Data presented at ENDO 2026 highlighted investigational approaches for difficult-to-control type 2 diabetes and acquired hypothalamic obesity, real-world outcomes with tirzepatide, and wider health impacts of GLP-1-based therapy.
New data presented at ENDO 2026 in Chicago reflected the rapid evolution of obesity and diabetes management, with several abstracts extending the conversation beyond weight loss alone. Across investigational agents, approved incretin-based therapies, and digital care models, the findings pointed toward a broader cardiometabolic treatment landscape focused on glycaemic control, appetite, quality of life, fracture risk, and long-term metabolic health.
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Clofutriben study identifies elevated post-DST cortisol in difficult-to-control type 2 diabetes
Interim findings from CAPTAIN-T2D suggested that elevated post-dexamethasone suppression test (DST) cortisol may be common among people with difficult-to-control type 2 diabetes (T2D).1 Clofutriben is an investigational oral 11β-hydroxysteroid dehydrogenase type 1 inhibitor designed to reduce intracellular cortisol regeneration in tissues including the liver, adipose tissue, muscle and pancreas.
The phase 2 CAPTAIN-T2D trial is assessing the prevalence of elevated cortisol and the dose-response relationship between clofutriben and haemoglobin A1c (HbA1c) reduction. Participants have difficult-to-control T2D, defined as HbA1c ≥7.5% despite at least two antidiabetic medications, together with additional treatment burden, hypertension therapy, diabetes complications, osteoporosis or a prior Cushing syndrome diagnosis.
Among 332 participants screened by overnight DST to date, 27.7% had post-DST cortisol levels >1.8 µg/dL. Further analysis of baseline characteristics and cardiometabolic measures is ongoing. Blinded interventional results, including effects on HbA1c, body habitus, blood pressure, lipids and other cardiometabolic risk factors, are expected after trial completion in Q4 2027.
We asked presenting author Dr Elena Christofides (Endocrinology Associates) what clinicians can take away from the research for future clinical practice:
“Clinicians should recognize that difficult-to-control type 2 diabetes may not simply reflect inappropriate lifestyle choices or medication non-adherence. CAPTAIN-T2D suggests elevated cortisol is quite common in these patients and may help explain persistent cardiometabolic risk despite modern therapy. The practical takeaway is to look for clinical signals such as concomitant hypertension or inadequate response to incretin-based treatment. We need to keep cortisol dysfunction in the forefront of our differential when caring for these patients.”
Oral bivamelagon shows sustained weight and hunger reductions in acquired hypothalamic obesity
One-year data from a phase 2 study of oral bivamelagon suggested sustained benefits in people with acquired hypothalamic obesity, a rare condition caused by hypothalamic injury that can disrupt melanocortin-4 receptor signalling and lead to severe hunger, reduced energy expenditure and rapid weight gain.2
In the initial 14-week double-blind phase, 28 participants aged ≥12 years were randomized to once-daily bivamelagon 200 mg, 400 mg or 600 mg, or placebo. Participants who demonstrated adequate safety and tolerability and were considered likely to benefit could enter a 38-week open-label extension and receive bivamelagon 600 mg.
At Week 14, participants receiving placebo had a mean body mass index (BMI) increase of 2.2%, while those receiving bivamelagon had dose-dependent BMI reductions ranging from 2.7% to 9.3%. At Week 52, mean BMI changes were −8.7% in the placebo/600 mg bivamelagon cohort, −6.7% in the 200/600 mg cohort, −10.8% in the 400/600 mg cohort and −16.6% in the 600/600 mg cohort. Hunger scores also improved, with mean changes in weekly average maximal daily hunger score ranging from −1.94 to −4.84 across cohorts.
The most common adverse events during open-label extension treatment were vomiting, nausea and diarrhoea, most of which were grade 1. The investigators concluded that these sustained reductions in weight-related and hunger measures support the planned double-blind, placebo-controlled phase 3 trial.
