InsufficientPreprint
This paper presents a theoretical hypothesis arguing that current GLP-1 and dual GIP/GLP-1 receptor agonist therapies (e.g., semaglutide, tirzepatide) produce weight loss plateaus because they only address one side of what the authors term the "mass balance equation" — net mass inflow (NMI) — while net mass outflow (NMO) passively and actively declines over time. The authors propose a "mass balance model" (MBM) as an alternative explanatory framework to the conventional energy balance model, framing the plateau as a predictable physical consequence rather than a vague compensatory metabolic adaptation. Based on this framework, the authors hypothesize that combining an NMI-reducing agent with an NMO-stabilizing or NMO-enhancing agent could produce greater, more durable weight loss and improved body composition. Candidate NMO-targeting agents discussed include SGLT2 inhibitors, activin/myostatin pathway inhibitors, and mitochondrial uncouplers. The paper is entirely theoretical; no original experimental data, clinical trials, or systematic evidence synthesis are presented. Its primary limitation is that the MBM framework and the dual-action hypothesis remain untested in human or animal studies.
Unknown journal · Jun 2026DOI ↗ Limited · human
This case report describes the use of tirzepatide — a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist — in a 31-year-old woman diagnosed with Smith-Magenis syndrome (SMS), a rare neurodevelopmental disorder associated with intellectual disability, behavioral dysregulation, and hyperphagia-driven obesity. The patient had a lifelong history of obesity and aggressive behaviors that had not responded adequately to standard management. Following initiation and titration of tirzepatide, the authors report that the patient achieved approximately 9.4% body weight loss (~7.3 kg) over 10 months, along with improvements in fasting glucose levels. Caregivers also noted behavioral benefits, including reduced food-seeking behavior and impulsivity, and quantitative analysis reportedly showed a significant reduction in aggression. The treatment was described as well tolerated. The authors hypothesize that tirzepatide may engage both metabolic and central nervous system pathways relevant to the SMS phenotype. Key limitations include the single-patient design, the absence of a control condition, and the inherent difficulty in attributing behavioral improvements to tirzepatide alone in a complex neurodevelopmental disorder.
JCEM case reports · Jun 2026DOI ↗ 🧪 TrialInsufficient
Registered observational trial (active not recruiting). Investigators are building an empirical evidence base for real world data through large-scale emulation of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies.
ClinicalTrials.gov · Jun 2026View trial ↗ Limited · human
This retrospective cohort study used the TriNetX Global Research Network to examine whether GLP-1 receptor agonist (GLP-1 RA) use was associated with a reduced risk of total knee arthroplasty (TKA) in adults with knee osteoarthritis (OA) diagnosed between 2010 and 2024. Patients exposed to GLP-1 RAs (either any agent or newer agents—semaglutide or tirzepatide) were propensity score matched to unexposed controls, balancing for age, sex, race, musculoskeletal diagnoses, obesity-related conditions, BMI, and healthcare access proxies. Matched cohort sizes ranged from approximately 13,000 to 42,000 patients depending on the exposure class and treatment duration analyzed (1 or 3 years). The primary outcome was cumulative TKA incidence at 1, 3, 5, and 8 years, estimated via Kaplan-Meier curves and Cox proportional hazards models. The study found that GLP-1 RA use was associated with significantly lower TKA incidence across all subgroups, with larger reductions observed with longer treatment durations and with newer-generation agents. The authors suggest the findings are consistent with possible disease-modifying activity beyond weight loss, but acknowledge that as a retrospective observational design, causality cannot be established, and prospective randomized trials are needed.
Regional anesthesia and pain medicine · Jun 2026DOI ↗ Moderate · humanPreprint
This systematic review and meta-analysis, conducted following PRISMA 2020 guidelines, examined the effects of GLP-1 receptor agonists (semaglutide, liraglutide) and the dual GIP/GLP-1 receptor agonist tirzepatide on obstructive sleep apnea (OSA) severity, as measured by apnea-hypopnea index (AHI). The authors searched PubMed, Google Scholar, and SciSpace through May 2026 and included 40 studies involving adults with OSA receiving GLP-1–based therapies with quantitative AHI outcomes. The review found that tirzepatide was associated with greater AHI reductions (−25.3 to −29.3 events/h; approximately 50.7%–58.7%) compared with liraglutide (−12.2 events/h; ~25%), and a pooled meta-analytic estimate showed an overall AHI reduction of −16.57 events/h across therapies. The authors attributed these effects primarily to weight loss, while noting emerging evidence for potential weight-independent mechanisms. Limitations include the heterogeneity of included studies, reliance on a preprint-stage document, and the inability to fully disentangle weight-mediated versus direct effects. The authors conclude that GLP-1–based therapies, particularly tirzepatide, may represent meaningful treatment options for obesity-related OSA, especially among patients with poor CPAP adherence.
