For much of its history, obesity research has struggled to find a place in clinical development.
Image Credit: hVIVO
Too medical to dismiss outright, too entangled with lifestyle narratives to command the same seriousness as closely related conditions such as cardiovascular disease or diabetes. It has frequently been studied through a narrow lens – short trials, blunt endpoints, and the underlying assumption that weight loss was the only outcome that mattered.
That framework is currently under sustained pressure. The fast increase of GLP-1 medications has altered expectations of efficacy and spurred a larger reconsideration of how obesity is understood, quantified, and studied.
Professor Thomas Andreas Forst, Chief Medical Officer at hVIVO, said: “Obesity is a chronic disease.”
“It’s a malignant disease which drives a lot of other comorbidities like diabetes, fatty liver disease, hypertension, and lipid disorder – together increasing the morbidity and mortality of these patients.”
For contract research organizations (CROs) such as hVIVO, the shift is more than semantics. It changes what a viable trial looks like. How long research should last, what outcomes are important to regulators and payers, and, most importantly, how patients participate – all of these are areas where trials progress in tandem with our understanding of the disease.
As a result, obesity research has grown to resemble the lengthy, morally complicated trials more frequently found in the cardiometabolic area, with all of the operational implications it involves.
As Forst points out, quantifying weight reduction alone is no longer sufficient, especially in a quickly saturated market like GLP-1s. “If you develop a new drug and you see you lose body weight, that is fine,” he explained.
“But then everyone says, ‘We have other drugs doing exactly the same thing – what is special about your drug?”
That question is at the center of obesity study design.
Retention, placebo, and the visibility problem
Retention has always been a major concern in long-term investigations, but obesity trials pose a unique challenge. For individuals assigned to receive the drug candidate in question, the effects are evident, immediate, and frequently dramatic, and participants do not require a medical degree to determine whether or not something is happening.
“They see others lose 10 %, 15 %, 20 % of their weight and nothing happens with them,” Forst says, “So, it is clear in the studies who is taking a placebo and who is not.”
In practical terms, this visibility undermines one of the basic assumptions of placebo-controlled research. Even when formal blinding is maintained, experiential unblinding can rapidly derail a study.
As a result, CROs' options are becoming increasingly limited. On the one hand, there is a need for robust comparative data. On the other hand, there is rising ethical concern about keeping patients on placebos for extended periods of time when effective treatments are available.
“In type 2 diabetes, it is no longer possible to run these kinds of endpoint studies against placebo,” Forst notes. “You want to treat patients for years with a placebo while we have other drugs where we know they are cardioprotective – this is not possible anymore.”
Obesity is trending in the same direction. Early cardiovascular outcomes data is already altering expectations, and with each additional indication of benefit, the ethical reason for continued placebo exposure becomes more difficult to maintain.
Some sponsors have responded by incorporating extension phases into their programs, allowing placebo subjects to receive the active medicine after the core study is completed.
“If the core trial is completed, then everyone can get the real drug,” Forst explained. “This is a key motivation for some people.”
That method can be beneficial, but it also adds layers of complexity, necessitating lengthier commitments, greater resources, and more demanding logistics. In this circumstance, retention is becoming increasingly dependent on the study design itself.
Redesigning obesity trials in real time
As the limitations of placebo-controlled obesity trials become more apparent, different designs are gaining traction as viable substitutes. Among these are active comparator trials and potential placebo techniques.
The theory behind these options is rather simple, even if the implementation is not. Rather than randomly assigning patients to placebos, new therapies are compared to already approved treatments. Statistical matching is used to reconstruct a comparative arm based on historical placebo data from previous studies.
“What we now do is we compare the new drug against an already registered drug that has done a placebo-controlled study,” Forst said. “You can bring this data together and do some matching […] We call that putative placebo.”
Since the early 2000s, putative placebo designs have been widely used in diabetes research to assess cardiovascular endpoints. However, in the case of obesity, it represents a substantial shift from previous practices.
The ramifications for CRO are significant. Putative placebo techniques rely heavily on data quality, compatibility of inclusion and exclusion criteria, and careful alignment of outcomes across trials that were never intended to speak to each other.
Forst said: “This is a complex statistical method. It is not against placebo groups, it is against single patients in the other database, which fit with the inclusion and exclusion criteria.”
The burden does not end there. As medicines advance, demonstrating distinction becomes ever more difficult. Superiority over an active comparator is now considered the gold standard, but achieving it often requires longer trials, larger populations, or extremely specific end objectives.
“The best thing you can show is superiority against the active comparator,” Forst says. “But the drugs are becoming better and better. Then, you need longer time periods, maybe five years instead of three, or more people in the studies.”
Reflect the whole patient, not just the scale
As trial designs evolve alongside our understanding of disease, so does the question of what obesity research is attempting to evaluate.
Forst points out that there are countless possibilities; while weight loss remains a visible and significant outcome, it merely scratches the surface.
The use of BMI has been heavily criticized for oversimplifying the success of weight loss medications. According to Forst, while BMI correlates with risk at the population level, it tells clinicians little about key parameters such as fat distribution, metabolic health, and individual vulnerability.
