NEJM Interview: Sarah Schmitz on protections for people enrolled in trials of investigational agents for obesity.

Manufacturers have been racing to develop increasingly potent therapies for obesity. But in this pursuit, protections for people enrolled in trials of investigational drugs may be inadequate. I'm Stephen Morrissey, managing editor of the New England Journal of Medicine, and I'm talking with Sarah Schmitz, an obesity medicine specialist at Weill Cornell Medicine and an assistant attending physician at NewYork-Presbyterian Hospital. Dr. Schmitz has written a perspective article about promoting participant welfare in trials of agents for obesity. Dr. Schmitz, how are trials for new obesity products typically structured, and what endpoints are generally used?

So trials of obesity pharmacotherapies have largely been designed with change in BMI as the primary endpoint and a goal of maximizing weight loss. So my concern is that these trials aren't built to detect the harms that have become more likely as obesity pharmacotherapy is becoming more and more effective.

So in fact, what levels of weight loss have the newer generation agents produced in recent studies?

Retatrutide is a next-generation triple agonist that I think has received the most attention because of the efficacy, which in a phase two clinical trial produced more than twenty-four percent weight loss in under a year. And the phase three trials are currently underway, but some of the top-line results show even more weight loss, which is approaching and rivaling that of bariatric surgery.

What's known about the physical health effects associated with that amount of weight loss?

Most of what we know about that degree of weight loss comes from the bariatric surgery literature, so in some sense, we are in uncharted territory. And I mentioned before, obesity trials are structured to look at percent body weight loss, and there's more considerations with this degree of weight loss, including things like nutritional status and functional status and body composition changes that currently are not routinely assessed in these trials.

And then in your perspective, you also discuss some of the other potential consequences of profound and rapid weight loss. What psychosocial factors are worth considering?

Again, this comes from the bariatric surgery literature, and one of the studies that I find very interesting is they looked at relationship status of people who had bariatric surgery, and basically, they were twice as likely compared to the general population at that time to both get married or get divorced, depending on their relationship status at the time. So that is a consideration that has not been really, I think, thought of, and we don't know the impact of GLP-1 receptor agonists on relationship status or psychosocial changes in general, but that's definitely something that I believe warrants prospective assessment in studies and future study as well independently.

You also say in your article that participants' motivations for joining a study can further complicate the ethics of obesity trials. Why is that the case?

Many of the people in these trials have tried repeatedly to lose weight, often while dealing with obesity-related medical complications and a lot of stigma. So for someone in that