Search Results (937)

Over the last years, incretin receptor agonists—including glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RA) and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide—have dramatically improved the management of type 2 diabetes, overweight and obesity. However, as the use of incretin receptor agonists continues to increase worldwide, micronutrient deficiencies—including iron deficiency—have emerged as newly recognized adverse effects of these drugs. The present article aims to discuss recent preliminary observational evidence on the potential relationship between incretin receptor agonist-based therapies and the development of iron deficiency and iron deficiency anemia (IDA), as well as the potential mechanisms by which incretin receptor agonists may affect iron homeostasis. Potential mechanisms and factors underlying the development of iron deficiency and IDA in patients treated with incretin receptor agonist-based therapies include inadequate dietary iron intake (due to incretin receptor agonist-mediated reduction in food intake and/or gastrointestinal adverse effects of incretin receptor agonists), low dietary variety, monotonous diets, and changes in food preferences, as well as impairment of intestinal iron absorption (due to delayed gastric emptying, reduced small intestinal motility and/or decreased gastric acid secretion caused by incretin receptor agonists). Moreover, vitamin B2 (riboflavin) deficiency and changes in gut microbiota composition are hypothetical mechanisms that may partly explain iron deficiency in patients treated with incretin receptor agonists, although these hypotheses require confirmation through mechanistic studies. Even though iron deficiency and IDA currently appear to be uncommon adverse effects of incretin receptor agonist-based therapies, clinicians should be aware of the possibility of their occurrence to ensure appropriate prevention and management of these nutritional complications. Nevertheless, future prospective studies are certainly needed to better establish the causal relationship between the initiation of incretin receptor agonist-based therapies and the development of iron deficiency/IDA, as well as the exact mechanisms underlying the potential development of these nutritional complications in patients treated with incretin receptor agonists. Meanwhile, the prescription of incretin receptor agonists should not be unjustifiably restricted by the possible and modest risk of iron deficiency and IDA in patients with one or more approved indications for therapeutic use of these agents. Since no established guidelines currently exist for the prevention and management of iron deficiency and IDA in patients treated with incretin receptor agonists, we herein propose practical strategies to address these possible nutritional complications of incretin receptor agonist-based therapies. These proposed strategies should only be regarded as practical clinical approaches deriving from the existing recommendations for the prevention and management of iron deficiency and IDA, although their cost-effectiveness for the prevention and management of incretin receptor agonist-associated iron deficiency/IDA should be appropriately assessed in future clinical trials. Full article

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) central to metabolic regulation, and its potential modulation by dietary phytochemicals is increasingly recognized as physiologically relevant. Understanding how such compounds interact with GLP-1R is important for clarifying mechanisms that may contribute to gut-to-brain signaling. In this study, we examined three structurally related dietary ginsenosides, Rg1, Rg2, and Rg3, as potential modulators of GLP-1R using luciferase reporter assays and computational analyses. Despite sharing similar molecular weights, a common dammarane scaffold, and comparable sugar moieties, the three ginsenosides displayed distinct effects on GLP-1R activity: Rg2 and Rg3 potently reduced receptor activation in a dose-dependent manner when co-administered with Exendin-4, whereas Rg1 had minimal effect. Computational screening of the GLP-1R structure for binding sites identified a putative extracellular pocket on the protein that can accommodate these compounds, while molecular docking and binding free energy calculations provided predicted affinities qualitatively reflecting the phytochemicals’ experimental activities. These findings point to a plausible extracellular mechanism through which dietary ginsenosides may influence GLP-1R responsiveness at the intestinal interface. Our results point to the possibility that non-absorbed phytochemicals can differentially modulate gut-expressed receptors, suggesting a novel pathway for dietary signaling relevant to ethnopharmacology and metabolic health. Full article

Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, restores hyperglycemic conditions in patients with type 2 diabetes and has recently shown promising anti-inflammatory properties. In this study, we explored its potential to suppress osteoclast formation and bone loss triggered by lipopolysaccharide (LPS), an inflammatory agent. In animal models, the co-administration of liraglutide with LPS on the calvaria regions in mice markedly reduced osteoclast numbers and bone resorption areas relative to treatment with LPS alone. Furthermore, the expression levels of receptor activators of the NF-κB ligand (RANKL) and tumor necrosis factor (TNF)-α mRNA were notably lower in the group receiving liraglutide and LPS compared to treatment with LPS alone. Moreover, in vitro tests revealed that liraglutide has no direct inhibitory effect on RANKL-induced osteoclastogenesis and TNF-α-induced osteoclastogenesis. In addition, liraglutide had no direct inhibitory effect on LPS-stimulated RANKL expression in osteoblasts. Moreover, liraglutide effectively suppressed TNF-α mRNA expression in macrophages stimulated by LPS. These findings suggest that liraglutide prevents inflammatory bone destruction not by targeting osteoclast formation directly but by inhibiting the production of TNF-α within macrophages. Full article

Background/Objectives: Composite endpoints are commonly used in chronic kidney disease (CKD) trials to enhance statistical efficiency but may not reflect clinically meaningful outcomes. We assessed agreement between composite endpoints and key components using the bias attributable to composite outcome (BACO) index and explored determinants of variability. Methods: We performed a meta-epidemiological analysis of randomized controlled trials evaluating sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists in CKD. BACO was defined as the ratio of the log-hazard ratio for the composite endpoint to that of the reference outcome (kidney failure or cardiovascular death), with variance estimated using the delta method. Determinants were analyzed using inverse-variance weighted mixed-effects meta-regression. Results: Eight trials comprising 38 composite endpoints were included. Higher reference-event rates were associated with higher BACO values overall (β: 0.06, 95% CI: 0.02; 0.10) and in kidney failure-referenced analyses (β: 0.07, 95% CI: 0.02; 0.12). Stronger composite treatment effects correlated with higher BACO (β: −1.07, 95% CI: −1.84; −0.30). The number of components and follow-up duration showed no significant association. In cardiovascular death-referenced models, BACO was associated with trial size (β: 0.12 per 1000 participants), mean age (β: −0.04 per 10 years), and female proportion (β: 0.09 per 10% increase). Conclusions: Agreement between composite endpoints and clinically relevant outcomes is driven by the relative frequency and treatment responsiveness of component events rather than endpoint complexity. Composite endpoints in which clinically important outcomes are infrequent may not reliably reflect treatment effects, underscoring need for clinically aligned endpoint strategies. Full article

Non-alcoholic fatty liver disease (NAFLD), now increasingly termed metabolic dysfunction-associated steatotic liver disease (MASLD), is a growing cause of chronic liver disease with limited treatment options. Glucagon-like peptide-1 (GLP-1) receptor agonists, approved for type 2 diabetes and obesity, possess metabolic effects that may render them suitable for treating NAFLD and metabolic dysfunction-associated steatohepatitis (MASH). To evaluate the therapeutic effects of GLP-1 receptor agonists in adults with NAFLD, non-alcoholic steatohepatitis (NASH), MASLD, or MASH. PubMed, Scopus, Embase, and the Cochrane Library were systematically searched using keywords related to NAFLD and GLP-1 receptor agonists. Given heterogeneity in populations, designs, and outcomes, findings were synthesized narratively. The review is registered with PROSPERO (CRD420261337353). Twelve studies met the inclusion criteria. The most consistent outcome was a reduction in hepatic fat, seen with semaglutide, liraglutide, dulaglutide, and beinaglutide. Improvements in liver enzymes, particularly alanine aminotransferase, were less consistent and best regarded as supportive rather than definitive evidence of histological improvement. Histological benefits were strongest for steatohepatitis resolution in non-cirrhotic MASH. Fibrosis findings were mixed, with the greatest benefit in F2–F3 MASH and limited improvement in established cirrhosis. GLP-1 receptor agonists were generally well tolerated, with gastrointestinal symptoms the most common adverse effects. GLP-1 receptor agonists show promising liver-related benefits in NAFLD and MASH, particularly in obesity, type 2 diabetes, or earlier-stage disease. Their effects on advanced fibrosis and long-term outcomes remain uncertain, warranting larger, longer-term studies. Full article