Unknown journal · Jun 2026DOI ↗ Review
This commentary examines the Institute for Clinical and Economic Review (ICER) report on GLP-1 receptor agonists (GLP-1 RAs) — specifically semaglutide and tirzepatide — for obesity management, evaluating both their clinical value and the challenges surrounding their financing. The authors note that while these agents demonstrate meaningful weight loss and cardiometabolic benefits and were deemed cost-effective versus lifestyle modification alone by ICER, even modest real-world uptake surpasses ICER's annual budget impact threshold, raising access concerns. The commentary highlights that real-world persistence with these medications is notably lower than in clinical trials, leading to frequent weight regain upon discontinuation and limiting anticipated long-term medical cost offsets. Evidence on medical spending is described as mixed: cost-offset signals appear primarily in patients with both obesity and diabetes using high-potency injectable agents, while obesity-only populations may see spending increases. To address these tensions, the authors recommend pairing drug coverage with lifestyle management programs, avoiding arbitrary treatment duration limits, applying targeted prior authorization, and exploring innovative payment models. Key limitations include the commentary format, reliance on heterogeneous real-world data, and lack of primary data collection.
Journal of managed care & specialty pharmacy · Jun 2026DOI ↗ Insufficient
This scoping review, conducted following PRISMA-ScR guidelines, examines whether GLP-1 receptor agonists (GLP-1 RAs) — including semaglutide, liraglutide, tirzepatide, and retatrutide — may interfere with autologous fat grafting outcomes. The authors note that millions of patients using GLP-1 RAs for weight loss now present to aesthetic surgeons with facial volume loss and soft tissue deflation, conditions commonly treated with fat grafting. The review synthesizes preclinical and clinical evidence on how GLP-1 RA medications affect adipocyte biology, adipose-derived stem cell (ASC) function, and tissue revascularization. The authors identify several theoretical interference points: GLP-1-mediated adipocyte "browning" and thermogenic activation (including UCP1 upregulation), enhanced lipolysis via ATGL and HSL pathways, suppression of white adipogenic differentiation in ASCs favoring beige/thermogenic lineages, and altered angiogenic and inflammatory signaling during the revascularization window critical to graft survival. The authors explicitly acknowledge that no clinical or preclinical studies have directly examined fat graft outcomes in patients receiving these therapies. The review's conclusions are framed as hypothesis-generating, and any clinical considerations offered are described as mechanism-based rather than evidence-based. This limits the paper's direct applicability to patient care.
Aesthetic surgery journal · Jun 2026DOI ↗ Limited · human
This observational pharmacovigilance study analyzed Individual Case Safety Reports (ICSRs) from the European EudraVigilance (EV) database to investigate whether GLP-1 receptor agonists (semaglutide, liraglutide, exenatide, lixisenatide, dulaglutide) and the dual GLP-1/GIP agonist tirzepatide are disproportionately associated with thyroid cancer-related adverse events. The study retrieved 34,956 ICSRs reported between January 2022 and September 2024. Most adverse events affected adult and elderly female patients, with gastrointestinal disorders being the most commonly reported category. Using disproportionality analysis (Reporting Odds Ratio, ROR), the study found that semaglutide had a statistically significantly lower probability of thyroid cancer-related adverse event reporting compared to tirzepatide (ROR = 0.54, 95% CI 0.37–0.81). The authors acknowledge key limitations inherent to pharmacovigilance databases, including reporting bias, confounding by indication, and the inability to establish causality. They conclude that findings must be interpreted cautiously and that further prospective studies are needed to clarify whether a true causal relationship exists between GLP-1 RAs and thyroid cancer risk.
Pharmacological reports : PR · May 2026DOI ↗ Limited · human
This pharmacovigilance study analyzed reports submitted to the FDA Adverse Event Reporting System (FAERS) to compare biliary adverse events (AEs) across five GLP-1 receptor agonists (GLP-1RAs): semaglutide, tirzepatide, liraglutide, exenatide, and dulaglutide. After deduplication, 3,460 reports were included. Using semaglutide as the reference, the authors calculated proportional reporting ratios (PRR), reporting odds ratios (ROR), and Fisher exact tests across five biliary outcomes: cholelithiasis, cholecystitis, biliary colic, bile duct stone, and cholangitis. The study found that compared with semaglutide, exenatide and tirzepatide showed lower relative reporting for bile duct stone, while exenatide and dulaglutide showed lower relative reporting for biliary colic. Dulaglutide showed higher relative reporting for cholangitis. Exenatide, liraglutide, and tirzepatide all showed higher relative reporting for cholecystitis and cholelithiasis. Sensitivity and subgroup analyses were broadly consistent, though rarer outcomes lost statistical significance. Key limitations include the inherent biases of spontaneous reporting databases (underreporting, confounding by indication, and lack of denominator data), which preclude causal inference. The authors concluded that biliary AE reporting patterns differ meaningfully across agents within the GLP-1RA class.
