That framing is now under sustained pressure. The rapid rise of GLP-1 therapies has transformed expectations of efficacy, and forced a broader reckoning with how obesity is understood, measured, and studied.

“Obesity is a chronic disease,” says Professor Thomas Andreas Forst, chief medical officer at hVIVO. “It’s a malignant disease and it drives a lot of other comorbidities like diabetes, fatty liver disease, hypertension, and lipid disorder – all together increasing the morbidity and mortality of these patients.”

For contract research organisations (CROs) like hVIVO, that shift extends beyond simple semantics. It changes what a viable trial looks like. How long a study needs to run, what endpoints carry weight with regulators and payers and, critically, how patients experience participation – all areas where trials evolve along with our understanding of the disease. As such, obesity studies have begun to resemble the long, ethically complex trials more commonly found in the cardiometabolic space, including all the operational consequences that entails.

As Forst puts it, measuring weight loss on its own is no longer sufficient, particularly in a rapidly saturating market like GLP-1s. “If you develop a new drug and you see you lose body weight, that’s fine,” he explains. “But then everyone says, ‘yes, we have other drugs doing exactly the same thing – what is special about your drug?”

That question now sits at the heart of obesity trial design.

“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’s taking placebo and who is not.”

In practical terms, that visibility erodes one of the foundational assumptions of placebo-controlled research. Even when formal blinding remains intact, experiential unblinding can quickly derail a study.

Consequently, CROs find themselves navigating a narrowing path. On one side sits the need for robust comparative data. On the other, a growing ethical discomfort with keeping patients on placebo for extended periods when effective therapies exist.

“In type 2 diabetes, it’s no longer possible to run these kind of endpoint studies against placebo,” Forst notes. “You want to treat patients for years with placebo while we have other drugs where we know they are cardioprotective – this is not possible anymore.”

Obesity is moving in the same direction. Early cardiovascular outcomes data is already reshaping expectations and, with each new signal of benefit, the ethical justification for prolonged placebo exposure becomes harder to sustain. Some sponsors have responded by building extension phases into their programmes, allowing placebo participants access to the active drug once the core study concludes.

“If the core trial is completed, then everyone can get the real drug,” Forst explains. “This is motivating some of the people.”

That approach can help, but it also adds layers of complexity, requiring longer commitments, additional resourcing, and more demanding logistics. Retention, in this scenario, is increasingly bound up with study design itself.

The logic behind these options is relatively straightforward, even if the execution is not. Rather than randomising patients to placebo, new therapies are compared against already approved treatments. Historical placebo data from earlier trials is then used to reconstruct a comparator arm through statistical matching.

“What we now do is we compare the new drug against an already registered drug that has done a placebo-controlled study,” Forst says. “You can bring this data together and do some matching […] We call that putative placebo.”

The method itself is not new. Putative placebo designs have been prominently used in diabetes research for cardiovascular endpoint evaluation since the early 2000s. However, in obesity, it marks a significant departure from past practice.

From a CRO perspective, the implications are substantial. Putative placebo approaches are highly dependent on data quality, compatibility of inclusion and exclusion criteria, and careful alignment of endpoints across studies that were never originally designed to speak to one another.

“This is a complex statistical method,” Forst acknowledges. “It’s not against placebo groups, it’s against single patients in the other database, which fit with the inclusion and exclusion criteria.”

The burden does not end there. As therapies improve, demonstrating differentiation becomes even more complex. Superiority against an active comparator is now the gold standard, but achieving it often requires longer trials, larger populations, or highly specific endpoints.

“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.”

The use of BMI, in particular, has come under sustained criticism for oversimplifying the efficacy of a weight loss medication. As Forst explains, while BMI does correlate with risk at a population level, it tells clinicians little about vital metrics such as fat distribution, metabolic health, or individual vulnerability.

“BMI has an association with elevated risk, but it’s not the best marker,” Forst says. “It doesn’t tell you about the kind of adipose tissue you have and the distribution.”

The distinction matters. Visceral and ectopic fat carry far greater cardiometabolic risk than subcutaneous fat, yet, BMI doesn’t differentiate between the two. Consequently, there is a risk of treating patients who look unwell, but who are metabolically stable, while missing others whose risk is higher, but less externally visible.

“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 outcomes complicate matters further. GLP-1 therapies have proven highly effective, but they are not curative, and lean muscle mass can be lost alongside adipose tissue. This means that patients who opt to discontinue treatment often experience weight regain, and not all tissue returns equally.

“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 doesn't work because they have weight gain again,” says Forst. “This is not very 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's mostly adipose tissue.”

Repeated cycles of loss and regain can risk leaving patients both obese and sarcopenic – a combination with serious functional consequences. It is one reason why Forst emphasises that lifestyle factors, particularly resistance training and protein intake, continue to matter, even in the era of highly effective pharmacotherapy.

Yet, the most striking insights are not always captured in traditional endpoints. Forst recounts a patient describing a constant “food noise” that dominated her waking hours, only disappearing after her first injection. Compared to the clear numerical and scientific evidence famous in clinical research, this anecdote is easy to overlook, but it highlights a core challenge in obesity research: appetite regulation, mental load, and quality of life influence adherence, retention, and long-term outcomes in ways the scale cannot capture.

“It’s fascinating how fast we are learning things that we had not even considered a couple of years ago,” Forst says. “I’m absolutely convinced that we are at the very beginning.”

Obesity trials are becoming longer, more complex, and more ethically scrutinised. They demand careful design, sustained patient engagement, and endpoints that speak to regulators, payers, and patients simultaneously. For CROs, the challenge is not simply to keep up, but to help shape how evidence is generated in a field that is redefining itself.

As obesity continues its transition from a marginalised condition to a core focus of metabolic medicine, the trials that underpin its therapies will need to reflect that seriousness.

“It's about becoming healthier. That's the important thing,” explains Forst. “We now have the first studies with semaglutide in place, where it's also shown that for obese people you reduce the risk of cardiovascular events by 20%.

“It's not only making obese people leaner, it's treating a very, very malignant and dangerous disease; making really ill people much healthier.”