The migrating myoelectric complex (MMC) is the electrical basis of fasting small intestinal motility. Although oxytocin (OT) regulates gastrointestinal functions through oxytocin receptors (OTRs), its effect on jejunal MMC activity during fasting remains unclear. This study investigated the effects of OT on jejunal MMC activity in fasted rats and evaluated the involvement of OTRs, glucagon-like peptide-1 receptors (GLP-1Rs), and nitric oxide (NO) pathways. Bipolar electrodes were implanted at three jejunal sites in adult male Sprague Dawley rats for MMC recordings. After recovery and 18 h fasting, OT was administered intraperitoneally (4–32 µg/kg) following one hour of basal recording. To assess mechanisms, rats were pretreated with the OTR antagonist atosiban (2 mg/kg), the GLP-1R antagonist exendin (9–39) (200 µg/kg), or the nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NNA; 5 mg/kg) before OT (16 µg/kg). Oxytocin dose-dependently reduced spike frequency and MMC cycle number (p < 0.05–0.001 vs. vehicle). Atosiban completely reversed these effects (p < 0.001 vs. OT), while exendin (9–39) partially attenuated them (p < 0.01–0.001 vs. OT). L-NNA showed no significant effect. These findings indicate that OT inhibits jejunal MMC activity via OTR-dependent mechanisms with partial involvement of GLP-1R signaling but not NO pathways. Full article

Background and Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for type 2 diabetes and obesity treatment and may influence reward-related behaviors, including alcohol use. This study aimed to evaluate the effects of GLP-1RAs on alcohol consumption and related outcomes in adults with alcohol use or alcohol use disorder (AUD). Methods: A systematic review was conducted following PRISMA 2020 guidelines. PubMed and Web of Science were searched from inception to December 2025. Eligible studies included randomized controlled trials (RCTs), secondary analyses of RCTs, and observational studies reporting quantitative alcohol consumption outcomes. Data extraction and risk of bias assessment (RoB 2 and ROBINS-I) were performed independently by two reviewers. Results: Five studies (n = 49,892) were included, comprising three RCT-based analyses and one large cohort study. Semaglutide and dulaglutide were associated with modest reductions in alcohol consumption and craving in several studies, with statistically significant improvements in selected behavioral outcomes. In contrast, exenatide did not demonstrate significant effects in the overall AUD population, with signals limited to subgroups. The cohort study showed small but statistically significant reductions in AUDIT-C scores following GLP-1RA initiation. Objective measures (e.g., PEth, breath alcohol concentration) showed reductions in selected contexts but were reported in a few studies. Conclusions: GLP-1RAs may be associated with modest reductions in alcohol consumption, but evidence remains limited and heterogeneous. Larger, well-designed RCTs are needed to define their role in the management of AUD. Full article

Background: As glucagon-like peptide-1 (GLP-1) receptor agonist use expands globally, reports of psychiatric adverse events (AEs) have increased in spontaneous reporting databases. However, which case-level characteristics are associated with these reporting patterns remains insufficiently characterized. This study aimed to characterize case-level features associated with psychiatric AE reporting in GLP-1 receptor agonist users through pharmacovigilance and explainable machine learning methods. Methods: The FDA Adverse Event Reporting System (FAERS) data (2021 Q2–2025 Q3) were analyzed using a comparator-based approach comprising other antidiabetic and anti-obesity agents. Disproportionality analyses (PRR, ROR, and IC) were performed to detect consolidated safety signals at the Preferred Term (PT) level, with additional drug-specific analyses for individual GLP-1 receptor agonists. Three classification models (logistic regression, XGBoost, and LightGBM) were developed, and SHAP values were used to identify case-level features associated with psychiatric AE reporting patterns. Results: A total of 211,195 unique cases were included (111,105 for GLP-1 receptor agonists; 100,090 for comparators). Sixteen PTs met consolidated signal criteria, with suicidal ideation being the most frequently reported (ROR 2.95). Drug-specific analyses indicated that signal magnitudes were consistently higher for semaglutide than tirzepatide. The XGBoost model achieved an AUROC of 0.816. SHAP analysis showed that age ≥65 years had the highest mean |SHAP| value (0.57) with a negative direction, corresponding to a lower predicted probability of psychiatric AE reporting in older adults. Semaglutide use ranked second (0.35) and showed a positive direction. Absence of concomitant medications (0.20) and diabetes indication (0.10) showed negative directions, while younger age (19–44 years, 0.08) showed a positive direction. These patterns remained consistent in sensitivity analysis excluding concomitant psychotropic medication users (AUROC 0.797). Conclusions: Older age status was associated with decreased predicted probability of psychiatric AE reporting, while semaglutide use and younger age showed positive contributions. These case-level patterns, identified through pharmacovigilance analysis using a comparator-based approach and explainable machine learning, suggest that reporting patterns may differ across subgroups and that the observed reporting heterogeneity among younger adults and semaglutide users merits further investigation in prospective studies. Full article