Digestive diseases and sciences · May 2026DOI ↗ Review
This review synthesizes evidence from randomized controlled trials and high-quality meta-analyses on approved and investigational obesity medications, examining their effects beyond weight loss alone. Medications reviewed include phentermine-topiramate, naltrexone-bupropion, GLP-1 receptor agonists (liraglutide, semaglutide), and newer multiagonist agents (tirzepatide, survodutide, mazdutide, retatrutide, cagrilintide-semaglutide, and amycretin). The authors evaluated impacts across a broad range of obesity-related comorbidities, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, heart failure, cardiovascular disease, obstructive sleep apnea, polycystic ovary syndrome, osteoarthritis, muscle mass, depression, quality of life, food cravings, binge-eating disorders, substance use disorders, and neurodegenerative diseases. The review concludes that GLP-1-based and multiagonist therapies demonstrate beneficial effects across these conditions. Notably, the authors report that while many benefits appear to be mediated through weight reduction, accumulating evidence suggests weight loss-independent mechanisms, particularly for GLP-1 receptor agonist-based therapies. Key limitations include its reliance on synthesized rather than primary data and variability in evidence quality across the individual conditions reviewed.
The lancet. Diabetes & endocrinology · May 2026DOI ↗ Limited · humanPreprint
This large pharmacovigilance study analyzed 20.3 million FDA FAERS adverse event reports (2004–2024) to investigate impaired gastric emptying (IGE) as a potential class-wide adverse effect of GLP-1 receptor agonists (GLP-1 RAs). Researchers identified 6,868 IGE reports across nine GLP-1 RA agents and applied the proportional reporting ratio (PRR) method with sensitivity analyses, supplemented by cross-national validation using 29 reports from Brazil's pharmacovigilance database. The study found that all nine agents exceeded established Evans signal detection criteria, with PRRs ranging from 4.4 (exenatide) to 83.9 (injectable semaglutide). Notably, oral and injectable semaglutide showed comparable PRRs, suggesting a systemic rather than route-dependent mechanism. Tirzepatide prescribed for type 2 diabetes showed a substantially higher PRR than the same drug prescribed for obesity, which the authors interpret as a possible effect of diabetic autonomic neuropathy. A pre-litigation signal analysis was also conducted to account for potential notoriety bias. Key limitations include the inherent constraints of spontaneous pharmacovigilance data—including reporting bias, lack of denominator data, and inability to establish causation—as well as the small cross-national validation sample (n=29). The authors conclude that findings support pre-treatment risk stratification discussions for gastroparesis in GLP-1 RA candidates.
Unknown journal · May 2026DOI ↗ Limited · humanPreprint
This large pharmacovigilance study extracted 412,643 adverse event reports for five GLP-1 receptor agonists (semaglutide, tirzepatide, liraglutide, dulaglutide, and exenatide) from the FDA Adverse Event Reporting System (FAERS) spanning 2004–2024, comparing disproportionality signals using proportional reporting ratios (PRR) and reporting odds ratios (ROR). The study identified 154 drug-event signals overall. The most notable finding was a strong gastroparesis signal for semaglutide (PRR 88.9, 95% CI 85.4–92.6), which the authors describe as substantially higher than prior published estimates and as robust across three pre-specified sensitivity analyses using different comparator groups. All five agents showed statistically significant gastroparesis signals. Gastroparesis reports were consistently female-predominant across all agents (female-to-male ratio 2.7–3.6×). Tirzepatide's adverse event profile was notably dominated by device-usability reports rather than clinical events. Case-fatality rates varied across agents (0.6% to 3.7%). Key limitations include inherent FAERS biases (underreporting, stimulated reporting, lack of denominator data, and confounding by indication), which preclude causal inference or incidence estimation. The authors acknowledge the preprint status of this work.
