Natalie Bellini, DNP, FNP-BC, BC-ADM, CDCES

TRIUMPH-4: Topline Data Highlights Retatrutide's Significant Weight Loss Effects

On December 11, 2025, Eli Lilly announced positive topline results from the phase 3 TRIUMPH-4 trial, evaluating retatrutide in patients with overweight or obesity and osteoarthritis. The investigational once-weekly triple hormone receptor agonist, delivered at the 2 highest doses approved for investigation, provided substantial weight loss while reducing WOMAC pain subscale score and various markers for cardiovascular risk. Full data from the trial will be presented at an upcoming medical conference.

Diabetes Dialogue cohosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, discuss TRIUMPH-4 and its results, highlighting the promising efficacy data surrounding retatrutide in weight loss.

Check out the full episode on recent GLP-1 trials and results 

In this segment, Isaacs and Bellini discuss emerging topline findings from the TRIUMPH-4 phase 3 trial evaluating retatrutide, a novel triple-agonist therapy targeting GLP-1, GIP, and glucagon receptors, in individuals with obesity and osteoarthritis. Over 68 weeks, participants receiving the highest dose (12 mg) achieved an average weight loss of 71.2 pounds, representing 28.7% of body weight, while the 9 mg dose produced 26.4% weight loss, compared with 2.1% in the placebo group despite concurrent lifestyle counseling. With a baseline average BMI of 40 and mean starting weight of 248 pounds, the magnitude of weight reduction was described as unprecedented in clinical trials.

Beyond weight outcomes, investigators evaluated osteoarthritis symptoms using the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index), a validated patient-reported measure of pain, stiffness, and physical function. The results demonstrated substantial improvements in osteoarthritis-related symptoms, including a striking finding that one in eight participants treated with retatrutide reported complete resolution of knee pain by the end of the trial. Improvements in WOMAC scores were observed across dosing groups, with similar symptom benefits between the 9 mg and 12 mg doses despite the incremental difference in weight loss.

Secondary endpoints further underscored the drug’s efficacy: 47% of participants on the 9 mg dose and 58% on the 12 mg dose achieved at least 25% weight loss, while 30–39% achieved 30% weight loss, and 18–23.7% achieved 35% weight loss depending on dose. These results suggest that clinically meaningful outcomes may be attainable even at lower doses, which may have implications for tolerability and treatment adherence.

The hosts also review the emerging safety profile. Gastrointestinal events were the most common adverse effects, including nausea (38.1% with 9 mg; 43% with 12 mg vs 10% with placebo), along with diarrhea and constipation. Treatment discontinuation occurred in 12% of participants receiving 9 mg and 18% receiving 12 mg, compared with 4% in the placebo group, highlighting the importance of managing side effects in clinical practice.

Finally, the discussion highlights the broader development program for retatrutide, with seven additional phase 3 trials underway evaluating the once-weekly therapy in obesity and type 2 diabetes, all expected to conclude in 2026. Isaacs and Bellini emphasize the medication’s novelty as a triple-agonist metabolic therapy, which may explain its exceptional weight-loss efficacy. They conclude by underscoring the importance of multidisciplinary care, including dietitians and diabetes education specialists, to help patients optimize nutrition, mitigate gastrointestinal side effects, and sustain treatment adherence as this new class of therapies continues to evolve.

Editor’s Note: Isaacs reports disclosures with Dexcom, Abbott, Lilly, Novo Nordisk, Medtronic, Insulet, and others. Bellini reports disclosures with Abbott Diabetes Care, MannKind, Povention Bio, and others.

Eli Lilly. Lilly’s triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful phase 3 trial. December 11, 2025. Accessed March 6, 2026. 

https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average

Eli Lilly and Company. A Study of Retatrutide (LY3437943) Once Weekly in Participants Who Have Obesity or Overweight and Osteoarthritis of the Knee (TRIUMPH-4). ClinicalTrials.gov Identifier: NCT05931367. Updated January 21, 2026. Accessed March 6, 2026. 

https://clinicaltrials.gov/study/NCT05931367

Videos

Diabetes Dialogue cohosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, discuss topline results from the TRIUMPH-4 trial, demonstrating retatrutide's efficacy in promoting weight loss.

