Diabetes, Obesity and Metabolism

Importance Women have been under-represented in clinical trials of type 2 diabetes mellitus (T2D), and evidence on sex differences in effectiveness of T2D treatments remains limited. Objective To assess sex differences in comparative effectiveness and safety of four second-line antidiabetic agents: glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), and sulfonylureas (SU). Design Retrospective cohort study using an active-comparator new-user design, following each participant till treatment discontinuation or end of data. Setting Multinational study across ten real-world databases from the Observational Health Data Sciences and Informatics (OHDSI) network in the United States, United Kingdom, Germany, and Spain. Participants 5.15 million adults with T2D who initiated one of the four second-line therapies following metformin during 1992-2021. Exposures GLP-1RA, SGLT2i, DPP4i, or SU. Main Outcomes and Measures Cardiovascular effectiveness as measured through 7 outcomes (major adverse cardiovascular events and glycemic control) and safety through 18 outcomes as highlighted by ADA guideline. Hazard ratios (HRs) are estimated separately for women and men using propensity score-stratified Cox models with empirical calibration. Sex differences were tested using Z-tests on log-HR differences. Results Drug initiation rates differed by sex with 9.28% of women initiating on GLP-1RA, 11.91% SGLT2i, 27.81% DPP4i, and 50.99% SU; the rates among the men were 5.41%, 12.84%, 24.64%, and 57.10%. No significant sex differences were observed for cardiovascular effectiveness outcomes. Several safety outcomes showed significant sex differences that are consistent across drug comparisons. Focusing on GLP-1RA compared to SGLT2i for brevity, GLP-1RA users experienced the following comparative benefits and risks: higher risk of acute pancreatitis among women (HR 1.39 [1.13, 1.70]) while non-differential risk among men (HR 0.91 [0.74, 1.12]) with p = 0.005 for the test of difference; non-differential risk of hypotension among women (HR 1.08 [0.98, 1.19]) while lower risk among men (HR 0.87 [0.78, 0.96]) with p = 0.003. Where no sex differences were found, our findings were consistent with existing evidence. Conclusions and Relevance This large-scale multinational study on antidiabetic agents identified clinically relevant sex differences, which are biologically plausible but previously lacked clinical evidence. Our findings reinforce the importance of tailoring T2D management according to sex.

PurposeTo investigate the association between glucagon-like peptide-1 receptor agonist (GLP-1RA) use and nonarteritic anterior ischaemic optic neuropathy (NAION) in type 2 diabetes, examining treatment recency and cumulative duration. MethodsThis nationwide registry-based nested case-control study utilised Danish health registries (1996-2023). Among 201,776 metformin-treated adults initiating second-line antihyperglycaemic therapy, 123 incident NAION cases were matched to 4,920 controls by birth year and sex (incidence-density sampling). Conditional logistic regression estimated adjusted hazard rate ratios (HRs) for GLP-1RA exposure by recency (current 0-90 days; recent 91-365 days) and cumulative duration, adjusting for socioeconomic factors, hypertension, hypercholesterolaemia, sleep apnoea, and diabetes duration. ResultsGLP-1RA use occurred in 63/123 cases (51.2%) and 1,688/4,920 controls (34.3%). Ever use was associated with a higher NAION rate than other second-line therapies (HR 2.13, 95% CI 1.43-3.18). Current use was associated with elevated rates (HR 2.28, 95% CI 1.49-3.48), whereas the estimate for recent use was imprecise (HR 1.69, 95% CI 0.88-3.25). By cumulative duration, no clear evidence of an increase was seen within 0-[1/2] years (HR 0.80, 95% CI 0.32-2.05), and rates were highest at [1/2]-1 year (HR 3.63, 95% CI 2.06-6.40) and 1-1[1/2] years (HR 3.52, 95% CI 1.73-7.17). Findings were consistent after HbA1c adjustment and in a new-user analysis. ConclusionGLP-1RA use is associated with a higher NAION rate in type 2 diabetes. This association appears time-dependent, being most pronounced during current treatment and peaking after 6-18 months of cumulative exposure.

