Between 2013 and 2016, 49.1 percent of U.S. adults surveyed had attempted to lose weight within the last 12 months. Weight loss medications have reached the public eye in popular culture and practice. To be considered effective in a clinical trial by the FDA, the drug candidate must demonstrate a statistically significant difference in mean weight loss between the active product and placebo-treated group of at least five percentage points. Additionally, the proportion of subjects who lose 5 percent or more of their baseline body weight must be at least 35 percent of the overall group, approximately twice the proportion of the placebo-treated group, with a statistically significant difference. The FDA states that the source of this weight loss should be primarily through fat content, not lean body mass. To ensure measurable fat loss, sample subjects should receive baseline and follow-up measurements of body composition through dual-energy X-ray absorptiometry (DEXA) or a suitable alternative.
With regards to the actual metrics of these patients, reporting the amount of fat vs. lean body mass loss is not required and total weight loss in pounds is often reported as the endpoint or primary marker of efficacy. This lack of transparency may lead to confusion in the average consumer. Several weight loss drugs, such as Ozempic, are a part of the semaglutide hormone class, which mimic glucagon-like peptide 1 (GLP-1) to suppress appetite. However, anecdotal evidence from some physicians suggests that Ozempic patients may primarily lose weight from lean mass rather than fat, increasing their body fat percentage as they lose weight. Thus, these individuals may not actually be getting healthier. This phenomenon is one that physicians have already witnessed in the clinic. Nevertheless, under the current FDA standards, drugs like Ozempic are receiving approval and popularity due to their impressive weight loss results, without evidence of targeted fat loss.
The FDA can increase accountability by mandating body composition changes as the principal metric for weight loss drugs in clinical trials, primarily through DEXA scans. This method utilizes an X-ray technique to examine body density, affording an estimate of the amount of lean muscle mass and fat tissue in the body, and is the gold standard of measuring a patient’s body composition (e.g., amount of body fat, amount of lean muscle mass). For clinical trials testing new weight loss drugs, a required baseline level of fat should be established for each patient, with body fluctuations monitored throughout the study. By doing so, this would also alert the medical community to potential side effects, facilitating the determination of the best treatment plan for a patient. Moreover, if medication-induced weight loss is not coming primarily from fat, the drug should potentially be barred from FDA approval.
On the other hand, there are demonstrated risks to using DEXA as a benchmark for weight loss drug outcomes. First, the technique is susceptible to human error. For instance, there is a large degree of variability in the skills of the technologists who perform the tests and those who interpret them. This can lead to error from movement, patient positioning, region of interest (ROI) placement, and mixed readings. Additionally, the process can have issues due to the machine itself. For instance, scan errors can result from equipment with hardware or software problems, resulting in detector streaks or typing errors. Furthermore, patients who are extremely overweight may struggle receiving accurate readings, since the manufacturer’s algorithms are based on a normal BMI. DEXA exam tables are also specifically limited to individuals under 300 pounds, which may limit access to obese or overweight individuals. To address these issues, there should be ongoing research for developing DEXA exam tables and algorithms which perform equitably across a large range of patient weights, in addition to increased training for DEXA technicians. Regardless, DEXA is the gold standard for body composition measurement and could effectively ensure patient medication-induced weight loss is primarily due to fat loss.
Due to the mechanisms through which recent weight loss drugs operate, the FDA’s current standard for approval does not reflect what genuinely makes patients healthier–which should be the ultimate goal of medical therapies. The FDA should consider accepting body mass composition metrics through DEXA scans as the primary outcome in weight loss studies. Numerous popular semaglutide drugs, such as Wegavy and Mounjaro, cite their impressive weight loss results during clinical trials to attract consumers and gain FDA approval. The FDA’s current guidelines require metrics that only report total weight loss, so many weight loss drugs are using this outcome as the primary marker of efficacy. This behavior penalizes drugs that selectively target fat loss, rather than muscle loss, and rewards drugs that cause significant weight loss through potentially unhealthier means. The FDA should require weight loss drugs to prove their efficacy for reducing fat content by requiring baseline levels of fat and body composition, and monitoring changes in these levels as a part of each clinical study. By enforcing this, the FDA can better safeguard patient interests.
Tatum R. Dam is a health care researcher. Diana A. Hla, Aditya Narayan, and Ank A. Agarwal are medical students.