Search Results (127)

Background/Objectives: Glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists are used long term for obesity and diabetes, but their oesophageal safety is uncertain: weight loss may reduce Barrett’s oesophagus and adenocarcinoma risk, whereas delayed gastric emptying may worsen reflux. We performed a genetic assessment of target-mediated oesophageal safety. Methods: Two-sample drug-target Mendelian randomisation used cis-expression quantitative trait loci for both receptors (31,684 participants). Outcomes were European genome-wide association studies of gastro-oesophageal reflux disease and the Barrett’s oesophagus/oesophageal adenocarcinoma axis, with a trans-ancestry squamous cell carcinoma comparator. A prespecified gated workflow required positive-control validation, and target specificity required genetic colocalisation (posterior probability of a shared causal variant ≥ 0.70). Candidate metabolic mediators were examined in two-step analyses, and findings were replicated in an independent Finnish population (FinnGen R12). Results: Genetically proxied GLP-1 receptor expression was not associated with reflux disease (odds ratio 0.97, 95% confidence interval 0.85–1.11), arguing against a substantial target-mediated reflux liability; the GIP receptor estimate was not estimable. For the Barrett’s oesophagus/adenocarcinoma endpoint, estimates were near the null for both receptors (GLP-1R 0.96, 0.47–1.96; GIPR 1.00, 0.42–2.37); colocalisation was uninformative because the outcome loci carried no detectable association signal, and wide intervals did not exclude moderate effects. The null reflux findings were reproduced in FinnGen. Adiposity showed the most consistent pathway association, whereas glycaemic traits did not, including when HbA1c was instrumented from a population-based genome-wide association study providing an order of magnitude more variants. Conclusions: GLP-1 receptor perturbation was not associated with reflux disease, providing cautious genetic reassurance. For the Barrett’s oesophagus/adenocarcinoma axis, no target-specific association was demonstrated, but colocalisation was uninformative because the outcome loci carried no detectable signal, and imprecision precludes firm safety conclusions; larger adenocarcinoma-specific studies are warranted. Full article

Glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists have transformed obesity management by producing substantial, sustained weight loss and improving metabolic health. Alongside these benefits, their effects on appetite, food intake, and gastrointestinal function have raised increasing interest in the nutritional consequences of pharmacologically induced weight loss. Although reductions in energy intake contribute to therapeutic efficacy, they may also influence protein intake, dietary quality, micronutrient adequacy, and skeletal muscle health, particularly in individuals with pre-existing nutritional vulnerability. This narrative review summarizes current evidence regarding nutritional considerations during GLP-1-based therapy, including changes in dietary intake, protein and micronutrient adequacy, body composition, muscle health, and nutritional assessment. Particular attention is given to populations at increased nutritional risk, practical approaches to nutritional monitoring, and strategies to support adequate nutrition during treatment. Current evidence suggests that nutritional responses to GLP-1-based therapy are heterogeneous and cannot be adequately evaluated using body weight alone. Assessment of dietary intake, body composition, muscle function, physical performance, and individual clinical characteristics provides a more comprehensive understanding of nutritional status than anthropometric measures alone. While routine supplementation or intensive monitoring is not supported for all patients, a risk-based and individualized approach appears appropriate, particularly for older adults and individuals with sarcopenic obesity, previous bariatric surgery, chronic gastrointestinal disease, or persistent treatment-related gastrointestinal symptoms. Future research should establish clinically meaningful nutritional outcomes and determine which nutritional interventions improve patient-centered outcomes during long-term obesity management. Full article