Importance: Glucagon like peptide 1 receptor agonists (GLP 1 RAs) and dual glucose dependent insulinotropic polypeptide/glucagon like peptide 1 receptor agonists have demonstrated what may be considered transformative efficacy in recent randomized clinical trials for the treatment of obesity, yielding substantial weight loss in a majority of participants. However, the extent to which these trial results translate into routine clinical practice particularly within the rapidly expanding direct to consumer (DTC) telehealth sector serving self pay populations remains insufficiently characterized. As access to and affordability of these therapies broaden beyond traditional insurance based care models, evaluating real world effectiveness, safety, and patient engagement among individuals shouldering the full financial cost of treatment is essential for informing future models of obesity care delivery. Objective:To assess long term medication specific weight loss outcomes, including gender specific responses and discrepancies, and explore usage trends in a real world, self pay telehealth cohort receiving GLP 1 RA therapy, using an Observational study design (Retrospective data analysis). Setting and Participants:Retrospective data of patients enrolled in electronic health records (EHR) from Carevalidate, a national US telehealth platform provider for Online TeleHealth companies. The data collected ranged for a total of 703 days from January 12, 2024, to December 15, 2025. The analysis included 572 adults with overweight or obesity diagnosis who initiated treatment with semaglutide or tirzepatide and completed a minimum of 9 months of active follow up. Patients with insufficient follow up or those utilizing insurance coverage were excluded to isolate the self pay phenotype. Exposures: Prescription of semaglutide or tirzepatide (injectable or oral formulations) via synchronous or asynchronous telehealth consultations, titrated according to standard clinical protocols adapted for patient tolerance and financial sustainability. Main Outcomes and Measures: The primary outcome was percentage total body weight loss (%TBWL) from baseline to the last recorded encounter. Secondary outcomes included categorical responder rates (5%, 10%, 15%, >20% weight loss), weight loss velocity analysis, and telehealth utilization metrics (frequency of encounters and visit intervals) including gender differences in approaching the telehealth program. Results: The final analytical cohort included 572 patients (79.2% female; 20.8% male). Overall, 95.8% (548/572) achieved weight loss, while 3.7% experienced weight gain. At 12 months, the mean %TBWL was 13.8% for the semaglutide cohort (n=450) and 12.5% for the tirzepatide cohort (n=122), with no statistically significant difference between the two medications (P >.05), contrary to standard clinical trial data suggesting tirzepatide superiority. A significant gender difference was observed: females were significantly more in number comprising 80% of the cohort and were likely to be "major responders" (>20% weight loss) compared to males (29.8% vs 5.9%; P <.001). Conversely, males demonstrated significantly higher utilisation rates, attending more frequent encounters (mean 13.5 vs 12.7; P =.028) with shorter intervals between visits (35.6 vs 44.1 days; P =.009) compared to females. Weight loss velocity for both medications peaked during months 1 to 3 (~1.07 lbs/week) and declined substantially by months 12 to 15, indicating a plateau effect independent of the specific agent used. Conclusions and Relevance: Telehealth-managed GLP 1 treatment in a self pay population demonstrates high efficacy comparable to clinical trials for semaglutide. However, tirzepatide outcomes fell short of trial benchmarks, likely due to economic barriers preventing optimal dose titration and lower sample size. The study identifies a discrepancy where females approach the telehealth based self pay system more but males engage more frequently with the digital platform which could be due to inferior physiological outcomes ( less weight loss and more non responders) compared to females.This suggests that while telehealth is a viable model for long term obesity care, the "one size fits all" approach may be insufficient for under responders, who may require distinct titration strategies or tailored behavioral interventions to overcome baseline genetic and biological resistance.

BackgroundGLP-1 receptor agonists (GLP-1RAs) and SGLT2 inhibitors (SGLT2Is) have established cardiovascular benefits for patients with type 2 diabetes mellitus (T2DM), with similar class-level effectiveness found in previous studies. However, real-world comparative effectiveness assessments of individual agents remain limited. ObjectivesTo compare the cardiovascular effectiveness of individual GLP-1RAs and SGLT2Is. MethodsWe conducted a multi-national, retrospective, new-user active-comparator cohort study using 10 US and non-US administrative claims and electronic health record databases. The study included 1,245,211 adults with T2DM receiving metformin who initiated second-line therapy with one of six GLP-1RAs (albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide) or one of four SGLT2Is (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin). Empagliflozin (393,499; 31.6%), semaglutide (235,585; 18.9%), dapagliflozin (208,666; 16.8%), and dulaglutide (207,348; 16.8%) were most commonly used. A secondary subgroup analysis included 316,242 patients with established cardiovascular diseases (CVD). Primary outcomes were 3-point major adverse cardiovascular events (MACE: acute myocardial infarction, stroke, sudden cardiac death) and 4-point MACE (adding hospitalization/ER visit with heart failure). Secondary outcomes included the individual components. Hazard ratios (HRs) were estimated for pairwise agent comparisons while on-treatment (per-protocol) and over total follow-up using Cox proportional hazards models, with propensity score adjustments, negative control calibration, and pre-specified study diagnostics to guard against potential confounding. Random-effects meta-analysis produced summary HR estimates across data sources that passed diagnostics. ResultsAcross the study cohort, individual GLP-1RAs and SGLT2Is demonstrated broadly similar cardiovascular effectiveness, both within and across drug classes. For example, semaglutide and empagliflozin showed comparable risks for 3-point MACE (meta-analytic HR 1.05; 95% CI 0.79-1.39) and 4-point MACE (meta-analytic HR 0.95; 95% CI 0.81-1.12), with consistent findings in the CVD subgroup. Study diagnostics confirmed adequate equipoise, covariate balance and statistical power to detect similarity in HRs between 0.8 and 1.2 for commonly used agents. ConclusionsIn this large-scale real-world study, individual GLP-1RAs and SGLT2Is exhibited largely comparable cardiovascular benefits, including in patients with established CVD. These findings align with network meta-analytic estimates from major cardiovascular outcome trials and broadly support current treatment guidelines. Clinical choices should be guided by relevant factors such as safety, adherence, tolerability, cost, and patient preference, where further work is needed.

ImportanceSemaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is a highly effective medication to treat type 2 diabetes and obesity. However, concerns about potential suicidality persist, creating clinical uncertainty about its neuropsychiatric safety. ObjectiveTo assess risks of suicidality after initiating semaglutide compared to initiating SGLT2i and by duration of continuous semaglutide treatment. DesignActive-comparator, new-user target trial emulation to estimate inverse probability-weighted marginal cause-specific hazard ratios (HRs). For duration-of-treatment analyses, we used clone-censor-weight methods to estimate exposure-adjusted effects. SettingVeterans Health Administration. ParticipantsU.S. Veterans with type 2 diabetes receiving care from March 1, 2018 to September 1, 2025. ExposureInitiation of semaglutide vs SGLT2i; duration of semaglutide use ([&le;]6, 7-12, >12 months). OutcomesIncident suicidal ideation; suicide attempt or death; and a composite outcome. ResultsA total of 102,361 Veterans met inclusion criteria, including 11,478 new initiators of semaglutide and 90,883 new initiators of an SGLT2i. After overlap weighting, baseline characteristics were well balanced between treatment groups (mean [SD] age, 60.1 [11.7] years; BMI, 37.8 [6.8] kg/m2; hemoglobin A1c, 7.0% [1.4]; 85.5% male; 61.9% non-Hispanic White). During a median follow-up of 2.2 years, 9077 incident suicidal ideation events and 696 suicide attempts or deaths occurred. The incidence rate of suicidal ideation was 56.3 and 37.7 per 1000 person-years among semaglutide initiators and SGLT2i initiators, respectively (hazard ratio [HR], 0.99; 95% CI, 0.93-1.06; P = 0.86). For suicide attempts or deaths, the incidence rates were 4.30 and 2.64 per 1000 person-years, respectively (HR, 1.05; 95% CI, 0.84-1.31; P = .86). In adherence-adjusted analyses, sustained semaglutide treatment for more than 12 months, compared with 6 or fewer months, was associated with a 74% lower risk of suicide attempts or deaths (HR, 0.27; 95% CI, 0.14-0.54; P<.001). ConclusionAmong U.S. Veterans with type 2 diabetes, initiators of semaglutide were not observed to have an increased risk of suicidality compared with initiators of SGLT2i. Those with longer semaglutide treatment (beyond 12 months) had decreased risk of suicide attempt or death, suggesting longer term treatment is safe and may protect against for those outcomes.

This updated systematic review and network meta-analysis evaluated the efficacy and safety of obesity management medications (OMMs) in terms of reducing body weight and obesity related complications. Medline and Embase were searched up to 21 November 2025 for randomized controlled trials comparing OMMs versus placebo or active comparators in adults. The primary endpoint was percentage total body weight loss (TBWL%) at the end of the study. Secondary endpoints were TBWL% at 1, 2 and 3 years, anthropometric, metabolic, mental health and quality of life outcomes, cardiovascular morbidity and mortality, remission of obesity related complications, serious adverse events and all cause mortality. Sixty six RCTs (66 comparisons) were identified: orlistat (22), semaglutide (18), liraglutide (11), tirzepatide (8), naltrexone/bupropion (5) and phentermine/topiramate (2), enrolling 63,909 patients (34,861 and 29,048 with active compound and placebo, respectively). All OMMs showed significantly greater TBWL% versus placebo; tirzepatide and semaglutide exceeded 10% TBWL and showed the most favourable glycaemic effects. Semaglutide reduced major adverse cardiovascular events and all cause mortality. In dedicated complication specific trials, semaglutide and tirzepatide showed benefit on heart failure related outcomes; tirzepatide was associated with improved obstructive sleep apnoea syndrome and semaglutide with knee osteoarthritis pain remission. Tirzepatide and semaglutide were associated with improvements in metabolic dysfunction-associated steatohepatitis remission, and semaglutide with improvement in liver fibrosis. No OMMs were associated with an increased risk of serious adverse events. These updated results reinforce the need to individualize OMMs selection according to weight loss efficacy, complication profile and safety.

Background: Obesity has become increasingly common among US adults with hypertension. However, national data are limited on weight-loss efforts among adults with hypertension and overweight/obesity, and whether these efforts have translated into clinically meaningful weight loss at the population level. Methods: We analyzed repeated cross-sectional data from the National Health and Nutrition Examination Survey, 1999-2023. Adults aged 20 years with hypertension and body mass index 25 kg/m2 were included. Weight-loss attempt was defined as self-report of trying to lose weight during the prior 12 months. Among those attempting weight loss, successful weight loss was defined as 5% or 10% reduction in body weight over the prior year. Survey-weighted logistic regression was used to assess temporal trends and associations between strategies and successful weight loss. Results: Overall, 57.6% reported a weight-loss attempt, increasing from 55.9% in 1999-2000 to 60.4% in 2021-2023 (P for trend=0.002). The most reported strategies were eating less food (65.3%) and exercise (52.4%). Among those attempting weight loss, 33.4% achieved 5% weight loss and 14.7% achieved 10% weight loss; neither improved over time (P for trend=0.976 and 0.174, respectively). Weight-loss surgery was strongly associated with success but was rarely reported (0.35%). Eating less fat and changing eating habits were also positively associated with successful weight loss, whereas skipped meals and use of diet foods or products were inversely associated. Conclusions: Weight-loss attempts increased, but clinically meaningful weight-loss success did not improve, highlighting a persistent gap between effort and outcome in hypertension care.

