Search Results (60)

Background/Objectives: Obesity is a chronic, multifactorial condition driven by complex neuroendocrine and metabolic pathways that limit the long-term success of lifestyle interventions. Pharmacotherapy has advanced from early monoaminergic agents to incretin-based and multi-receptor agonists with substantially improved efficacy. This review aims to provide pharmacodynamics-focused synthesis of current and emerging anti-obesity medications, emphasizing mechanistic targets, receptor interactions, and translational implications. Methods: We conducted a narrative review integrating Phase I–III clinical trials, mechanistic pharmacology data (receptor affinity, potency, and signaling bias), and regulatory summaries for FDA-approved and selected emerging, investigational, repurposed, or regionally approved anti-obesity agents. Inclusion focused on clinical relevance, pharmacodynamic novelty, and weight-loss efficacy. Results: Approved anti-obesity medications act through diverse pathways, including the inhibition of fat absorption (orlistat), the modulation of central appetite circuits (phentermine/topiramate, naltrexone/bupropion), and incretin-based mechanisms (liraglutide, semaglutide, tirzepatide, and the oral GLP-1 receptor agonists semaglutide 25 mg and the nonpeptide orforglipron). GLP-1 receptor agonists achieve approximately 6–15% weight loss, while dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists such as tirzepatide reach 15–20%. Emerging agents—including triple agonists (retatrutide), glucagon-based co-agonists, amylin analogs with Phase III efficacy data, earlier-stage growth differentiation factor 15 (GDF15) pathway agonists, and peripherally restricted cannabinoid-1 receptor inverse agonists—demonstrate enhanced metabolic effects and potential improvements in lean-mass preservation. Obesity-related alterations in pharmacokinetics and pharmacodynamics highlight the need for individualized dosing strategies. Conclusions: Clinical efficacy and tolerability cannot be inferred from receptor identity alone. They emerge from relative receptor potency and efficacy, exposure, tissue access, receptor trafficking, and mechanism-linked adverse effects. Dual and triple agonists can broaden efficacy, but receptor balance and standardized comparative pharmacology remain essential for rational development and individualized dosing. Full article

