Inside the VESPER-3 Results: Berobenatide's Weight Loss Potential

With VESPER-3's 28-week interim results showing placebo-adjusted weight loss of up to 12.3% with once-monthly berobenatide dosing, attention is now turning to what the 64-week final analysis will add and how phase 2b findings should inform expectations for the upcoming phase 3 program.¹

Berobenatide Monthly Dosing Shows Weight Loss Efficacy in VESPER Trials, With John Buse, MD, PhD

Scientific Sessions of the American Diabetes Association (ADA)

, John Buse, MD, PhD, offered his perspective on how clinicians and researchers should contextualize the current data.

The phase 3 VESPER-4 and VESPER-6 trials will test a 9.6 mg monthly maintenance dose, a threshold not directly evaluated in VESPER-3. How the drug performs at higher doses, in larger and more diverse populations, and under real-world self-administration conditions remains to be established.

Berobenatide Efficacy Benchmarking and Future Directions

Buse noted the investment community is focused on whether berobenatide will match or exceed tirzepatide, semaglutide, or orforglipfron in weight reduction. His assessment: the drug will likely fall within a competitive range, and the 64-week readout will clarify the ceiling of achievable weight loss.

He cautioned, however, against drawing firm comparative conclusions from phase 2 data. Phase 2 programs involve modest patient numbers and limited site counts, and in the VESPER trials specifically, drug administration was conducted in-clinic rather than by patients at home.

"It's sort of an estimate and challenging to compare from one drug to another how they perform in phase 2," Buse said. "And then we'll have to see whether they can duplicate that performance in phase 3."

He added the phase 3 program incorporates dosing modifications designed to improve on what was tested in VESPER-1 and VESPER-3, suggesting the efficacy signal seen in phase 2 may not represent the drug's full potential.

Buse also addressed the absence of a weight loss plateau at week 28, a finding he described as directionally informative but not definitive. The 28-week data appear on par with the most active agents currently available, he said, but the precise landing point in phase 3 remains uncertain. Regarding head-to-head comparisons, he noted that only a proper comparative trial will settle differences between agents.

Berobenatide 9.6 mg Monthly Dose Rationale and Tolerability Expectations

The 9.6 mg monthly maintenance dose for phase 3 was derived from VESPER-1 OLE data, where 2.4 mg weekly was administered, and 9.6 mg represents the monthly equivalent of 4 such weekly doses.¹ VESPER-1 did not directly test 9.6 mg once monthly, and a different titration scheme was used, but the data suggest 9.6 mg will be both tolerable and associated with additional efficacy relative to lower doses.

Buse estimated the phase 3 dose could yield weight loss approximating 20%, while characterizing this as a reasoned projection rather than an established finding. Tolerability across the berobenatide phase 2 program has been favorable, with Buse noting berobenatide appeared surprisingly well tolerated in some studies. He added adverse event assessment methodology differs between phase 2 and phase 3, meaning the full safety picture will come into sharper focus only with the larger trial.¹

Editors’ note: Buse reports relevant disclosures with Corcept, Dexcom, GentiBio, Novo Nordisk, Amgen, AstraZeneca, Boehringer-Ingelheim, Corcept Therapeutics, and others.

Buse J. Long-Term Treatment with the Ultra-Long-Acting GLP-1 Receptor Agonist MET-097 (PF-08653944) in Adults with Obesity or Overweight: The VESPER-1 Open-Label Extension. Presented at: American Diabetes Association 2026 Scientific Sessions; June 6, 2026; New Orleans, LA.

Buse J. Monthly Dosing of MET-097 (PF-08653944) for Weight Management: Primary Outcomes of the VESPER-3 Phase 2 Trial. Presented at: American Diabetes Association 2026 Scientific Sessions; June 6, 2026; New Orleans, LA.

