John Buse, MD, PhD 

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

Videos

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

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

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.

HCPLive Five at ADA Scientific Sessions 2025

2025 American Diabetes Association (ADA) Scientific Sessions, held June 20–23 in Chicago

, reflected a shifting paradigm in diabetes care prioritizing comprehensive approaches to glucose management, cardiometabolic health, and patient-centered outcomes. This year’s meeting featured a diverse slate of groundbreaking research spanning automated insulin delivery, weekly insulin alternatives, and novel interventions tackling unique drivers of glycemic dysregulation.

Among the most talked-about data were CIRCUIT trial findings on automated insulin delivery systems improving time-in-range during pregnancy; the QWINT program’s demonstration that once-weekly insulin efsitora alfa can effectively replace daily basal insulin; and evidence supporting prediabetes remission as a superior goal to weight loss for type 2 diabetes prevention. Additional highlights included the CATALYST trial’s success with mifepristone in hypercortisolism-related diabetes and the STRIDE trial’s new insights into semaglutide’s effects on walking capacity and disease progression in patients with type 2 diabetes and peripheral artery disease.

Hybrid Closed Loop Insulin Improves Time in Range for T1D During Pregnancy, with Lois Donovan, MD, and Denice Feig, MD, MSc

The CIRCUIT trial compared an automated insulin delivery (AID) system using Control-IQ technology to standard care in pregnant women with type 1 diabetes, presented at ADA 2025 by Lois Donovan, MD, and Denice Feig, MD. Participants using the hybrid closed-loop system achieved a 12.6% (95% CI, 9.9–15.2; 

<.001) higher time in range during pregnancy (TIRp) compared with standard care (65.4% vs. 50.3%). Additionally, the AID group had 11.4% (95% CI, 8.6–14.2; 

<.001) less time above range, 1.04% (95% CI, 0.6–1.48; 

<.001) less time below 63 mg/dL, and a mean glucose 11.2 mg/dL lower than standard care (95% CI, 7.2–16.2; 

Once-Weekly Insulin Efsitora a Practical Option for Type 2 Diabetes, with Athena Philis-Tsimikas, MD

The QWINT-3 phase 3 trial investigated weekly insulin efsitora alfa versus daily insulin degludec in patients with type 2 diabetes switching from basal insulin, presented at ADA 2025 by Athena Philis-Tsimikas, MD. Weekly efsitora injections were non-inferior to daily degludec for glycemic control, supporting its potential as a practical alternative. Philis-Tsimikas noted the findings suggest switching to weekly insulin could substantially reduce treatment burden for patients.

Glycemic Control Trumps Weight Loss for Type 2 Diabetes Prevention, with Arvid Sandforth, MD

A prediabetes lifestyle intervention study presented by Arvid Sandforth, MD, at ADA 2025 showed achieving normal glycemia, regardless of weight change, provided the same protective effect against developing type 2 diabetes. Participants achieving glycemic remission experienced significantly reduced T2D incidence even if they maintained or gained weight, compared to those who did not normalize glycemia. The multicenter German study highlighted that while weight loss remains a powerful tool, achieving glycemic control should be prioritized as the primary prevention target.

Diabetes Dialogue: CATALYST Trial, Mifepristone, and Hypercortisolism in T2D, with John Buse, MD, PhD

The phase 4 CATALYST trial enrolled 1055 adults with type 2 diabetes and HbA1c >7.5% despite optimized therapy, screening for hypercortisolism using dexamethasone suppression testing, which identified a 24% prevalence (95% CI, 21.4–26.7%). In part 2, 136 patients with confirmed hypercortisolism were randomized 2:1 to mifepristone or placebo for 24 weeks, with mifepristone reducing HbA1c by 1.3 percentage points versus placebo (95% CI, –1.81 to –0.83; 

 <.001). Secondary outcomes showed reductions of 5.12 kg in body weight (95% CI, –8.20 to –2.03) and 5.1 cm in waist circumference (95% CI, –8.23 to –1.99) relative to placebo.

New Data Supports Protective Vascular Effects of Semaglutide in T2D and PAD, with Subodh Verma, MD, PhD

The STRIDE trial randomized 792 adults with T2D and PAD to semaglutide (n=396) or placebo (n=396) for 52 weeks, presented by Subodh Verma, MD, PhD, at ADA 2025. Patients receiving semaglutide showed a median baseline-adjusted maximum walking distance ratio of 1.21 compared with 1.08 for placebo. Semaglutide also reduced the risk of a composite disease progression endpoint—including death, major adverse limb events, or rescue medication use—by 54% relative to placebo.

These 5 represent only some of the data the 

 team covered at this year's meeting! Check out more KOL insight and our full conference coverage on our 

From uncovering new benefits of semaglutide to targeting hypercortisolism in people with type 2 diabetes, here are 5 key updates from the annual meeting.

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

, hosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, speak with John Buse, MD, PhD, of the University of North Carolina School of Medicine, about the treatment phase of the CATALYST trial.

Findings from the phase 4 CATALYST trial suggest that mifepristone (Korlym), a glucocorticoid receptor antagonist, significantly improves glycemic control, reduces body weight, and lowers waist circumference in patients with hypercortisolism and difficult-to-control type 2 diabetes—offering a promising therapeutic option for a population with limited treatment success.

The two-part, multicenter study enrolled 1055 adults with type 2 diabetes and HbA1c >7.5% despite optimized therapy. In part 1, participants underwent dexamethasone suppression testing to identify hypercortisolism, defined by post-test cortisol levels >1.8 µg/dL and dexamethasone >140 ng/dL. Results revealed a 24% prevalence of hypercortisolism in this population (95% CI, 21.4–26.7%).

Part 2 randomized 136 patients with confirmed hypercortisolism in a 2:1 ratio to receive mifepristone or placebo for 24 weeks. The primary endpoint was change in HbA1c. Mifepristone treatment led to a least squares mean HbA1c reduction of 1.3 percentage points compared to placebo (95% CI, –1.81 to –0.83; 

Secondary endpoints also favored mifepristone: body weight decreased by 5.12 kg (95% CI, –8.20 to –2.03), and waist circumference dropped by 5.1 cm (95% CI, –8.23 to –1.99) relative to placebo.

Despite its efficacy, 49% of mifepristone-treated patients discontinued therapy, compared to 18% on placebo. Adverse events included hypokalemia, fatigue, nausea, vomiting, and elevated blood pressure, consistent with the drug’s known safety profile.

During the episode, which was recorded during the 

85th Scientific Sessions of the American Diabetes Association (ADA 2025)

, Buse provides hosts with a deep dive into the background of the trial, prevalence of hypercortisolism in difficult-to-control type 2 diabetes, and the historic relevance of the CATALYST results. Buse also discusses how the trial offers insight into dosing approaches with mifepristone and advocates for broader cortisol screening in patients with complex type 2 diabetes—suggesting that ADA Standards of Care should reflect these findings.

Relevant disclosures for Isaacs include Eli Lilly and Company, Novo Nordisk, Sanofi, Abbott Diabetes Care, Dexcom, Medtronic, and others. Relevant disclosures for Bellini include Abbott Diabetes Care, MannKind, Provention Bio, and others. Relevant disclosures for Buse include Altimmune, AstraZeneca, Boehringer-Ingelheim, CeQur, Corcept Therapeutics, Eli Lilly, embecta, Moderna, Novo Nordisk, Tandem, Vertex, and others.

Podcasts

Discover how the CATALYST trial reveals mifepristone's potential to enhance glycemic control and weight loss in challenging type 2 diabetes cases.

John Buse, MD, PhD

Articles