Search Results (147)

GLP-1 receptor agonists (GLP-1RAs), dual GLP-1/GIP agonists, and the more recent triple GLP-1/GIP/glucagon agonists have transformed the treatment of type 2 diabetes mellitus (T2DM) and obesity, resulting in significant weight reduction. However, a substantial proportion (20–40%) of this weight loss is attributable to a decrease in lean mass, thereby raising concerns regarding potential sarcopenia-related risk. However, decreased lean mass is not sufficient to determine sarcopenia, which is now defined by the combined presence of decreased muscle mass, diminished strength, and impaired physical function, particularly in older or frail individuals. Thus, a further clarification of the potential mechanisms through which these molecules affect skeletal muscle is needed to optimize their use. The objective of this study is to synthesize preclinical, metabolomic, and clinical evidence on the effects of GLP-1RAs and dual/triple agonists on skeletal muscle, with a specific comparison between semaglutide and tirzepatide. This narrative review was based on a comprehensive literature search of PubMed/MEDLINE, Scopus, and Google Scholar, encompassing articles published through June 2026. This search was supplemented by manual citation tracking, which identified additional studies including preclinical and metabolomic investigations, randomized controlled trials, observational studies, and meta-analyses. Preclinical data suggest that GLP-1R/GIPR activation can positively modulate anabolic pathways, mitochondrial biogenesis, and muscle inflammation. Metabolomic evidence reveals lipid and amino acid remodeling compatible with improved mitochondrial function. Clinically, lean mass loss proportional to weight reduction is consistently observed, generally without meaningful declines in strength or performance; data for tirzepatide are more limited. Lean mass, however, is not synonymous with skeletal muscle. A paradox emerges between the presence of protective molecular signals and the clinical evidence of lean-mass loss. This phenomenon may be explained by a systemic energy/protein deficit rather than a direct catabolic effect of the drugs, although current evidence does not fully distinguish these mechanisms. The effectiveness of weight reduction should be considered a pivotal metric in clinical practice, particularly in populations susceptible to sarcopenia. Full article

GLP-1 receptor (GLP-1R) agonists are increasingly investigated in epilepsy, but antiseizure activity, neuroprotection, and disease modification are distinct therapeutic claims. This critical narrative review with structured evidence mapping separates these claims across 21 preclinical primary publications and eight human studies identified through 6 August 2026. Selected GLP-1R-related interventions show antiseizure and anti-kindling signals, but effects vary across compounds, models, treatment timing, and seizure types; null and pro-seizure findings in absence epilepsy preclude a uniform class-wide antiseizure effect, and concurrent anti-kindling does not establish antiepileptogenesis. Neuroprotective evidence is broader, although direct neuronal or tissue preservation is demonstrated only in selected studies; many findings remain biomarker-based, and seizure reduction may itself lessen downstream injury. Evidence for durable disease modification remains suggestive rather than established. Causal support is strongest at the receptor level, whereas most downstream synaptic, inflammatory, glial, oxidative, and mitochondrial evidence remains associative. Semaglutide has high translational relevance but remains directly under-tested in epilepsy, and human evidence is predominantly observational or safety-oriented and does not establish therapeutic epilepsy efficacy. Progress requires chronic epilepsy studies with longitudinal EEG/video-EEG and baseline seizure burden, post-insult designs controlling initial-insult severity and assessing persistence after withdrawal, and linked pharmacokinetic, target-engagement, and causal mechanistic testing. Full article

Genetic variation may contribute to interindividual differences in the efficacy and tolerability of glucagon-like peptide-1 receptor agonists (GLP-1RAs), although the available evidence remains limited. Certain gene variants may underlie variability in glycemic control and weight loss outcomes among patients treated with GLP-1RAs for diabetes and/or obesity. A better understanding of these genetic variations could have significant implications for the development of personalized medicine, contributing to predicting patient responses to GLP-1RAs. Within this review, we collected and synthesized information from different studies about genetic variants that have been reported to be associated with altered therapeutic response to GLP-1RAs, mostly in GLP1R, but also in TCF7L2 and PNPLA3 genes. For the same variants, the differences obtained in the outcomes were, however, inconsistent between studies. Such disparities may partly reflect the diversity of the outcomes analyzed, the specific GLP-1RA in use, and/or the characteristics of each population. Additional genes, such as PPARD, WFS1 and VTRNA2-1, exhibited differences in at least one study. Although still limited, considering the fast expansion of the prescription of this therapeutic class, these results reflect the need for additional studies, before enabling the implementation of pharmacogenetics in clinical practice. Full article

