Obesity is associated with risk for chronic health problems and increased mortality. Weight stigma, which entails negative attitudes and behaviors directed at people based solely on their body size, is psychologically harmful and contributes to obesity and obesity-related health problems. Yet, weight stigma is pervasive in society and commonly experienced by patients in healthcare settings, which lowers the quality of patients' healthcare experiences. Healthcare providers and trainees report feeling underprepared to treat obesity, which may lead to overreliance on weight-management strategies that are not evidence-based and are susceptible to weight stigma, such as fad diets emphasizing unrealistic dietary restriction. In the current manuscript, we discuss current weight stigma interventions with other populations and the rationale for integrating training in evidence-based approaches to treat obesity with weight stigma interventions, specifically cognitive dissonance-based interventions. Current learning theories emphasize empathic perspective-taking, and current methods to reduce weight stigma use social-cognitive theories to raise awareness of stereotypes. However, current methods are insufficient because they create discomfort but fail to alter internalized bias nor advise providers on how to deliver non-stigmatizing, evidence-based obesity interventions. Cognitive dissonance theory posits that resolving tension between beliefs and behaviors will change future behaviors. Cognitive dissonance-based interventions have effectively reduced personal weight stigma and are promising to be similarly effective in reducing weight stigma among healthcare providers. In this manuscript, we highlight how cognitive dissonance theory can help improve interventions to reduce bias and support providers' efforts treating obesity.
Obesity is increasingly encountered among patients requiring extracorporeal membrane oxygenation (ECMO) for severe respiratory or cardiac failure. It alters respiratory and cardiovascular physiology and drug pharmacokinetics and introduces technical and logistical challenges that may complicate patient selection, ECMO initiation, cannulation, anticoagulation, and monitoring. This review summarizes current evidence regarding the epidemiology, physiological implications, outcomes, and management of obesity in patients supported with veno-venous (VV) or veno-arterial (VA) ECMO. Available evidence, largely retrospective and based on body mass index classifications, suggests that obesity should not be considered a contraindication to VV-ECMO, with outcomes comparable to or potentially better than those of patients without obesity. However, obesity-related respiratory mechanics may exaggerate the apparent severity of lung injury, emphasizing the need for optimized conventional ARDS management, including appropriate ventilatory strategies and prone positioning, before ECMO initiation. In contrast, outcomes during VA-ECMO are more heterogeneous, particularly in extracorporeal cardiopulmonary resuscitation (ECPR), and may be influenced by patient selection, comorbidities, and timing of support. Obesity also creates important technical challenges requiring individualized cannulation, anticoagulation, and perfusion strategies. Obesity alone should not preclude access to ECMO, particularly VV-ECMO. Successful management requires anticipation of obesity-related challenges, appropriate infrastructure, and structured multidisciplinary protocols. Further prospective studies are needed to clarify obesity-specific risks, optimize management strategies, and evaluate long-term outcomes.
Background: With the increasing widespread use of GLP-1 RA and dual GIP/GLP-1 RAs in the treatment of obesity, their safety profile remains a concern for healthcare professionals (HPs). Objective: This study aimed to characterize and evaluate safety data from the EudraVigilance (EV) database for semaglutide (SEM), liraglutide (LIR), and tirzepatide (TIR). Methods: A hierarchical pharmacovigilance approach was applied, integrating SOC- and PT-level analyses with SmPC-based evaluation and both frequentist (ROR, 95% CI) and Bayesian (IC025) disproportionality methods. Within each molecule, reporter type-stratified analyses were performed, while across all molecules, disproportionality analyses were conducted separately in HP reports and in the full database to identify reporting patterns and potential safety signals, including those not described in the SmPCs. Results: Some ADRs, listed in the SmPC of only one or two of the three GLP1-RAs were also reported in the EV database for the other agents whose SmPCs do not specify these ADRs including optic ischemic neuropathy (TIR: 0.28% and LIR: 0.17%), alopecia (LIR: 0.81%), headache (TIR: 2.51%), intestinal obstruction (TIR: 1.55%), angioedema (LIR: 0.19%), hypersensitivity (SEM: 0.58% and LIR: 0.73%), etc. Pancreatitis, in particular, showed a significant but low-magnitude signal, being more frequently reported by HPs compared with non-HPs across all three GLP1-RAs. Additionally, statistically significant signals (IC025 > 0) were observed in both the HPs and full datasets. For example, for SEM vs. TIR, signals were identified for optic ischemic neuropathy (0.17; 0.13), gallbladder disorder (0.09; 0.11), and dysesthesia (0.42; 0.43), respectively. For TIR vs. SEM, signals were observed for injection site erythema (0.05; 0.11), injection site pruritus (0.01; 0.11), and injection site reaction (0.02; 0.08). Conclusions: These findings suggest potential safety signals beyond current SmPC information, emphasizing the need for continuous pharmacovigilance and cautious interpretation of reporting biases.