ADA. Ultra-long-acting injectable GLP-1 RA shows promise for supporting weight management in individuals with and without type 2 diabetes. Published June 6, 2026. 

https://www.prnewswire.com/news-releases/ultra-long-acting-injectable-glp-1-ra-shows-promise-for-supporting-weight-management-in-individuals-with-and-without-type-2-diabetes-302793181.html

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Buse discusses phase VESPER results, berobenatide's weight loss potential, and expectations for the upcoming phase 3 program

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What Comes Next for Berobenatide? VESPER-3 and Phase 3 Expectations, With John Buse, MD, PhD

Ryan Livingston joined the MJH Life Sciences team in March of 2025, shortly after graduating from TCNJ with a bachelor’s degree in English. He enjoys creative writing, reading, and scuba diving. He can be reached at rlivingston@mjhlifesciences.com.

Ania Jastreboff, MD, PhD | Image Credit: Yale School of Medicine

Retatrutide, Eli Lilly’s GLP-1/GIP/glucagon triple agonist, has substantially reduced body weight among patients with 

 in the TRIUMPH-1 trial, moving them below the clinical threshold for obesity.

American Diabetes Association (ADA) Scientific Sessions 2026

 in New Orleans, Louisiana, by Ania Jastreboff, MD, PhD, the Harvey and Kate Cushing Professor of Medicine and professor of pediatrics at Yale School of Medicine, these data highlight retatrutide’s substantial efficacy in patients with overweight or obesity, alongside similarly positive results from the TRANSCEND-T2D-1 trial.

“In TRIUMPH-1 and TRANSCEND-T2D-1, treatment with retatrutide resulted in substantial weight reduction together with clinically meaningful improvements in glycemia, knee osteoarthritis pain, and obstructive sleep apnea, with many individuals reaching what are classified as healthy-range weight and normal blood sugar levels,” Ania Jastreboff, MD, PhD, professor of medicine and pediatrics at the Yale School of Medicine, director of the Yale Obesity research Center, and lead investigator of TRIUMPH-1. “These findings demonstrate what may be possible when we treat obesity and impact overall health, and what this could mean for people living with obesity and its related complications.”

TRIUMPH-1 is a phase 3, randomized, double-blind, placebo-controlled master trial comparing retatrutide’s safety and efficacy versus placebo in adults with overweight and obesity. In addition, the study included 2 basket trials for knee osteoarthritis pain and moderate-to-severe obstructive sleep apnea. The trial ran for 80 weeks, with 2339 patients randomly assigned in a 1:1:1:1 ratio to either retatrutide 4 mg, 9 mg, 12 mg, or placebo. Those assigned to retatrutide began treatment with 2 mg once weekly before increasing in a stepwise approach every 4 weeks to the target dose.

Patients were eligible for inclusion if they had a body mass index (BMI) of ≥30 kg/m2 or ≥27 kg/m2 with hypertension, dyslipidemia, obstructive sleep apnea, and/or cardiovascular disease. Patients were excluded if they had a self-reported or documented change in body weight >11 lbs within 90 days, had taken weight loss drugs within 90 days, had a prior or planned surgical treatment for obesity, or had diabetes mellitus or pancreatitis, among other criteria.

The study’s primary endpoint was the percent change from baseline in body weight at week 80. Key secondary endpoints included change in BMI, waist circumference, systolic blood pressure, fasting insulin, and HbA1c, among others. Retatrutide met this primary endpoint by week 80, with patients on retatrutide 9 and 12 mg losing an average of 64.4 lbs (25.9%) and 70.3 lbs (28.3%), respectively. Patients receiving the 4 mg dose lost an average of 47.2 lbs (19%).

Additionally, 65.3% of participants on retatrutide 12 mg achieved a BMI <30, and 33.3% achieved a BMI <25. These values are below the minimum threshold for a clinical diagnosis of obesity. In a prespecified extension for patients with a baseline BMI ≥35, those receiving the 12 mg dose lost an average of 85 lbs (30.3%).

The basket trials also demonstrated positive results, with retatrutide reducing Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale scores by ≤4.3 points (73.1%) from a baseline of 6 among patients with knee osteoarthritis and apnea-hypopnea index (AHI) by ≤36.1 events per hour (60.6%) from a baseline of 58.6 events per hour in patients with obstructive sleep apnea.