Unknown journal · May 2026DOI ↗ Moderate · human
This systematic review and network meta-analysis (NMA) evaluated the comparative efficacy of pharmacological interventions—at specific dosages—for improving liver fibrosis in adults with metabolism-associated steatotic liver disease (MASLD) and fibrosis stages F1–F3. Researchers searched three databases through July 2025, identifying 13 randomized controlled trials encompassing 3,871 patients and 12 distinct drug regimens. Using both direct comparisons and network meta-analysis, the study found that six interventions—resmetirom (two doses), survodutide, and tirzepatide (three doses)—were significantly more effective than placebo at achieving NASH resolution without worsening fibrosis. Surface Under the Cumulative Ranking (SUCRA) analysis ranked survodutide 6 mg/week highest, followed by tirzepatide 15 mg/week; emricasan 10 mg/day ranked lowest. The authors concluded that survodutide, efruxiferimin, resmetirom, and denifanstat showed the most promise for this population, while emricasan was not supported. Limitations include the moderate number of included trials, potential heterogeneity across study populations and outcome definitions, and the indirect nature of many NMA comparisons, which may limit the precision of the relative effect estimates.
Journal of translational medicine · May 2026DOI ↗ Insufficient
This brief report, authored for nurse practitioners (NPs), examines the clinical and regulatory challenges arising from patient-driven "microdosing" of GLP-1 receptor agonists (semaglutide and tirzepatide) in the context of FDA restrictions on compounded versions following resolution of drug shortages. The authors describe how affordability barriers push patients toward subtherapeutic dosing strategies, unregulated "research-grade" peptides purchased online, and unsupervised sources such as medical spas. The paper outlines specific safety concerns associated with these practices, including pen manipulation, medication sharing, compounded vials, and dosing errors, as well as the side effect profiles encountered. It also explores how provider weight bias may inadvertently drive patients toward unregulated alternatives and offers practical stigma-reduction strategies for clinical encounters. The authors discuss the legal risks of compounded "copies" and acknowledge a narrow legitimate role for compounding in patients with documented allergies. As a brief report rather than an empirical study, the paper does not present original data or a systematic review; its conclusions are based on regulatory context, clinical observation, and expert opinion. Its primary value lies in synthesizing emerging practice-relevant issues for NPs navigating a rapidly evolving regulatory environment.
Journal of the American Association of Nurse Practitioners · May 2026DOI ↗ Review
This narrative review examines the role of lifestyle interventions before, during, and after treatment with second-generation obesity management medications (OMMs), specifically semaglutide and tirzepatide. The authors note that these agents have demonstrated weight losses of approximately 15–20% in recent trials, prompting a reconsideration of how lifestyle programs should be integrated into obesity care. The review identifies several emerging concerns in the literature, including lean mass loss, nutritional deficiencies, gastrointestinal side effects, and significant weight regain following medication discontinuation. The authors argue that lifestyle modification remains the foundation of obesity treatment but that the focus may need to shift from weight reduction toward broader health promotion in the context of highly effective pharmacotherapy. Key lifestyle strategies discussed include protein intake and physical activity to preserve muscle mass, and dietary approaches to manage gastrointestinal side effects. The review also explores pre-treatment lifestyle programs as potential prerequisites for pharmacotherapy while cautioning that such requirements could limit access and reinforce weight stigma. Limitations include the narrative (non-systematic) design, lack of primary data, and the rapidly evolving evidence base. The authors conclude that optimal timing, frequency, and content of lifestyle interventions alongside OMMs remain unclear and warrant further research.
Current atherosclerosis reports · May 2026DOI ↗ Review
This review article argues that GLP-1 receptor agonists (GLP-1 RAs) — such as semaglutide and tirzepatide — should be understood as catalysts for, rather than replacements of, lifestyle intervention in cardiometabolic care. The authors propose the guiding principle "lifestyle first and lifestyle always, but not lifestyle only," acknowledging that GLP-1 RAs have produced meaningful clinical benefits including substantial weight loss, improved glycemic control, and reduced cardiovascular and renal risk. However, the authors contend that pharmacotherapy alone cannot address the full spectrum of cardiometabolic risk drivers, including sarcopenia, physical deconditioning, poor sleep, psychological stress, and social determinants of health. The article highlights that discontinuation of GLP-1 RAs without structured lifestyle support is commonly associated with weight regain. Key lifestyle pillars emphasized include high-quality nutrition, regular physical activity (including resistance training), restorative sleep, stress management, and social connectedness. The authors advocate for integrated, interprofessional care models combining pharmacologic and lifestyle strategies, supported by systemic and policy-level change. As a narrative review, the paper does not present original data, conduct a systematic literature search, or include a meta-analysis, which limits the directness of its evidentiary contribution.