GLP-1 receptor agonist (GLP-1RA) discontinuation has been associated with weight regain. However, the real-world association between discontinuation of GLP-1RA prescriptions and weight change has not been explored. We assessed weight trajectories of 4,182 patients in the six months following their last GLP-1RA prescription. Approximately two-thirds of patients showed stable weight or continued weight loss during this period post the last known GLP-1RA prescription. In a representative subset of patients with clinician-documented discontinuation near the last prescription (N=300), a similar distribution of weight regain in a minority of patients was observed vs no regain in the majority of patients during the six-month post-GLP-1RA prescription period. To mirror clinical trial-style discontinuation definitions, we also evaluated cohorts with no subsequent GLP-1RA prescription for 1 year after the last prescription (semaglutide N=1,755; tirzepatide N=1,312), observing weight regain in a minority of patients (39.3% semaglutide; 26.6% tirzepatide) and no weight regain in the majority (60.7% semaglutide; 73.4% tirzepatide) in the year following the last known GLP-1RA prescription. Exercise counseling was documented more frequently among patients with durable weight loss post-last GLP1 prescription compared with those with weight regain (26.2% vs. 14.7%; p=0.04). Further studies are warranted to infer the mechanisms underlying these real-world patterns.

Objectives To estimate population-level eligibility for glucagon-like peptide-1 receptor agonist (GLP-1RA) medications among adults in Australia, according to Therapeutic Goods Administration (TGA) approved indications for chronic weight management and secondary prevention of cardiovascular disease. Design Cross-sectional analysis of data from the Australian Bureau of Statistics 2022 National Health Survey. Setting, Participants Non-pregnant adults [&ge;] aged 18 years who are usual residents of Australia and living in a private dwelling. Main outcome measures Total number of adults who are eligible for GLP-1RA medications according to TGA approved indications for chronic weight management and secondary prevention of cardiovascular disease, across subgroups defined by body mass index, weight-related comorbidities, and/or socio-demographic factors. Results In total, 39.7% (95% CI 38.4 - 41.0%) of adults in Australia are eligible for GLP-1RA use for chronic weight management, accounting for 7.8 million (95% CI, 7.6 - 8.1 million) individuals. Among those eligible under this indication, 2.9 million (95% CI 2.7 - 3.1 million) adults had no weight-related comorbidities, 3.3 million (95% CI 3.1 - 3.4 million) adults had at least 1 weight-related comorbidity, and 1.7 million (95% CI 1.6 - 1.8 million) adults had at least 2 weight-related comorbidities. The proportion of adults eligible under this indication varied across clinical and sociodemographic factors. Among those eligible under the chronic weight management indication, up to 338.9 thousand (95% CI 271.3 - 406.5 thousand) adults also meet the indication for secondary prevention of cardiovascular disease. Conclusions More than one third of Australian adults are eligible to access GLP-1RAs for chronic weight management, with 3.7-4.3% of adults also qualifying according to the indication for established cardiovascular disease. This study provides a valuable reference to allow policy makers to understand the number of adults in Australia that may benefit from access to GLP-1RA medications under a range of coverage scenarios.

ObjectiveTo introduce and evaluate the clinical utility of the "adipo-B index" as a novel metric of the adipose tissue-pancreatic beta cell axis. To our knowledge, no prior clinical metric has integrated adipose tissue insulin resistance and pancreatic beta-cell function into a single index applicable across therapeutic classes. MethodsTreatment-naive subjects with T2DM received monotherapy with modified traditional diet for diabetes (MJDD, n=61), canagliflozin (n=67), pioglitazone (n=54), or sitagliptin (n=63). Correlations between the baseline and changes in adipo-IR or adipo-B and clinical parameters were analyzed. This is a prospective, non-randomized observational study. ResultsAt baseline, among all the subjects, adipo-B significantly correlated with FBG, HbA1c, non-HDL-C and BMI, while adipo-IR did not. At 3 months, across all therapeutic strategies, significant negative correlations were observed between the changes in ({Delta})adipo-B and baseline adipo-B. By contrast, in MJDD, canagliflozin and pioglitazone, significant negative correlations were seen between {Delta}adipo-IR and baseline adipo-IR, while with sitagliptin, no correlations were noted. {Delta}adipo-B, but not {Delta}adipo-IR, correlated with the improvements of glycemic (FBG, HbA1c) and lipid (non-HDL-C) parameters across all these therapies. While significant correlations were seen between {Delta}adipo-B and {Delta}adipo-IR with MJDD, pioglitazone and sitagliptin, canagliflozin uniquely "decoupled" this axis. With sitagliptin and pioglitazone, adipo-B improved despite weight gain. ConclusionThe adipo-B index is a superior indicator of systemic metabolic status and therapeutic response and could serve as a useful tool for precision therapy for diabetes.

