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.

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 progresses faster, is harder to control, and carries earlier and more severe complications, making early intervention critical.

However, no GLP-1RAs are currently approved for children younger than six, representing a therapeutic gap. Although this patient showed improvements in HbA1c and a decrease in body mass index ([BMI] from 205% of the 95th percentile, BMI 41 kg/m² to 202%, BMI 39 kg/m²) with all prescribed medications (e.g., metformin, topiramate), adherence challenges prompted introduction of semaglutide to simplify her regimen. Additionally, explains, Vidmar, “Topiramate provided minimal appetite suppression for her, which is consistent with what we sometimes see, its effects are modest, and individual response varies widely. Additionally, her hyperphagia was quite severe, and medications with stronger mechanisms for appetite regulation (like GLP-1 RAs) were ultimately more impactful.”

Despite extensive evaluation for monogenic and syndromic causes of hyperphagia, a clear diagnosis was not reached. Genetic testing for monogenic diabetes and Prader-Willi syndrome was negative. Her phenotype raised concern for rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD), a potentially life-threatening disorder, although this was not definitively confirmed. “Ultimately, her hyperphagia is best understood as part of her complex obesity phenotype, possibly with hypothalamic involvement, but without a clearly identifiable single underlying disorder,” says Vidmar.

“Liraglutide was available and studied earlier, and the infrastructure for pediatric trials was already established around that molecule. Semaglutide, although more effective in older populations, entered the pediatric research pipeline later. Trials in younger children require cautious stepwise evaluation, and liraglutide was simply the first GLP-1 RA far enough along in the pediatric research timeline. Semaglutide may eventually be studied in younger children, but those trials take years to launch and complete.” — Alaina Vidmar, MD, medical director, Obesity Medicine, and Bariatric Surgery, Children’s Hospital, Los Angeles, Calif.

Clinical trials have only recently begun enrolling younger children. “Pediatric drug development typically lags behind adult studies because of safety, ethical considerations, and logistical challenges. Before regulatory approval, the FDA requires age-specific efficacy and safety data, and until the SCALE Kids trial (published in 2025), we had essentially no randomized controlled data for GLP-1 RAs in children under 12. Approval can only follow evidence, and that evidence is just now emerging,” says Vidmar. “Liraglutide was available and studied earlier, and the infrastructure for pediatric trials was already established around that molecule,” she explains. “Semaglutide, although more effective in older populations, entered the pediatric research pipeline later. Trials in younger children require cautious stepwise evaluation, and liraglutide was simply the first GLP-1 RA far enough along in the pediatric research timeline. Semaglutide may eventually be studied in younger children, but those trials take years to launch and complete.”

The bottom line is, “very young children can and do present with severe, rapidly progressive metabolic disease, and they require early, aggressive, multidisciplinary treatment. GLP-1 RAs may be a valuable tool, even off label, with careful monitoring,” says Vidmar. “And importantly, clinicians should remain open to considering rare diagnoses like ROHHAD when the phenotype includes hypoventilation, autonomic dysregulation, or extreme hyperphagia.” Perhaps one of the most exciting takeaways is that this patient’s hyperphagia improved markedly (and likewise quickly worsened during medication interruptions), suggesting that some of her hyperphagia was being modulated by GLP-1 RA therapy.

With that in mind, the team has plans for important future studies. “This case underscores the need for structured clinical trials evaluating GLP-1 RAs and other obesity medications in younger children. We are actively working on research initiatives focused on early onset obesity, hyperphagia phenotyping, and optimizing multimodal treatment, including the integration of metabolic surgery, in younger pediatric populations.” In this case, the team titrated semaglutide very slowly and were extremely proactive about education, hydration, and recognizing side effects. “Interestingly, she had none of the nausea or vomiting typically seen with GLP-1 RAs,” says Vidmar, a finding that surprised the team. “This may suggest that some younger children, when closely monitored and titrated conservatively, may not experience the same level of gastrointestinal sensitivity described in adolescent trials. It may also reflect individual physiology or gut–brain signaling differences at younger ages.”

Most importantly of all, their patient is doing well: “Her most recent HbA1c was 5.1% (from an initial 8%), her BMI trajectory has significantly improved (35 kg/m²), her sleep apnea has lessened, and her hyperphagia is much better controlled. The family is continuing discussions with our bariatric surgery program to determine long-term treatment options.”

