he clinical management of obesity has entered an era of unprecedented therapeutic efficacy. As global obesity burden continues to rise, incretin-based and multireceptor agonists capable of producing both significant and sustained weight loss have fundamentally disrupted the treatment landscape, creating new opportunities to improve long-term outcomes for patients but also raising new questions for clinical drug development.

As therapies become more effective, the amount of weight loss achieved is no longer sufficient on its own. The quality of weight loss should be characterized and better understood. It is also important to consider whether physical function is preserved, or improved, and how obesity comorbidities are affected alongside reducing excess body weight. That way, we can measure benefits that are meaningful to both patients and clinicians, as well as regulators.

Total body weight reduction remains a foundational endpoint, reinforced by both current European Medicines Agency (EMA) and US FDA regulatory guidance. However, gross body mass is a crude metric for metabolic health, since it may conflate desirable visceral fat loss with deleterious lean muscle loss. That is why the quality of weight loss is just as important as its magnitude.

The DIA Obesity Consortium, a neutral precompetitive public-private research partnership, focused its initial work on exploring body composition and physical function as promising efficacy endpoints, alongside methodology for evaluating multiple comorbidities within a single trial. Additional information about the insights from the collaboration have been described in detail in our September 2026 publication in the DIA Global Forum, “Obesity Drug Development: Time to Revisit Endpoints, Trial Design, and Evidence Generation.” (See History for additional information.)

Building on this work, the 2026 DIA European Executive Roundtable on Obesity Drug Development (held in Rotterdam on March 23, 2026) convened EMA regulators, industry representatives, clinicians, and academic and reimbursement experts to pressure-test emerging concepts and identify practical barriers to efficient drug development. The purpose of the meeting was not to generate formal guidance or drive consensus statements but rather to discuss and highlight key themes: the context-dependence of endpoint utility, the need to balance scientific ambition with operational feasibility, and the importance of developing collaborative evidence strategies to capture obesity’s broader metabolic, hepatic, musculoskeletal, and reproductive consequences. Below, we summarize these insights and their implications for the Consortium’s next phase.

Aligning Data Generation to Validate Label-Enabling Endpoints for Body Composition and Physical Function in Obesity Clinical Trials

Participants reviewed preliminary proposals and discussed how a more harmonized approach to endpoint selection, modality choice, and data collection could strengthen the scientific and regulatory framework for evaluating the quality of weight loss beyond total body weight reduction alone. The field is at an important inflection point: There is broad interest in moving beyond traditional measures, but progress will depend on generating consistent, high-quality evidence that is scientifically credible, operationally feasible, and relevant to patients, clinicians, and regulators.

Standardizing Data Generation for Body Composition Endpoints
The consortium discussed a draft proposal for assessing body composition via dual-energy X-ray absorptiometry (DXA), magnetic resonance imaging (MRI), and bioelectrical impedance analysis (BIA) as exploratory modality. DXA and BIA were proposed to assess whole-body fat mass and lean mass, while MRI was proposed to measure visceral fat mass, with data collected at baseline, an optional intermediate timepoint, and end of treatment.

Participants agreed that these proposals provide a useful starting point for future alignment. Total body weight loss does not distinguish between reductions in adipose tissue and lean mass. At the same time, questions remain regarding which measures are most robust, how they should be standardized across studies, and what degree of change would be clinically meaningful. Consistency in data generation will be essential if future pooled analyses are to support endpoint validation or broader regulatory relevance.

A central theme was the need to balance analytical rigor with operational feasibility. DXA was viewed as a practical option for whole-body assessment. MRI, while informative for visceral fat mass, may present operational challenges in large development programs. BIA was recognized as attractive from an implementation perspective and was included as exploratory, although further work is needed to understand its reproducibility and potential role in regulatory-grade evidence generation. Overall, modality selection should be informed not only by measurement characteristics, but also by study burden, cross-site consistency, and broader clinical applicability.