Background: Thoracic aortic aneurysm (TAA) remains a high-risk vascular condition despite major advances in imaging surveillance, operative repair, and endovascular therapy. Medical management still relies largely on blood pressure control and global cardiovascular risk reduction. Renin–angiotensin–aldosterone system (RAAS) inhibitors are frequently used in TAA, but contemporary data evaluating survival and cardiovascular outcomes in broad TAA populations are limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) have established cardiometabolic benefits, yet their role in TAA has not been well defined. Methods: We performed a retrospective multicenter cohort study of adults with imaging-confirmed TAA diagnosed between 1 January 2018 and 1 January 2026 using a Mayo Clinic electronic data platform encompassing more than 15 million patient records. Primary exposures were documented use of RAAS inhibitors, GLP-1 RAs, and SGLT2 inhibitors, evaluated individually and in prespecified combination-therapy analyses. Propensity score matching was used to balance demographics, comorbidities, aortic procedural history, and concomitant cardiovascular medications. Primary outcomes were all-cause mortality and major adverse cardiovascular events (MACE) through 60 months. Results: The study included 162,126 patients with TAA. After matching, RAAS inhibitor use was associated with higher 60-month overall survival (88.3% vs. 85.5%; hazard ratio [HR], 0.79; 95% CI, 0.76–0.83; p < 0.001) and MACE-free survival (86.1% vs. 84.2%; HR, 0.87; 95% CI, 0.83–0.91; p < 0.001). GLP-1 RA therapy was associated with higher overall survival (97.5% vs. 92.5%; HR, 0.32; 95% CI, 0.27–0.38; p < 0.001) and MACE-free survival (93.2% vs. 89.3%; HR, 0.62; 95% CI, 0.56–0.70; p < 0.001). SGLT2 inhibitor therapy was similarly associated with higher overall survival (89.8% vs. 81.5%; HR, 0.51; 95% CI, 0.47–0.54; p < 0.001) and MACE-free survival (86.3% vs. 79.1%; HR, 0.62; 95% CI, 0.58–0.66; p < 0.001). Combination therapy with RAAS inhibitors plus either GLP-1 RAs or SGLT2 inhibitors was associated with incremental improvements in overall survival and MACE-free survival compared with GLP-1 RA or SGLT2 inhibitor monotherapy. Conclusions: In this large propensity-matched TAA cohort, RAAS inhibitors, GLP-1 RAs, and SGLT2 inhibitors were each associated with improved survival and fewer major cardiovascular events, with additional benefit observed for RAAS-based combination therapy. These findings support further prospective investigation of integrated cardiometabolic and vascular-targeted therapy in TAA, while underscoring that observational associations should not be interpreted as proof of aneurysm-specific disease modification. Full article