Waist circumference (WC) in combination with body mass index (BMI) provides unique opportunities to capture the heterogeneous nature of obesity and identify phenotypes that convey the greatest health risk. This review summarizes evidence supporting global recognition that WC and BMI should be routinely documented in health care. Differences in risk stratification when WC and BMI are used in categorical versus continuous models are examined, and strategies to increase routine measurement in clinical settings are discussed. Leading authorities worldwide including the Lancet Obesity Commission and the European Association for the Study of Obesity recognize obesity as a heterogeneous condition requiring combined interpretation of WC and BMI to identify distinct phenotypes. Obesity-related risk differs substantially depending on whether WC and BMI are treated as categorical or continuous measures. Current risk stratification systems rely on categorical approaches that have clinically relevant limitations, including loss of risk resolution from applying a single WC cut-point across BMI categories. Evidence further shows that associations between WC and adverse outcomes strengthen after adjustment for BMI, and that when WC and BMI are modeled simultaneously as continuous variables, WC consistently emerges as a stronger predictor of health outcomes, while associations with BMI are attenuated or reversed. WC and BMI combined are simple tools that facilitate the identification of obesity heterogeneity and phenotypes associated with elevated health risk. Risk estimates differ depending on whether WC and BMI are modeled as categorical or continuous variables, with implications for how obesity-related risk is assessed and interpreted in practice. Recommendations for their optimal combined use, including a proof-of-concept nomogram to support clinical interpretation, are provided. Despite guideline recommendations worldwide, BMI and WC remain infrequently documented in clinical practice. This implementation gap represents a missed, low-cost opportunity to improve public health messaging, risk stratification, and clinical management of obesity-related risk.
Opaganib is a first-in-class, clinical stage drug that modulates sphingolipid metabolism resulting in anticancer and anti-inflammatory activity in vivo in many rodent models. Of particular relevance, we previously showed that opaganib has anti-obesity efficacy in mice fed a high fat diet. A recent publication by another group reported that opaganib has no beneficial activity in the same model. We argue herein that those studies were flawed because of the use of an unusually low opaganib dose, as well as a route and schedule of administration that do not provide sufficient blood levels for opaganib efficacy. We are concerned that these limitations provide a misleading representation of opaganib efficacy in this model of obesity and type 2 diabetes.
Acquired hypothalamic obesity (aHO) is a rare and severe condition caused by injury to hypothalamic centers regulating appetite, energy balance, and neuroendocrine function. It is characterized by rapid weight gain, hyperphagia, and significant metabolic complications, and current treatment options remain limited. We report the case of a 22-month-old child who developed severe acquired hypothalamic obesity following neonatal Escherichia coli sepsis complicated by meningoencephalitis and brain abscess. Treatment with the melanocortin-4 receptor agonist setmelanotide was initiated at 0.25 mg daily and gradually titrated to 1.5 mg. Over 13 months of treatment, the patient experienced stabilization and a subsequent reduction in body weight, improvement in liver enzymes and lipid profile, increased motor activity, and marked improvements in interaction and quality of life. The most pronounced clinical response occurred at doses ≥1.25 mg daily. This case represents, to our knowledge, the youngest reported patient treated with setmelanotide and the first case of inflammation-related acquired hypothalamic obesity treated with this therapy. These findings suggest that setmelanotide may represent a promising therapeutic strategy for selected patients with acquired hypothalamic obesity beyond currently approved genetic indications.