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of obesity and type 2 diabetes mellitus (T2DM). Although randomized clinical trials have demonstrated substantial weight loss and metabolic benefits with incretin-based therapies, real-world evidence is needed to characterize anthropometric outcomes, safety, prescribing patterns, and treatment use under routine clinical conditions. Objectives: The objective of this study was to characterize real-world anthropometric outcomes, safety, and use patterns of GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists in patients with obesity or glucose metabolism disorder receiving treatment through Spanish community pharmacies. Methods: A nationwide multicentre cross-sectional study with retrospective data collection was conducted between January and April 2026 across community pharmacies in Spain. Adult patients receiving GLP-1 receptor agonists or dual GIP/GLP-1 receptor agonists were consecutively enrolled and classified according to therapeutic indication (obesity or glucose metabolism disorder). Changes in body weight and body mass index (BMI) were assessed using paired-sample t-tests, while multivariable linear regression explored independent determinants of weight loss. Crude safety signals were initially evaluated using exploratory crude safety association analysis based on Odds Ratios (ORs). Subsequently, multivariable logistic regression was performed to identify independent predictors of suspected digestive adverse drug reactions after adjustment for demographic characteristics, treatment-related variables, lifestyle factors, and concomitant glucose-lowering therapies. Baseline body weight was retrospectively reported by participants and was not independently verified against clinical records or other objective sources, whereas current body weight was measured by the pharmacist at the study visit. Results: A total of 531 patients were included (52.2% with obesity; 47.8% were classified in the glucose metabolism disorder (GMD) cohort, comprising 200 patients with type 2 diabetes mellitus and 54 with prediabetes/fasting glucose disturbance; the mean age was 56.5 ± 12.5 years; and 66.7% were women). The mean observed reduction in body weight from treatment initiation to the study assessment was 12.17 ± 10.64 kg, corresponding to an 11.71% ± 9.40% reduction relative to retrospectively reported baseline weight. Overall, 73.9% and 54.1% of participants achieved ≥5% and ≥10% weight loss, respectively. No statistically significant unadjusted difference in relative weight loss was detected across treatment groups; however, equivalence was not formally assessed. Gastrointestinal suspected adverse drug reactions were the most frequently reported safety outcomes. Exploratory crude analyses showed nominal associations between Wegovy^® and nausea/vomiting and between Mounjaro^® and constipation, as well as between concomitant insulin and dizziness and SGLT2 inhibitor therapy and urinary disorders; however, none of these associations remained statistically significant after Benjamini–Hochberg correction for multiple testing. In the exploratory multivariable linear regression model, treatment duration, treatment agent, dietary adherence, light physical activity, and age showed statistically significant adjusted associations with observed percentage weight loss. In the multivariable logistic regression model, increasing age was the only variable significantly associated with lower odds of reported suspected digestive adverse drug reactions (adjusted OR = 0.97 per year; 95% CI 0.96–0.99; p = 0.003). Conclusions: Observed percentage weight loss varied across treatment groups, although between-treatment comparisons should be interpreted cautiously because of differences in treatment duration, therapeutic indication, sample size, and dose exposure. Given the retrospective ascertainment of baseline weight and the cross-sectional design, these findings should be interpreted as real-world estimates of observed weight change rather than causal estimates of treatment effectiveness. Reported suspected adverse drug reactions were common, particularly gastrointestinal events. Although several nominal associations were observed in exploratory crude analyses, none remained statistically significant after correction for multiple testing. These findings support the importance of individualized monitoring in community pharmacy settings. These findings provide a rationale for the prospective development and evaluation of a standardized pharmacy-led dispensing and follow-up protocol to support patient safety and treatment adherence. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as systemic cardiometabolic disorders rather than isolated liver diseases. Cardiovascular disease (CVD) represents the leading cause of mortality in patients with MASLD/MASH, highlighting the need for therapeutic strategies that address both hepatic and cardiovascular risk. MASLD/MASH and CVD are connected through a network of interdependent mechanisms, including adipose tissue dysfunction, insulin resistance, altered insulin–glucagon signaling, atherogenic dyslipidemia, lipotoxicity, mitochondrial and endoplasmic reticulum stress, innate immune activation, chronic inflammation, endothelial dysfunction, thrombogenic signaling, and dysregulated hepatokine and adipokine pathways. These mechanisms provide potential therapeutic entry points across the liver–adipose tissue–vascular axis. Lifestyle modification and conventional cardiometabolic therapies remain foundational, while several pharmacological agents increasingly target specific components of this network. We summarize the mechanistic rationale and clinical evidence for emerging therapies, including glucagon-like peptide-1 receptor agonists, dual incretin agonists, fibroblast growth factor 21 analogs, thyroid hormone receptor-β agonists, peroxisome proliferator-activated receptor agonists, and agents targeting de novo lipogenesis. We further discuss why residual metabolic, inflammatory, and fibrogenic activity may limit monotherapy and how mechanism-based combination therapy could improve efficacy while mitigating treatment-related metabolic liabilities. Finally, we outline future priorities, including biomarker-guided patient selection, longitudinal noninvasive monitoring, integrated hepatic–cardiovascular trial endpoints, adaptive combination strategies, and development of therapies targeting immune, fibrogenic, and inter-organ signaling pathways. Full article

Obstructive sleep apnea (OSA) is a highly prevalent and heterogeneous sleep disorder characterized by recurrent upper airway collapse during sleep, resulting in intermittent hypoxia, sleep fragmentation, sympathetic activation, and increased cardiometabolic risk. Although obesity is the most recognized modifiable risk factor, growing evidence indicates that nutritional factors influence OSA through mechanisms extending beyond body weight regulation, including systemic inflammation, oxidative stress, endothelial dysfunction, gut microbiota alterations, and metabolic dysregulation. The emergence of precision medicine and incretin-based therapies has further highlighted the need to integrate personalized nutritional approaches into OSA management. A literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science to identify experimental studies, observational studies, randomized clinical trials, systematic reviews, meta-analyses, and international clinical guidelines addressing nutritional mechanisms, dietary patterns, gut microbiota, chrononutrition, incretin-based therapies, and precision nutrition in adults with OSA. Current evidence suggests that nutritional interventions may influence OSA through multiple biological pathways beyond weight reduction. Mediterranean and DASH dietary patterns are associated with favorable cardiometabolic effects, while dietary fiber, polyphenols, omega-3 fatty acids, and other antioxidant compounds may modulate pathways related to inflammation, oxidative stress, endothelial function, and metabolic regulation. However, evidence directly demonstrating improvements in objective respiratory outcomes remains limited and heterogeneous. Emerging research also suggests potential roles for gut microbiota modulation and chrononutrition in metabolic and sleep regulation, although most evidence remains mechanistic, observational, or indirect. In addition, glucagon-like peptide-1 receptor agonists and dual incretin agonists have demonstrated clinically relevant reductions in body weight and OSA severity, providing opportunities for integration with nutritional management. Nevertheless, evidence supporting phenotype-specific and biomarker-guided nutritional interventions remains insufficient. Nutrition represents a promising adjunctive strategy in the multidisciplinary management of OSA by targeting inflammatory, metabolic, vascular, and microbiome-related mechanisms that extend beyond weight loss alone. Future research should focus on precision nutrition approaches integrating metabolic phenotyping, biomarkers, gut microbiota, and digital health technologies to optimize personalized treatment and improve long-term clinical outcomes. Full article