GLP-1 RAs and Psychiatric Treatment Related Weight Gain

In the November issue of the Journal of the Endocrine Society, Luciana Verçoza Viana, PhD, post-graduate program in Medical Sciences, Endocrinology, Federal University of Rio Grande do Sul, in Porto Alegre, Brazil, and team also looked at an important, possibly understudied population. In “GLP-1R Agonists for Weight Loss in Psychiatric Disorders: A Systematic Review and Meta-analysis,” the team correctly guessed that GLP-1 RAs could be beneficial for patients with psychiatric disorders who gain a substantial amount of weight after starting psychotropic medications. “For a long time, metformin was essentially the only option available to help mitigate weight gain and manage related metabolic complications,” says Viana. “GLP-1RAs represent a promising new strategy for patients with psychiatric disorders, offering the possibility of meaningful weight loss while also improving metabolic health — changes that can significantly enhance quality of life.”

They undertook a systematic review and meta-analysis of ultimately nine RCTs to assess the efficacy and safety of GLP-1 RAs in individuals with psychiatric disorders (specifically, schizophrenia or schizoaffective disorder, bipolar disorder, psychosis, major depressive disorder, binge-eating disorder, or a combination) and obesity/overweight, focusing on weight and metabolic outcomes. The trials compared liraglutide, exenatide, or oral semaglutide with usual care. Although GLP-1 RAs have been shown to promote greater weight loss than lifestyle intervention in patients without psychiatric disease, the efficacy, safety, and overall applicability of this strategy for patients with psychiatric disease was uncertain.

Their primary outcomes were changes in body weight and BMI. Secondary outcomes were cardiometabolic risk factors (e.g., fasting glucose, total cholesterol, high-density lipoprotein, systolic blood pressure, triglycerides, and waist circumference) and adverse effects.

Says Viana, “Although there has been concern that psychiatric medications might blunt the metabolic effects of improving glycemic control and promoting weight loss, we still anticipated clinically meaningful weight loss. Our findings confirmed this expectation, showing that even earlier GLP-1 agents, such as liraglutide, were associated with significant weight reduction in this population. It is also important to note that these medications were well tolerated by these groups of patients without major adverse effects described in the evaluated trials.”

Specifically, GLP-1 RAs produced a mean weight loss of 5.03 kg (corresponding to 4.15% body weight reduction) compared to controls, along with significant improvements in BMI (−1.59 kg/m²), waist circumference (−3.40 cm), and fasting glucose (−0.29 mmol/L). Semaglutide showed the greatest effect with 6.14-kg weight loss (an expected effect, given the pharmacological profile, including a longer half-life and stronger receptor activity, of this newer agent) followed by liraglutide at 4.83 kg and exenatide at 3.91 kg. GI side effects were more common in the GLP-1RA groups — with relative risks of 1.84 for diarrhea, 2.01 for nausea, 2.46 for vomiting, and 2.69 for constipation — but these were generally mild and did not increase treatment discontinuation rates. Although the weight loss observed in this study was less pronounced than in populations without psychiatric comorbidities, this could be due to shorter trial durations and concurrent use of medications known to promote weight gain, such as clozapine or olanzapine, and the influence of antidepressants.

“It is also worth noting that, since the publication of our review, RCTs evaluating subcutaneous semaglutide in psychiatric populations — particularly among patients with schizophrenia and those receiving antipsychotic medications — have reported findings consistent with ours. These trials typically used overweight status and metabolic abnormalities as inclusion criteria, like the studies we reviewed,” explains Viana.

“GLP-1RAs are an effective option for managing weight gain and metabolic complications in patients with psychiatric disorders without serious adverse events. Clinicians should recognize these agents as an important and underutilized tool when caring for this high-risk population.” — Luciana Verçoza Viana, PhD, post-graduate program, Medical Sciences, Endocrinology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil

Looking ahead, the team is planning a long-term review of metabolic complications among their outpatient population with schizophrenia over the past two decades, a project led by Professor of Psychiatry Clarissa Gama and her student Luiza Sperb that aims to identify key factors associated with increased metabolic risk. “We believe RCTs are needed to determine which psychiatric populations may benefit most from early initiation of GLP-1RAs to prevent medication-related weight gain and metabolic complications. Unfortunately, funding for such trials is not currently available to us,” says Viana. She also laments the current limited access to these medications in Brazil, noting that, “From a clinical standpoint, broader affordability would represent a major step forward in expanding access to evidence-based obesity and diabetes treatments.”

For now, she says the message for clinicians is clear: “GLP-1RAs are an effective option for managing weight gain and metabolic complications in patients with psychiatric disorders without serious adverse events. Clinicians should recognize these agents as an important and underutilized tool when caring for this high-risk population.”

Horvath is a freelance writer based in Baltimore, Md. In the February issue, she wrote about the impact of GLP-1 RAs on cardiovascular health.