Background/Objectives: Chronic metabolic inflammation is associated with pro-inflammatory macrophage activation and mitochondrial dysfunction. Semaglutide, a widely used GLP-1 receptor agonist, has been reported to possess systemic anti-inflammatory properties, but its action on human macrophages, especially in the context of mitochondrial regulation, remains poorly understood. The aim of the study was to evaluate the direct effect of semaglutide on macrophage polarization and to investigate the roles of cAMP signaling and mitochondrial regulation in this process. Methods: THP-1 and U-937 monocytic cell lines were differentiated into macrophages and polarized into the M1-like phenotype using LPS/IFN-γ. Cells were treated with 100 nM semaglutide in the presence or absence of the adenylyl cyclase inhibitor SQ22536. Intracellular cAMP levels, mRNA expression of macrophage markers and key regulators of mitochondrial biogenesis (SIRT1 and PGC-1α), and levels of pro- and anti-inflammatory cytokines were determined. The COX-1/SDH-A and mtDNA/nDNA ratios were analyzed as markers of mitochondrial biogenesis. Results: Semaglutide induced cAMP accumulation in M0- and M1-like macrophages derived from both cell lines. This response was significantly attenuated by GLP-1R antagonist exendin(9–39), supporting the presence of functional GLP-1R signaling. Semaglutide supplementation during inflammatory polarization resulted in reduced levels of pro-inflammatory markers (CD80/CD86, TNF-α, IL-6) and increased expression of M2-associated genes CD206 and CD163 and secretion of the anti-inflammatory cytokine IL-10. Semaglutide also increased SIRT1 and PGC-1α expression, the COX-1/SDH-A ratio, and the mtDNA/nDNA ratio, suggesting activation of processes associated with mitochondrial biogenesis. All of the effects of semaglutide described above were attenuated by SQ22536, supporting an important contribution of cAMP signaling to these responses. Conclusions: Semaglutide acts directly on human monocytic cell line-derived macrophages, attenuating the M1-like program and promoting a shift toward a less inflammatory phenotype. These effects strongly depend on cAMP signaling and are accompanied by increased expression of SIRT1 and PGC-1α and mitochondrial changes consistent with enhanced biogenesis. Full article

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

Background/Objectives: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, characterised by hyperandrogenism, ovulatory dysfunction, and metabolic disturbances. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has emerged as a promising therapeutic option for weight management and metabolic optimisation in PCOS. This scoping review evaluates the efficacy and safety of semaglutide in women with PCOS, with pre-specified primary outcomes (weight loss, metabolic parameters) and secondary outcomes (menstrual cyclicity, hormonal regulation, ovarian function, safety). Methods: A systematic literature search was conducted across four electronic databases (SciSpace Deep Search, SciSpace Full Text, Google Scholar, and PubMed) from inception through July 2026. Studies were included if they evaluated semaglutide in women with confirmed PCOS and reported outcomes related to weight loss, hormonal regulation, metabolic parameters, ovarian function, or safety. Two independent reviewers screened 356 unique records; 28 reports were assessed for eligibility, of which full-text access was confirmed for 5, and the remaining 23 were assessed using published abstracts or conference summaries. Two additional records were subsequently excluded due to unverifiable source identification, yielding a final corpus of 25 studies. The review adhered to the PRISMA-ScR reporting guidelines. Results: Twenty-five studies met the inclusion criteria. Semaglutide produced clinically relevant weight reduction (mean 7.6–11.5 kg over 3–6 months; ≥5% weight loss in approximately 80% of patients in responsive cohorts) with concurrent improvements in fasting insulin and HOMA-IR, based predominantly on observational and small-sample study designs. Improvements in menstrual regularity were reported by several studies; however, these data derive largely from conference abstracts or small pilot studies and should be interpreted cautiously. Gastrointestinal adverse events were the most frequent side effects, generally mild-to-moderate and transient. Important safety considerations include gallbladder disease, pancreatitis, and the risk of inadvertent pregnancy exposure following the potential restoration of ovulatory function; semaglutide must be discontinued before planned conception. Conclusions: Based on preliminary evidence from heterogeneous and predominantly low-quality studies, semaglutide shows potentially beneficial effects on weight, metabolic health, and menstrual regularity in women with PCOS. Confirmatory data on ovulation rates, reproductive outcomes, and long-term safety from large-scale RCTs with standardised endpoints are needed before definitive clinical recommendations can be made. 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