Orforglipron linked to lower predicted cardiovascular and type 2 diabetes risk in ATTAIN-1 analysis
A post hoc analysis of ATTAIN-1 suggested that orforglipron may reduce long-term predicted cardiometabolic risk in adults with obesity or overweight without T2D.3 Orforglipron is a once-daily, small-molecule, non-peptide oral glucagon-like peptide-1 (GLP-1) receptor agonist.
ATTAIN-1 randomized 3,127 participants to orforglipron 6 mg, 12 mg or 36 mg capsules, or placebo, for 72 weeks. The analysis used three validated prediction models: the Framingham risk engine for total cardiovascular disease (CVD), the PREVENT engine as a sensitivity analysis, and the enhanced Cardiometabolic Disease Staging model for T2D risk.[3]
At 72 weeks, orforglipron 36 mg reduced predicted total CVD risk by 6.7% of baseline risk, compared with a 15.3% increase with placebo, corresponding to an estimated hazard ratio of 0.82. Findings were consistent using the PREVENT model, with a 10.3% reduction from baseline in predicted total CVD risk with orforglipron 36 mg compared with an 11.3% increase with placebo. For predicted T2D risk, orforglipron 36 mg was associated with a 59.4% reduction from baseline compared with a 10.5% reduction with placebo, corresponding to an estimated hazard ratio of 0.43.[3]
Reductions in predicted CVD and T2D risk were observed across all orforglipron doses. These findings suggest potential preventive cardiometabolic benefits, but they should be interpreted as modelled risk estimates rather than observed cardiovascular or diabetes outcomes.[3]
Switching from semaglutide to tirzepatide associated with further real-world weight loss
A real-world retrospective cohort study suggested that adults with obesity or overweight who switched from semaglutide injection to tirzepatide achieved clinically meaningful additional weight reduction after 12 months of persistent tirzepatide use.4
The study used the Komodo Research Dataset and included adults without diabetes who met obesity medication eligibility criteria, had initiated tirzepatide between November 8, 2023, and June 30, 2024, and had previously used semaglutide injection. Participants were required to have 12 months of continuous tirzepatide persistence, defined as no treatment gap of ≥45 days, and weight measurements at baseline and 12 months.
A total of 532 adults were included. The cohort had a mean age of 48.5 years, 76.5% were female, and mean weight at tirzepatide initiation was 231 lb. Most participants had at least one obesity-related complication, and 33.5% had four or more. Before starting tirzepatide, the mean duration of semaglutide use was 129 days, and 39% of participants had received semaglutide 2.4 mg.
After 12 months of persistent tirzepatide use, mean weight reduction was 13.8%, equivalent to 29 lb. Weight loss thresholds were achieved by a substantial proportion of participants, with 81.6% achieving ≥5% weight loss, 63.0% achieving ≥10%, 41.9% achieving ≥15%, 26.5% achieving ≥20% and 12.8% achieving ≥25%.
PERCEPTIONS survey highlights persistence, weight loss and quality-of-life gains with tirzepatide
Two 3-month analyses from the ongoing PERCEPTIONS survey provided early insight into patient-reported experiences with tirzepatide among employed adults with obesity or overweight and without T2D in the USA.5,6
In the first analysis, 468 adults who initiated tirzepatide completed both baseline and 3-month assessments.5 Mean age was 46.0 years, 76.9% were female, and mean BMI was 38.4 kg/m². Most participants were GLP-1 receptor agonist-naïve at baseline. At 3 months, 98.5% remained on tirzepatide, while 1.5% had discontinued treatment.