ACHIEVE-3: Orforglipron Demonstrates Superiority to Semaglutide in Poorly Controlled T2D

Eli Lilly’s investigational once-daily GLP-1 receptor agonist orforglipron has outperformed oral semaglutide 7 and 14 mg in patients with type 2 diabetes inadequately controlled with metformin. Over 52 weeks, orforglipron resulted in superior improvements in weight and A1C, demonstrating superiority over the primary and all key secondary endpoints. Notably, orforglipron exhibits no food or water restrictions, setting it apart from existing oral GLP-1s.

Diabetes Dialogue cohosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, discuss the results of ACHIEVE-3 and the promise of orforglipron as an oral GLP-1 with no dietary restrictions.

Check out the full episode on recent GLP-1 trials and results 

In this segment, Isaacs and Bellini discuss the recently published results of the ACHIEVE-3 Trial, a phase 3 study evaluating the investigational oral GLP-1 receptor agonist Orforglipron. Unlike peptide-based GLP-1 therapies, orforglipron is a non-peptide molecule that does not require fasting administration and can be taken alongside food, beverages, and other medications, potentially improving convenience and adherence compared with Semaglutide in its oral form.

The hosts review the head-to-head trial, which enrolled 1,698 patients with type 2 diabetes already taking metformin and compared two doses of orforglipron (12 mg and 36 mg) with oral semaglutide (7 mg and 14 mg). Results showed greater glycemic reductions with orforglipron, with mean A1C decreases of approximately 1.7% and 1.9% for the two doses, compared with reductions of 1.2% and 1.5% with semaglutide. All primary noninferiority comparisons were met, and the investigational agent demonstrated statistical superiority in A1C lowering.

The conversation then turns to tolerability. Gastrointestinal adverse events were reported more frequently with orforglipron, affecting roughly 58–59% of participants compared with 37–45% among those receiving semaglutide. The hosts discuss the nuances of adverse-event reporting in clinical trials, noting that even a single episode of nausea may be recorded as an event, which can inflate incidence rates. Despite higher rates of GI symptoms, discontinuation due to these effects remained relatively low, occurring in approximately 6% of patients receiving orforglipron compared with 3% with semaglutide, suggesting that most patients were able to continue therapy.

The panel highlights the potential clinical implications of these findings. The greater glucose-lowering efficacy may reflect the drug’s potency, but clinicians will need more information on dose-titration strategies and the duration of GI side effects to determine real-world tolerability. They also note that the comparison did not include the highest available dose of semaglutide, representing a limitation when interpreting relative efficacy.

Looking ahead, the hosts discuss the regulatory outlook for orforglipron, which has reportedly been submitted to regulators in more than 40 countries, including the United States, with initial approval efforts focused on obesity. They also emphasize the importance of cardiovascular outcomes data, which are currently available for semaglutide through large trials but not yet for orforglipron, which will likely play a critical role in determining how the therapies are positioned in clinical practice.

The discussion concludes with cautious optimism about expanding oral GLP-1 options. While the convenience and potency of orforglipron are promising, the hosts stress the importance of established cardiovascular evidence when selecting therapies for patients with diabetes and obesity who are at elevated cardiovascular risk.

Eli Lilly. Lilly’s oral GLP-1, orforglipron, delivered superior blood sugar control and weight loss compared to oral semaglutide in head-to-head type 2 diabetes trial published in The Lancet. February 26, 2026. Accessed March 5, 2026. 

https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-delivered-superior-blood-sugar

Rosenstock J, Yabe D, Cox D, et al. Efficacy and safety of once-daily oral Orforglipron compared with oral semaglutide in adults with type 2 diabetes (achieve-3): A multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial. The Lancet. Published online February 26, 2026. 

Diabetes Dialogue cohosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, cover the recently published trial results and what they mean for Eli Lilly’s newest GLP-1 molecule.