Background and Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly prescribed for obesity and type 2 diabetes mellitus. While these agents provide substantial metabolic benefits, concerns have emerged regarding their effects on nutritional status and potential implications for perioperative outcomes. Materials and Methods: A scoping review was conducted in accordance with PRISMA-ScR guidelines. A structured literature search was conducted from 2 May 2026 to 8 June 2026 examining GLP-1RA therapy, nutritional status, body composition and surgical outcomes. Eligible studies included investigations of postoperative outcomes associated with GLP-1RA use, nutritional and body composition effects of GLP-1RAs, associations between nutritional abnormalities and surgical outcomes, and perioperative nutritional optimisation strategies. Data were extracted and synthesised narratively. Results: Twenty studies met the inclusion criteria. Four major themes were identified: (1) nutritional and body composition changes associated with GLP-1RA therapy, (2) effects of malnutrition, sarcopenia, myosteatosis and micronutrient deficiencies on surgical outcomes, (3) postoperative outcomes associated with GLP-1RA use, and (4) perioperative nutritional assessment and optimisation strategies. GLP-1RA therapy was consistently associated with reduced energy intake, inadequate protein intake, micronutrient deficiencies and loss of lean body mass. These abnormalities overlap with recognised risk factors for adverse postoperative outcomes. Despite this, clinical studies generally reported neutral or favourable postoperative outcomes among GLP-1RA users, particularly in arthroplasty and hand surgery populations, although increased wound-healing complications were reported in selected plastic surgery cohorts. Conclusions: Current evidence suggests that GLP-1RAs do not consistently worsen postoperative outcomes; however, their use is associated with nutritional and body composition changes that may influence perioperative recovery. Nutritional assessment and optimisation may therefore represent an important component of perioperative care in patients receiving GLP-1RA therapy. Full article

GLP-1 receptor (GLP-1R) agonists, widely used for diabetes and obesity management, have shown preclinical and clinical promise as potential therapeutics for neurological conditions. Until 2026, all U.S. Food and Drug Administration (FDA)-approved GLP-1 drugs were peptide-based, with most requiring daily or weekly subcutaneous injections. Despite their large size and low brain penetrance, several peptide-based GLP-1 drugs are in clinical trials for neurologic indications. Recently, the FDA approved orforglipron as the first small-molecule, non-peptide, orally bioavailable human GLP-1 receptor agonist, and it may offer advantages over peptide-based counterparts. We hence evaluated whether it possesses similar neurotrophic, neuroprotective, and anti-inflammatory attributes. Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties. Orforglipron activated cAMP signaling and shielded neuronal cells from excitotoxic glutamate and oxidative stress, which are common in neurodegenerative diseases and injuries. Additionally, orforglipron effectively mitigated LPS- and glutamate-induced proinflammatory protein secretion (IL-6, IL-8, and MCP-1) from a human microglial cell line. Actions were replicated under insulin resistance—a potential cause of neurodegenerative conditions—in which orforglipron significantly upregulated phosphorylation of protein kinase B (Akt), providing an additional neuroprotective mechanism. Measured orforglipron brain uptake in rat was low (brain/plasma and CSF/plasma ratios: 0.0078), and in the ballpark of peptide-based GLP-1 drugs. Nevertheless, orforglipron may provide potential value in specific neurological conditions. Full article

Background: Endometrial cancer (EC) is one of the most prevalent cancers in women globally, which has recently gained attention as an increase has been noted among premenopausal women. Improving fertility-sparing treatments is crucial to assist women in completing their family planning. Methods: This study aims to explore the current evidence on the mechanisms of action and correlation between Glucagon-like Peptide-1 (GLP-1) and its agonists with EC, as well as the potential application in the conservative therapy for early-stage EC. A narrative review of the worldwide literature was conducted according to Scale for the Assessment of Narrative Review Articles (SANRA) principles, intending to analyze the correlation of GLP-1 receptor agonists (GLP-1RAs) with EC and their precise effect in the fertility-sparing treatment in women with atypical endometrial hyperplasia (AEH) or early-stage EC. Results: Preclinical studies indicate that GLP-1 receptor (GLP-1R) expression on healthy and malignant endometrial tissues of models regulates apoptosis via the AMPK-mTOR pathway. Observational and early clinical studies conclude that their role in the improvement of metabolic and hormonal imbalance increases the risk for the development of EC, as well as anti-tumour and anti-inflammatory effects. Conclusions: GLP-1RAs represent a potentially promising addition to the conservative management of AEH and early-stage EC in premenopausal women; however, further extensive clinical trials are required to ensure their safety and efficacy in future treatment algorithms and preconception exposure. Full article