The most common reasons for continuing tirzepatide were having experienced weight loss, reported by 76.1% of participants, and wanting to improve health and wellbeing, reported by 65.5%. Other reasons included not yet reaching goal weight, clinician recommendation and improved physical functioning. Among the seven participants who discontinued treatment, the most common reasons were inability to afford the monthly cost and loss of insurance coverage. Among those with available weight data who remained on treatment, mean body weight change at 3 months was −13.8 lb in GLP-1 receptor agonist-naïve participants and −10.2 lb in GLP-1 receptor agonist-experienced participants.[5]
The second PERCEPTIONS analysis evaluated patient-reported outcomes in 461 participants who were persistent on tirzepatide at 3 months.6 Improvements were reported across work, quality of life, sleep, appetite, eating behaviours and weight-bias measures. Work Productivity and Activity Impairment scores showed reductions in absenteeism and presenteeism, along with improvements in overall work and activity impairment. The Impact of Weight on Quality of Life-Lite Clinical Trials tool showed improvements in physical function and psychosocial scores, while PROMIS sleep-related impairment scores improved. Participants also reported better appetite control and eating behaviours, as well as reduced internalized weight bias.[6]
Together, the PERCEPTIONS findings suggest that early tirzepatide persistence may be driven not only by weight loss, but also by perceived improvements in health, functioning and day-to-day wellbeing. However, affordability and insurance coverage remained important barriers to ongoing treatment, and findings should be interpreted in the context of self-reported survey data.
Newer GLP-1 and GLP-1/GIP therapies associated with lower fragility fracture risk
A large real-world study suggested that newer GLP-1 and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist therapies may be associated with lower fragility fracture risk in older adults with T2D.7
Using Epic Cosmos data from 2018 to 2025, investigators used a target trial emulation framework to compare GLP-1 and GLP-1/GIP receptor agonists with dipeptidyl peptidase 4 inhibitors. Newer agents included semaglutide and tirzepatide, while older GLP-1 receptor agonists were analysed separately. The primary endpoint was first fragility fracture.
After propensity score matching, newer GLP-1 and GLP-1/GIP receptor agonists were associated with significantly lower fracture risk overall compared with dipeptidyl peptidase 4 inhibitors, with a hazard ratio of 0.904. Older GLP-1 receptor agonists were also associated with a more modest reduction in overall fracture risk. Among adults aged ≥60 years, newer agents were associated with lower fracture risk, while older agents were not.[7]
In older adults, men appeared to have greater fracture risk reduction than women. Among women aged >60 years, newer GLP-1 and GLP-1/GIP receptor agonists were consistently associated with lower fracture risk across BMI categories and fracture sites, with the strongest association observed in those with HbA1c <7%. Risk reduction persisted across modest 1-year weight loss strata, suggesting that the association may not be explained by weight loss alone.[7]
These findings may provide reassurance regarding skeletal outcomes in older adults with T2D who are receiving newer incretin-based therapies, although further research is needed to clarify mechanisms and causality.
We asked presenting author Dr Thayer Idrees (Grady Hospital/Emory University) about the key takeaways to clinical practice:
“Clinicians can be reassured that newer GLP‑1 and dual GLP‑1/GIP receptor agonists are not linked to increased fragility fracture risk in older adults with type 2 diabetes and may offer modest risk reduction versus DPP‑4 inhibitors. Benefits appear consistent sex and possibly are independent of weight loss. Clinical trials are needed to confirm that these agents can be used without added fracture concern, alongside routine bone health and fall prevention care”
Digital metabolic reset program supports sustained weight loss and biomarker normalization
A 24-month longitudinal analysis of a digital metabolic reset program suggested that combining GLP-1 pharmacotherapy with intensive lifestyle intervention can support both substantial weight loss and broad cardiometabolic improvements.8
The study included 1,921 participants enrolled in a comprehensive digital program that combined GLP-1 pharmacotherapy with coaching and lifestyle support. Participants were predominantly female and White, and most were aged ≥46 years. Outcomes included percentage total body weight loss, HbA1c, lipid profiles and liver function tests.
At 24 months, participants achieved a mean total body weight loss of 19.1%, and 77% normalized at least one cardiometabolic marker. Among participants with abnormal baseline HbA1c, defined as ≥5.7%, 81% achieved normalization to <5.7%. Liver enzyme improvements were also notable, with 91% normalizing aspartate aminotransferase and 84% normalizing alanine aminotransferase. Most other biomarkers normalized in 64-78% of participants, although low-density lipoprotein cholesterol normalized in 24%.