Obesity and type 2 diabetes (T2D) increase the risk of sarcopenia and mobility decline, yet the underlying muscle contractile alterations remain poorly understood. This study investigated how severe obesity and T2D affect muscle power, force-velocity relationships, and muscle quality. In this cross-sectional study, 45 middle-aged individuals were categorized as non-obesity (Non-O; BMI 18.5-30 kg/m2), obesity (O; BMI ≥ 35 kg/m2), and obesity with T2D (O + T2D; BMI ≥ 35 kg/m2). Isokinetic torque and power of knee extensors (KE) and dorsiflexors (DF) were measured (DF: 0-120°/s; KE: 0-270°/s). Muscle volume and fat infiltration (FF, %) were quantified using MRI. Outcomes included absolute, specific (relative to muscle volume), and normalized (relative to body weight) power. Functional capacity was assessed with five-times sit-to-stand (5xSTS) and 10-m walk (10MWT) tests. KE power was 51W lower in O + T2D than O (P = 0.008) with larger deficits at higher velocities (interaction, P = 0.027). O and O + T2D exhibited lower normalized KE power (-0.8 and -1.1 W/kg vs. Non-O; both P < 0.001). KE FF was higher in O (5%) than Non-O (3%, P = 0.003), and highest in O + T2D (7%, P = 0.023). DF torque declined faster with velocity in O and O + T2D (P ≤ 0.012). Specific power did not differ. KE normalized power was the strongest predictor of performance (5xSTS: R2 = 0.57,P = 0.003; 10MWT: R2 = 0.71,P < 0.001). Severe obesity impairs normalized muscle power, with T2D exacerbating KE power deficits and fatty infiltration. These muscle contractile impairments may contribute to functional decline already in middle-aged individuals.
Obesity stems from a chronic imbalance between energy intake and expenditure. Current therapeutic strategies primarily focus on reducing caloric intake, yet their long-term efficacy is often limited by compensatory metabolic adaptations that lead to weight regain. This review outlines the neural mechanisms through which the central nervous system regulates appetite and the peripheral metabolic pathways that drive adipose thermogenesis. Furthermore, it examines how integrated approaches-spanning from approved to preclinical and clinical-stage investigational agents (e.g., dual- or multi-target agonists), microbiome-targeted interventions (e.g., probiotics), and exercise therapy-can synergistically overcome the limitations of single-pathway strategies. Ultimately, this review provides a theoretical foundation for designing next-generation, personalized, multimodal obesity management regimens. Traditional weight-loss drugs primarily act by centrally suppressing appetite, reducing food intake through modulation of neural circuits in regions such as the hypothalamus. However, studies show that relying on appetite suppression often triggers compensatory metabolic adaptation, ultimately leading to weight regain. Current anti-obesity drug development is therefore shifting toward integrated central-peripheral dual mechanisms. GLP‑1/glucagon dual-receptor agonists and triple-receptor agonists (such as retatrutide) have exhibited unprecedented weight-loss efficacy in clinical trials. These novel agents overcome the limitations of single-target appetite suppression by synergistically integrating central anorexigenic signaling with peripherally mediated increases in energy expenditure, thereby achieving more potent and durable weight reduction. The sustainability of obesity treatment relies on a dual-pronged intervention strategy: suppressing appetite to reduce energy intake while actively promoting energy expenditure, thereby overcoming the metabolic adaptation and weight rebound associated with monotherapy.
Obesity is a complex condition encompassing behavioral, psychological, and physiological factors, frequently associated with elevated mental health burden. Digital Mental Health Interventions (DMHIs) have emerged as promising tools to enhance accessibility, personalization, and scalability of psychological care in obesity management. However, evidence on their effectiveness across delivery modalities and outcomes remains fragmented. This systematic review aimed to evaluate the effectiveness of DMHIs on obesity-related clinical, behavioral, and psychological outcomes; examine whether specific delivery modalities are differentially associated with particular outcomes; and identify methodological gaps to guide future research and implementation. A systematic search was conducted in PubMed, Scopus, PsycINFO, Cochrane Library, Web of Science, and Google Scholar. The review followed PRISMA guidelines, applying rigorous inclusion criteria and independent screening by two reviewers. Quality appraisal was performed using the Cochrane Risk of Bias Tool (RoB 2.0), and studies rated as high risk of bias were excluded. Due to heterogeneity in study design and outcomes, data were synthesized narratively, and no claims of statistical superiority between modalities were made. Thirty-eight randomized controlled trials were included. DMHIs effectively targeted behavioral and psychological aspects of obesity when based on evidence-based psychotherapeutic frameworks - often independently of weight-related improvements. No single delivery format emerged as universally superior; rather, each modality appeared to serve distinct therapeutic purposes. Outcomes were more favorable in interventions that incorporated human guidance, although this finding should be interpreted cautiously because of heterogeneity and the absence of meta-analytic comparisons. Digital mental health approaches-particularly when integrated into stepped-care or hybrid models-represent scalable, person-centered strategies to improve both physical and emotional well-being in adults with obesity.