Background/Objectives: Obesity is a chronic, progressive, and relapsing disease that requires long-term, multidisciplinary management rather than episodic weight-loss treatment. Although novel incretin-based anti-obesity pharmacotherapies, including GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists, have markedly improved the clinical management of obesity, weight reduction alone does not fully capture treatment success. Body composition, lean mass preservation, physical function, nutritional adequacy, psychological well-being, adherence, and long-term weight-loss maintenance are increasingly recognized as essential therapeutic outcomes. This narrative review critically examines the role of lifestyle medicine as a co-therapeutic strategy during modern anti-obesity pharmacotherapy, with particular attention to physical activity, nutrition, behavioral support, and individualized monitoring. Methods: A narrative literature search was conducted in PubMed up to June 2026. The review included studies addressing adults with overweight or obesity and evidence related to anti-obesity pharmacotherapy, physical activity, nutrition, body composition, functional outcomes, eating behavior, quality of life, treatment tolerability, adherence, weight regain, and long-term maintenance. Results: Current evidence indicates that incretin-based therapies produce substantial and clinically meaningful weight loss, but pharmacological efficacy may be limited by reductions in lean mass, gastrointestinal adverse events, inadequate nutritional intake, treatment discontinuation, and weight regain after drug withdrawal. Physical activity should be considered a therapeutic component rather than only a tool for increasing energy expenditure, as aerobic exercise supports cardiometabolic health and cardiorespiratory fitness, while resistance training helps preserve muscle strength, bone health, and functional capacity. Nutritional strategies are equally important, particularly during appetite suppression, to maintain adequate protein, fiber, fluids, micronutrients, and diet quality. Behavioral factors, including sleep, stress, mood, stigma, self-regulation, and the food environment, may influence adherence and long-term outcomes. Conclusions: Novel anti-obesity drugs should not be viewed as replacements for lifestyle medicine but as powerful tools within an integrated chronic-care model. The goal of treatment should move beyond maximal body-weight reduction to durable improvements in body composition, metabolic health, physical function, nutritional status, quality of life, and weight-loss maintenance. Full article

Background/Objectives: Male hypogonadism affects 35–50% of men with type 2 diabetes mellitus (T2DM) and obesity. The relationship between testosterone deficiency and response to incretin-based therapies (GLP-1 and GIP receptor agonists) remains incompletely understood. This systematic literature review, conducted following PRISMA 2020 guidelines, examines whether male hypogonadism represents a risk factor for poor response to incretin therapy or, conversely, whether these agents offer therapeutic benefits for this population. Methods: A comprehensive systematic literature search was conducted on 31 December 2024, across PubMed/MEDLINE, Scopus, and Web of Science using three search domains: (1) hypogonadism and incretin therapy response; (2) testosterone deficiency and GLP-1/GIP receptor agonists; (3) incretin response and testosterone. Eligibility criteria included human studies (randomized controlled trials [RCTs], observational studies, cohort studies, cross-sectional studies, systematic reviews, and meta-analyses) in adult men reporting testosterone levels and/or incretin response. Animal studies, pediatric populations, case reports with n < 5, editorials, and letters without data were excluded. Study selection followed PRISMA 2020 guidelines with independent dual screening. Risk of bias was assessed using the Cochrane Risk-of-Bias 2.0 tool (ROB2) for RCTs, the Newcastle–Ottawa Scale (NOS) for observational studies, and AMSTAR-2 for systematic reviews and meta-analyses. Due to substantial heterogeneity in study designs, populations, interventions, and outcome measures, a meta-analysis was not feasible; therefore, a narrative synthesis was performed. Results: From 326 records identified, 29 studies were included after deduplication and screening (primary studies: 14; systematic reviews/meta-analyses: five; narrative reviews/expert opinion: 10). Risk-of-bias assessment revealed moderate-to-high overall risk: RCTs had small sample sizes (n = 12–42) and short follow-up (12–24 weeks), raising concerns about statistical power; observational studies were of fair-to-good quality (NOS 4–7 stars) but subject to confounding; and systematic reviews were of low-to-moderate confidence (AMSTAR-2). Primary evidence from RCTs and observational studies demonstrates that GLP-1 receptor agonists (GLP-1RAs)—particularly semaglutide and liraglutide—and the dual GIP/GLP-1 receptor agonist tirzepatide significantly increase total testosterone levels in men with obesity-related functional hypogonadism (mean increase 2.5–5.2 nmol/L). This effect is largely mediated by weight loss and improvement of insulin resistance rather than direct androgenic action. Evidence regarding whether baseline hypogonadism impairs glycemic or weight-loss response to incretin therapy is limited and indirect; no adequately powered comparative trials stratified by baseline testosterone status were identified. Conclusions: Incretin-based therapies, particularly GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide, appear to improve testosterone levels in men with obesity-related functional hypogonadism, an effect that is largely mediated by weight loss and improvement of insulin resistance rather than a direct androgenic action. However, direct comparative evidence between hypogonadal and eugonadal men regarding glycemic or weight-loss response to incretin therapy remains insufficient to draw firm conclusions. The hypothesis that male hypogonadism does not impair incretin therapy response is biologically plausible but is currently supported only by indirect evidence. Prospective, adequately powered trials stratified by baseline testosterone status are needed to resolve this question. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the dual GIP/GLP-1 co-agonist tirzepatide are increasingly prescribed for obesity and type 2 diabetes in populations enriched for binge-spectrum eating pathology. A recurring controversy asks whether these agents treat eating pathology or merely mask it. This critical narrative review argues that, posed as a simple binary, the question is under-specified, and reframes it around three problems. The central is a measurement problem: several intended effects of GLP-1 RAs are scored as improvement by eating-disorder instruments, creating a diagnostic blind spot. In the one disorder where a weight-acting drug has been tested against a placebo, efficacy on weight coincided with no effect on the psychological core—the dissociation that confounds measurement during GLP-1 RA therapy. The second is a phenotype problem: because BED subtypes already moderate response to drug versus psychological treatment, an agent acting on appetite and reward should not act uniformly, though this remains a hypothesis. The third concerns the post-discontinuation trajectory, and a therapy–harm asymmetry emerges across the spectrum. A factorial, phenotype-stratified trial with disorder-core endpoints and drug-free follow-up could resolve these questions; meanwhile, prudent practice combines uncontaminated pre-treatment screening, monitoring not reliant on confounded self-report, discontinuation planning, and integration with psychological care. Full article