Higher program engagement was associated with significantly greater weight loss and improvements in HbA1c and insulin levels compared with low engagement. The findings suggest that digital, multi-pillar obesity care models may help extend the benefits of GLP-1 pharmacotherapy beyond weight loss, particularly when participants remain actively engaged with lifestyle support.
What this means for clinical practice
The ENDO 2026 obesity and diabetes therapy abstracts reflect a field moving beyond single-metric success. Investigational agents such as clofutriben, bivamelagon and orforglipron may expand therapeutic options for specific or emerging cardiometabolic phenotypes, while real-world tirzepatide data continue to show clinically meaningful weight reduction and patient-reported benefits outside trial settings.
At the same time, the broader GLP-1 literature is beginning to address questions that matter in routine practice, including treatment persistence, affordability, quality of life, fracture risk and the role of structured digital support. For clinicians, these data reinforce the need to evaluate obesity and diabetes therapies not only by weight or glucose outcomes, but also by cardiometabolic risk, function, patient experience and long-term health impact.
References
- Christofides EA. Prevalence of Elevated Cortisol in Difficult-to-Control Type 2 Diabetes: Interim Results for CAPTAIN-T2D, a Phase 2 Trial of Clofutriben. Abstract SAT-634. Presented at ENDO 2026, San Francisco, CA, USA, June 13-16, 2026.
- Grishman EK. Weight Reduction After 1 Year of Oral Bivamelagon in Acquired Hypothalamic Obesity. Abstract MON-732. Presented at ENDO 2026, San Francisco, CA, USA, June 13-16, 2026.
- Kahles F. Orforglipron and the 10-year Predicted Risk of Cardiovascular Disease and Type 2 Diabetes: A Post Hoc Analysis from the ATTAIN-1 Trial. Abstract MON-738. Presented at ENDO 2026, San Francisco, CA, USA, June 13-16, 2026.
- Updhyay N, Bonakdar A. 12-month Real-World Weight Loss with Tirzepatide among Individuals with Obesity/Overweight who switched from Semaglutide. Abstract SAT-679. Presented at ENDO 2026, San Francisco, CA, USA, June 13-16, 2026.
- Gerber C. Participant-Reported Weight Reduction and Reasons for Continuing or Discontinuing Tirzepatide Treatment: Insights from the PERCEPTIONS Longitudinal Survey at 3 Months. Abstract MON-727. Presented at ENDO 2026, San Francisco, CA, USA, June 13-16, 2026.
- Makin H. Patient-reported improvements in appetite control, quality of life, and work-related outcomes following tirzepatide treatment for obesity or overweight in the US: Results from 3-month PERCEPTIONS survey. Abstract MON-728. Presented at ENDO 2026, San Francisco, CA, USA, June 13-16, 2026.
- Idrees T. Fragility Fracture Risk Associated with GLP-1 and Dual GLP-1/GIP RA Therapies in Older adults with Type 2 Diabetes. Abstract SUN-810. Presented at ENDO 2026, San Francisco, CA, USA, June 13-16, 2026.
- May C. Weight Loss and Improvements in Cardiometabolic Markers: A 24-Month Longitudinal Analysis of a Digital Metabolic Reset Program. Abstract SAT-720. Presented at ENDO 2026, San Francisco, CA, USA, June 13-16, 2026.
Cite: ENDO 2026: Obesity and diabetes studies look beyond weight loss. touchENDOCRINOLOGY. 30 June 2026.
Editor: Nicola Cartridge, Director of Content
Acknowledgment: This content has been developed independently by Touch Medical Media for touchENDOCRINOLOGY. It is not affiliated with ENDO. No funding was received in the publication of this short article. This article was created by the touchENDOCRINOLOGY team utilizing AI as an editorial tool (ChatGPT (GPT-5.4) [Large language model]. https://chat.openai.com/chat.) The content was developed and edited by human editors. No funding was received in the publication of this article. Thank you to the presenting authors for sharing their perspectives.
