No Patient Left Behind: Expanding Semaglutide’s Reach

Recent studies from Endocrine Society journals have shown that GLP-1 RAs are not only successful in reducing obesity, but they have positive impacts on a range of other conditions. From improving taste sensitivity and positive results in a pediatric patient with several comorbidities to being an effective treatment in patients with a variety of psychiatric disorders, these drugs are routinely exceeding expectations. Three recent studies published in Endocrine Society journals reveal converging evidence about semaglutide’s effects beyond simple weight reduction. From the molecular changes occurring in taste perception to its application in young patients with complex metabolic needs, and finally to its effectiveness across psychiatric populations, these investigations illuminate both the mechanisms and clinical utility of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in managing obesity and its complications. These articles approach the story about semaglutide’s role in treating complex obesity from different perspectives, moving from mechanism (“why it works”) through application (“how we use it” through evidence (“what the evidence shows”), all in all providing a fuller picture, and an attractive one at that. At a Glance • In women with obesity and PCOS, semaglutide improved their overall taste recognition score, altered RNA expression in the tongue, and modified brain activity in response to sweet and savory food cues, suggesting that the mechanism behind its efficacy may be partly related to enhancing taste sensitivity. • A four-year-old girl with severe obesity, newly diagnosed type 2 diabetes, and extreme hyperphagia (among other conditions) was successfully treated with semaglutide as part of a comprehensive treatment approach over 27 months, demonstrating both the safety and efficacy of GLP-1 RAs in extremely young patients with complex metabolic disease, and pointing to semaglutide’s potential to modulate hyperphagia. • A meta-analysis of nine RCTs of patients with psychiatric disorders (including schizophrenia, bipolar disorder, and binge-eating disorder) found that GLP-1 RAs, in particular semaglutide, produced significant weight loss (5.03 kg-mean reduction) and metabolic improvements compared to controls, with semaglutide showing the greatest effect (6.14 kg), offering an effective treatment option for a vulnerable population facing both obesity and weight-promoting psychiatric medications. A Matter of Taste In “ Semaglutide and Taste in Women With Obesity and Polycystic Ovary Syndrome: A Randomized Placebo-Controlled Study ,” published in JCEM in May, Andrej Janež, MD, PhD, of the Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, in Zaloska, Slovenia, and team sought to better understand the complex, often inconsistent relationship between obesity and taste perception, coupled with a major evidence gap on how GLP-1 analogues like semaglutide affect taste function. “In humans, the tongue has not yet been addressed as a clinically relevant target for GLP-1 based therapies,” says Janež. “Anecdotal reports note altered food preferences in mixed-sex obesity trials like in a STEP clinical program, but these focus on energy intake, not sensitivity metrics. One meta-analysis suggests GLP-1RAs may impair taste function overall, though without sex stratification.” In the team’s previous studies with liraglutide, they observed different eating behaviors measured with validated questionnaires, which prompted the desire to broaden their understanding with a randomized study using a methodology that clinically answers the question, namely chemical gustometry and functional magnetic resonance imaging (fMRI). To date, no previous randomized controlled trials (RCTs) or large trials report taste outcomes in men using validated gustometry or biopsies. Semaglutide is known to lower relative preference for high-fat, sweet foods. “We usually see about 20% to 35% reduced intake from fatty foods, better eating control, and fewer cravings for energy-dense options, leading to 24% total daily energy reduction,” says Janež. “It is important to stress that unlike broad suppression, this targets hedonic over homeostatic drive, preserving interest in nutrient-balanced foods.” “We knew that individuals living with obesity often perceive tastes as less intense. Subjects prone to obesity have an inherently elevated desire for sweet and energy-dense foods. We found the findings of our study interesting, because we think about all the factors that this new second generation of antiobesity medications are able to improve, but taste is often not something that we look at, though there have been very strong associations.” — Andrej Janež, MD, PhD, Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Zaloska, Slovenia Against this backdrop, the researchers hypothesized that semaglutide would alter taste recognition in women with obesity and polycystic