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

Diabetes Dialogue: Orforglipron, Retatrutide, and Other GLP-1 Updates

In this episode, cohosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, provide a comprehensive update on the rapidly evolving landscape of incretin-based therapies, focusing on newly published and top-line clinical trial data across oral GLP-1 receptor agonists and emerging triple agonists.

00:00:22 Orforglipron in the ACHIEVE-3 trial

00:10:28 Retatrutide in the TRIUMPH-4 trial

00:18:26 Topline data on Novo Nordisk's UBT251

00:21:47 Price cuts on Ozempic, Rybelsus, and Wegovy in 2027

The discussion begins with the phase 3 ACHIEVE-3 trial evaluating orforglipron, a novel, nonpeptide, once-daily oral GLP-1 receptor agonist, studied head-to-head against oral semaglutide in 1,698 adults with type 2 diabetes inadequately controlled on metformin. Orforglipron demonstrated superior glycemic efficacy, achieving mean A1C reductions of 1.7% and 1.9% at the 12 mg and 36 mg doses, respectively, compared with 1.2% and 1.5% reductions seen with 7 mg and 14 mg oral semaglutide. All primary noninferiority endpoints were met, with statistical superiority observed across comparisons. Weight reduction also favored orforglipron.

However, the enhanced efficacy was accompanied by higher rates of gastrointestinal adverse events. Nausea and other GI symptoms were reported in approximately 58–59% of patients receiving orforglipron versus 37–45% with semaglutide. Importantly, treatment discontinuation due to GI events remained relatively low (6% with orforglipron vs 3% with semaglutide), suggesting tolerability may be manageable in clinical practice. The hosts emphasize the importance of understanding how adverse events are captured in trials and highlight the role of dose titration, dietary counseling, and supportive medications in mitigating side effects. A key limitation noted is the absence of cardiovascular outcomes data for orforglipron, particularly given established cardiovascular benefit with oral semaglutide, underscoring the need for outcomes-driven decision-making in high-risk populations.

Attention then shifts to top-line results from the phase 3 TRIUMPH-4 trial evaluating retatrutide, a first-in-class triple agonist targeting GLP-1, GIP, and glucagon receptors, in individuals with obesity and osteoarthritis. Over 68 weeks, retatrutide achieved mean weight reductions of 26.4% to 28.7% (up to 71.2 pounds), representing some of the most substantial weight loss observed in pharmacotherapy trials to date. Nearly half of participants achieved ≥25% weight loss, and up to 23.7% achieved ≥35% reduction. Clinically meaningful improvements in osteoarthritis symptoms were documented via WOMAC scoring, with one in eight participants reporting complete resolution of knee pain. Gastrointestinal adverse events were dose-dependent, and discontinuation rates ranged from 12% to 18%, reinforcing the importance of balancing efficacy with tolerability.

The hosts also review early phase 2 data from Novo Nordisk’s investigational triple agonist (UBT251), which demonstrated 19.7% weight loss over 24 weeks in a Chinese cohort, along with improvements in waist circumference, glycemia, blood pressure, and lipids. Although preliminary, these findings highlight growing competition in the triple-agonist space and suggest continued acceleration in therapeutic innovation.

The episode concludes with broader reflections on expanding indications for incretin-based agents, including cardiovascular disease, osteoarthritis, sleep apnea, and potentially other cardiometabolic and inflammatory conditions, alongside discussion of anticipated price reductions and increased market competition. Isaacs and Bellini characterize the current era as transformative, with incretin-based therapies poised to substantially reshape cardiometabolic risk reduction strategies in type 2 diabetes and obesity.

Eli Lilly. Lilly’s oral GLP-1, orforglipron, delivered superior blood sugar control and weight loss compared to oral semaglutide in head-to-head type 2 diabetes trial published in The Lancet. February 26, 2026. Accessed March 2, 2026. 

Eli Lilly. Lilly’s triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial. December 11, 2025. Accessed March 2, 2026. 

Novo Nordisk. Triple agonist UBT251 delivers up to 19.7% mean weight loss after 24 weeks in phase 2 trial in China. 