Background: Incretin-based therapies (IBTs), including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists (GIP/GLP-1 RAs), have transformed the management of obesity and type 2 diabetes mellitus (T2DM). Although these agents provide substantial metabolic and cardiometabolic benefits, their effects on skeletal muscle, particularly in older adults at increased risk of sarcopenia and functional decline, remain incompletely understood. Methods: This narrative review synthesizes evidence from randomized controlled trials (RCTs) and observational studies evaluating the effects of semaglutide and tirzepatide on skeletal muscle mass (SMM), muscle quality, strength, and physical performance. Current evidence on nutritional and exercise strategies aimed at preserving skeletal muscle during IBT was also reviewed. Results: Both semaglutide and tirzepatide induce substantial weight loss accompanied by reductions in lean body mass (LBM). However, current evidence indicates that LBM loss is generally proportional to the magnitude of weight loss and should not be interpreted as a direct surrogate for skeletal muscle loss or drug-induced myotoxicity. Tirzepatide appears to improve skeletal muscle composition by reducing muscle fat infiltration (MFI), whereas semaglutide shows more heterogeneous effects on muscle strength and physical performance, particularly in older or frail individuals. Emerging evidence highlights the importance of muscle quality, nutritional adequacy, and resistance exercise as key determinants of muscle preservation, although functional outcomes and data in older adults remain limited. Conclusions: The effects of incretin-based therapies (IBTs) on skeletal muscle are multifactorial and influenced by age, baseline muscle reserve, nutritional status, and physical activity. Preserving skeletal muscle health should be considered an integral component of obesity management through individualized nutritional care, adequate protein intake, resistance exercise, and regular functional assessment. Future research should prioritize the standardized evaluation of muscle quality and function and determine whether targeted nutritional interventions can improve the quality of weight loss and support healthy aging during IBT. Full article