Semaglutide 2.4 mg is approved for the secondary prevention of major adverse cardiovascular events (MACE) among individuals with overweight/obesity. We investigated its association with MACE among individuals with overweight/obesity without diabetes who had risk factors for atherosclerotic cardiovascular disease (ASCVD) in the real-world setting. Adults (≥45 years) with overweight/obesity and ≥3 risk factors for ASCVD but without diabetes were identified from a U.S. database (01/01/2016-12/31/2024). Patients initiating semaglutide 2.4 mg were propensity-score matched 1:2 to those not on semaglutide 2.4 mg. The primary outcomes included revised 3-point MACE (rMACE-3: myocardial infarction, stroke, and all-cause mortality) and revised 5-point MACE (rMACE-5: rMACE-3, coronary revascularization, and hospitalization for heart failure [HF]). Secondary outcomes included MACE-3 and MACE-5 (replacing all-cause mortality with cardiovascular-related mortality), and HF composite outcomes. A total of 48,184 individuals on semaglutide 2.4 mg were matched to 96,368 individuals not on semaglutide 2.4 mg; patient characteristics were well-balanced between cohorts. Semaglutide 2.4 mg was associated with lower risks of rMACE-3 (HR: 0.59; p < 0.001), rMACE-5 (HR: 0.65; p < 0.001), MACE-3 (HR: 0.73; p < 0.01), MACE-5 (HR: 0.75; p < 0.01), and composite HF outcomes over a mean follow-up of 9 months. Semaglutide 2.4 mg was associated with lower risk of incident MACE and HF composite outcomes in this real-world study of patients with overweight/obesity without diabetes, who were at risk for developing ASCVD. Further research is warranted to confirm the role of semaglutide 2.4 mg in the primary prevention of ASCVD in this population.
To assess the effect of tirzepatide, a glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide agonist, on cardiovascular outcomes and mortality in subjects with overweight/obesity, or type 2 diabetes mellitus (T2DM). We searched MEDLINE, Embase and CENTRAL up to January 14, 2026, selecting randomized controlled trials studying tirzepatide in adults with T2DM or overweight/obesity with a minimum follow-up of 24 weeks. We independently extracted data and assessed risk of bias and quality of evidence. We conducted meta-analysis using a fixed-effects model. Trial sequential analysis (TSA) was employed to assess if current information support definitive conclusions. We included 22 trials encompassing 29,023 participants. Overall risk of bias was low. Tirzepatide was associated with a reduction in MACE (OR 0.87, 95% CI 0.79-0.94; high certainty); TSA estimated that sample size was sufficient for definitive conclusions. A dose-response association was observed, with 2.8% lower odds of MACE for every 1 mg increase in tirzepatide dose. Tirzepatide was associated with a reduction in all-cause mortality (OR 0.84, 95% CI 0.75-0.93), however no association was observed for individual components of MACE or heart failure hospitalizations. Tirzepatide is associated with a significant reduction in MACE in subjects with T2DM or overweight/obesity.
Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is widely used for the management of type 2 diabetes, metabolic syndrome, and obesity. Concerns regarding its potential association with thyroid cancer, particularly medullary thyroid carcinoma, have emerged, although current human evidence remains inconclusive. Reports of papillary thyroid carcinoma (PTC) while using semaglutide therapy are exceedingly rare. We describe a 40-year-old man with metabolic syndrome and obesity who had been treated with semaglutide for several years before discontinuation. A routine chest computed tomography (CT) performed for an unrelated diaphragmatic hernia identified a suspicious thyroid lesion, later confirmed by ultrasound as a 1 × 1 cm irregular hypoechoic nodule in the left lobe with several small ipsilateral lymph nodes demonstrating suspicious features. Fine-needle aspiration cytology revealed classic PTC (Bethesda VI). The patient underwent total thyroidectomy with left selective neck dissection and central compartment dissection. Histopathology confirmed a unifocal classic variant PTC, 16 mm in size, with negative margins, no lymph node involvement, and no extrathyroidal extension. After an uncomplicated postoperative course, he was prescribed levothyroxine for TSH suppression and discharged. This case of PTC discovered concomitantly while the patient was on semaglutide therapy highlights an important clinical scenario but does not provide evidence of causation. The totality of available human data continues to support the safety of semaglutide with respect to thyroid cancer risk. Further long-term surveillance and high-quality epidemiological studies remain warranted.
