An Elixir for Weight Loss? The Skinny on Semaglutide
For the first time in human history, more people will die from obesity and its comorbid conditions than famine. By 2030, an estimated half of the U.S. population will have obesity, with a disproportionate rise in those with severe obesity.
Popular opinion around obesity falls into camps: those who believe that being overweight is a slothful choice and a moral failing due to a lack of willpower. Those who maintain that obesity is a genetically determined fate. Those who view obesity as a product of a so-called toxic food environment. And a growing crowd who condemn fat-shaming and embrace body positivity. All perspectives discount the metabolic complexity that makes sustainable weight loss so vexing.
As more research accumulates, we now appreciate obesity as a “chronic, relapsing, multifactorial, neurobehavioral disease” in which our brain becomes desensitized to normal appetite signals, making it more difficult to sense how much we’ve eaten and how much fat we have stored. Our lifestyle—primarily the quantity and quality of our food, movement, sleep, and stress—is certainly a primary driver. But our behaviors interact with and are influenced by our genetics, hormones, socioeconomic realities, and environment to determine our health status. Excess energy is likely an inciting factor, but culprits of weight gain also include systemic inflammation, hormone dysregulation, changes in the microbiome and even certain medications. This excess weight, particularly the visceral fat that surrounds the internal organs, fuels the inflammation that stokes chronic disease.
When we try to shed the excess pounds—by aggressively dieting and exercising—our biology bucks based on its evolutionary adaptations. A normal amount of adipose tissue—what we colloquially call “fat”—likely confers a safeguard against famine and may provide the extra energy needed to survive the stress of life-threatening illness. This adipose tissue is an endocrine organ that releases and responds to hormonal signals to help regulate energy balance. When we lose weight, this triggers a dramatic drop in leptin, the hormone that signals satiety and registers the body’s fat storage. The concurrent increase in ghrelin signals hunger. The brain reacts to weight loss by blunting fullness, intensifying the feeling of reward from food, and increasing cravings. It tells our muscles to burn fewer calories and to store extra calories as fat so the body can return to its previous weight or “set point.” This explains why weight loss diets are often short-lived and unsustainable.
This is where the semaglutide— a glucagon-like peptide 1 receptor agonist (GLP1a)—comes into play. Obesity medicine practitioners like myself have long been optimistic about the potential of GLP1a therapy to safely and effectively promote sustainable weight loss.
All the rage nowadays thanks to Dr. TikTok, the first GLP1a, exenatide, was approved for use in 2005. Given their ability to increase insulin release from the pancreas and enhance insulin sensitivity in the peripheral tissues, GLP1a medications began as and remain a mainstay therapy for type 2 diabetes. Semaglutide for type 2 diabetes was approved under the brand name Ozempic in 2017. At higher doses, GLP1a’s contribute to significant weight loss by increasing feelings of fullness and acting on appetite centers in the brain and gut to reduce cravings. In February 2021, results from the STEP 3 trial showed that people with overweight and obesity who used high dose semaglutide combined with intensive behavioral therapy for 68 weeks lost 16% of their body weight (as compared to 5.7% body weight loss in the control group). A few months later, the FDA approved semaglutide for weight loss alone under the brand name WeGovy.
In America, the land of yo-yo diets and fitness fads, a drug for sustainable weight loss is perhaps more exhilarating than discovering the fountain of youth. This elixir has triggered a gold rush to capitalize on our cultural obsession with slimness. Direct to consumer telemedicine startups are dolling out semaglutide like Tic Tacs based on self-reported weights. Med spas are tacking on semaglutide prescription packages. And compounding pharmacies are offering what they maintain is generic semaglutide for those who may not qualify for Ozempic or WeGovy, both of which are under patent by Novo Nordisk.
The coinciding clinical efficacy, capitalist impulses, consumer eagerness, and cultural craze around semaglutide have collided to expose various ethical and clinical concerns.
Given current rates of obesity and comorbid chronic conditions, millions of Americans qualify and stand to significantly benefit from GLP1a therapy. Despite the widespread recognition from major medical societies that obesity is a chronic disease, insurance coverage is still spotty at best. Medicare does not cover WeGovy or other weight loss drugs, and many commercial insurers follow Medicare’s lead. Nor do most state-based Medicaid programs despite the fact that the highest rates of obesity occur in Black and Hispanic adults, the uninsured, and low-income Americans. When insurance does not cover semaglutide, out of pocket cost for brand name WeGovy runs about $1400 per month, entirely unaffordable for most Americans. While Novo Nordisk maintains its current monopoly on weight loss medications, this price tag is unlikely to budge. The massive gap in insurance coverage for weight loss medications exposes the inequities and biases that limit access to comprehensive obesity care in a society that still largely perceives obesity as a cosmetic issue of willpower, not a result of metabolic pathophysiology.
GLP1a therapy, and semaglutide in particular, undeniably works to produce effective, and often times remarkable weight loss. But as with all powerful medical interventions comes the responsibility to repeatedly reassess risk and benefit and determine the proper use cases and protocols. Current guidelines specify a body mass index (BMI) of 27 or above with an associated comorbid condition (high blood pressure, type 2 diabetes, obstructive sleep apnea, etc.) or a BMI of 30 or greater without a comorbid condition as qualifying criteria for semaglutide (and other weight loss medications). This is based on the FDA-specified primary endpoint of percent change in body weight from the STEP trials.
