Kailera Therapeutics is taking a somewhat unusual step in its effort to bring a new weight-loss drug to market. One of its phase 3 studies of ribupatide will test the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist not only against placebo, but against the already approved GLP-1 semaglutide.
Drugmakers Eli Lilly & Co. and Novo Nordisk also have included comparisons to approved drugs in studies of experimental weight-loss medicines.
But a Medscape Medical News analysis shows that for the most part, Kailera, Eli Lilly, Novo Nordisk and other pharmaceutical companies continue to test their experimental weight-loss drugs only against placebo.
This strategy might raise practical and ethical issues for clinical trials because most patients are aware of the effectiveness of already approved currently GLP-1s.
The potential practical impact on clinical trials was mentioned by the authors of the study that supported the April 2026 FDA approval of the once-daily oral GLP-1 orforglipron (Foundayo, Eli Lilly).
Sean Wharton, MD, and coauthors reported that 6.2% of patients in the placebo group discontinued treatment because of a lack of efficacy, compared with up to 1% in the orforglipron group, depending on drug dosage. Other weight-management interventions were started by 2.5% of the patients in the placebo group who stuck with the trial.
“Although the higher discontinuation rate in the placebo group in the current trial was consistent with earlier clinical trials of GLP-1 receptor agonists in patients with obesity, the increasing availability of efficacious obesity-management medications may have an adverse effect on trial retention,” the researchers wrote in The New England Journal of Medicine last year.
A special challenge with obesity medicines now is that people in clinical trials can often tell if they are in the active or placebo group, said Beverly Tchang, MD, associate professor of clinical medicine at Weill Cornell Medicine, New York, and a fellow of The Obesity Society. That makes it difficult to maintain the blinding in trials.
“In addition, access to FDA-approved medications, as well as the gray market of compounded peptides, make it challenging for research participants to stay in a trial, knowing that they might have better results elsewhere,” Tchang said.
“A participant has every right to leave a trial and seek care elsewhere, so this is something we all have to keep in mind when we examine future data from placebo and if that placebo arm seems to be losing more weight than you’d traditionally expect (ie, 0%-2% weight loss),” she told Medscape Medical News.
In terms of ethics, placebo groups in weight-loss trials could be viewed as denying care to patients because there are effective, approved options that any experimental drug could be tested against.
Potentially bolstering that view is a recommendation by the European Association for the Study of Obesity last year, which said that semaglutide or the dual GIP/GLP-1 agonist tirzepatide should be used as the first-line treatment for people living with obesity and most of its complications.
Tchang used other medical conditions to illustrate the point that could be made against placebo arms in weight-loss drug trials. “In the realm of new diabetes medications, everyone in the clinical trial would still be on a background of metformin. For cardiovascular disease, everyone is expected to be on standard of care (a statin, etc.) plus the experimental drug,” she said. “Expectations are changing for research to better align with clinical practice.”
Earlier Ethical Debates
Questions have long surrounded the ethics of using placebos in experimental drug trials when proven, effective therapies already are available.
In 1997, Peter Lurie, MD, MPH, and Sidney Wolfe, MD, of the nonprofit Public Citizen Health Research Group, published an article in The New England Journal of Medicine criticizing the design of trials in developing countries testing methods of preventing maternal-child HIV transmission.
By that time, research had established that zidovudine could reduce the incidence of such transmission by two thirds. Yet some pregnant women with HIV infection who participated in clinical trials in developing nations were given placebos.
Concerns about these kinds of studies led the World Medical Association, an international umbrella group of physician organizations, in 2000 to strengthen wording about placebos in the Declaration of Helsinki principles for medical research. It shifted from saying every patient — including those of a control group, if any — should be assured of the best proven diagnostic and therapeutic method in 1996 to, in 2000, saying that the “benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.”
The 2000 tweak drew fierce criticism for being too strict about placebos and was subsequently softened.
The current Declaration of Helsinki, adopted in 2024, says that new treatments should be tested against the “best proven” interventions when available, unless comparison to placebo or no treatment is the only way to prove whether the experimental treatment is safe and effective and participants would not be subject to added risks for serious or irreversible harm as a result of not receiving the best proven intervention. “Extreme care must be taken to avoid abuse of this option,” it says about the exception.
Still, researchers continue to consider questions about when placebo arms are appropriate in clinical studies of conditions for which there are approved treatments, Lurie, who worked as associate commissioner for the FDA from 2009 to 2017 and is now president of the nonprofit Center for Science in the Public Interest, told Medscape Medical News.
“Reasonable people do disagree about where the line is on this,” Lurie said.
Placebo arms remain important in testing of treatments for conditions that ebb and flow or resolve spontaneously, he said.
For example, although depression has many approved treatments, placebo arms are needed in research into new therapies to counter the effects of the natural tendency of depression symptoms to ease and then return, Lurie said. Even in those circumstances, informed consent is a must, treatment trials should not be excessively long, and provisions must be made for unblinding and treatment if the patient’s condition worsens, he said.
Placebo-controlled trials may also provide more clear answers about potential side effects, and they usually give faster answers about whether experimental medicines have the expected effect on conditions.
“It’s easier to demonstrate effectiveness compared to nothing than to detect effectiveness compared to something that actually works, which is why pharmaceutical companies tend to favor them,” Lurie said.
In the case of obesity drugs, questions about ethical use of placebos in studies would involve looking at what potential harms people face by taking placebo for the course of a study, not just the missed opportunity to lose weight, Lurie said. This would be difficult to do. Researchers would need to calculate the risk of whether taking a placebo instead of an approved weight-loss drug could, for example, increase the risk for heart attack in a measurable way, he said.
“What, quantitatively, are you denying people? That’s what the question really is,” Lurie said. “And I don’t think that there is a magical answer to this question.”
Tchang has been an adviser for Novo Nordisk and Eli Lilly. Lurie reported no relevant financial disclosures.
Kerry Dooley Young is a freelance journalist based in Washington, DC. She has covered medical research and healthcare policy for more than 20 years.