The most common adverse events in TRIUMPH-1 in retatrutide 4 mg, 9 mg, 12 mg, and placebo, respectively, were nausea (28.8%, 38.4%, 42.4% vs 14.8%), diarrhea (25.2%, 34.1%, 32% vs 13.5%), constipation (23.8%, 25.9%, 26.1% vs 10.9%), vomiting (10.6%, 22.8%, 25.3% vs 4.8%), and upper respiratory tract infection (14.2%, 12.2%, 13.1% vs 11.6%). Dysesthesia (5.1%, 12.3%, 12.5% vs 0.9%) and urinary tract infections (7.5%, 8.8%, 8.4% vs 5.3%) were also noted, although these were generally mild to moderate and most resolved during treatment.

“TRIUMPH-1 highlights the importance of options and the potential for retatrutide to help people across various stages of their obesity journey,” Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health, said in a statement released at the time of TRIUMPH-1’s topline data in May 2026. “From the 4 mg dose, reaching nearly 20% weight loss with one escalation step, to the 12 mg dose that delivered a level of weight loss long associated with bariatric surgery, retatrutide offers the potential for a patient-centric approach to obesity.”

Jastreboff A, et al. Results of First Phase 3 Study of Retatrutide, a GIP, GLP-1, and Glucagon Receptor Agonist in Patients with Obesity (TRIUMPH-1). Abstract presented at the American Diabetes Association (ADA) Scientific Sessions 2026, New Orleans, LA. June 5-8, 2026.

Eli Lilly and Company. A Study of Retatrutide (LY34437943) in Participants Who Have Obesity or Overweight (TRIUMPH-1). ClinicalTrials.gov Identifier: NCT05929066. Updated June 3, 2026. Accessed June 6, 2026. 

https://clinicaltrials.gov/study/NCT05929066

Eli Lilly. Lilly’s triple agonist, retatrutide, delivered powerful weight loss in pivotal Phase 3 obesity trial. May 21, 2026. Accessed June 6, 2026. 

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

Articles

Retatrutide, a GLP-1/GIP/glucagon triple agonist, produced robust, dose-dependent weight loss over 80 weeks in adults with overweight/obesity, with many participants crossing below BMI-defined obesity thresholds and some achieving normal-range BMI. Metabolic parameters, including glycemia, improved in parallel. In prespecified higher-BMI subgroups, absolute and percent weight reductions were even greater. Dedicated basket cohorts showed clinically meaningful improvements in knee osteoarthritis pain and obstructive sleep apnea severity. Adverse events were predominantly gastrointestinal and generally mild-to-moderate, with additional signals including dysesthesia and urinary tract infection.

Eli Lilly’s investigative GLP-1/GIP/glucagon triple agonist has demonstrated its efficacy in reducing several major factors of obesity versus placebo.

TRIUMPH-1: Retatrutide Substantially Lowers Weight, BMI in Patients With Obesity or Overweight

Harpreet Singh Bajaj, MD, MPH | Image Credit: Bio

Eli Lilly’s investigative triple agonist retatrutide has displayed substantial results in A1c reduction and weight loss among patients with 

, according to data from the phase 3 TRANSCEND-T2D-1 trial.

 in New Orleans, Louisiana, by Harpreet Singh Bajaj, MD, MPH, a clinical endocrinologist at LMC Diabetes & Endocrinology and chief medical officer of the Canadian Diabetes Prevention Program, these data reflect the GLP-1/GIP/glucagon triple agonist’s first phase 3 trial in this patient population.

 drives more than 200 downstream diseases, yet we have historically treated those conditions one at a time and in silos,” Ania Jastreboff, MD, PhD, professor of medicine and pediatrics at the Yale School of Medicine and the director of the Yale Obesity Research Center, said in a statement. “These findings demonstrate what may be possible when we treat obesity and impact overall health, and what this could mean for people living with obesity and its related complications.”

TRANSCEND-T2D-1 is a phase 3, randomized, double-blind, placebo-controlled study investigating the efficacy and safety of retatrutide with placebo in adults with T2D inadequately controlled with diet and exercise alone. The study’s primary outcome was to demonstrate retatrutide’s superiority to placebo in A1c reduction from baseline after 40 weeks.