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as liraglutide (LIR), are widely used in humans to treat type 2 diabetes mellitus, obesity, and non-alcoholic fatty liver disease. In mammals, GLP-1 RAs have been shown to influence hepatic lipid metabolism, although the underlying mechanisms remain unclear. In fish, GLP-1 also plays an important role in regulating hepatic processes, including glycogenolysis, gluconeogenesis, and lipolysis. However, the effects of GLP-1 RAs on liver lipid metabolism in fish remain largely unexplored. Objective: This study aimed to evaluate the effects of LIR on lipid target genes using primary hepatocytes from brown trout as an in vitro model. Methodology: After 24 h, a hepatocyte monolayer culture was established, and cells were exposed for 24 and 48 h to supplemented L-15 medium (control), 0.1% dimethyl sulfoxide in supplemented L-15 medium (solvent control), and five single exposures to LIR at 1, 10, 100, 500, and 1000 nM. After 24 and 48 h, cell viability was assessed using the trypan blue exclusion assay. Gene expression was analysed by real-time qPCR, targeting genes involved in lipogenesis, lipid transport, and cholesterol efflux. Results: No concentration-dependent effects on cell viability were observed. Gene expression analysis showed that LIR exposure modulated the mRNA levels of lipid-related genes, including acetyl-CoA carboxylase (ACC), acyl-CoA long-chain synthetase 1 (Acsl1), and fatty acid synthase (FAS), with time being the main influencing factor. Overall, expression levels were higher at 48 h compared to 24 h. Additionally, dose-dependent effects were observed for ACC expression, with higher LIR concentrations showing significant differences compared to controls. Conclusions: These findings indicate that LIR modulates lipid-related gene expression in primary hepatocytes of brown trout without affecting cell viability. The results suggest that GLP-1 receptor activation may influence key pathways involved in hepatic lipid metabolism, with time-dependent effects playing a predominant role. Overall, this study supports the use of brown trout primary hepatocytes as a suitable in vitro model for investigating hepatic lipid responses to LIR and other GLP-1 receptor agonists, while providing initial insight into their potential effects in fish. Full article

Insulin resistance (IR) is traditionally viewed within the context of type 2 diabetes. However, it increasingly appears to represent a broader systemic metabolic risk state with potential relevance for carcinogenesis. Chronic hyperinsulinemia can activate insulin-like growth factor-1-dependent pathways, including phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin and mitogen-activated protein kinase signaling, promoting cellular proliferation while limiting apoptosis. At the same time, IR is closely linked to oxidative stress, chronic low-grade inflammation, and epigenetic alterations, together shaping a tumor-promoting microenvironment. Epidemiological studies report consistent associations between IR and increased cancer risk, particularly for endometrial, liver, and colorectal cancers. Yet causality remains uncertain and likely varies by tumor type. Notably, metabolic dysfunction may also occur in individuals with normal body mass index (BMI), underscoring the limitations of BMI-based risk assessment. Unlike previous reviews that primarily focused on individual mechanisms or epidemiological associations, this review examines IR as a systemic metabolic risk state by integrating molecular, epidemiological, biomarker-based, and prevention-oriented perspectives. Particular emphasis is placed on strategies for earlier risk identification using integrated biomarker approaches, including fasting glucose, homeostatic model assessment of insulin resistance, triglyceride-to-high-density lipoprotein ratio, high-sensitivity C-reactive protein, and insulin-like growth factor-1. Emerging tools such as continuous glucose monitoring and hepatokine profiling may further refine risk detection. Sustained lifestyle modification—diet, physical activity, sleep, and stress regulation—remains central to prevention. Pharmacological therapies, including glucagon-like peptide-1 receptor agonists and dual incretin agents, offer additional metabolic benefits, although their long-term impact on cancer risk is still unclear. Therefore, IR is best understood not as an isolated risk factor, but as a systemic metabolic risk state that may influence cancer development, with implications for prevention and early risk stratification. Full article

The gut hormone glucagon-like peptide-2 (GLP-2) plays important roles in regulating lipid handling and promoting anti-inflammatory functions in the intestine. During the postprandial state, it increases lipid absorption. During post-absorptive state, it mobilizes pre-formed chylomicrons. GLP-2 acts through vasoactive intestinal peptide (VIP) in reducing inflammation in rat ileum. However, this pathway has not yet been tested for GLP-2’s effects on intestinal lipid handling. Here, in mesenteric lymph duct cannulated rats, we examined whether VIP signaling mediates GLP-2’s effects on postprandial lipid absorption and post-absorptive lipid mobilization in the intestine. We administered a VIP receptor antagonist and analyzed lipid output in response to intraperitoneal GLP-2 or PBS during postprandial and post-absorptive states. VIP receptor antagonism reduced GLP-2 mediated lipid output in the post-absorptive state but had no effect during the postprandial state. These results show that GLP-2 functions differently during postprandial and post-absorptive states and VIP aids in GLP-2-mediated lipid output during the post-absorptive state. Full article