Advancing Physical Function as a Clinically Meaningful Dimension of Treatment Benefit
The roundtable also considered physical function as a complementary and clinically meaningful dimension of treatment benefit. The consortium’s draft proposal included the 6-minute walk test (6MWT), 30-second sit to stand (STS) test, and hand grip strength (HGS) test, together with IWQoL-Lite-CT, SF-36v2 Acute Form, and PGI-S Physical Function as patient-reported outcome instruments, with assessments at baseline, an optional intermediate timepoint, and end of treatment. Participants agreed that this framework reflects growing recognition that treatment benefit in obesity should not be evaluated solely through body weight reduction or body composition changes, but also through effects on how patients function and experience daily life.

There was broad agreement that physical function endpoints may help bridge physiological change and patient benefit. While body composition measures provide insight into tissue change during treatment, functional measures may help determine whether those changes translate into improvements in mobility, endurance, and quality of life. The 6MWT, STS, and HGS were generally (though not unanimously) viewed as pragmatic performance-based assessments, while patient-reported measures were recognized as important for capturing the patient perspective.

Composite Endpoints
Composite endpoints, encompassing body composition, physical function, and cardiometabolic effects consistent with the June 2026 Cardiovascular-Kidney-Metabolic clinical guidelines, were briefly discussed at the roundtable. However, the group considered these endpoints challenging to construct, as the individual components may differ in clinical relevance, measurement characteristics, and responsiveness to treatment. Their interpretation may also be difficult, particularly if the treatment effect is not consistent across all components of the composite. Further discussion is therefore needed to assess the feasibility, clinical rationale, and appropriate methodology for developing such endpoints.

Hot Topics in Obesity Drug Development

Alternatives to Large Placebo Arms
Obesity now has multiple highly effective pharmacotherapies with modern GLP-1 receptor agonists and dual/triple agonist therapies achieving up to 15%-25% body weight reductions, creating an unprecedented ethical dilemma in research design.

The Declaration of Helsinki states that placebo controls are justifiable only when no proven effective intervention exists or when patients face no serious harm. Yet patients in multiyear placebo arms face progressive weight gain, worsening comorbidities, declining quality of life, and lost opportunities for disease modification during critical treatment windows. Crucially, this ethical dilemma deepens when considering that modern anti-obesity medications have proven benefits extending far beyond weight loss alone, specifically robust cardio-protection. Having high-risk patients remain on a prolonged placebo regimen when active therapies are proven to significantly reduce major adverse cardiovascular events (MACE) and mortality is increasingly difficult to justify ethically. This prolonged placebo exposure in the context of available effective therapies raises serious ethical concerns about balancing scientific rigor with patient welfare.

The most recent 2025 FDA draft guidance for Overweight and Obesity, referenced above, requires a minimum of 1,500 subjects randomized to placebo for at least one year, powered to detect a 50% increase in background adverse event rates (3% to 4.5%). These parameters were never designed to detect rare, serious events ( <1%), which generally require robust post-market surveillance. Notably, as described in the 2022 publication, the EMA has previously acknowledged that active-control designs may be more relevant, and that large placebo arms may increase dropout rates, thereby compromising trial integrity. Participants at the roundtable therefore discussed a proposal for a two-pillar framework to reduce unnecessary exposure to placebo in clinical studies of agents in well-understood classes, such as GLP-1 receptor analogs. That framework included:

– A reduced concurrent placebo strategy component, targeting 500–750 patients (versus 1,500), which represents a 50%–75% reduction. It was agreed that this type of cohort still provides directional confirmation, detects the most prevalent safety signals, and preserves assay sensitivity while minimizing ethical concerns.
– An active comparator bridging component, incorporating indirect treatment comparisons via shared active comparators and historical studies to generate placebo-anchored estimates, while maintaining statistical rigor with reduced placebo exposure.

Other proposed solutions included capping placebo duration at ≤52 weeks, supported by open-label extensions, adaptive titration, or rescue medication. Continued consortium work will develop further and more detailed recommendations for alternatives to full placebo arms in the next year.

Obesity requires lifelong management, yet clinical trials focus on acute phases of the disease. Modern frameworks and guidance must address safety when transitioning from high-dose induction to lower-dose maintenance. Participants agreed that the key remaining question is whether an indirect comparison via active comparators could reduce placebo requirements. Unpublished proof-of-concept studies show strong concordance between direct and indirect estimates, supporting rigor while enabling FDA–EMA harmonization. The validation pathway for this issue would require standardizing cross-trial comparability, developing statistical frameworks, and defining bridging acceptance criteria. Managing placebo duration offers multiple options: rescue therapy, open-label extensions, adaptive designs, and robust ethical oversight.