Background/Objectives: People living with HIV (PLWH) who undergo prolonged antiretroviral therapy (ART) may experience weight gain as a potential side effect. Many of these individuals are prescribed glucagon-like peptide 1 (GLP-1) receptor agonists (RAs), or dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) RAs, which are known for their weight-reducing effects and positive impact on metabolic health. However, studies investigating their effects on PLWH are limited. Methods: We conducted a retrospective study at a public hospital in the Bronx, New York, among PLWH with obesity and/or type 2 diabetes mellitus (T2DM) prescribed GLP-1 or dual GLP-1/GIP RAs between August 2020 to March 2024. We collected baseline measurements of weight, body mass index (BMI), glycated hemoglobin (HbA1c), and lipid panel, before and after initiation of treatment, to assess the potential metabolic changes associated with the therapy. Logistic regression was used to analyze the factors associated with reductions in HbA1c and weight. Results: A total of 202 patients were included in the final study, with a mean duration of 24.2 months of GLP-1 or GLP-1/GIP RA therapy. A mean HbA1c reduction of 1.0% (p < 0.001), a mean BMI reduction of 0.7 kg/m² (p < 0.001), and an average mean weight loss of 3.55% were observed. In the univariate analysis, the duration of GLP-1 or GLP-1/GIP RA use was the only factor independently associated with HbA1c reduction greater than 1% (p = 0.027). However, no correlation was found between the duration of their use and the percentage of weight loss (p = 0.126). Insulin use was associated with less weight loss (p = 0.048), while younger age was associated with greater weight loss (p = 0.048). No significant differences in weight loss were observed when the population was stratified by sex, race, comorbidities, type of GLP-1 RA therapy, or other antidiabetic or ART regimens. Conclusions: Use of GLP-1 RAs among PLWH with obesity and/or T2DM is associated with reductions in HbA1c and BMI. In this diverse cohort, which predominantly consists of Black and Hispanic individuals, longer duration of treatment was associated with reductions in HbA1c greater than 1%. These findings encourage GLP-1 RA-related treatment for PLWH with obesity and/or T2DM. Further prospective studies with larger cohorts are needed to confirm these benefits and better define their effects on long-term metabolic health. Full article

Background and Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including semaglutide and the dual GIP/GLP-1 receptor agonist tirzepatide, have transformed the management of type 2 diabetes mellitus (T2DM) and obesity through once-weekly subcutaneous administration. While their efficacy and safety are well-established, the potential impact of administration timing—specifically, the day of the week—on clinical outcomes, adherence, and tolerability remains unexplored. Understanding whether specific days optimize therapeutic outcomes could inform personalized dosing strategies and improve long-term treatment success. Materials and Methods: We conducted a systematic literature review following PRISMA 2020 guidelines to identify studies examining the effect of weekly administration timing of semaglutide or tirzepatide on clinical outcomes in adults with T2DM or obesity. Comprehensive searches were performed across SciSpace (Deep Search, Basic Search, Full Text Search), Google Scholar, and PubMed databases through June 2026. Studies were screened using a two-stage process (abstract and full-text screening) with predefined PICO-based inclusion criteria. Data extraction focused on study design, population characteristics, administration timing, glycemic control, weight loss, adherence, and adverse events. Results: From 1471 identified records, 1000 unique papers underwent screening after deduplication and trimming. Three studies met inclusion criteria: the SUSTAIN 4 randomized controlled trial evaluating once-weekly semaglutide, a retrospective case series examining alternate-day oral semaglutide dosing, and an expert panel discussion on flexible dosing schedules. No studies directly compared different days of the week for injectable semaglutide or tirzepatide administration. Available evidence suggests that flexible dosing schedules may support adherence and tolerability without compromising glycemic control, though this suggestion derives primarily from indirect evidence and expert opinion rather than direct comparative clinical studies; direct comparative data on day-of-week effects are absent. Conclusions: Current evidence does not support a specific optimal day of the week for semaglutide or tirzepatide administration. The limited literature emphasizes flexible dosing schedules tailored to individual patient preferences and lifestyles to maximize adherence. Future prospective studies are needed to systematically evaluate whether administration timing influences clinical outcomes in real-world settings. Full article