This review provides an overview of adipose tissue plasticity and adipogenesis as central processes regulating adipose tissue expansion, remodeling, and metabolic function in health and obesity, highlighting their relevance as potential therapeutic targets. Adipogenesis is a tightly regulated process involving the differentiation of adipose progenitor cells into mature adipocytes through coordinated transcriptional cascades, primarily driven by peroxisome proliferator-activated receptor (PPAR)γ and CCAAT/enhancer-binding protein (C/EBP) family members. This process is further modulated by multiple signaling pathways, including wingless-related integration site (Wnt), bone morphogenetic proteins (BMPs), and insulin signaling, which collectively regulate adipocyte differentiation and metabolic function. Under physiological conditions, the adipose tissue exhibits remarkable plasticity, with adipogenesis supporting lipid buffering capacity and tissue renewal. In obesity, however, chronic nutrient excess and hormonal dysregulation impair this process, favoring adipocyte hypertrophy, hypoxia, and chronic inflammation. These alterations disrupt adipokine secretion and promote ectopic lipid deposition, thereby contributing to metabolic disorders, including insulin resistance and cardiometabolic disease. Adipose tissue plasticity and adipogenesis are critical determinants of metabolic health. Dysregulation of these processes underlies adipose tissue dysfunction and contributes to the development of obesity-related comorbidities. Targeting adipogenesis and promoting healthy adipose tissue remodeling represent promising strategies for restoring metabolic homeostasis and mitigating obesity-associated diseases.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide GLP-1 RAs are increasingly prescribed for diabetes and obesity, leading to a growing number of surgical patients receiving these agents. Their ability to delay gastric emptying has raised concerns about residual gastric contents (RGCs) and potential aspiration during anaesthesia. Available evidence from mechanistic studies, clinical investigations, and case reports indicates that GLP-1-based therapies consistently impair solid-phase gastric emptying and may increase RGC, particularly during early treatment and dose escalation, with effects that can persist despite standard fasting and short-term drug interruption. Although clinically apparent aspiration events remain uncommon, multiple reports have described perioperative regurgitation or unexpected solid gastric contents at induction. Early guidance favoured routine preoperative drug interruption; however, more recent multisociety recommendations increasingly support continuation of therapy in most asymptomatic patients and endorse enhanced perioperative mitigation strategies, such as dietary modification, strict adherence to fasting, selective use of point-of-care gastric ultrasound, preference for regional anaesthesia when feasible, and tailored airway management. Overall, current data support an individualised, risk-adapted approach rather than uniform interruption of GLP-1 therapy. Continuation of structured mitigation appears reasonable for many patients, whereas heightened caution and full-stomach precautions remain appropriate in higher-risk situations. Further prospective studies are required to define true perioperative aspiration risk and to establish evidence-based management pathways.
Patients with obesity who are admitted to an ICU bring specific challenges for rehabilitation during and after critical illness. This narrative review explores impact of differences in body compositions and pathophysiology on outcomes to summarise interprofessional, patient-centred rehabilitation strategies across the trajectory of recovery. The interprofessional expert panel reviewed major trials and guidelines, integrating their clinical expertise with the current evidence. Three distinct phenotypes potentially influence outcomes for survivors. Whilst patients with preserved muscle mass may have a survival advantage, the phenotypes characterised by ectopic visceral fat or sarcopenia are frequently complicated by multimorbidity and polypharmacy, likely increasing the risk of adverse effects such as suboptimal sedation, prolonged ventilation and immobilisation, malnutrition, and impaired recovery. Targeted respiratory interventions, including secretion-clearance techniques and appropriate patient positioning to prevent atelectasis, reduce the work of breathing. Optimisation of communication and swallowing function is an essential component for facilitating safe oral intake and promoting active patient participation in rehabilitation. Concurrently, targeted nutrition strategies combined with early, targeted, progressive mobilisation might mitigate ICU acquired weakness and support functional recovery. The availability of appropriate weight‑based equipment is fundamental to ensuring safe mobilisation for both patients and healthcare professionals. Interprofessional collaboration is central to optimising outcomes and should extend beyond the ICU to structured post-ICU follow-up to address persistent, worsening, or newly emerging health impairments. Early rehabilitation in critically ill patients with obesity should integrate physiological, logistical, and psychosocial considerations to support equitable and functional recovery.
