Beyond weight loss: How obesity trial design is evolving
For many years, body weight sat at the centre of obesity drug development. The knock-on effect of this was that clinical trials were largely designed around the primary question of whether the intervention produced clinically meaningful weight loss, alongside safety and tolerability. While it is true that this benchmark still matters, as competition in the GLP-1 market intensifies, the expectations placed on early-stage studies are beginning to shift.
Today, sponsors are under growing pressure to show that new therapies can do more than reduce body weight alone.
Cardiovascular protection, renal outcomes, liver health, inflammation, and signals of durable disease modification also influence how new candidates are positioned and assessed. At the same time, the practical realities of designing trials are becoming more complex.
These challenges formed the basis of a recent pharmaphorum webinar produced in partnership with hVIVO, where Dr Thomas Forst, chief medical officer at hVIVO, and Dr Esteban Jodar Gimeno, head of the Endocrinology Department at University Hospitals Quiron Salud Madrid, explored how cardiometabolic trial design is evolving in response to this changing landscape.
Here we explore some of the biggest themes shaping that discussion, while the full webinar, including audience Q&A and deeper analysis, is available to watch on demand.
Weight loss alone is no longer enough
The way that obesity is discussed within drug development has changed significantly over the past decade. Once viewed primarily through the lens of weight management, with responsibility placed largely on the patient, the disease is now increasingly understood as a complex, chronic condition tied to a wide array of issues, such as cardiovascular disease, fatty liver disease, renal complications, and several forms of cancer.
Forst argued that this revised understanding has, in turn, altered the research and development landscape. Weight reduction, he noted, remains an essential piece of the obesity puzzle, but it is no longer sufficient on its own. New therapies entering Phase 1 and Phase 2 studies are now expected to show signs that they can influence wider cardiometabolic health outcomes, particularly as existing GLP-1 and dual agonist therapies continue to produce evidence across multiple disease areas.
Jodar Gimeno also stressed the importance of viewing obesity through the lens of chronic disease management, rather than as a short-term intervention. Whether weight reduction should be rapid or gradual matters, not just clinically, but in terms of what a drug's long-term use profile will look like. As he framed it, the central question is how to use existing and future therapies to prevent the complications of obesity from developing at all.
That framing sets up a further challenge for researchers. With GLP-1 receptor agonists and dual GLP-1/GIP therapies already on the market, with several agents in these classes generating evidence of cardiovascular benefit and showing promising effects on renal and hepatic markers beyond weight reduction, any new candidate entering Phase 1 or 2 development must answer a more demanding question than its predecessors did.
“New drugs which are in early clinical stages have to show that they are safe, that they reduce body weight,” Forst acknowledged. “But then the challenge is to show something which makes them special.”
Rethinking the biomarker toolkit
If body weight is no longer the primary differentiator, the next question becomes considerably more complicated. What should sponsors be measuring instead?
The honest answer, Forst explained, is that hard endpoints, such as reductions in myocardial infarction, stroke, or cardiovascular mortality, cannot be captured in Phase 1 or 2. Instead, he highlighted that researchers can lay the mechanistic groundwork for predicting whether a drug might eventually hit those endpoints early in the process, provided that the right biomarkers and imaging modalities are built into the study design from the start.
He described a range of early-phase signals, which he argued may offer mechanistic and translational value, and in some contexts may help predict later clinical benefit: changes in inflammation markers and adipokines, ectopic fat distribution assessed by MRI, liver stiffness measured through elastography, shifts in energy expenditure and body composition. For renal risk, Forst noted that the urinary albumin-creatinine ratio (UACR) is widely used as a prognostically meaningful biomarker and, in selected kidney-disease settings, change in albuminuria has been considered a candidate or reasonably likely surrogate endpoint, and it can move within weeks of starting treatment. “This is a clinically meaningful renal biomarker that can be useful in early-phase studies, particularly when the mechanism of action is expected to affect albuminuria,” he said.
Jodar Gimeno pushed further, stating that the field now has the mechanistic data from GLP-1 trials to design studies that go in with a much clearer hypothesis. He detailed an approach that spans the full cardiometabolic-renal-liver (CMRL) complex, including functional cardiac MRI, liver MRI together with non-invasive fibrosis assessment, noting that FIB-4 is better suited to risk stratification than to detecting short-term treatment response, glucose clamps, muscle functionality assessments and glomerular filtration measurement alongside albumin excretion. “For me it is increasingly important to include a tailored set of markers covering the organ systems most relevant to the drug’s mechanism and intended label,” he said.
Neither speaker presented this as a one-size-fits-all protocol. The choice of biomarker package, they agreed, should be driven by what preclinical data has already suggested the drug might do, and by an honest assessment of which organ system is most likely to show early differentiation.
That translation from bench to bedside, Forst said, has to be planned drug by drug.
The Placebo Challenge
Alongside the scientific discussion, both speakers highlighted growing pressure around the structure of long-term obesity trials themselves. In particular, the ethical dilemma of using a placebo arm in obesity studies.