Obstructive sleep apnea (OSA) affects nearly one billion adults worldwide and involves mechanical upper-airway obstruction alongside metabolic dysfunction, systemic inflammation, and gut–brain axis disruption. Despite the efficacy of continuous positive airway pressure (CPAP), suboptimal long-term adherence highlights the need for complementary pharmacological strategies. This narrative review synthesizes preclinical and clinical evidence on GLP-1-based therapies, encompassing selective GLP-1 receptor agonists and tirzepatide, a dual GIP/GLP-1 receptor agonist, in obesity-associated OSA. Preclinical studies show that GLP-1 receptor activation can reduce visceral adiposity, attenuate pro-inflammatory signaling, improve glucose and lipid metabolism, and modulate hypothalamic appetite circuits. However, the only identified murine study evaluating liraglutide during intermittent hypoxia—an experimental model of one component of OSA rather than the complete disorder—did not reverse hypoxia-induced insulin resistance, indicating that persistent intermittent hypoxia may limit metabolic improvement in that model. Clinically, liraglutide and tirzepatide have reduced the apnea–hypopnea index (AHI) and improved several cardiometabolic outcomes. Numerically larger AHI reductions were reported in the tirzepatide trials, although no head-to-head comparison with selective GLP-1 receptor agonists is available. Tirzepatide is approved by the U.S. Food and Drug Administration for moderate-to-severe OSA in adults with obesity, together with a reduced-calorie diet and increased physical activity, and may be used without concomitant positive airway pressure in eligible patients or as an adjunct to ongoing therapy. The observed respiratory benefits appear to be mediated predominantly by weight loss and related reductions in mechanical and metabolic burden. Evidence supporting additional weight-independent mechanisms remains insufficient, and longer-term mechanistic studies in broader populations are required. Full article

Anti-obesity medications (AOMs), led by the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) semaglutide and liraglutide and the dual GIP/GLP-1 receptor agonist tirzepatide, have produced substantial weight reduction and growing signals of benefit that extend well beyond adiposity. These agents are now discussed in relation to longevity and aesthetic medicine, raising the question of whether their effects reach ageing biology and appearance. This narrative review (PubMed, EMBASE, Scopus, Web of Science, Cochrane Library, and Clinical trial registries; January 2010–June 2026) integrates mechanistic studies, randomised cardiovascular and renal outcome trials, ageing-biomarker analyses, body-composition data, and patient-facing aesthetic phenomena. The evidence indicates that AOMs reduce major cardiovascular events, slow kidney and liver disease progression, and lower all-cause mortality in selected populations; exploratory proteomic and epigenetic analyses further suggest effects partly independent of weight loss, though these do not establish slowed ageing. Newer multi-receptor agents act with greater metabolic specificity: glucagon-containing agents such as survodutide and the triple agonist retatrutide preferentially reduce visceral and hepatic fat (liver-fat reductions of roughly 60–80% in places), a quality of weight loss arguably more relevant to healthspan than its quantity. Concurrently, rapid large-magnitude weight loss drives soft-tissue and appearance changes colloquially termed “Ozempic face” and “Ozempic body”, alongside accelerated skin laxity and loss of lean mass, the latter tempered by data showing lean-loss proportions comparable to established agents. Full article

Background: Glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) receptor agonists have substantially improved the management of obesity and cardiometabolic disease, providing significant benefits on weight reduction, glycemic control, and cardiovascular outcomes. Despite these advances, gastrointestinal (GI) adverse events remain a major cause of dose reduction, treatment interruption, and poor long-term adherence. Increasing evidence suggests that interactions between incretin-based therapies and the intestinal microenvironment may contribute to GI tolerability and influence treatment persistence. Methods: We conducted a narrative review of the literature examining the relationship between incretin-based therapies, gut microbiota, intestinal barrier function, and microbial metabolites. Evidence from randomized clinical trials, observational studies, systematic reviews, and mechanistic investigations was evaluated to explore potential gut-directed supportive strategies during incretin-based treatment. Results: Preclinical and mechanistic evidence suggests possible bidirectional interactions between incretin pharmacology and the intestinal microenvironment, whereas direct human evidence remains limited and inconsistent. Alterations in gastrointestinal motility induced by GLP-1 receptor agonists could theoretically influence microbial composition and fermentation dynamics, although human studies have not consistently demonstrated significant microbiota changes. Based on these observations, we propose the Incretin–Microbiota Tolerance Axis (IMTA) as a conceptual framework linking gut homeostasis, GI tolerability, and treatment adherence. Among potential supportive interventions, partially hydrolyzed guar gum (PHGG) may promote SCFA-producing microbiota and improve bowel function, whereas simethicone may provide symptomatic relief of gas-related discomfort during dose escalation. SCFA-supportive nutritional approaches may further contribute to maintenance of intestinal homeostasis. Conclusions: Optimization of the intestinal microenvironment may represent a complementary strategy to improve GI tolerability and support long-term adherence during incretin-based therapy. Although the IMTA framework is supported by biological plausibility and emerging evidence, prospective clinical studies are required to determine whether microbiota-targeted interventions improve treatment persistence and cardiometabolic outcomes in patients receiving GLP-1 receptor agonists or dual GIP/GLP-1 receptor agonists. Full article