BMI, a ratio which describes one’s body weight relative to their height, is useful as metric to evaluate and monitor the prevalence of overweight and obesity across large populations; it is a limited and crude metric when applied to an individual. BMI does not distinguish between excess fat, muscle, or bone mass, nor does it provide any indication of the distribution of fat among individuals. There are significant differences in body types and cardiometabolic health risk based on biological sex, age, and race and ethnicity. A study of over 40,000 adults showed that nearly 1 in 3 “normal weight” individuals as classified by their BMI have poor metabolic health as assessed by other markers including blood pressure, cholesterol and C-reactive protein (a gauge of inflammation). Meanwhile, nearly half of those who classify as overweight and 1 in 3 of those who classify as obese by BMI were healthy as measured by the same metrics. The authors conclude that using BMI alone as a measure of health would misclassify almost 75 million adults in the U.S. In addition, body weight is notoriously under-reported, and height is often over-reported, which not only obscures the underlying links that exist between obesity and chronic health conditions but can be easily gamed if needed—to access weight loss medications in a telehealth setting, for example.
The mark of success—or clinical efficacy—on GLP1a therapy is pounds lost and the percent change in weight over time. The risk here is that patients start to conflate weight loss with health. In reality, body composition—the breakdown of fat mass, especially the visceral fat around the organs, and lean muscle mass—is a much better metric for overall health. Muscle mass is the primary driver of your body’s metabolic rate and is our most important longevity organ for function and injury prevention. However, weight loss, especially the rapid weight loss that can occur with GLP1a therapy, comes with the concurrent loss of lean muscle mass. For patients with obesity, the reduction in fat mass confers huge health benefits that outweigh the risks of some loss of lean muscle mass. For example, in a separate analysis of a subset of subjects with an average 43.4% body fat at the outset of the 68 weeklong STEP 1 Trial, researchers evaluated the impact of semaglutide on body composition using dual energy X-Ray absorptiometry and reported that overall, semaglutide was associated with reduced total fat mass and regional visceral fat mass and an improved proportion of lean body mass to fat mass. However, the weight loss promoted by these medications certainly takes an aggressive hit to lean muscle mass. And there is likely a subset of patients, particularly those who start with a lower body fat percentage, who will lose muscle mass at the same or greater rate than fat mass, which has adverse consequences for health and longevity.
Understanding the pathophysiology of obesity and treating it like any other chronic condition is a necessary part of a comprehensive approach to managing, reducing, and ideally preventing this public health epidemic. In addition to expanding insurance coverage, health care providers need more sophisticated training to help patients successfully and sustainably improve body composition.
Currently, medical students get a paltry 19 hours of nutrition education on average over four years. In the 3 or more years of residency, nutrition education is typically absent even though dietary interventions prevent and manage the most prevalent and costly conditions like diabetes and cardiovascular disease. Motivational interviewing, a technique to enable patient-centered behavior change, is not a core competency despite its efficacy for weight loss. Many providers avoid the topic of excess weight with patients in part because they do not appreciate the metabolic complexity, and hence, remain pessimistic that patients can make the necessary changes to lose weight. Estimates indicate that of those who have obesity and actually speak with a doctor about it, only about half get a formal diagnosis and a quarter receive no follow-up care. And the number of physicians qualified to deliver effective pharmacotherapy for weight management is not growing nearly as rapidly as the population is developing obesity.
GLP1a therapy, currently with semaglutide and soon enough with tirzepatide and others in the pipeline, is extremely effective—for the right people. Currently, the mass appeal of these medications is leading to overprescribing which unsurprisingly invites warranted criticism and increases safety risks. Moving forward, we must more assiduously identify appropriate candidates who would benefit from these medications where weight loss confers long term health benefits that outweigh the risks.
The inclusion criteria should focus on percent body fat, not BMI. Patients should be screened with body composition testing which also evaluates and establishes a lower limit for lean muscle mass. This should be coupled with concurrent testing for cardiometabolic risk—blood sugar control, lipid levels, vascular inflammation—given the proven efficacy of GLP1a therapy for cardiometabolic health. Successful clinical outcomes on these medications would include improvement in body composition (i.e. reduction in fat mass with limited loss of lean muscle mass), improvements in biomarkers of cardiometabolic health, and increased resting metabolic rate.
Achieving these outcomes would necessitate more focused education and tailored clinical management of patients on these medications, with a primary focus on countering the loss of lean muscle mass. Sarcopenia, the age-related loss of muscle mass, begins around the age of 35. Counseling for patients working towards weight loss—especially those supported by GLP1a therapy—would focus on strength training multiple times each week and eating a high protein diet of at least 1.5 grams of protein per kilogram of lean mass. This would likely necessitate a slower dose escalation of GLP1a to help each patient experience less appetite and cravings while maintaining increased protein requirements without the deterrent nausea or gastrointestinal distress that risks malnutrition. Regular body composition testing, especially with ongoing weight loss, would be used to titrate to the lowest effective dose or halt therapy altogether if lean muscle mass falls below a critical threshold.
GLP1a therapy is major advance in our arsenal to combat obesity. While we work to increase access to these medications for those who need them, we must also refine our inclusion criteria and clinical protocols in order to safeguard and improve patients’ long-term health. Otherwise, we risk following our reflexive impulse that more of a good thing is even better. Let’s learn from recent precedents with other medications to understand and prevent the detrimental risks of such an overeager and misguided approach.