The Mediterranean diet (MedDiet) has emerged as a promising dietary strategy for the prevention and management of type 2 diabetes mellitus (T2DM). This narrative review provides a comprehensive synthesis linking the biological pathways of the MedDiet with established clinical evidence. Adherence to this traditional dietary pattern—characterized by a high intake of fiber, complex carbohydrates, antioxidants, and healthy fats—has demonstrated significant benefits in terms of glycemic control, enhanced insulin sensitivity, and overall metabolic health. Mechanistically, the review explains how the MedDiet improves health by modulating key physiological processes, including anti-inflammatory and antioxidant pathways, the regulation of branched-chain amino acid metabolism, the enhancement of short-chain fatty acid production via gut microbiota modulation, and upregulated incretin effects. Importantly, this review explains how the MedDiet complements modern medications, including glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter-2 (SGLT-2) inhibitors. By integrating molecular mechanisms with human clinical outcomes, this narrative review addresses multiple aspects of the MedDiet in both the prevention and management of T2DM including glycemic control, weight management, and cardiovascular risk reduction, rendering it a valuable dietary strategy for both the prevention and treatment of this chronic condition. Full article

Atrial fibrillation (AF) is the most common tachyarrhythmia worldwide. Accompanying the increasing age of the general population, as well as an increase in underlying cardiovascular disease in the United States, is an explosive rise in the incidence and prevalence of this condition. We reviewed observational cohort studies, systematic reviews, meta-analyses, and randomized controlled trials (RCTs) to determine both underlying risk factors and treatment of AF, with particular focus on comorbid conditions influencing treatment success. Numerous studies have demonstrated a reciprocal relationship between maladaptive cardiac remodeling and AF, with the suggestion that aggressive management of both AF itself and resultant cardiovascular disease can lead to reversal of both conditions. Ultimately, many modifiable risk factors for AF exist, with treatment delays associated with a shift towards these conditions becoming unmodifiable. While a large area of focus for AF research has been on determining the optimal pharmacological strategy (i.e., rate versus rhythm control), results have been mixed, with emerging guidelines now pointing towards a flexible treatment strategy that allows for consideration of patient comorbid conditions, medication ease and affordability, and patient preference. Treatment of AF also includes prevention of thromboembolic events. In recent years, novel strategies for surgical or physical occlusion of the left atrial appendage (LAA) with devices such as the Watchman have arisen. Multiple large RCTs have demonstrated the safety and efficacy of these devices, but consideration must be given towards the patient’s bleeding risk, as short-term courses of blood thinners are still considered the standard of care. Finally, emerging therapies for AF include novel drug combinations, neuromodulation devices, and potentially glucagon-like peptide receptor-1 (GLP-1) agonist medications for reduction in overall metabolic disease. Full article

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide, have demonstrated efficacy for weight loss in obesity; however, up to 40% of weight lost may derive from lean body mass. The ketogenic diet independently improves insulin sensitivity and promotes fat oxidation while preserving lean tissue. This study aimed to describe changes in body composition, insulin sensitivity, and cardiometabolic markers in patients who followed a personalized ketogenic dietary protocol while receiving low-dose semaglutide over a 6-month insulin resistance reversal program. Methods: Seven analyzed adults (six female, one male) with overweight or obesity (baseline BMI 25.6–47.2 kg/m²) participated in a clinician-supervised 6-month program combining a whole-food ketogenic diet with semaglutide (≤1.0 mg/week). Body composition and fasting metabolic markers were assessed at 1, 3, and 6 months. Results: Mean total weight loss was 21.9 kg, of which a mean of 92% was attributable to BIA-estimated fat mass. Skeletal muscle mass was largely preserved as measured by BIA (mean loss 1.2 kg), and one patient gained lean tissue. Fasting insulin declined by a mean of 15.6 µIU/mL. Visceral fat decreased by a mean of 37.0%. Six of seven patients showed reductions in high-sensitivity C-reactive protein. Triglycerides decreased in six of seven patients, and HDL cholesterol increased in all seven. LDL cholesterol responses were heterogeneous. Conclusions: In this small, uncontrolled case series, combining a ketogenic diet with low-dose semaglutide was associated with substantial fat loss, apparent preservation of lean mass as measured by BIA, and improvements in insulin sensitivity and cardiometabolic markers. Because the semaglutide dose and dietary protocol were individualized to each patient’s response, the program illustrates a personalized approach to insulin resistance. These preliminary findings are hypothesis-generating and warrant confirmation in controlled prospective studies. Full article