Eligible participants were required to have A1c between ≥7% and ≤9.5% and a body mass index (BMI) ≥23 kg/m2 at visit 1, as well as having not taken anti-diabetes medication for ≥90 days prior to visit 1. A total of 537 patients were ultimately enrolled and randomly assigned in a 1:1:1:1 ratio to either retatrutide 4 mg, 9 mg, or 12 mg, or placebo. Those randomized to receive retatrutide began treatment with 2 mg once weekly and increased the dose in a stepwise approach every 4 weeks until reaching the target dose.

Ultimately, patients receiving retatrutide reached an average A1c reduction of ≤2.0% from a baseline of 7.9% - additionally, 90% of all participants on retatrutide achieved an A1c below 7%, the ADA’s general target for T2D, and ≤85% achieved ≤6.5%. Patients receiving retatrutide 12 mg lost an average of 36.6 lbs with no sign of plateauing by 40 weeks. Retatrutide also showed reductions of ≤39.6% in triglycerides, 19.8% in non-HDL cholesterol, 6.4 mmHg in systolic blood pressure, and 4.9 inches in waist circumference by 40 weeks.

The most common adverse events with retatrutide 4 mg, 9 mg, 12 mg, and placebo (respectively) were nausea (16.4%, 19.5%, 26.5% vs 3.7%), diarrhea (18.7%, 26.3%, 22.8% vs 4.5%), and vomiting (15.7%, 15%, 17.6% vs 2.2%). Dysesthesia (4.5%, 2.3%, 4.4% vs 0%) and urinary tract infections (0.7%, 1.5%, 2.9% vs 0%) were also noted, but results were generally mild to moderate and most resolved during treatment. Discontinuation rates due to adverse events were 2.2%, 4.5%, and 5.1% with retatrutide, respectively, compared with 0% among placebo recipients.

“For many people with type 2 diabetes, it is a struggle to achieve both A1c control and weight loss, since obesity has historically been harder to treat for those with type 2 diabetes,” Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health, said in a statement regarding TRANSCEND-T2D-1’s topline data announcement in March 2026. “With triple agonist retatrutide, we set out to make a molecule that could help patients achieve substantial A1c reduction and weight loss. These results support the remarkable potential of this novel molecule for people living with type 2 diabetes, with up to 2% A1c improvement and nearly 17% weight loss in 40 weeks of treatment.”

Bajaj H, Welch M, Shah P, et al. Results of First Phase 3 Study of Retatrutide, a GIP, GLP-1, and Glucagon Receptor Agonist in Patients with T2D (TRANSCEND-T2D-1). Abstract presented at the American Diabetes Association (ADA) Scientific Sessions 2026, New Orleans, LA. June 5-8, 2026.

Eli Lilly. Lilly’s triple agonist, retatrutide, demonstrated significant reductions in A1c and weight in first Phase 3 trial for treatment of type 2 diabetes. March 19, 2026. Accessed June 6, 2026. 

https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-demonstrated-significant

Phase 3 TRANSCEND‑T2D‑1 evaluated once‑weekly retatrutide, a GLP‑1/GIP/glucagon triple agonist, in 537 adults with type 2 diabetes uncontrolled on diet/exercise. Dose escalation began at 2 mg with 4‑week step‑ups to 4, 9, or 12 mg. Over 40 weeks, retatrutide produced up to ~2.0% mean A1c reduction from 7.9% baseline, with 90% achieving <7% and up to 85% ≤6.5%. The 12‑mg arm achieved ~36.6‑lb loss without plateau and improved triglycerides, non‑HDL cholesterol, systolic blood pressure, and waist circumference. GI events predominated; most were mild–moderate, with discontinuations 2.2%–5.1%.

Eli Lilly’s investigative GLP-1/GIP/glucagon triple agonist has outperformed placebo in patients with poorly-controlled T2D.

Type 2 Diabetes

TRANSCEND-T2D-1: Retatrutide Demonstrates Superior Weight Loss and A1c Results Versus Placebo

Abigail Brooks is a strategic content lead overseeing 

She joined MJH Life Sciences in August 2023 shortly after graduating from Monmouth University where she earned her BA in Communication with a concentration in Public Relations/Journalism and later an MA in Interactive Digital Media. She enjoys traveling, running, and reading books. She can be reached at abrooks@mjhlifesciences.com.