“BMI has an association with elevated risk, but it is not the best marker,” Forst said.
“It does not tell you about the kind of adipose tissue you have and the distribution.”
Visceral and ectopic fat pose a considerably greater cardiometabolic risk than subcutaneous fat, yet BMI does not differentiate between them. As a result, there is a risk of treating individuals who appear ill but are metabolically stable while ignoring those whose risk is greater but less evident.
“We treat obese people who do not have a problem from a medical aspect,” Forst explains, “and, on the other side, we miss people to treat who do not look obese.”
Long-term consequences complicate matters further. GLP-1 medications have been effective, however, they are not curative, and lean muscle mass can be lost alongside fat tissue. This implies that patients who choose to discontinue treatment often gain weight, and that not all tissues return to their original state.
“A lot of people think that they can reduce their body weight, and when they reach the level they want, they can stop it. But in most cases, it does not work because they have weight gain again,” said Forst.
“This is not good because during this treatment phase, you lose weight, you lose adipose tissue, and you lose muscle tissue. And then, if you stop treatment and increase weight again, it is mostly adipose tissue.”
Patients who experience repeated cycles of weight loss and gain risk becoming obese and sarcopenic, which has substantial functional repercussions. Forst emphasized the importance of lifestyle factors, particularly resistance exercise and protein nutrition, even in the era of very successful medication.
Standard endpoints cannot always capture the most remarkable insights. Forst reports a patient who described a constant "food noise" that consumed her waking hours and only went away after her first injection.
This anecdote may be overlooked in comparison to the clear numerical and scientific evidence famous in clinical research, but it highlights a core challenge in obesity research: appetite regulation, mental load, and quality of life all influence adherence, retention, and long-term outcomes in ways that the scale cannot capture.
Shaping the next phase of obesity research
The rate of change in obesity research has been remarkable. New mechanisms, combinations, and targets emerge faster than the old trial frameworks designed to handle them. However, Forst believes that this is one of the reasons obesity is such a fertile ground for research.
“It is fascinating how fast we are learning things that we had not even considered a couple of years ago,” Forst says. “I am absolutely convinced that we are at the very beginning.”
Obesity trials are becoming longer, more complex, and more ethically scrutinized. They require thoughtful design, ongoing patient interaction, and endpoints that address regulators, payers, and patients simultaneously. CROs face the task of not only keeping up but also shaping how evidence is generated in a field that is redefining itself.
As obesity progresses from a marginalized condition to a central focus of metabolic medicine, the trials that support its treatments must reflect this seriousness.
“It is about becoming healthier. That is the important thing,” explains Forst. “We now have the first studies with semaglutide in place, where it is also shown that for obese people, you reduce the risk of cardiovascular events by 20 %.”
It is not only making obese people leaner, but it is also treating a very, very malignant and dangerous disease, making really ill people much healthier.
About the author
Professor Thomas Andreas Forst is the chief medical officer of hVIVO and has been with Clinical Research Services (CRS), a division of the hVIVO Group, since 2018.
He formerly served as CEO and director of medical science at Profil Institute Mainz (2013-2018), as well as CEO and medical director of the Institute for Clinical Research and Development in Mainz (2001-2013). From 1999 to 2001, he worked as a clinical research physician at Eli Lilly in Indianapolis, overseeing clinical trials for cardiometabolic diseases.
Professor Forst, a board-certified physician specializing in internal medicine and endocrinology, began his career in 1989 at the German Diabetes Research Institute. He enrolled at Johannes Gutenberg University in Mainz in 1991, getting degrees in Internal Medicine (1996) and Endocrinology (1997). He was appointed Professor of Internal Medicine in 2006 and continues to instruct medical students to this day.
About hVIVO
hVIVO plc is a science‑led early‑phase drug development company purpose‑built to meet the growing complexity of modern clinical research. The Company operates an integrated early‑phase ecosystem that combines specialist clinical sites, advanced virology and immunology laboratories, human challenge expertise, and early drug development consulting. This unified model enables sponsors to generate rigorous, decision‑ready human data earlier in development, reducing uncertainty and accelerating progression through Phase I and II trials.
With industry‑leading capabilities in respiratory and infectious disease, alongside expanding expertise in cardiometabolic and other high‑growth therapeutic areas, hVIVO supports a diverse global client base that includes seven of the world’s ten largest biopharmaceutical companies. Its London quarantine facilities are the largest purpose‑built human challenge units in the world, complemented by additional early‑phase clinical capacity in Germany and a specialist consulting team providing strategic, regulatory, and biometry expertise.
The Company’s integrated approach delivers a seamless pathway from preclinical planning through early proof‑of‑concept, supported by continuous patient recruitment through FluCamp and a network of outpatient clinical sites for Phase II and III studies. By unifying scientific insight, operational control, and advanced laboratory capabilities, hVIVO provides sponsors with the clarity, speed, and reliability required to advance new medicines with confidence.
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