SGLT2 inhibitor (SGLT2i)-induced diabetic hyperketonemia is a life-threatening acute complication of diabetes. While Celastrol has been reported to exert beneficial effects on obesity; its potential role in ketogenesis remains unclear. In this study, Celastrol administration significantly attenuates the fasting-induced elevation of blood {beta}-hydroxybutyrate. Moreover, a 7-day course of Celastrol (1 mg/kg/day) leads to reductions in body weight and fat mass. Mechanistically, Celastrol specifically downregulates HMGCS2 expression and suppressess hepatic ketogenesis through inhibiting PPAR expression in the short term ([&le;] 2 days). However, after prolonged treatment for 7 days, Celastrol modulates both PPARand serum free fatty acids (FFAs) levels. Furthermore, anti-ketogenic effect of Celastrol is abolished in Ppar{square} /{square} mice. Importantly, Celastrol effectively ameliorates SGLT2i-induced hyperketonemia. In summary, Celastrol curbs hepatic ketone overproduction in a PPAR-dependent manner, indicating its protective potential against SGLT2i-induced hyperketonemia.

GLP-1 receptor agonists (GLP-1 RAs) are effective in delaying progression of chronic kidney disease in individuals with type 2 diabetes mellitus (T2DM). We evaluated whether GLP-1 RA prescription is associated with reduced nephrotoxicity in adults receiving long-term lithium therapy. We conducted a retrospective, propensity score-matched cohort study using electronic health records from the TriNetX global network, which includes de-identified data from over 127 million patients across 109 healthcare organizations. The study population consisted of adults aged [&ge;]18 years with T2DM, with lithium exposure within the 2 years preceding the index date and at least one prescription for a GLP-1 RA. The primary efficacy outcome was the rate of renal nephrotoxicity in persons with T2DM prescribed lithium and a GLP-1 RA versus those with T2DM prescribed lithium but no GLP-1 RA or other antidiabetic agents. Nephrotoxicity was a composite of ICD-10 and CPT-coded renal disease. Incidence and time-to-event outcomes were assessed using Kaplan-Meier curves and Cox proportional hazards models. In our 24-month analysis, 462 matched patient pairs were included. Initiation of a GLP-1 RA during lithium therapy was associated with a lower incidence of renal events versus lithium alone (6{middle dot}1% vs 10{middle dot}4%), corresponding to a risk difference of -4.3% (95% CI -7{middle dot}86 to -0{middle dot}80), a risk ratio of 0{middle dot}58 (95% CI 0{middle dot}37-0{middle dot}91; p=0{middle dot}017), and higher event-free survival (89{middle dot}0% vs 83{middle dot}2%; log-rank p=0{middle dot}037). GLP-1 receptor agonist therapy was associated with a reduction in reports of lithium-associated nephrotoxicity. Our findings provide impetus to conduct mechanistic renal histopathologic studies combining GLP-1 RAs with lithium.

ObjectivesAn update to the NICE Type 2 diabetes (T2DM) guideline in February 2022 recommended an SGLT2 inhibitor be offered to people with cardiovascular disease (CVD) or heart failure (HF) as comorbidities and considered for people at high CVD risk. We report uptake of this guideline in England 18 months after its publication. DesignObservational cohort study. SettingGeneral practices contributing to the Clinical Practice Research Data Link, linked to hospital admission records. Participants587,826 people aged over 18 years with T2DM on 1st September 2023, stratified according to their CVD category (CVD only; HF only; CVD and HF; high CVD risk score; low CVD risk score) and chronic kidney disease (CKD) status, and further by age, gender, ethnicity, deprivation, and T2DM diagnosis duration. Main outcome measuresPercentage of patients with a current SGLT2 inhibitor prescription; odds ratios for association between patient characteristics and a current prescription. ResultsIn people with T2DM, the percentage with a current SGLT2 inhibitor prescription was 19.5% for people with CVD, 29.4% for people with HF, 30.5% for people with both CVD and HF, and 19.9% and 20.2% respectively for people at high and low CVD risk. In age-stratified analyses, uptake ordered from lowest to highest was as follows: low CVD risk score, high CVD risk score, CVD only, HF only, CVD and HF. In models adjusted for clinical and patient characteristics uptake was lower in people aged >60, women, Black people, and people living in areas of higher deprivation. ConclusionsWhilst prescribing of SGLT2 inhibitors continues to rise in England, an opportunity remains to increase uptake and to reduce inequalities in people with T2DM in 2026. We report inequalities by ethnicity and deprivation, and lower uptake for people with CVD without HF than people with HF, despite an equal guideline recommendation for these two groups. Additional evidence is needed on the effectiveness of SGLT2 inhibitors in frailer populations. What is already known on this topic?O_LIIn 2020 approximately 10% of people with type 2 diabetes (T2DM) and cardiovascular disease (CVD) and 14% of people with T2DM but without CVD in England had a current SGLT2 inhibitor prescription. C_LIO_LIIn February 2022 NICE recommended that an SGLT2 inhibitor should be offered to people with T2DM with heart failure or CVD, and considered for people with T2DM at high risk of CVD; network meta-analyses have found 10% to 40% lower odds of cardiovascular mortality with treatment in these groups. C_LIO_LIUptake of NICE guidelines in general practice has historically been variable, although higher when accompanied by pay-for-performance schemes such as the Quality and Outcomes Framework. C_LI What this study addsO_LIBy September 2023 the percentage of people with T2DM with a current SGLT2 inhibitor prescription had reached 19.5% in those with CVD as a comorbidity, 30.5% in those with heart failure, and 19.9% in those at high risk of CVD. C_LIO_LIWomen, people of Black ethnicity, and people living in areas of high deprivation had lower odds of a current prescription in analyses adjusted for age, gender, cardiovascular comorbidity, and renal function. C_LI How might these results change the focus of research or clinical practice?O_LIThe results highlight the need for ongoing surveillance of uptake of NICE-recommended treatments for T2DM, and consideration of actions to address barriers to uptake. This is particularly important in the context of broader eligibility for SGLT2 inhibitor treatment in type 2 diabetes in England from 2026. C_LIO_LIThese results support the development of initiatives and quality improvement programmes to improve evidence-based prescribing and address inequalities between clinical and demographic subgroups. C_LI