Findings from the CONNECT randomized controlled trial suggest continuous glucose monitoring (CGM) may play an important role in the management of adults with 

 who are not on insulin, highlighting reduced hyperglycemia and subsequent reductions in A1C compared with a routine care control group.

2026 Scientific Sessions of the American Diabetes Association (ADA)

"Since many of the patients with type 2 diabetes who use oral or non-insulin injectable therapies are seen in primary care settings, continuous glucose monitoring provides an opportunity to close a visible care gap," Thomas Martens, MD, co-author of the study, said in a statement.¹ "As the first major randomized controlled trial evaluating CGM in individuals with type 2 diabetes not using insulin, these findings can help reshape diabetes management and expand treatment options for patients, improve glucose levels and A1C management for clinicians, and ultimately reduce diabetes-related complications."

CGM has well-established efficacy in insulin-treated diabetes, but evidence has been more limited for the substantially larger population of patients managing type 2 diabetes with oral or non-insulin injectable therapies. The CONNECT trial is the first major RCT to address this gap in a primary care setting, and its findings arrive as the ADA's 2026 Standards of Care have already moved to recommend CGM use for adults on any diabetes treatment in which CGM aids management.²

CONNECT Trial Design and Primary Glycemic Outcomes

The multicenter trial enrolled 283 adults with type 2 diabetes not on insulin across 22 US primary care practices.¹ Mean participant age was 60 years; 32% identified as racial or ethnic minority. Baseline mean A1C was 8.8%, with 31% of participants carrying an A1C of ≥ 9%. Concomitant therapy was heterogeneous: 37% of patients were on an SGLT2 inhibitor and 40% were on an incretin-based agent, including GLP-1 receptor agonist (GLP-1 RA)-based medications.

In the trial, participants were randomly assigned to either the Dexcom G7 CGM device or routine care with standard blood glucose meter testing. The primary outcome was change in A1C at 26 weeks.

Results showed the CGM group achieved a 0.9% greater A1C reduction compared with the routine care group at 6 months.¹ Time in the glucose target range of 70 to 180 mg/dL was 5 hours per day greater with CGM than with routine care, a clinically meaningful difference in daily glycemic exposure.

Secondary Outcomes: Patient-Reported Satisfaction and Distress in CONNECT

Beyond glycemic metrics, participants in the CGM group reported greater satisfaction with glucose monitoring and reduced diabetes-related distress compared with the routine care group.¹ These patient-reported outcomes are relevant to primary care, where engagement and adherence often determine whether glycemic targets are sustained over time. The combination of objective A1C benefit and reduced psychological burden strengthens the case for CGM deployment in this setting, where most non-insulin-treated patients with type 2 diabetes receive their care.

The ADA's 2026 Standards of Care updated Recommendation 9.25 to formally recommend CGM use for adults with type 2 diabetes on any treatment in which CGM aids management.² This positions CONNECT data as timely evidentiary support for a guideline posture already tilting toward broader CGM uptake. The Time in Range Coalition has noted increasing evidence of CGM benefits in non-insulin-treated type 2 diabetes across A1C, time in range (TIR), time above range, and user-reported satisfaction.³

A six-month extension phase of the CONNECT trial is currently underway, with 12-month durability data anticipated.¹ 

American Diabetes Association. 82% of adults with type 2 diabetes not on insulin improve blood glucose levels with continuous glucose monitoring. Published June 6, 2026. Accessed June 6, 2026. 

American Diabetes Association. Summary of revisions: Standards of Care in Diabetes — 2026. 

Time in Range Coalition. Time in range in the 2026 ADA Standards of Care. Published January 2026. Accessed June 6, 2026. 

https://www.timeinrange.org/time-in-range-in-the-2026-ada-standards-of-care/

CONNECT, a multicenter RCT in US primary care practices, evaluated Dexcom G7 CGM versus routine fingerstick monitoring in adults with type 2 diabetes not using insulin. Among 283 participants with a mean baseline A1C of 8.8%, CGM use produced a 0.9% greater A1C reduction at 26 weeks and increased time in range (70–180 mg/dL) by roughly 5 hours/day. CGM users also reported higher monitoring satisfaction and lower diabetes-related distress. A 12-month extension is ongoing, aligning with broadened 2026 ADA CGM recommendations.