Background: Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP-1R) activation exert anti-diabetic and anti-obesity effects. Tirzepatide, a dual GIPR/GLP-1R agonist, has demonstrated cardiovascular benefits in clinical studies. However, the direct vascular actions of tirzepatide and their potential advantages over selective GLP-1 receptor agonists (GLP-1RAs) remain unclear. We investigated the vasoprotective effects of tirzepatide and compared them with those of GLP-1 receptor agonists in vivo and in vitro. Methods: Non-diabetic C57BL/6 and diabetic KK-Ay mice received tirzepatide, semaglutide, or vehicle. Arterial remodeling was induced by femoral artery wire injury. A subset of mice was co-treated with the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). After 4 weeks, biochemical, morphometric, and immunofluorescence analyses were performed. In vitro, human umbilical vein endothelial cells (HUVECs) were stimulated with tirzepatide or liraglutide to assess nitric oxide (NO) production. Results: In non-diabetic mice, tirzepatide suppressed intimal hyperplasia, including at a low dose that did not affect metabolic parameters, whereas semaglutide had no significant effect on intimal hyperplasia at the same molar dose. The protective effects of tirzepatide were abolished by L-NAME. In diabetic mice, tirzepatide and semaglutide similarly improved metabolic parameters and attenuated intimal hyperplasia. In HUVECs, tirzepatide increased NO production in a dose-dependent manner, and this effect was preserved under hyperglycemic conditions. Tirzepatide and liraglutide induced comparable NO production at equivalent molar concentrations. Conclusions: Tirzepatide, but not semaglutide, exerted vasoprotective effects under non-diabetic conditions in a NO-dependent manner, whereas both agents exhibited comparable vasoprotective effects under diabetic conditions. Full article

Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, have revolutionized the management of type 2 diabetes and obesity. Recent evidence suggests these agents may influence athletic performance through effects on body composition, energy metabolism, and cardiovascular function. This narrative review critically evaluates whether incretin therapies could constitute doping under World Anti-Doping Agency (WADA) criteria. We narratively reviewed the literature on incretin pharmacology, metabolic effects relevant to athletic performance, and anti-doping regulations, searching PubMed, Scopus, and Web of Science using terms including “GLP-1 receptor agonists”, “DPP-4 inhibitors”, “doping”, “athletic performance”, “WADA”, and “sports pharmacology”, without date restrictions. GLP-1 RAs (semaglutide, liraglutide, tirzepatide, exenatide) induce substantial weight loss (predominantly fat mass) but also reduce lean mass by 20–30% of total weight loss. Preclinical studies demonstrate enhanced exercise endurance, mitochondrial biogenesis, and glucose uptake via GLP-1R/AMPK signaling. However, clinical trials show no consistent improvement in physical performance in humans. Currently, incretin therapies are not listed on the WADA Prohibited List. While incretin therapies offer theoretical performance-enhancing potential through weight management and metabolic optimization, current evidence does not support classification as doping agents. Continued surveillance is warranted as misuse patterns emerge. Full article

