Disease

The July discussion centers on the SURPASS-CVOT top-line results. Although tirzepatide did not demonstrate superiority over dulaglutide, it achieved cardiovascular noninferiority, reinforcing clinical comfort in using tirzepatide for patients with elevated CV risk. They highlight the pre-specified indirect comparison suggesting a potential 28% reduction in three-point MACE and 39% reduction in all-cause mortality relative to a putative placebo. Additional analyses indicating slowed eGFR decline in high-risk CKD populations further broaden the therapeutic rationale.

August: Semaglutide in MASH and Orforglipron in Obesity

August delivered another milestone with semaglutide gaining FDA approval for metabolic dysfunction–associated steatohepatitis (MASH), becoming only the second therapy approved for this increasingly recognized condition. The hosts describe how this approval is already changing clinical workflows—with broader screening, routine incorporation of FIB-4 scoring, and stronger justification for GLP-1–based therapy in metabolic liver disease. In parallel, orforglipron produced 12% weight loss in obesity trials, signaling likely future broad utility.

October: SOUL and Oral Semaglutide

By October, oral semaglutide achieved its own cardiovascular-risk-reduction indication via the SOUL trial, alleviating long-standing concerns about the CV efficacy of oral formulations. This new data also opened a new potential treatment pathway for patients unwilling or unable to receive injectable agents. Semaglutide is now the only oral GLP-1 receptor agonist currently available, but the promising results of SOUL promise more to come.

November: Semaglutide in Alzheimer’s Disease

Isaacs and Bellini review November’s disappointing termination of Novo Nordisk’s oral semaglutide Alzheimer’s disease trial, in which the GLP-1 agent was unable to prevent disease progression to a statistically significant degree. While progression was not slowed, the hosts point to expert commentary suggesting the possibility that therapy must begin earlier or use injectable formulations to meaningfully influence neurodegenerative pathways, leaving the door open for future investigation.

December: SURMOUNT-4 and Weight Gain After Withdrawal from Tirzepatide

The episode concludes with new post-hoc findings from SURMOUNT-4, showing that more than 80% of individuals withdrawing from tirzepatide regained at least 25% of their prior weight loss, accompanied by reversal of cardiometabolic improvements. Isaacs and Bellini stress the core message: obesity is a chronic disease requiring chronic treatment, and the accumulating benefits of incretin-based therapies—in renal protection, cardiovascular risk reduction, liver disease, and weight management—reinforce the importance of long-term continuity.

References:

1. Novo Nordisk. FDA approves Ozempic® (semaglutide) as the only GLP-1 RA to reduce the risk of worsening kidney disease and cardiovascular death in adults with type 2 diabetes and chronic kidney disease. January 28, 2025. Accessed January 28, 2025. https://www.novonordisk-us.com/media/news-archive/news-details.html?id=915253.

2. Novo Nordisk. FDA declares Wegovy® and Ozempic® shortage is over and that Novo Nordisk is fully meeting or exceeding nationwide demand for all doses. PR Newswire: press release distribution, targeting, monitoring and marketing. February 21, 2025. Accessed February 21, 2025. https://www.prnewswire.com/news-releases/fda-declares-wegovy-and-ozempic-shortage-is-over-and-that-novo-nordisk-is-fully-meeting-or-exceeding-nationwide-demand-for-all-doses-302382370.html.

3. Bonaca MP, Catarig A, Houlind K. Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE): a phase 3b, double-blind, randomised, placebo-controlled trial. The Lancet. Published online March 29, 2025. doi: 10.1016/S0140-6736(25)00509-4

4. Johnson V. ADA 2025 Recap: 5 Studies on Obesity to Know. Hcplive.com. Published June 25, 2025. Accessed December 3, 2025. https://www.hcplive.com/view/ada-2025-recap-5-studies-on-obesity-to-know

5. Eli Lilly and Company. Lilly's Mounjaro (tirzepatide), a GIP/GLP-1 dual agonist, demonstrated cardiovascular protection in landmark head-to-head trial, reinforcing its benefit in patients with type 2 diabetes and heart disease. July 31, 2025. Accessed July 31, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-mounjaro-tirzepatide-gipglp-1-dual-agonist-demonstrated

6. Novo Nordisk. Wegovy® approved by FDA for the treatment of adults with noncirrhotic MASH with moderate to advanced liver fibrosis. August 15, 2025. Accessed August 15, 2025. https://www.novonordisk-us.com/media/news-archive/news-details.html?id=916417.

7. Eli Lilly and Company. Lilly's oral GLP-1, orforglipron, delivers weight loss of up to an average of 27.3 lbs in first of two pivotal Phase 3 trials in adults with obesity. August 7, 2025. Accessed August 7, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-delivers-weight-loss-average-273.

8. Novo Nordisk, Inc. FDA approves Novo Nordisk’s oral semaglutide for cardiovascular (CV) risk reduction in adults with type 2 diabetes who are at high risk, including those who have not had a prior CV event. PR Newswire. October 17, 2025. Accessed October 20, 2025. https://www.prnewswire.com/news-releases/fda-approves-novo-nordisks-oral-semaglutide-for-cardiovascular-cv-risk-reduction-in-adults-with-type-2-diabetes-who-are-at-high-risk-including-those-who-have-not-had-a-prior-cv-event-302588005.html.

9. Novo Nordisk. Novo Nordisk A/S: Evoke phase 3 trials did not demonstrate a statistically significant reduction in Alzheimer’s disease progression. November 24, 2025. Accessed November 24, 2025. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916462.

10. Horn DB, Linetzky B, Davies MJ, et al. Cardiometabolic Parameter Change by Weight Regain on Tirzepatide Withdrawal in Adults With Obesity: A Post Hoc Analysis of the SURMOUNT-4 Trial. JAMA Intern Med. Published online November 24, 2025. doi:10.1001/jamainternmed.2025.6112