The CONNECT trial found CGM improved A1C and time in range in adults with type 2 diabetes not on insulin.

CONNECT Trial Backs CGM for Non-Insulin Type 2 Diabetes Management

Berobenatide Monthly GLP-1 Injectable Shows Promise for Weight Loss

VESPER-1 and VESPER-3 findings highlight the potential of berobenatide, an investigational ultra-long-acting GLP-1 RA, for 

 support the potential of berobenatide, an investigational ultra-long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA), as a monthly injectable option for individuals with overweight or obesity with or without type 2 diabetes.¹

Results from the VESPER-1 open-label extension (OLE) and VESPER-3 phase 2b trials arrive as monthly administration draws increased attention in obesity pharmacotherapy as a meaningful departure from weekly injection schedules standard to currently approved GLP-1 RAs, with potential implications for adherence, healthcare system logistics, and treatment cost.

Berobenatide Efficacy and Design in VESPER-1 OLE and VESPER-3

VESPER-1 enrolled adults with overweight accompanied by hypertension or dyslipidemia, or with obesity, randomized to various berobenatide doses in a double-blind, placebo-controlled phase 2b design. The ADA presentation focused on the OLE, which defined a new maximum dose of 9.6 mg monthly for phase 3 advancement and demonstrated a transition from weekly to monthly dosing without significant added tolerability burden.¹

VESPER-3, a separate phase 2b trial in adults with overweight or obesity without type 2 diabetes, showed placebo-adjusted weight loss of up to 12.3% with the 4.8 mg monthly dose at 28 weeks, with a safety profile consistent with the GLP-1 RA class.¹

Berobenatide Monthly Dosing Rationale, Clinical Context

"Berobenatide is a potentially important new option for people living with overweight or obesity, especially because a once-monthly dosing could offer a more manageable alternative to today's more frequent injections," said John Buse, MD, PhD, lead author of the VESPER presentations.

In an interview, Buse elaborated on the layered rationale behind monthly dosing: for patients, 12 or 13 injections per year versus 52 represents a straightforward convenience gain. For providers and health systems, monthly administration opens the door to clinic- or nurse-administered dosing for patients with injection reluctance or severe dexterity limitations.

Buse also emphasized the economic dimension, noting monthly delivery dramatically reduces packaging and shipping demands, a consideration central to Metsera's original design goals for the drug.

"From start to finish, the drug is designed to provide value to patients and to healthcare systems, and the monthly dosing is part of that strategy," he said.

VESPER-3's final analysis will follow 64 weeks of exposure; longer-term data remain pending. A third phase 2b study, VESPER-2, extended findings to individuals with type 2 diabetes, demonstrating an encouraging risk-benefit profile. Data from all 3 phase 2b studies are informing the design of the phase 3 VESPER-4 and VESPER-6 trials.¹

VESPER-1 and VESPER-3 findings highlight the potential of berobenatide, an investigational ultra-long-acting GLP-1 RA, for overweight or obesity with or without type 2 diabetes.

A post-hoc analysis of the STEP UP trial found that semaglutide 7.2 mg and 2.4 mg were linked to eGFR increases in adults with obesity who did not have diabetes. 


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Latest News

What Comes Next for Berobenatide? VESPER-3 and Phase 3 Expectations, With John Buse, MD, PhD

TRIUMPH-1: Retatrutide Substantially Lowers Weight, BMI in Patients With Obesity or Overweight

TRANSCEND-T2D-1: Retatrutide Demonstrates Superior Weight Loss and A1c Results Versus Placebo

CONNECT Trial Backs CGM for Non-Insulin Type 2 Diabetes Management

Berobenatide Monthly Dosing Shows Weight Loss Efficacy in VESPER Trials, With John Buse, MD, PhD