This review examines infancy as a sensitive period for the development of reward learning and self-regulation and evaluates how early experiences with food and non-food rewards shape obesity risk. We sought to address three questions: how biological susceptibility influences early reward processing, how caregiving practices use food as a reward, and how non-food reinforcement modifies the relative reinforcing value of food (RRVfood) during early development. Recent evidence indicates that obesity risk may depend less on absolute food motivation and more on the relative reinforcing value of food (RRVfood), a behavioral economic construct reflecting how motivated one is for food in the context of available non-food alternatives. Studies show that feeding to soothe, instrumental feeding, and restriction can strengthen food-based reward learning, particularly among biologically susceptible infants. Conversely, enriched environments, responsive parenting, and cognitively, socially, and physically engaging non-food activities support self-regulation and lower obesity risk, even in socioeconomically disadvantaged contexts. Early obesity risk reflects an imbalance in reinforcement rather than excessive food motivation alone. Shifting the balance toward non-food rewards represents a promising, strength-based direction for future mechanistic and intervention research.
Ghrelin is a gut-derived acylated hormone that regulates appetite, food reward-related behaviours, glycaemic control, and lipid metabolism. These actions are primarily mediated through activation of the growth hormone secretagogue receptor (GHSR), which is highly expressed in the brain and also present in key metabolic organs. Ghrelin acylation by ghrelin O-acyltransferase (GOAT) is required for receptor binding and biological activity. This review examines the physiological and pathophysiological roles of ghrelin and liver-expressed antimicrobial peptide 2 (LEAP2), with particular emphasis on its relevance to obesity and type 2 diabetes. LEAP2 has recently been identified as an endogenous antagonist and inverse agonist of GHSR that counteracts ghrelin signalling. Emerging evidence indicates that obesity and type 2 diabetes are generally associated with reduced circulating ghrelin levels and increased LEAP2 concentrations, particularly in the presence of insulin resistance. These reciprocal changes support the concept that the ghrelin/LEAP2 ratio functions as a dynamic regulator of energy balance, glucose homeostasis, and appetite control, and may influence metabolic responses to nutritional status and weight loss. The ghrelin-LEAP2 system represents a key regulatory pathway in metabolic homeostasis and a promising therapeutic target for obesity and related metabolic disorders. Pharmacological strategies targeting this axis, including ghrelin antagonists, LEAP2 analogues, GOAT inhibitors, and GHSR inverse agonists, are under active investigation, although further studies are required to establish their long-term efficacy and safety.
Obstructive sleep apnea (OSA) is highly prevalent, yet current treatment remains limited. Poor adherence to positive airway pressure (PAP) and barriers associated with injectable therapies can limit potential therapeutic options for moderate-to-severe OSA. The SURMOUNT-OSA trials demonstrated that tirzepatide contributes to OSA severity improvements; however, the injectable mode of administration introduces barriers that may limit accessibility and long-term adherence. Orforglipron, a once daily oral glucagon-like-peptide-1 receptor agonist, may offer a more feasible and accepted therapeutic option. ATTAIN-OSA was developed to evaluate the efficacy and safety of oral orforglipron in adults with moderate-to-severe OSA. ATTAIN-OSA is a master protocol with two multicenter, randomized, double-blind, placebo-controlled Phase 3 trials enrolling adults with moderate-to-severe OSA and obesity or overweight. Study 1 includes participants unable or unwilling to use PAP. Study 2 includes participants who use PAP and complete a protocol-mandated washout before baseline polysomnography. Participants are randomly assigned to placebo or orforglipron capsule formulation at maximum tolerated dose (12, 24, or 36 mg) for 52 weeks following a standardized dose escalation schedule. The primary endpoint is change in Apnea-Hypopnea Index (AHI) at Week 52. Key secondary endpoints include sleep apnea-specific hypoxic burden, Patient-Reported Outcomes Measurement Information System sleep-related impairment, high-sensitivity C-reactive protein, and body weight, and other AHI-related endpoints. Overall, 712 participants have been randomized to orforglipron or placebo (Study 1, n = 363; Study 2, n = 349). ATTAIN-OSA evaluates if once-daily oral orforglipron can provide an effective and more accessible therapeutic approach to treat moderate-to-severe OSA in adults with obesity or overweight. ClinicalTrials.gov, NCT06649045.