. February 24, 2026. Accessed March 2, 2026. 

https://www.globenewswire.com/news-release/2026/02/24/3243205/0/en/Novo-Nordisk-Triple-agonist-UBT251-delivers-up-to-19-7-mean-weight-loss-after-24-weeks-in-phase-2-trial-in-China.html

Podcasts

Isaacs and Bellini discuss recent updates on Eli Lilly's orforglipron and retatrutide and Novo Nordisk's UBT251, along with other recent GLP-1 news.

Novo Nordisk Gains European Approval for Semaglutide 7.2 mg, Submits Application to FDA

On February 17, 2026, the European Commission approved a semaglutide injection dose of 7.2 mg for adults living with obesity after a clinical trial displayed substantial body weight reduction on average. Additionally, parent company Novo Nordisk has submitted an application for semaglutide 7.2 mg to the US Food and Drug Administration (FDA), indicating its potential arrival in the US.

Diabetes Dialogue cohosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, discuss the efficacy and practicality of a 7.2 mg semaglutide formulation.

Check out the full episode on injectable GLP-1 receptor agonists 

In this segment, Isaacs and Bellini discuss recent regulatory developments involving high-dose semaglutide for obesity management, highlighting the European approval of a 7.2 mg injectable formulation. This represents a substantial increase from the current maximum 2.4 mg dose approved in the United States under Wegovy. The speakers clarify that this higher-dose formulation is indicated exclusively for chronic weight management and is distinct from Ozempic, which remains approved for glycemic control in type 2 diabetes. The distinction between obesity and diabetes indications is emphasized, particularly given ongoing public and clinical confusion surrounding semaglutide branding and dosing.

The panel notes that the 7.2 mg dose has been submitted to the FDA, with a potential approval anticipated later this year. European authorization signals that safety evaluations have been completed at this higher dose, which the speakers interpret as reassuring from a pharmacovigilance standpoint. Clinically, the higher dose appears to confer incremental weight loss beyond that achieved with 2.4 mg, potentially offering an enhanced therapeutic option for patients with overweight and obesity who require additional efficacy. The discussion frames this as part of a broader expansion of GLP-1 receptor agonist–based obesity treatment, underscoring the meaningful impact these agents have had for patients who have historically struggled with limited pharmacologic options.

Beyond efficacy, the speakers examine practical considerations related to drug delivery systems and real-world use. Current U.S. Wegovy formulations are dispensed as single-use pens designed for a defined treatment interval. It remains unclear whether the 7.2 mg formulation, if approved in the United States, would maintain this format or transition to a multi-dose, adjustable (“multi-click”) pen. This uncertainty leads to a broader caution regarding dose manipulation strategies. Some patients may attempt to extend higher-dose pens by administering smaller doses over prolonged periods to reduce costs. However, the speakers emphasize that such practices raise concerns regarding medication stability, sterility, and potency.

They note that existing semaglutide pens are typically stable at room temperature for approximately 30 days and are engineered for a limited number of injections. Extending use far beyond the intended timeframe—potentially for several months—could compromise efficacy or introduce contamination risk. While limited short-term extension may occur in practice, prolonged off-label use of a single pen is not supported by available stability data.

Overall, the conversation underscores both the therapeutic promise of higher-dose semaglutide in obesity care and the importance of adhering to approved dosing, storage, and administration guidelines as new formulations emerge.

Novo Nordisk. Novo Nordisk A/S: The European Commission approves more effective dose of injectable Wegovy for adults with obesity; clinical study showed people lost about 21% of their body weight on average. 

. February 17, 2026. Accessed February 24, 2026. 

https://www.biospace.com/press-releases/novo-nordisk-a-s-the-european-commission-approves-more-effective-dose-of-injectable-wegovy-for-adults-with-obesity-clinical-study-showed-people-lost-about-21-of-their-body-weight-on-average

Diabetes Dialogue cohosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, cover the recent approval and what it means for Wegovy 7.2 mg in the US.

Natalie Bellini, DNP, FNP-BC, BC-ADM, CDCES

Articles