Beyond Scales: Body Composition in Weight Loss Drug Trials

Obesity is the world’s most prevalent chronic disease and has increasingly been recognized as a global public health challenge. It has alarming health impacts and burdens healthcare systems globally. From 2013 to 2016, 49.1% of U.S. adults undertook weight loss initiatives, reflecting the widespread concern and efforts toward healthier living. Concurrently, the ascent of anti-obesity medications (AOMs) into mainstream consciousness is attributable to their reported efficacy and the scarcity of cost-effective or accessible alternatives for a vast proportion of the population¹. Crafting appropriate interventions for obesity, however, mandates the creation of proper clinical endpoints. We argue that by focusing only on weight loss as the primary weight medication endpoint, the FDA is encouraging inaccurate measures of medication efficacy.

To gain approval from the U.S. Food and Drug Administration (FDA) for a weight loss medication, two primary criteria must be met during clinical trials. First, the medication must yield a statistically significant weight loss difference of at least five percentage points compared to a placebo. Second, at least 35% of trial participants must experience a weight loss of five percent or more from their initial baseline and at least twice as high as that observed in the placebo group. However, specific studies challenge the notion that pure change in body mass invariably translates to improved health outcomes². This distinction is crucial, given the potential implications for metabolic health, muscle functionality, and overall well-being. The FDA explicitly states that the primary source of weight loss should be the reduction of fat mass rather than losing lean body mass.

Most clinical trials report total weight loss in pounds as the primary endpoint without distinguishing between fat – including a distinction between visceral and subcutaneous fat – and lean body mass loss. Such inconsistencies can mislead the average consumer, fostering a skewed understanding of what constitutes “healthy” weight loss. Patients need to understand that not all weight loss is beneficial, and the source of that loss matters. It is potentially more prudent for the FDA to require total fat loss, rather than weight loss, as the primary endpoint.

The propagation of a singular body ideal, especially one championed by celebrity endorsements, tends to shape public perceptions, leading to potential misuse of AOMs. However, an integral aspect often overlooked is the repercussions of using medications without fully comprehending their effects. Media outlets play an instrumental role in disseminating information; their narrative can bolster informed choices or inadvertently foster misconceptions about weight loss therapeutics. Patients need to understand that not all weight loss is beneficial, and the source of that loss matters.

Given the broad market, the pharmaceutical industry’s stake in developing and marketing AOMs is immense. However, the economic implications of erroneous drug approvals can be detrimental to the industry and national health expenditures. The costs associated with treating side effects, or potential long-term impacts of drugs that reduce lean mass instead of fat, can significantly strain an already burdened healthcare system. If FDA guidelines are not stringent enough, the resultant economic burden of ineffective drugs could inadvertently be transferred to patients, leading to rising medical costs.

Measuring What Matters: Adopting Body Composition Analysis in Trials

To enhance accountability, one solution lies in the FDA requiring DEXA scans as an endpoint in clinical trials. Establishing a baseline fat level for participants and monitoring body fluctuations would validate the origin of weight loss and unveil any side effects, including undesirable muscle mass loss³. Consequently, this methodology can pave the way for more tailored treatment plans and stringent approval benchmarks. Most importantly, this ensures that weight loss comes from fat, the primary cause of weight-related health conditions. Yet, as with any gold standard, there are inherent challenges to its widespread adoption.

While Dual Energy X-ray absorptiometry (DEXA) is widely considered the gold standard for assessing body composition, it has limitations. Factors such as patient positioning and the competency of the operating technologists can influence the accuracy of DEXA results. Additionally, it is necessary to address the limited accessibility of these scans for individuals with higher body mass index (BMI) due to the weight limits of DEXA tables. Moreover, DEXA scans are economically and logistically challenging at scale. To address these issues, it is crucial to advocate for developing advanced DEXA technology, the enhancement of computational algorithms, and specialized training for technicians. Alternatively, recent advances have enabled measurements of adiposity by more facile means. Two-dimensional photographs were captured via a conventional smartphone camera to estimate total body fat percentage. Such innovations, given the widespread availability of smartphones, hint at the potential for more accessible and accurate measures of body composition in diverse patient populations³.

Additionally, it is essential to recognize the potential drawbacks of mandating DEXA scans for drug approvals. Introducing such a requirement could inadvertently slow the approval process for upcoming therapeutics. This may also hold such medication trials to a higher standard than treatments for other chronic diseases, biasing against innovation for patients struggling with obesity. Thus, it is crucial to strike a delicate balance: ensuring rigorous standards without hampering the speed of critical advancements in creating or disseminating medical therapeutics.

Discrepancies between approval mechanisms and genuine patient health outcomes cast doubt on the longitudinal rollout of AOMs. Medications like Ozempic/Wegovy, otherwise known by its generic name of semaglutide, have gained FDA approval and public favor due to impressive weight loss outcomes. The FDA’s existing guidelines, which emphasize total body weight loss, inadvertently favor such outcomes. A more holistic framework is urgently needed, one that integrates body composition metrics and adopts comprehensive stepwise implementation studies. A reformed system could set a precedent for global healthcare agencies, ensuring a higher standard of patient care. Given the stakes, especially for the most vulnerable, we cannot afford to be shortsighted.

One such population is those served by Medicare – particularly given historically elevated rates of obesity in this population relative to previous decades alongside increased vulnerabilities associated with the condition. Moreover, older adults are particularly susceptible to lean muscle loss or sarcopenia. In light of this vulnerability, alongside policy challenges including, but not limited to, difficulty with healthcare delivery for rural older adults, limited coverage for certain approaches such as weight management counseling, and physiological complexity in the population, ensuring that AOMs do not exacerbate this natural decline becomes paramount. As policymakers grapple with pivotal decisions, such as whether to extend Medicaid or Medicare coverage for these medications^4,5 it is imperative that we have comprehensive, evidence-based practices in place. These should aim to deliver appropriate treatment considering age and health status, at the right juncture, and with minimal side effects. Establishing robust clinical metrics, then, is not just academic rigor; it’s pivotal for ensuring the health and safety of our aging demographic.

In the evolving landscape of weight loss therapeutics, the medical community and regulatory bodies like the FDA share responsibility to ensure individuals’ health, well-being, and safety in their quest for healthier lives. We call for transparency, responsibility, and, most importantly, prioritizing genuine health outcomes over potentially flawed metrics, ensuring patient safety and the best possible results in the fight against obesity.