For years now, companies behind weight loss drugs like Wegovy and Zepbound have been trying to convince the medical community and the public that obesity is a disease and medications are the answer. It seems the Food and Drug Administration has now shifted its perspective, too.
This week, amid a slew of new recommendations that the FDA released ahead of President-elect Trump’s inauguration, the agency posted draft guidance on obesity clinical trials, the first time it has done so since 2007.
The new draft calls obesity “a chronic disease,” whereas the previous guidance called it “a chronic, relapsing health risk.”
It mentions the importance of lifestyle interventions less than the previous guidance, omitting a reference to lifestyle modification being seen as “the cornerstone of overweight and obesity management.” It also takes a less conservative view of how companies should test drugs in the pediatric population, removing recommendations that drugmakers should first conduct studies in higher-risk adolescents than other children.
Draft guidance documents issued by the FDA are not binding, but revisions, even subtle, provide a look into the agency’s stances; they also have real-world implications for how experimental drugs and devices are assessed and approved.
The changes reflect “a cultural shift” around obesity medications, said Diana Zuckerman, president of the nonprofit National Center for Health Research, which analyzes and explains health research to the public. As a result, the new guidance “seems more favorable to the drug companies.”
Some doctors welcomed the changes, saying that the FDA now appears to be treating obesity drugs similarly to treatments for conditions like hypertension and diabetes; in none of those cases does the agency indicate it expects patients to wait and try to alter their behavior before trying medications. Other experts, however, were concerned that the changes seemingly assign less significance to lifestyle changes.
“I think it’s a missed opportunity to show a more neutral stance on weight loss strategies,” Zuckerman said.
In a statement, the FDA said that it “continues to recognize the important role of lifestyle intervention in the management of patients with obesity.” The new guidance, like the previous one, still says that during trials, drugs should be studied as an add-on to lifestyle intervention.
The reactions mirror the broader debate over whether new weight loss drugs, and drugmakers’ marketing efforts, will lead to an over-medicalized approach to addressing obesity rates. Pharma companies have been pushing the message that obesity is a biological disease that requires treatment with drugs, in both overt and subtle ways. Novo Nordisk has even funded medical school curricula on obesity.
Some doctors are also concerned that the FDA’s new guidance continues to place too much emphasis on weight instead of overall health. Like the previous guidance, it says percentage weight loss is the primary endpoint for assessing obesity drugs in clinical trials, rather than changes in body composition and fat mass specifically.
It’s not clear if the FDA under Trump would take a different approach to regulating obesity drugs. Some of his allies, notably Robert F. Kennedy Jr., Trump’s pick to lead the Department of Health and Human Services, which oversees the FDA, has criticized the proliferation of weight loss drugs and emphasized the importance of lifestyle changes instead.
Still, the revisions show just how much arguments about the importance of obesity drugs have permeated the medical establishment.
Less discussion of lifestyle changes
The previous guidance clearly emphasized the role of lifestyle changes in weight loss, saying: “Lifestyle modification, consisting of changes in patterns of dietary intake, exercise, and other behaviors, is considered the cornerstone of overweight and obesity management. Because all drug and biological therapies impose some risk for adverse events, the use of a weight-management product should be contemplated only after a sufficient trial of lifestyle modification has failed and the risks of excess adiposity and the anticipated benefits of weight loss are expected to outweigh the known and unknown risks of treatment with a particular weight-management product.” This language is not in the new guidance.
Angela Fitch, chief medical officer of knownwell, a company that treats people with obesity, supports the change, saying that it puts weight loss treatments on par with drugs for other types of conditions. Though patients on an obesity drug should still be counseled to make behavioral changes, they shouldn’t have to wait to start medication, she said.
“You don’t have to try to treat your hypertension with a low-salt diet,” said Fitch, who’s consulted for companies making obesity drugs. “We need to stop this bias and stigma” around obesity.
However, William Dietz, former director of the Division of Nutrition, Physical Activity, and Obesity at the Centers for Disease Control and Prevention, said lifestyle changes should still be the primary way to address obesity, even if drugs play a key role.
“I’m surprised it’s been omitted, and it’s an important omission that needs to be rectified,” said Dietz, who is now a professor in the department of exercise and nutritional sciences at George Washington University.
Less stringent recommendations for pediatric trials
The new guidance also removes the recommendation that for pediatric trials, companies should limit initial studies to adolescents ages 12 to 16 and to higher-risk children who have a weight-related condition like type 2 diabetes or hypertension.
The new draft does not specify an order in which companies should conduct pediatric trials — only that they should conduct separate trials for adolescents ages 12 and up and for younger children ages 6 to 11.
Tom Robinson, a professor of pediatrics at Stanford University, said that while it’s important to eventually test drugs in younger children, he would prefer they first be tested in older teenagers who have gone through puberty. From there, “carefully move down, because the unknowns are much greater when you’re dealing with children who are still growing and developing,” he said.
Novo has already asked regulators to approve the use of an older drug called in the same GLP-1 class as Wegovy and Zepbound, called Saxenda, in children as young as 6, raising concerns from some doctors that there isn’t yet enough data on the drug’s long-term effects on puberty and development. Novo and Eli Lilly have also been testing Wegovy and Zepbound, respectively, in that young age group.
The new guidance says that trials of any drugs that act in the brain should assess kids for depression and suicidality. But Sarah Hampl, a pediatrician at Children’s Mercy Kansas City, said she would have wanted to see the FDA explicitly recommend companies track changes in children’s overall mental and emotional health and any signs of eating disorders.
“Non-BMI outcomes need to really be a standard for pharmacotherapy trials as well, like self esteem, body image, anxiety, depression, disordered eating, all those factors,” said Hampl, who was lead author on the American Academy of Pediatrics’ guidelines on obesity.
Continued focus on weight, not body composition
The medical community has been shifting away from using weight and body mass index as the sole metrics to assess patients with obesity, with the American Medical Association last year asking doctors to de-emphasize the use of BMI in clinical care.
At the same time, doctors have called out the importance of tracking body composition and changes in fat versus lean mass, especially amid concerns that patients may be losing too much lean mass on the new highly potent weight loss drugs. Some drugmakers have even started to develop treatments that aim to preserve muscle while cutting fat mass.
However, in its new guidance, the FDA still defines obesity using BMI and primarily looks at overall weight loss when assessing drugs. It does say that companies that want to specifically get approval on body composition should consult with the agency.
Steven Heymsfield, a professor of metabolism at Pennington Biomedical Research Center, would have liked to have seen the agency propose a range of endpoints that companies could prioritize in general obesity trials, such as a change in body fat and waist circumference, in addition to overall weight loss.
Heymsfield, who’s been involved in research on a drug that aims to preserve muscle mass, also said he thought the FDA should have taken loss of lean mass more seriously as a potential concern.
The new guidance said that while companies should track the body composition of a subset of trial participants to ensure most of the weight that’s lost is fat, the lean mass loss that has been observed so far — around 10% to 40% of overall weight loss — “has not been considered adverse.”
“How do they know it’s not adverse?” Heymsfield said. It’s possible that if patients didn’t lose the lean mass, they could be better off metabolically, such as having more insulin sensitivity, less inflammation, and better physical functioning, but studies haven’t tested for that, he said.