Background: Obesity is a chronic, relapsing disease that often proves resistant to lifestyle measures alone. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are reshaping treatment, yet prospective real-world data remain limited. Objective: To prospectively assess the effects of once-weekly Semaglutide on weight, body composition, and metabolic health in obesity. Methods: An exploratory observational study of 37 patients initiating Semaglutide (mean age 31 years; 11 children and adolescents; 22 females) was conducted. All met obesity criteria (baseline BMI 34.7 kg/m²). Anthropometry, bioimpedance body composition, and fasting biochemistry were obtained at baseline and 3 months. Variables were reported as mean ± SD or median (IQR) according to normal/non-normal distribution, whether a parametric test or a Wilcoxon one was used. Parametric or non-parametric paired tests (two-sided α = 0.05) were applied. We also explored tri-ponderal mass index (TMI, kg/m³) and its correlations with metabolic markers. Results: At 3 months, body weight decreased by a median 8.0 kg (p < 0.001), BMI by 1.6 kg/m² (p < 0.001). Body fat percentage declined: 43.4% to 42.8% (p = 0.009), with a small reduction in skeletal muscle mass (−0.6 kg; p = 0.035). Fasting glucose improved (p = 0.030) and HOMA-IR fell significantly. HbA1c changes were minimal, consistent with near-normal baseline values. Triglycerides decreased, while total cholesterol, LDL-C, HDL-C, liver enzymes, creatinine, uric acid, and 25-OH vitamin D remained stable. Baseline TMI (median 20.13 kg/m³; IQR 3.80) correlated strongly with HOMA-IR (r = 0.766, p < 0.001) and moderately-to-strongly with body fat percentage (r = 0.621, p < 0.001). Conclusions: In this real-world cohort, Semaglutide produced rapid, clinically meaningful improvements in weight, adiposity, and insulin resistance within 3 months. Findings suggest that Semaglutide may represent a promising adjunct to lifestyle therapy in obesity management. Full article

GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes and obesity and are increasingly relevant in periodontal and implant practice. This review covers mechanisms, preclinical and early human evidence, and practical periodontal considerations; the structured database search is conducted in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA) and the International Committee of Medical Journal Editors (ICMJE) principles. Two pathways explain GLP-1RAs’ relevance: indirect effects from better glycemic control, weight loss, and reduced inflammation; and direct tissue effects involving GLP-1R signaling and the GLP-1/dipeptidyl peptidase-4 (DPP-4) axis. Preclinical studies show reduced inflammation, osteoclast activity, and alveolar bone loss, along with improved periodontal stem cell function under hyperglycemia or inflammation via Nuclear Factor-kappaB (NF-kappaB), Wingless-related integration site (Wnt)/beta-catenin, and Mitogen-Activated Protein Kinase (MAPK) pathways. Animal studies on implants and local delivery, including exendin-4 platforms, suggest osteometabolic benefits. Human data are limited and mostly observational, and confounders include metabolic status, smoking, medication, and nutrition. Oral side effects such as xerostomia and dehydration are also noted. At present, GLP-1RA therapy should be regarded as a contextual modifier of periodontal risk and healing capacity rather than as a stand-alone periodontal therapy. Full article

Objective: Insulin resistance is a key pathophysiological driver linking obesity and type 2 diabetes (T2D) with cardiovascular risk. Composite surrogate indices derived from routine clinical parameters, such as the Metabolic Score for Insulin Resistance (METS-IR) and the Single Point Insulin Sensitivity Estimator (SPISE), may provide a practical means of capturing multidimensional metabolic changes. Given that comparative data are limited, we aimed to evaluate the effects of sodium–glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) on these indices in individuals with T2D and overweight or obesity. Methods: In this retrospective observational study, 100 individuals with T2D treated with either GLP-1RA (n = 54) or SGLT2i (n = 46) were evaluated over 6 months. Strict inclusion criteria ensured treatment stability without initiation or modification of concomitant pharmacotherapy. Changes in METS-IR and SPISE were assessed alongside body mass index (BMI) and glycated hemoglobin (HbA1c). Multivariable regression and exploratory analyses, including stratification by BMI and correlation analyses, were performed. Results: Both treatment groups demonstrated significant improvements in METS-IR (GLP-1RA: −3.9 ± 5.9; SGLT2i: −2.5 ± 2.6; both p < 0.001) and SPISE (GLP-1RA: +0.46 ± 0.52; SGLT2i: +0.44 ± 0.61; both p < 0.001), with no significant between-group differences. In the GLP-1RA group, changes in METS-IR correlated with changes in BMI (r = 0.48, p < 0.001) and HbA1c (r = 0.29, p = 0.030), whereas no significant correlations were observed in the SGLT2i group. Stratified analyses indicated greater reductions in METS-IR among individuals with BMI ≥30 kg/m² treated with GLP-1RA. Conclusions: Both SGLT2i and GLP-1RA improve composite surrogate markers of insulin resistance, with distinct associations with weight and glycemic changes. METS-IR and SPISE may serve as practical tools for monitoring multidimensional metabolic responses in clinical practice. Full article