The physiological effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RAs extend beyond glucose metabolism and body weight regulation. Accumulating clinical evidence has highlighted an association between these incretin-based therapies and hair loss; however, the underlying molecular mechanisms are not fully understood. White adipose tissue (WAT) is increasingly recognized as a critical regulator of hair follicle homeostasis that may undergo substantial drug-associated functional alterations. Thus, GLP-1RAs and GIP/GLP-1RAs may indirectly modulate hair follicle biology and promote hair loss through changes in adipocyte function. This review assesses the effects of GLP-1RAs and GIP/GLP-1RAs on WAT, synthesizing findings from cellular systems, animal models, and human clinical research. Collectively, these therapies may influence adipocyte differentiation, adipokine secretion, and pro-inflammatory cytokine signaling in a context-dependent manner; however, most data are derived from subcutaneous WAT and have yet to be established in the distinct dermal WAT compartment that surrounds hair follicles. Accordingly, we propose a hypothetical, non-exclusive model in which drug-associated adipocyte reprogramming may alter the hair follicle microenvironment and disrupt normal follicular cycling, potentially contributing to increased hair shedding. Validation of this potential pathway is required and may inform the development of targeted strategies to prevent or treat this adverse event. Full article

Pediatric obesity is a chronic, multifactorial neuroendocrine disease in which disrupted gut–brain signaling, hypothalamic appetite regulation, adipose tissue dysfunction, and altered inter-organ communication sustain positive energy balance. Incretin-based therapies translate this biology into mechanism-based treatment, yet their developmental implications remain incompletely defined. This narrative review integrates evidence on GLP-1 and GIP receptor signaling with pediatric trial data and clinical implementation, with particular attention to developmental modifiers of gut–brain signaling and treatment during growth and puberty. We describe how GLP-1 receptor agonists act across central and peripheral tissues to reduce appetite, delay gastric emptying, and enhance glucose-dependent insulin secretion and examine the rationale for dual GIP/GLP-1 receptor agonism. Randomized pediatric trials demonstrate clinically meaningful BMI reduction with liraglutide and semaglutide, with the largest mean effect reported for semaglutide in adolescents; however, long-term effects on growth, puberty, bone health, body composition, and weight maintenance remain uncertain. Tirzepatide has shown greater weight-loss efficacy than selective GLP-1 receptor agonism in adults, but no randomized trial has evaluated it in pediatric obesity without diabetes. Incretin-based therapies should be integrated with nutritional, behavioral, psychological, and family-based care. Their future value will depend on durable efficacy, developmental safety, equitable access, and identification of patients most likely to benefit. Full article

Antipsychotic-associated metabolic dysfunction contributes substantially to cardiometabolic morbidity and premature mortality in schizophrenia spectrum disorders, with the greatest burden among patients treated with clozapine and olanzapine. This review focuses on patients with schizophrenia spectrum disorders receiving these two agents, in whom the relevant psychiatric evidence is concentrated. Existing pharmacological interventions, including metformin and glucagon-like peptide-1 receptor agonists (GLP-1RAs), produce clinically meaningful but often incomplete benefits. Retatrutide (LY3437943) is a once-weekly triple agonist of the GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptors that produced a mean body-weight reduction of 24.2% at 48 weeks under the efficacy estimand in a Phase 2 obesity trial; company-reported Phase 3 results from four trials, not yet peer-reviewed, describe reductions of up to 28.7%. This narrative review examines the rationale for investigating retatrutide in this setting, drawing on retatrutide trials in non-psychiatric populations, the pathophysiology of antipsychotic-induced weight gain, and emerging evidence for incretin-based therapies in antipsychotic-treated populations. The glucagon component is of particular mechanistic interest because it increases basal energy expenditure, a pathway not engaged by mono- or dual agonists; whether this could partially compensate for the reduced physical activity associated with antipsychotic-related sedation is untested and is presented here solely as a hypothesis. Indirect support comes from randomized trials and meta-analyses of GLP-1RAs in clozapine- or olanzapine-treated patients, which report reductions in body weight and glycemic impairment without evidence of worsening psychotic symptoms. No trial has evaluated retatrutide in an antipsychotic-treated population. Future studies should therefore characterize gastrointestinal tolerability, potential interaction with clozapine-associated gastrointestinal hypomotility, possible effects on clozapine and olanzapine exposure, adherence and feasibility, and the dysesthesia observed in retatrutide trials, which was dose-related in most but not all trials. Dedicated randomized controlled trials are needed to determine the efficacy and safety of retatrutide in patients with schizophrenia spectrum disorders receiving clozapine or olanzapine. 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

