Two recent documents—one from the FDA, the other from a commission organized by The Lancet Diabetes & Endocrinology—indicate an evolving mindset toward treating obesity as a chronic disease.
The World Health Organization has been sounding the alarm on obesity since the 1990s. Now, regulators and other leading experts are redefining the terms of the global obesity epidemic—with potential implications for patients, practitioners and drug developers.
In an update to a 2007 guidance regarding weight loss drugs, the FDA issued a new draft guidance last month dubbed “Obesity and Overweight: Developing Drugs and Biological Products for Weight Reduction.” The new document is open to feedback through early April.
Meanwhile, a global commission organized by The Lancet Diabetes & Endocrinology published its recommendations of new diagnostic criteria for clinical obesity, moving beyond the standard body mass index (BMI) measurement.
Perhaps one of the biggest changes to the FDA guidance is the agency’s definition of obesity. In its 2007 guidance, obesity was referred to as a “chronic, relapsing health risk,” according to IQVIA (the old guidance is no longer publicly available, an FDA spokesperson confirmed to BioSpace). Now, obesity is being defined as a “chronic disease,” reflecting a shift in the understanding of the condition and emphasizing the importance of long-term management.
“What the FDA is saying is that they’re recognizing obesity is a real health crisis,” Ray Stevens, CEO of Structure Therapeutics, told BioSpace.
Mark Bagnall, CEO of Phenomix Sciences, agreed that the healthcare system as a whole is moving toward recognizing obesity as a disease. The American Medical Association declared obesity to be a complex, chronic disease in 2013.
Eli Lilly was also supportive of the definition. “We believe that guidance should recognize the abundance of clinical evidence that identifies obesity as a complex, chronic disease and that additional or alternate criteria may be needed to help appropriately identify patients with obesity for inclusion in clinical trials,” a company spokesperson told BioSpace in an email.
Interestingly, the FDA did not change the efficacy standard it set forth in 2007. The bar remains at “weight reduction greater than or equal to 5% of baseline body weight or BMI” after one year of treatment. Considering the efficacy of currently approved GLP-1s and others in development—Novo Nordisk’s Wegovy, for example, can elicit up to 18.7% weight loss in 72 weeks—this seems woefully low, Bagnall told BioSpace.
“Five percent is, well, it’s not meaningful,” he said, adding, “Everybody deserves to lose a percentage that gets their disease resolved.”
Maintenance Matters
In addition to redefining obesity as a chronic disease, the FDA’s new draft guidance also puts more emphasis on the use of weight loss drugs as maintenance therapy, with the document repeatedly referring to drugs “intended for weight reduction and maintenance.”
This could be the agency recognizing the phenomenon of patients unable to stay on GLP-1 drugs for long periods of time, Blai Coll, chief medical officer at Structure, told BioSpace. A recent study by Prime Therapeutics and Magellan Rx Management found that 85% of people who begin taking a GLP-1 agonist for obesity are no longer on the drug after two years.
The study also showed that patients taking GLP-1s for obesity without diabetes paid an average of $4,206 more in their second year of treatment than those taking the drug for non-obesity indications.
“By [FDA] putting more emphasis on the maintenance, I think it opens the door for therapeutic options that can be more accessible to all,” Coll said.
The new draft guidance also places less emphasis on lifestyle interventions than the previous document, while placing greater importance on pharmacological treatments, according to STAT News. It is also less conservative in its approach to the pediatric population, removing prior recommendations that studies should first be conducted in higher-risk children.
Another potential positive for companies in the obesity space is that the new guidance does not include a requirement for a cardiovascular outcome trial in order to gain approval for chronic weight management. There was speculation that the FDA would add this requirement, as it had for type 2 diabetes, Coll said. However, if no cardiovascular signals are detected in earlier stage studies, a cardiovascular outcome trial is not required as part of the registrational package.