American journal of lifestyle medicine · May 2026DOI ↗ Moderate · human
This systematic review and meta-analysis synthesized evidence from three placebo-controlled randomized controlled trials (total n = 258) examining semaglutide in adults with schizophrenia spectrum disorders (SSDs). The authors conducted a preregistered search, pooled outcomes using random-effects meta-analysis, and assessed evidence certainty using GRADE criteria. The included trials tested semaglutide over 26–36 weeks. The study found that, compared to placebo, semaglutide was associated with statistically significant reductions in body weight (approximately −11.3 kg), BMI (approximately −3.6 kg/m²), HbA1c (approximately −0.37%), and fasting glucose. On the safety side, semaglutide was associated with meaningfully higher risks of abdominal pain, vomiting, and constipation, consistent with the known gastrointestinal profile of GLP-1 receptor agonists; no elevated risk of serious adverse events was observed. The authors note that the overall evidence base is limited by a small number of trials, modest combined sample size, and relatively short follow-up durations. No trials of tirzepatide in this population were identified. The authors conclude that semaglutide shows promise as an adjunctive metabolic treatment in SSDs but call for larger, longer trials.
BJPsych open · May 2026DOI ↗ Review
This systematic review examined the clinical outcomes of GLP-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 receptor agonists in children and adolescents (aged 6–19 years) with overweight or obesity, with or without type 2 diabetes. Researchers searched PubMed, Scopus, and ClinicalTrials.gov following PRISMA 2020 guidelines, ultimately analyzing 15 studies (12 interventional, 3 observational) comprising 1,448 participants across six agents: liraglutide, exenatide, semaglutide, dulaglutide, tirzepatide, and lixisenatide. Study durations ranged from 6 to 68 weeks. The review found that BMI reductions varied across agents and study designs, with semaglutide trials reporting reductions of up to –16.1%. A key finding was the substantial heterogeneity in how concomitant lifestyle interventions were reported—ranging from general dietary advice to structured multidisciplinary programs—making it impossible to isolate the independent contributions of pharmacological versus behavioral components. The authors conclude that while GLP-1 RAs appear to be a promising therapeutic option in this population, the evidence base is limited by inconsistent lifestyle co-intervention reporting. They call for standardized reporting frameworks (e.g., TIDieR), validated behavioral measures, and factorial or stratified study designs to disentangle drug and lifestyle effects in future pediatric trials.
Nutrients · May 2026DOI ↗ Limited · human
This pharmacovigilance study investigated reports of dysesthesia (abnormal skin sensations, particularly burning sensations) associated with GLP-1 receptor agonists, including semaglutide, tirzepatide, exenatide, and others. The researchers conducted a disproportionality analysis using VigiBase — the WHO's global drug safety database — focusing on the High Level Term "Paraesthesia and dysesthesia," supplemented by a qualitative review of case narratives from the French Pharmacovigilance database and a broader literature review. The analysis found that exenatide was significantly associated with hypoesthesia and oral paraesthesia, while semaglutide and tirzepatide were associated with hyperaesthesia; semaglutide was also linked to dysesthesia and burning sensations specifically. The study suggests dysesthesia may be dose-dependent and more frequent with more potent agents used at higher doses. Many reported cases involved drug discontinuation followed by spontaneous resolution, and some rechallenge cases were documented. Key limitations include the inherent biases of spontaneous reporting systems (underreporting, confounding, notoriety bias), the inability to establish causality, and the absence of controlled comparison groups. The authors conclude that pharmacovigilance data reinforces signals already observed in clinical trials of semaglutide, tirzepatide, and retatrutide.
European journal of clinical pharmacology · May 2026DOI ↗ Review
This review examines the evolution of GLP-1–based pharmacotherapies for obesity, tracing the discovery of glucagon-like peptide-1 (GLP-1) and assessing the clinical efficacy of GLP-1 receptor agonists (GLP-1RAs), with particular focus on semaglutide. The authors explore proposed central mechanisms by which GLP-1RAs may reduce appetite and body weight. A substantial portion of the review addresses the "paradox" surrounding glucose-dependent insulinotropic polypeptide receptor (GIPR) targeting: both dual GLP-1R/GIPR agonism (as seen with tirzepatide) and GLP-1R agonism combined with GIPR antagonism (as seen with maridebart cafraglutide) appear to yield favorable metabolic outcomes. The authors note a lack of evidence that GIPR agonism or antagonism alone produces meaningful anorectic effects in humans, raising mechanistic questions about how GIPR modulation enhances GLP-1RA efficacy. The review concludes by exploring additional explanations for why dual-targeting compounds appear to outperform semaglutide monotherapy. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, and its conclusions are dependent on the quality and scope of the studies reviewed.
Annual review of nutrition · May 2026DOI ↗