ovary syndrome (PCOS). “Anovulatory, premenopausal women with obesity and PCOS, without any severe chronic illness, provided us a homogeneous clinical population to control key variables known to affect taste perception, including sex, age, smoking, diabetes and other chronic conditions, as well as variability related to cyclical hormonal fluctuations,” says Janež. They randomized 30 participants meeting their criteria to a semaglutide or placebo group, each receiving once weekly injections. The primary outcome was change in overall taste recognition threshold of four concentrations each of four basic tastes (sweet, sour, salty, and bitter). Semaglutide improved the overall taste recognition score from 11.9 ± 1.9 points to 14.4 ± 1.0 points, with an estimated treatment difference of 2.5 points, which was mainly attributed to the improved ability to detect lower concentrations of sweet and salty tastes in the semaglutide group. Says Janež: “We knew that individuals living with obesity often perceive tastes as less intense. Subjects prone to obesity have an inherently elevated desire for sweet and energy-dense foods. We found the findings of our study interesting, because we think about all the factors that this new second generation of antiobesity medications are able to improve, but taste is often not something that we look at, though there have been very strong associations.” Secondary outcomes were alterations in the transcriptomic profile of tongue tissue and brain responses to visual cues of high-caloric sweet and savory foods as well as to a sweet solution dripping directly on the tongue while scanned by fMRI before and after a standardized meal intake. They looked specifically at EYA, PRMT8, CRLF1, and CYP1B1 , genes associated with taste transduction, taste bud development and, the pathway involved in the renewal and differentiation of taste bud cells. “Aligned with a clinically detectable change in the taste recognition threshold,” says Janež, we demonstrated that semaglutide treatment affected gene transcription in the tongue. Our mRNA expression analysis could indicate potential improvements in taste transduction, neural maturation and plasticity of gustatory nerve fibers, and taste bud cell renewal. Notably, no significant gene expression changes were detected in the placebo group after correction for multiple testing. This absence of transcriptomic response in the placebo arm supports the specificity of semaglutide’s effects on peripheral taste related pathways.” Janež points out that the team’s study did have limitations in terms of generalizability — specifically, that the study environment may not reflect everyday experience and that the study cohort was strictly defined. Nevertheless, he explains, “A new generation of drugs for the pharmacologic treatment of obesity offers more than just weight loss,” he says. “They affect many interesting pathways, and with our study results give a hint that GLP-1RAs could also be a matter of taste.” The team is currently investigating GLP-1RAs’ effects on brown adipose tissue (BAT) activation, the results of which they plan to present at ENDO 2026 in Chicago. “We will present for the first time the effects of tirzepatide treatment on BAT activation and browning of white adipose tissue beyond weight loss in obese subjects. In a large, randomized study — TABFAT — lasting 24 weeks, we have studied these effects with a very complex methodology. The results are very interesting and indicate a new mechanism of action for tirzepatide and suggest a potential new mechanism for BAT activation.” When Obesity Can’t Wait: Treating Metabolic Disease in Early Childhood In “ Type 2 Diabetes in a 4-Year-Old With Obesity: Considerations for Use of Semaglutide and Bariatric Surgery in Children ,” published in JCEM Case Reports in July, Alaina Vidmar, MD, medical director, Obesity Medicine, and Bariatric Surgery at Children’s Hospital Los Angeles in California and team describe a case they believe may help other clinicians treat the growing population of very young children with similar conditions. Says Vidmar: “We were seeing increasing numbers of very young children presenting with severe obesity and metabolic disease, but virtually no real-world data existed on how to manage type 2 diabetes and hyperphagia in children this young. When this four-year-old patient presented with rapid-onset obesity, hyperphagia, and new type 2 diabetes, it became clear that her case highlighted multiple gaps in pediatric obesity and diabetes care. We felt it was important to document her clinical course to inform clinicians facing similarly complex patients.” Indeed, children with early-onset obesity develop insulin resistance, liver dysfunction, and beta cell decline much more rapidly than adults because their organs and metabolic systems are developing, which makes them more vulnerable to the harmful effects of excess adiposity. Youth-onset type 2 diabetes progr…