Combination Drug Products and Treatment Regimes for Obesity and Related Conditions
Traditional fixed-dose combination (FDC) evaluation has previously focused on additive weight loss. But “meaningful contribution” should expand beyond kilograms lost to include muscle preservation, improved fat-to-lean ratio, and cardiometabolic benefits like insulin sensitivity and lipid profiles. Moreover, enhanced tolerability with fewer side effects, better titration, and lower discontinuation is known to directly impact real-world effectiveness. Frameworks should recognize FDCs achieving similar weight loss with improved tolerability as meaningful advances. Therefore, robust phase 2 trials could establish component contributions and dose optimization, allowing phase 3 to focus on FDC versus standard care without replicating all monotherapy arms.

Participants concluded that the field stands at a critical juncture where outdated requirements may potentially harm patients while providing diminishing value. This evolution represents a fundamental shift in balancing scientific rigor with ethical responsibility, demanding courage to challenge paradigms and compassion for the patients who benefit from research.

Next Steps

The next stage of the DIA Obesity Consortium will translate the multistakeholder scientific alignment developed during the initial portion of the collaboration, and further advanced during the 2026 DIA–EMA Executive Roundtable, into a concrete work plan.

The overall obesity field has largely accepted that total body weight alone is an incomplete measure of treatment benefit. The more difficult task now is to determine what data need to be collected and utilized to support the broader interpretation of new clinically meaningful endpoints in obesity drug development.

A central priority will be the continued refinement of data elements needed to support future pooled analyses that can inform existing global regulatory guidance and start potential biomarker qualification efforts. This work will focus on two closely related areas: (1) quality of weight loss and body composition, and (2) physical function. For body composition, the consortium will continue to evaluate which measures are most appropriate for consistent use across studies, including assessment of fat and lean mass, as well as visceral adiposity. For physical function, the focus will be on identifying measures that are feasible to implement, interpretable across populations, and clinically meaningfully to patients’ quality of life.

The goal is to develop a disciplined evidence-generation framework that can clarify whether changes in body composition and function reflect true clinical benefit. We are aligning our work to be complementary to other ongoing public-private partnerships in the space, including the FNIH REAL BODY project.

A second major deliverable will be the development of a draft protocol design for evaluating multiple comorbidities related to obesity. The roundtable discussions highlighted the potential value of master protocol or basket trial approaches, particularly for conditions such as metabolic, hepatic, musculoskeletal, and reproductive comorbidities, but also outcomes related to vascular complications or heart or kidney failure, as a relevant area to explore. This builds on discussions first introduced at the 2025 Obesity Roundtable, summarized in our September 2026 article referenced above.

The next stage will begin to define how such a protocol may be structured, including population selection, endpoint differentiation across comorbidity cohorts, shared or condition-specific comparators, and statistical considerations that are needed to preserve interpretability. Ongoing regulatory engagement will remain essential. Future discussions with FDA, EMA, and other global regulators will be staged around specific scientific questions, proposed data frameworks, and draft protocol concepts rather than broad theoretical issues. The consortium will also expand regional dialogue through anticipated executive roundtables in Asia and the Middle East, creating opportunities to understand how global regulators view endpoint development, trial design innovation, placebo use, and evidence requirements for obesity-related comorbidities. Communication and dissemination will also be built into the future work plan. A planned public DIA webinar in 2027 will communicate progress, share emerging themes, and broaden awareness of the consortium’s work. Strategic in-person sessions aligned with major DIA global meetings will provide additional opportunities for member engagement, regulator interaction, and refinement of deliverables.

The DIA Obesity Consortium will produce updated consensus frameworks, white papers, and guidance concept submissions to global regulatory agencies, as well as publish them through DIA channels and other appropriate scientific outlets that would use this collaborative partnership to improve the efficiency of obesity drug development. The outputs of the next stage will establish foundational elements for future phases of the work beyond 2027. Ultimately, this work will move the field from general agreement to usable tools, clearer data standards, and focused global regulatory dialogue leading to unified approaches around the world.