The new guidance does recommend that trials “include subjects with comorbidities, such as cardiovascular disease, heart failure, liver disease and chronic kidney disease.”
It’s a “fleshing out of things people are doing but hadn’t necessarily been formalized in a prior guidance document,” Brian Lian, CEO of Viking Therapeutics, said in a presentation at the JP Morgan conference in January, adding that the guidance did not impact Viking’s Phase III study design for its obesity candidate VK2735.
Beyond BMI
Obesity has historically been defined solely by body mass index. If someone has a BMI of 30 kg/m2 or higher, they are diagnosed with the disease.
While the new FDA guidance recommends that patients included in Phase II efficacy trials have a BMI of at least 30 kg/m2, or at least 27 kg/m2 with one or more comorbidities, it also includes a recommendation to monitor body composition in a subset of patients to assess the quality of weight loss. Many experts have emphasized the need to distinguish between fat loss and lean mass loss, as loss of muscle mass is associated with poor outcomes, especially in the elderly.
Both Wegovy and Eli Lilly’s Zepbound were initially approved with BMI requirements. In March 2024, Novo removed the BMI descriptor from Wegovy’s label “based on feedback from the FDA,” a company spokesperson told BioSpace in an email. The label for Eli Lilly’s Zepbound has also dropped the term, instead listing the drug as intended for “adults with obesity or with overweight in the presence of at least one weight-related comorbid condition.”
In the same vein, a commission of 58 metabolic surgeons, internists, exercise specialists, dietitians and patients recently convened to come up with a better way to define obesity. They published their findings in The Lancet Diabetes & Endocrinology in January.
David Cummings, director of the weight management program in the VA Puget Sound Health Care System and a member of the commission, said that the problem with obesity defined solely by BMI is that there are people with a BMI over 30 kg/m2 who are not obese, but rather “relatively short and maybe muscular.” There are also people with a BMI under 30 kg/m2 who might be sick because of excess adipose tissue (body fat), he said, so the BMI criterion used alone can both overdiagnose and underdiagnose the disease.
The commission didn’t throw out BMI completely, however. Cummings said it is still a useful screening tool in clinical practice to identify patients for additional testing. The range likely relevant for the new classification is between 25 kg/m2 and 40 kg/m2. Practitioners would assess patients within this range using a variety of tools, including physical measurements and a DEXA scan, he explained.
The official recommendation of the group is to then divide patients identified with excess adiposity into two classes: preclinical obesity—in which patients with excess adipose tissue are not yet ill—and clinical obesity, where they are.
“People with preclinical obesity should not be ignored; they just might be a bit lower on the priority scale for treatment with aggressive and frankly expensive interventions,” Cummings said.
The commission defined clinical obesity—where patients are ill because of too much body fat—as a disease in and of itself “which deserves covered treatment just like any other disease.” Any compromise to daily living activities due to excess body fat would also constitute clinical obesity.
Eli Lilly appears to be in agreement with this line of thinking. “We also stress the need for new clinical endpoints that include measures of adiposity,” the company spokesperson wrote to BioSpace.
Currently, the group is discussing what to do with the information. How it is ultimately implemented, Cummings said, will likely vary between countries.
Noting the expense and supply issues often associated particularly with GLP-1 drugs, Cummings said it is the commission’s hope that these new definitions of obesity could allow the improved allocation of limited resources to people most in need of them.
Coll said that, unfortunately, there is “a little bit of discrepancy” between The Lancet report’s new definition of obesity and the FDA’s requirements for drug developers. While he does not believe there are currently any major changes for drug developers within the two documents, Structure is incorporating some of the new recommendations from the commission so it will be available for prescribers and in the event of future FDA guidances.
For Coll, the metabolic space is moving into an “unprecedented” situation where, for the first time, a precision medicine approach is possible, as it is for oncology and cardiovascular diseases.
“The field is evolving with this new, precise definition,” he said. “It’s not a one-size-fits-all.”