Obesity is a multifactorial condition that profoundly affects female reproductive health through endocrine, metabolic, and inflammatory mechanisms that disrupt the hypothalamic–pituitary–gonadal (HPG) axis. Women with obesity frequently develop menstrual irregularities, anovulation, amenorrhea, infertility, polycystic ovary syndrome (PCOS), impaired endometrial receptivity, and adverse pregnancy outcomes. Central obesity and insulin resistance contribute to hyperinsulinemia, reduced sex hormone-binding globulin (SHBG) levels, hyperandrogenism, altered gonadotropin secretion, and impaired folliculogenesis, while adipokines such as leptin and chronic inflammation further impair ovarian steroidogenesis and ovulatory function. Obesity-related oxidative stress and lipotoxicity also negatively affect oocyte quality, embryo development, implantation, and assisted reproductive technology outcomes, increasing the risk of gestational diabetes, preeclampsia, miscarriage, and preterm birth. This review evaluates the therapeutic potential of pharmacological weight-loss therapies in obesity-associated female reproductive dysfunction. A comprehensive literature review was conducted using various databases, focusing on anti-obesity pharmacotherapy on obesity, infertility and fertility in reproductive-aged women. Evidence suggests that several FDA-approved and off-label anti-obesity agents, including orlistat, liraglutide, semaglutide, phentermine/topiramate, bupropion/naltrexone, metformin, exenatide, and tirzepatide, may improve reproductive outcomes primarily indirectly through weight reduction and metabolic improvement. GLP-1 receptor agonists, particularly liraglutide, semaglutide, and exenatide, appear especially promising, demonstrating beneficial effects on insulin sensitivity, menstrual regularity, ovulation, androgen levels, and pregnancy rates in women with PCOS. Tirzepatide, a dual GLP-1/GIP receptor agonist, has shown potent weight-loss and metabolic effects with potential indirect fertility benefits. Metformin improves insulin sensitivity and is widely used in PCOS to regulate androgen levels and restore ovulation, although its effects on pregnancy and live birth rates remain controversial. However, evidence for several agents remains limited, and concerns persist regarding reproductive safety during pregnancy. Overall, anti-obesity pharmacotherapy may represent an important adjunctive strategy for improving reproductive and metabolic health in women with obesity, although larger randomized clinical trials are still required. Full article

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and GLP-1/glucose-dependent insulinotropic polypeptide (GIP) dual agonists have revolutionized the treatment of type 2 diabetes and obesity. The rapid growth in public interest, off-label use, and the emergence of counterfeit drugs underscores the need for timely monitoring of information demand. Objective: The objective of this study is to quantitatively characterize the temporal dynamics, market concentration, seasonality, and semantic structure of Russian-language search queries regarding GLP-1RAs and GLP-1/GIP dual agonists and to assess their correlation with pharmaceutical demand. Materials and Methods: This was a retrospective study of Yandex.Wordstat data from March 2018 to March 2026 (covering 97 months, 27 INNs and brand names). Time series analysis (trends, structural breaks, Seasonal-Trend decomposition based on Loess (STL decomposition)), calculation of the Herfindahl–Hirschman Index (HHI), and semantic analysis of 4562 unique formulations (bigrams, trigrams, Term Frequency–Inverse Document Frequency (TF-IDF), thematic classification, morphological normalization) were performed. Validation was conducted using DSM Group pharmacy sales data. Results: A total of 46.05 million queries were analyzed. Interest in semaglutide increased 215-fold, with the structural break point identified in January 2021. The HHI decreased from 0.311 (indicating a highly concentrated market) to 0.141 (indicating a competitive market). The share of diabetes-related queries did not exceed 0.46%, while the share of weight-loss-related queries reached 13.91%, and the share of commercial-component queries reached 41.1%. Four semantic signatures were identified: brand-dominant (Ozempic), instruction-targeted (Saxenda), dose-commercial (Tirzetta), and instruction-commercial (Trulicity). No statistically significant seasonality was confirmed after adjustment for multiple comparisons. The correlation between search interest and pharmacy sales was the strongest for Tirzetta (r = 0.976; n = 8; p < 0.001) and remained significant after trend removal (first differences: r = 0.819; p = 0.024). Conclusions: Yandex.Wordstat data provide a valuable supplementary source for digital pharmacoepidemiology. A systematic discrepancy was found between registered indications and actual information demand, a finding that has significant implications for pharmacovigilance and healthcare planning. Full article

