New research suggests that more than 1 in 4 women in midlife experience treatment-resistant obesity. 

Coined by Virginia Commonwealth University researchers, TRO refers to the inability to achieve clinically meaningful (> 5%) total body weight loss after 1 year of medically specialized, professionally supervised obesity management. But identifying treatment-resistant obesity might be more of an art than science: The condition does not fit neatly into treatment-refractory or -resistant definitions because its underlying mechanisms have not been thoroughly explored. 

"The issue is we don't have a good definition for what resistance actually means or how to conceptualize TRO," said lead study author Emily Stevens PhD, RN, a family nurse practitioner and advanced certified obesity medicine specialist at Augusta Health Metabolic Clinic in Fishersville, Virginia. "Obesity is more complex than potentially similar medical chronic conditions like hypertension. We have to think about diet changes, movement, sleep, and stress," she said. 

Tara K. Iyer, MD, medical director of the Menopause and Midlife Clinic, and associate physician for the Center for Weight Management and Wellness at Brigham and Women's Hospital in Boston, agreed. 

"There are a lot of confounding factors and a compilation of reasons why we see difficulty with weight loss and weight gain in this population," she said. 

She pointed to factors like chronological aging, which, along with menopausal hormonal changes, is associated with a reduction in lean muscle mass and an increase in total and visceral adiposity. 

"We also know that there are potential changes in skeletal mass," she said. 

Secondarily, there are hot flashes, night sweats, insomnia — symptoms that themselves can drive weight gain and difficulty with weight loss. "It's my expectation (and clinical experience) what patients have tried in the past is no longer going to be effective." 

What the Data Show

Stevens shared that her interest in treatment-resistant obesity was motivated by the number of women coming to her office with complaints of weight gain, the inability to shed weight, and consistently being told to diet and exercise. Others, she said, were already patients of hers, and despite being on medication, were not achieving clinically meaningful weight loss. 

She decided to investigate. 

Stevens and her colleagues retrospectively analyzed the electronic health records of 203 midlife women who attended a single metabolic management clinic between Oct. 1, 2021, and Sept. 30, 2024. Subjects had been diagnosed with obesity (BMI > 30) and saw their doctor at least four clinical visits over a year or longer. 

Nearly 28% (n = 56) of these women demonstrated TRO, despite having received an FDA-approved injectable medication, oral medication, or a medication used off-label for weight management. 

In the final multivariable analysis, only two biopsychosocial variables — FDA-approved injectables and lower reported intake of carbohydrates — were significantly associated with treatment-resistant obesity. More than half (56%) of patients who did not use FDA-approved injectables developed TRO. In comparison, TRO occurred in only 14% who used injectables and followed a low-carbohydrate diet. 

The study had several limitations due to notable gaps in the EHRs. They included details regarding the elements in a low-carbohydrate diet, or lack of data on confounders (eg, genetic, environmental, and hormonal factors) that might influence the response to obesity treatment. Self-reporting bias, particularly around reports on diet and sleep, was also pervasive. 

"It's only one study, but it's starting to give us a bit of baseline evidence of how often this might be happening; for a long time, obesity has been framed as an issue of individual responsibility. It shouldn't be assumed that if a person does not reach the minimum threshold for weight loss, that they're not doing the things they're supposed to be doing," said Stevens. 

Treatment-Resistant Obesity Management

Novel research suggests that menopausal hormone therapy (MHT) might be part of an overall management strategy for midlife women with overweight and obesity, albeit with several important caveats. 

"There's some studies that show that midlife women using MHT in conjunction with semaglutide or tirzepatide had a more profound response," said Iyer. This was especially true of tirzepatide, which was shown to produce a 35% greater absolute weight loss  in women also taking MHT. Of these subjects, 45% also achieved > 20% total body weight loss, compared to 18% of nonusers. 

Courtney Younglove, MD, a dual board-certified physician in obesity medicine and obstetrics/gynecology, and a certified menopause practitioner at Heartland Weight Loss in Overland Park, Kansas, author of a recent review on MHT in weight management, reinforced the message that obesity treatment is a comprehensive strategy where you need to be looking at all of the factors that contribute to abnormal fat storage. 

"The four-pillar treatment strategy accounts for behavior and psychology and movement and nutrition, all of which are individualized to the patient," she told Medscape Medical News. "It's a more complex discussion than if a medicine works or not.

Despite the lack of data around TRO, Tracy Norfleet MD, MBA, an internal medicine physician and obesity medicine specialist in St. Louis and a spokesperson for the Obesity Society, said the TRO moniker might help to change the narrative surrounding obesity from patient failure to something that is recognized and commonly seen in clinical practice. 

"This concept of TRO reframes the disease — that this is not a compliance issue or compliance problem," she said. 

"It further raises the idea that we should not blame the patient for their inability to lose weight. Obesity is complex and chronic, and there are many factors that play into it, including genetics and epigenetics; even the medications that we use and prescribe can increase weight," Norfleet said. 

"If we can jump on this in a preventive or early treatment phase, we will be doing a service to our patients. I think we need to move from focusing on numbers to focusing on health; you cannot ignore that overweight comorbidities and obesity increase the risk of many other conditions," she said. 

Stevens and Younglove report no relevant financial relationships. Iyer sits on the Medical Advisory Board and is a consultant for Bayer and Amissa Health. Norfleet is on the Speaker's Bureau and is a consultant for Currax Pharmaceuticals and Eli Lilly, and is on the Speaker Bureau for Novo Nordisk. 

Liz Scherer is an independent health and medical journalist. She has written on menopause and the menopausal transition for several decades.

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