BackgroundPET-CT scans of radioactive exendin-4, a ligand of the GLP-1 receptor, are claimed to provide a biomarker of pancreatic beta cell mass (BCM), although the GLP-1 receptor is expressed also in the exocrine pancreas (PX). Parotid glands may be a reference tissue for GLP-1 receptor expression in exocrine cells of the GI system. Our aims were 1. To assess biomarker(s) of BCM derived from 68Ga-NODAGA-exendin-4 PET-CT scans in participants with long-standing type 1 diabetes (T1DM) or in subjects with obesity (OBESE); 2. To investigate the relationship between biomarker(s) of BCM and a biomarker of beta cell functional mass (BCFxM) in OBESE. MethodsT1DM (n=8, Age: 50.4{+/-}3.8 yrs; T1DM duration: 34.2{+/-}3.0 yrs; BMI: 26.6{+/-}1.1 kg/m2; HbA1c: 7.5{+/-}0.36%) and OBESE (n=9; Age:48.2{+/-}2.2 yrs; BMI: 37.4{+/-}1.1 kg/m2; HbA1c: 5.4{+/-}0.17%) underwent two studies: 1) 68Ga-NODAGA-exendin-4 PET-CT scan of both PX and parotid glands 45-60 after i.v. injection and with CT-assessment of PX volume to compute biomarkers of BCM based on SUV (BCMSUV) or clearance (CLEAR; BCMCLEAR); 2) Mixed meal test (MMT), with measurement of plasma glucose, C-peptide, GLP-1 and GIP curves to assess BCFxM with state-of-art mathematical modeling. ResultsThe C-peptide response to the MMT in T1DM participants was absent or negligible, whereas the OBESE displayed a robust BCFxM. The PX volume was smaller in T1DM than in OBESE (51.7{+/-}6.6 vs 92.9{+/-}10.9 cc; p=0.007). The biomarkers of BCM, as assessed by 68Ga-NODAGA-exendin-4 SUV or CLEAR, were 6.6-fold (p=0.003) and 5.0-fold (p=0.002) lower, respectively, in T1DM than in OBESE. BCFxM was correlated in OBESE to both biomarkers of BCM (r=0.91 p<0.001, and r=0.82 p=0.006, respectively). Conclusion/interpretation68Ga-NODAGA-exendin-4 derived biomarkers of BCM can discriminate T1DM from OBESE. In OBESE 68Ga-NODAGA-exendin-4 derived BCM appears to be a pivotal determinant of the beta cell response to MMT and may be valuable to compare and monitor BCM both in research and in clinical settings. Research in contextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIChanges in pancreatic beta cell functional mass are at the heart of alterations in glucose regulation, including diabetes mellitus. Beta cell functional mass can be assessed by mathematical modeling of the in vivo beta cell response to intravenous or oral challenges. C_LIO_LIBeta cell functional mass is the product of beta cell mass times beta cell function per mass unit, i.e. the result of two distinct entities, mass and function. No in vivo methods can dissect out beta cell mass and function. C_LIO_LIPancreatic 68Ga-exendin-4 uptake, as measured by PET-CT, has been proposed as a non-invasive biomarker of beta cell mass. However, the ratio of 3.6:1 between endocrine and exocrine pancreas 68Ga-exendin 4 uptake suggests that there is room for improvement. C_LI What are the key questions?O_LIDoes an improved 68Ga-exendin4 method provide a better separation between participants with type 1 diabetes and expected zero/nil beta cell mass vs people with nondiabetic obesity? C_LIO_LIWhat is the role of beta cell mass in determining beta cell functional mass in people living with obesity? C_LI What are the new findings?O_LIThe improvement in the quantitation of beta cell 68Ga-exendin-4 binding to beta cells resulted in a clearcut separation of participants with type 1 diabetes and expected zero/nil beta cell mass from people living with obesity C_LIO_LIIn people living with obesity, beta cell mass, as assessed by 68Ga-exendin-4 PET-CT scan, is a pivotal determinant of beta cell functional mass, as assessed by mathematical modeling of a frequently sampled mixed meal test C_LI How might this impact on clinical practice in the foreseeable future?O_LIThis method has the potential to track changes in beta cell mass both between-subjects and within-subjects over time C_LIO_LINatural history of glucose (in)tolerance and the impact of disease modifier candidates in diabetes mellitus can be assessed with the present method C_LI