Background/Objectives: Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder caused by recurrent upper-airway collapse during sleep, leading to intermittent hypoxia, sleep fragmentation, and excessive daytime sleepiness. Although continuous positive airway pressure (CPAP) remains the first-line therapy, long-term adherence is often suboptimal, underscoring the need for more tolerable and flexible treatment options. This review aims to summarize the pathophysiological rationale for pharmacotherapy in OSA and to discuss recent developments in drug-based interventions. Methods: We conducted a narrative review of the literature on pharmacological interventions for OSA, with a systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov up to 4 August 2026. We included randomised controlled trials, observational studies, meta-analyses, and mechanistic human or animal studies that reported relevant sleep and respiratory outcomes, and graded evidence according to the principles of GRADE framework. Results: Several drug classes have shown promise: agents that increase upper-airway dilator muscle activity, respiratory stabilizers that reduce loop gain, medications that raise the arousal threshold, topical anti-inflammatory drugs for mucosal edema, and systemic metabolic modulators such as glucagon-like peptide-1 receptor agonists and dual incretin receptor agonists. Emerging strategies, including gene therapy directed at the hypoglossal motor system, are also under investigation at the preclinical stage. Moreover, combining pharmacotherapy with CPAP or other devices can produce synergistic benefits, enabling lower device pressures and enhanced patient comfort. Conclusions: Pharmacotherapy for OSA is progressively moving from exploratory research towards targeted, phenotype-driven personalized treatment. Future studies should focus on robust patient phenotyping, multi-mechanistic combination regimens, and long-term clinical outcome evaluations to facilitate the integration of drug-based therapies into routine OSA management, particularly in specific subgroups such as those with COMISA. 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: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual incretin therapies have significantly advanced obesity management by facilitating clinically significant weight loss and enhancing cardiometabolic outcomes. Nevertheless, their growing application calls for careful consideration of nutritional and behavioural factors, including decreased dietary intake, gastrointestinal symptoms, loss of lean mass, micronutrient deficiencies, and potential weight regain following treatment cessation. Methods: This narrative review synthesises evidence from clinical trials, observational studies, reviews, professional guidelines, and MBS nutrition protocols to evaluate the role of structured dietetic care in adults receiving GLP-1 RAs or related incretin-based therapies for weight management. MBS pathways provide a comparative framework for investigating how established principles of nutritional assessment, monitoring, and dietetic follow-up may inform pharmacological treatments of obesity. Results: The literature indicates that pharmacological weight-loss treatments should not be administered solely as prescription-based treatments. Structured dietetic care can facilitate nutritional assessment, personalised dietary interventions, the management of gastrointestinal symptoms, protein optimisation, behavioural counselling, physical activity support, and long-term weight maintenance. MBS pathways illustrate the role of dietitians in pre-, peri-, and post-major weight-loss interventions through assessment, guidance on supplementation, dietary progression, biochemical monitoring, and long-term maintenance. Although these principles require adaptation rather than direct application to GLP-1 RA pathways, they offer a valuable system for integrating dietitians into comprehensive obesity pharmacotherapy. Conclusions: Structured dietetic care should be regarded as a fundamental component of the pharmacological management of obesity, especially as GLP-1 RAs and incretin-based therapies become more prevalent. Dietitians are well positioned to help optimise nutritional adequacy, preserve lean mass, manage gastrointestinal symptoms, and support sustained weight maintenance. Future research should investigate effective models for delivering dietetic care alongside incretin-based therapies, including strategies to identify patients who need more intensive support. 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

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and emerging dual incretin therapies have demonstrated substantial effects on weight reduction and metabolic improvement, with growing evidence supporting favorable cardiovascular outcomes. This narrative review provides a focused overview of key cardiovascular outcomes trials (CVOTs) and HFpEF-oriented clinical studies evaluating GLP-1 RA and dual incretin therapies in patients living with obesity, including completed and ongoing investigations. We summarize trial characteristics, critically appraise their outcomes, and briefly discuss mechanistic pathways potentially linking incretin-based therapies to cardiovascular and HFpEF-related benefits. Because available data derive from heterogeneous study designs, we explicitly distinguish evidence from type 2 diabetes cardiovascular outcomes trials, obesity-without-diabetes cardiovascular outcomes trials, HFpEF-specific randomized trials, mechanistic substudies, ongoing trials, and real-world observational analyses. We also situate incretin-based therapies within contemporary obesity, diabetes, cardiovascular, and HFpEF guideline-directed care. Finally, we identify current knowledge gaps, future research priorities, and innovative approaches needed to refine personalized therapeutic strategies and optimize patient-centered outcomes in obesity-associated HFpEF. 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