Semaglutide and tirzepatide, glucagon-like peptide-1 (GLP-1) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists, respectively, have revolutionized the management of type 2 diabetes mellitus and obesity. Beyond their established metabolic indications, emerging preclinical and clinical evidence suggests these incretin-based therapies exert pleiotropic effects across multiple organ systems through mechanisms extending beyond glycemic control and weight reduction. This comprehensive review synthesizes current evidence for unconventional applications of semaglutide and tirzepatide across five distinct therapeutic domains: oncology, psychiatry and addiction medicine, orthopedics, aesthetic medicine, and human reproduction. In oncology, both agents demonstrate antitumor activity primarily through immune and metabolic reprogramming rather than direct cytotoxicity, with promising signals in pancreatic, thyroid, breast, and colorectal cancers. In psychiatry, modulation of mesolimbic dopamine reward pathways and GABAergic neurotransmission underlies robust preclinical and observational evidence for reducing alcohol use disorder, substance use, and binge-eating behaviors. Orthopedic applications include clinically meaningful improvements in knee osteoarthritis pain and function, though bone health signals remain mixed. Aesthetic medicine faces the dual challenge of managing GLP-1 receptor agonist-associated facial volume loss while exploring therapeutic potential in inflammatory dermatoses. In reproductive medicine, metabolic improvements translate to benefits in polycystic ovary syndrome and male fertility, though periconception safety concerns persist. Across all domains, evidence derives predominantly from preclinical models, observational cohorts, and pharmacoepidemiologic studies, with randomized controlled trials remaining limited. This review critically evaluates mechanisms, efficacy signals, safety considerations, and research priorities for each application domain, providing a roadmap for translating unconventional uses of semaglutide and tirzepatide into evidence-based clinical practice. Full article

Background/Objectives: Glucagon-like Peptide 1 receptor agonists (GLP-1s) have increased in popularity for obesity management and treatment of various metabolic conditions. The medications, however, have significant side effects and carry a risk for adverse events. The objective of this study was to investigate the prevalence of patients taking these medications presenting to the Emergency Department (ED). Methods: We conducted a multi-center retrospective study at two EDs: an urban level 1 trauma center and an academic quaternary medical center (combined annual census approximately 90,000) over a 9-year period (2017–2025). We collected data on all ED encounters involving patients taking GLP-1s, including dual GLP-1/GIP (Glucose-dependent Insulinotropic Polypeptide) agonists, at the time of admission, including demographic information, presenting complaints, comorbidities, and disposition. Descriptive and comparative statistics were used to characterize GLP-1 patient encounters vs. non-GLP-1 patient encounters overall and by diabetes status. The change in encounters over the study period was also assessed. p-values < 0.05 were considered statistically significant. Results: Over the 9-year study period, the proportion of ED encounters involving patients on GLP-1s increased from 0.4% in 2017 to 5.8% in 2025 (p < 0.001). Patients taking GLP-1s were more often female (53.9%), obese (59.4%), and middle-aged, ranging from 35 to 64 years of age (57.3%), and commonly presented with complaints of abdominal or other pain, weakness, or dizziness. Nearly three-quarters of all patients had a Charlson Comorbidity Index (CCI) score of 3 or higher (74.0%). These patients had a higher rate of inpatient admission from the ED (33.5% vs. 23.7%, p < 0.001). Conclusions: The number of patients presenting to the ED who were taking GLP-1s significantly increased over time as these medications became more widely utilized. Patients taking GLP-1s were more often obese with multiple comorbidities and were more likely to be admitted for inpatient care. Further studies are needed to determine whether GLP-1 use independently influences emergency care utilization and the need for hospitalization. Full article