BackgroundDysbiosis of gut microbiota plays a key role in type 1 diabetes mellitus (T1DM). Fecal microbiota transplantation represents a novel therapeutic avenue. We hypothesize that youth-derived fecal microbiota transplantation (yFMT) can remodel the gut microecosystem and improve clinical outcomes. This study aims to investigate the efficacy and safety of orally administered yFMT capsules in adults with T1DM. Methods and analysisThis single-center, randomized, double-blind, placebo-controlled pilot study will enroll adults with T1DM who have suboptimal glycemic outcomes (glycated hemoglobin[HbA1c] of 7-14% and time in range [TIR] <70%). Following a 17-day run-in period for insulin optimization, continuous glucose monitoring(CGM) wearing, baseline assessments and bowel preparation, participants will be randomly allocated (1:1) to take yFMT or placebo capsules for consecutive 6 days, alongside their standard insulin therapy, and then complete a 12-week follow-up. The primary efficacy endpoint is the change from baseline in the rate of achieving the composite target of TIR>70% and time below range<4% at 4 and 12 weeks post-randomization. Secondary efficacy endpoints comprise changes from baseline at weeks 4 and 12 in other glycemic metrics (including HbA1c, fasting glucose, 2-hour postprandial glucose, and additional CGM metrics), C-peptide, immune responses, infection markers, and gut microbiota composition. Changes from baseline at week 12 in serum metabolomic profiles will also be assessed, encompassing bile acids, short-chain fatty acids, and other related metabolites. Safety endpoints include the incidence of adverse events and serious adverse events. DiscussionOur findings will offer new insight into the feasibility and effects of oral yFMT in adult with T1DM and provide the necessary evidence to power a subsequent multicenter large-scale study. Exploratory biomarker analyses conducted within this study may further pave the way for future individualized microbiome-based therapeutics. Trial registrationChinese Clinical Trial Registry identifier: ChiCTR2500111955 (November 7, 2025).

ObjectiveHbA1c thresholds used to define dysglycemia in autoantibody-positive individuals at risk for type 1 diabetes do not account for age-related increases in HbA1c and may overestimate progression risk in adults. We evaluated whether age-adjusted HbA1c or a higher HbA1c threshold improves risk stratification across age groups. Research Design and MethodsWe analyzed 5,024 autoantibody-positive relatives (3,720 children and 1,304 adults) participating in the TrialNet Pathway to Prevention study. Age-related HbA1c effects were modelled using 6,273 adults from the population-based Exeter 10,000 cohort. Progression risk was compared using the standard dysglycemia threshold (HbA1c [&ge;] 5.7% [39 mmol/mol]), age-adjusted HbA1c, and an alternative threshold of HbA1c [&ge;]6.0% (42 mmol/mol). ResultsUsing HbA1c [&ge;] 5.7%, children had higher 1-year progression risk than adults among single autoantibody-positive participants (38% [95% CI 28, 47] vs. 13% [7.2, 19]) and multiple autoantibody-positive participants (55% [49, 60] vs. 38% [27, 47]; both p<0.001). Age adjustment reduced these differences; progression risk was similar among single autoantibody-positive participants (38% [28, 47] vs. 27% [13, 39]; p=0.32), with attenuated differences among multiple autoantibody-positive participants. An HbA1c threshold [&ge;]6.0% yielded comparable progression risk between adults and children across autoantibody subgroups. In post hoc analyses, adults aged <30 years had progression risk similar to children (p=0.1). ConclusionsAge-related variation in HbA1c influences dysglycemia classification in adults at risk for type 1 diabetes. Age-adjusted HbA1c or a higher HbA1c threshold ([&ge;]6.0% [42 mmol/mol]) in adults [&ge;]30 years identifies individuals with progression risk comparable to children and may improve age-specific risk stratification in prevention seungs.