While nutrient-stimulated hormone (NuSH) therapies (e.g., glucagon-like pepide-1 receptor agonists and dual/triple agonists) have transformed the landscape of obesity pharmacotherapy, the next generation of medications may target body composition optimization or other cardiovascular benefits. This review examines novel obesity mechanisms outside of the NuSH class. Unique mechanisms for obesity treatment include peripherally restricted cannabinoid-1 receptor antagonism, myostatin/activin inhibitors, selective androgen receptor modulators, melanocortin-4 receptor agonism, mitochondrial modulation, thyroid receptor agonists, and fibroblast growth factor analogues. By targeting fat distribution, muscle preservation, inflammatory/oxidative stress pathways, lipid metabolism, and energy expenditure, these agents may improve both the magnitude and quality of weight loss. Early evidence suggests complementary roles alongside NuSH-based therapies for induction, augmentation, and maintenance strategies. Several non-NuSH agents have demonstrated potential in preclinical and early clinical studies to optimize body composition, but additional studies are required to prove large-scale, long-term safety and efficacy.
The management of the disease of obesity has been transformed by incretin-based therapies; however, additional and alternative therapeutic strategies are needed to address its biological complexity. This narrative review examines the physiology of amylin and the emerging role of amylin-based therapies in obesity management. We conducted a narrative review of amylin-based therapies that were approved or remained in human clinical development for obesity as of 30 April 2026. PubMed/MEDLINE, ClinicalTrials.gov, Google Scholar, company press releases, investor reports, and major congress abstracts were searched for relevant preclinical and clinical evidence. Amylin, co-secreted with insulin from pancreatic β-cells, slows gastric emptying, suppresses glucagon secretion, and promotes meal termination through central mechanisms. Pramlintide, the first approved amylin analogue, established proof of concept but was limited by modest efficacy and frequent dosing. More recently, long-acting amylin-based therapies, including cagrilintide, eloralintide, petrelintide, MET-233i, ABBV-295, and AZD6234, as well as combination approaches such as cagrilintide with semaglutide and zenagamtide, have demonstrated clinically meaningful weight loss with generally favorable tolerability profiles. Amylin-based therapies represent a promising addition to the evolving treatment landscape of obesity. Their emerging efficacy as both standalone and combination therapies supports a multi pathway approach to addressing the biological complexity and heterogeneity of the disease. Obesity is a chronic disease driven by complex biological mechanisms, meaning that no single treatment is likely to work for everyone. Amylin based therapies are an emerging group of medications that target appetite regulation through pathways different from those used by current glucagon‐like peptide‐1 (GLP‐1) based treatments. Amylin is a natural hormone released by the pancreas after meals that helps people feel full, slows stomach emptying, and reduces food intake. The first amylin medicine, pramlintide, demonstrated that this pathway could promote weight loss, but its clinical use was limited by the need for multiple daily injections and relatively modest efficacy. Newer long acting amylin analogues have overcome many of these limitations. Early clinical trials show that agents such as cagrilintide, eloralintide, petrelintide, MET‐233i, ABBV‐295, and AZD6234 can produce clinically meaningful weight loss with very good tolerability profiles. Combining amylin with GLP‐1 based therapy has produced even greater weight loss, with reductions exceeding 20% in clinical studies. Although most of these medicines are still under clinical development, the available evidence suggests that amylin based therapies could become an important addition to obesity treatment. By targeting complementary biological pathways, they may expand treatment options, improve long term management, and allow a more personalised approach to caring for people with the disease of obesity.