To illustrate his point, Forst highlighted how a decade ago, the landmark cardiovascular outcomes trials for SGLT-2 inhibitors and incretin-based therapies all compared against placebo, generating data that transformed the field. The problem, he explained, was that it also rendered placebo controls increasingly difficult to justify in some high-risk populations. Now, the same ethical questions are emerging around the use of placebo in obesity trials.
One prominent response has been a move toward active comparator designs – studies that compare a new candidate against an established cardioprotective drug, then use statistical methods, including what is known as a putative placebo approach, to contextualise efficacy against historical placebo data, although such approaches rely on assumptions and are not a full substitute for direct randomised placebo evidence.
Jodar Gimeno was clear that this shift requires more than methodological ingenuity. It needs alignment between regulatory agencies, payers and academia, and it has implications for how drugs are ultimately approved and priced. In the interim, he argued strongly for open-label extensions where scientifically and operationally appropriate: patients who commit years to a placebo-controlled trial are contributing to the scientific record and deserve the option to receive the active drug. “They are helping us to develop science,” he said simply.
Of course, a fundamental element of a placebo arm is that patients don’t know whether they are receiving the drug candidate or not. However, in obesity trials specifically, maintaining blinding can be challenging, especially when treatments produce marked weight loss or recognisable adverse effects because patients know whether they are losing weight. If the answer is no, keeping them enrolled becomes a serious operational challenge. According to Forst, open-label extensions, where patients are told they will cross to the active arm at a defined point, can be an effective way to counter this issue.
Why smarter failure decisions matter
The final theme running through the discussion centred on speed, although not necessarily in the way the industry often frames it.
The pressure to move quickly in cardiometabolic drug development can be intense. Timelines are tightening and companies are eager to establish differentiation early. Yet both speakers repeatedly returned to the idea that faster development is only valuable if the underlying decisions are sound.
Forst advocated for reassessing what 'fast' should mean. “If you have a signal before where you can consider that it might be better not to move forward with the drug – this will spare a lot of money,” he said. In that sense, a high-quality stop decision in Phase 1 or 2 can be just as valuable as a rapid progression into Phase 3.
Both speakers pointed to AI as an effective tool for making those early decisions. Jodar Gimeno highlighted the large stores of biomarker and genetic data from biobanked samples and datasets collected under appropriate informed consent and governance frameworks, much of which has never been formally published or analysed. Applied intelligently, he suggested, AI could help identify which patient phenotypes respond to particular mechanisms, and therefore which populations to target from the outset.
Population selection, both agreed, is one of the hardest design errors to correct later in development. Choose the wrong subgroup in Phase 1, and the signal you generate may simply not be transferable to the patients who will ultimately receive the drug. As the obesity market continues evolving, the discussion suggested that trial design itself may increasingly become a point of competitive advantage.
Check out the full webinar on-demand to hear the panellists' answers to audience questions on regulatory expectations, the role of digital health tools in cardiometabolic trials, and how sponsors should think about the balance between biological depth and operational feasibility.
About the panel
Esteban Jódar Gimeno, MD, PhD is Head of the Endocrinology Department at University Hospitals Quirónsalud Madrid, overseeing services across three hospitals and two outpatient centres, and is Full Professor of Endocrinology at the European University of Madrid. An internationally recognised expert in metabolic and bone diseases, he has held senior roles within SEEN, SEIOMM and the European Society of Endocrinology. Professor Jódar has authored over 250 original publications, with more than 24,000 citations, and is a frequent national and international speaker. His research focuses on diabetes, obesity, osteoporosis and cardiovascular risk, with extensive experience in clinical drug development.
Chief Medical Officer — Professor Thomas Forst
Professor Thomas Andreas Forst is a board-certified physician in internal medicine and endocrinology with more than 30 years of experience in cardiometabolic research. He began his scientific career at the German Diabetes Research Institute and later held academic and clinical roles at the Johannes Gutenberg University Mainz, where he continues to contribute to medical training. Thomas has held senior positions at Eli Lilly, the Institute for Clinical Research and Development, and the Profil Institute Mainz, and has served as CMO at Clinical Research Services Germany. He has contributed to more than 300 clinical trials across obesity, metabolic disease, diabetes, lipid disorders, and cardiovascular disease, and is an active member of major diabetes associations. He has authored over 300 peer-reviewed publications and serves as Associate Editor of Endocrinology, Diabetes & Metabolism.
About hVIVO
hVIVO is a full-service early phase CRO offering end-to-end drug development services from preclinical consultancy through to Phase III clinical trials, including world leading end-to-end human challenge trials services. With decades of experience in rapidly delivering data for our global client base, our team brings together strategic insight and operational expertise to deliver a variety of clinical study types across multiple locations.
To support rapid study start-up and reliable delivery, our dedicated recruitment teams in Germany and the UK provide direct access to both healthy volunteers and patient populations. This is complemented by our integrated drug development consultancy as well as our infectious disease and immunology laboratories and biobanking services.
Learn more about how hVIVO is helping to drive innovation in cardiometabolic research through deep expertise, advanced diagnostics, and end-to-end clinical support.