Uric acid (UA) is traditionally regarded as a metabolic risk marker; however, its dynamic behavior during glucose-lowering therapy remains incompletely understood. We compared UA responses to a modified traditional Japanese diet (MJDD) and the DPP-4 inhibitor alogliptin in patients with early-stage type 2 diabetes mellitus (T2DM). In this prospective observational study, drug-naive patients received MJDD (n=58) or alogliptin (n=52) monotherapy for 3 months. Changes ({Delta}) in serum UA were analyzed in relation to glycemic control, insulin resistance, adipose tissue insulin resistance (adipo-IR), and beta-cell function. Both interventions significantly reduced fasting blood glucose and HbA1c while paradoxically increasing serum UA and HOMA-B. Baseline UA was the primary determinant of {Delta}UA in both cohorts. MJDD significantly reduced body mass index, insulin, free fatty acids, HOMA-R, and adipo-IR, with effects most pronounced in subjects with baseline BMI >25. In contrast, alogliptin selectively reduced adipo-IR in leaner subjects (BMI <25). Across both treatments, {Delta}UA correlated positively with {Delta}HOMA-B and inversely with {Delta}HbA1c. Notably, during MJDD, {Delta}UA showed a paradoxical negative correlation with {Delta}BMI and {Delta}FBG, and a positive correlation with {Delta}FFA. Patients exhibiting the greatest UA increases demonstrated the most marked improvements in beta-cell function and, with MJDD, the greatest weight loss. These findings indicate that MJDD and alogliptin exert distinct metabolic effects in early T2DM, yet both link rising UA to enhanced beta-cell function, suggesting that UA may serve as a dynamic pharmacometabolic biomarker reflecting therapy-specific metabolic adaptation rather than metabolic deterioration.

BackgroundUndiagnosed diabetes represents a major challenge for health systems worldwide. While low socioeconomic status is typically associated with reduced healthcare access, the relationship between socioeconomic position and diabetes detection remains poorly characterized in Latin American settings with fragmented health systems. MethodsWe analyzed data from 4,409 Argentine adults who underwent capillary glucose measurement in the Third Step of the 2018 National Survey of Risk Factors. Among 471 individuals with elevated glucose ([&ge;]110 mg/dL), we examined the association between household income quintile and undiagnosed status using multivariable logistic regression, adjusting for age, sex, health coverage type, education, body mass index, physical activity, and smoking. ResultsContrary to expectations, undiagnosed dysglycemia increased with socioeconomic status: from 45.8% in the lowest quintile to 67.8% in the fourth quintile, with a slight decrease to 61.1% in the highest quintile. After full adjustment, each higher income quintile was associated with 22% greater odds of remaining undiagnosed (OR=1.22; 95% CI: 1.04-1.44; p=0.014). Notably, enrollment in public assistance programs (Plan Estatal) was associated with substantially lower odds of undiagnosed dysglycemia compared to social security coverage (OR=0.27; 95% CI: 0.09-0.79). Results were robust across multiple weighting specifications. ConclusionsHigher socioeconomic status paradoxically increases the likelihood of undiagnosed dysglycemia in Argentina, challenging conventional assumptions about healthcare access. Targeted public programs appear effective at identifying cases among vulnerable populations, while gaps persist in higher-income groups. These findings suggest that diabetes screening strategies should not overlook populations traditionally considered to have adequate healthcare access.

IntroductionDysglycemia is a well-established risk factor for cardiovascular disease (CVD); yet traditional glycemic traits, including fasting plasma glucose (FPG) and HbA1c, do not capture dynamic glucose fluctuations that may inform CVD risk. We cross-sectionally investigated the association of continuous glucose monitor (CGM)-derived metrics and 2-h post-prandial glucose (2-h PPG) with estimated 10-year CVD risk among individuals without diabetes. MethodsWe included 1,360 Framingham Heart Study participants (Third Generation, New Offspring Spouse, and Omni 2 cohorts at exam 4) without prevalent diabetes or CVD who had [&ge;]3 days of CGM data and completed a mixed meal tolerance test (MMTT) with corresponding 2-PPG. We included 7 CGM summary metrics and defined data-driven glucotypes according to CGM measures of glycemic burden and variability. The 10-year CVD risk was estimated using the Predicting Risk of CVD EVENTs (PREVENT) base equations. We performed linear regression on standardized glycemic traits and glucotypes with log-transformed PREVENT risk scores and multinomial regression to relate standardized CGM metrics and 2-h PPG with PREVENT categories (low <5%[reference], borderline 5-<7.5%, intermediate/high [&ge;]7.5%). All models were adjusted for FPG and body mass index (BMI). ResultsAmong participants (55.9% women, 43.4% with prediabetes), mean age was 59.3 years, and mean BMI was 27.9 kg/m2. All CGM-derived metrics and 2-h PPG were positively associated with higher overall 10-year CVD risk (per 1 SD increase of each exposure variable, {beta} range: 0.06-0.16, all p<0.001). A glucotype representing high glycemic burden and high glycemic variability was associated with higher overall 10-year CVD risk, compared with the glucotype representing low glycemic burden and low glycemic variability. Higher CGM-derived metrics and 2-h PPG were also associated with higher odds being in the intermediate/high CVD risk (OR range: 1.20-1.65, all p<0.001), adjusting for FPG and BMI. ConclusionDynamic glycemic traits, including novel glucotypes that capture glycemic burden and variability, may provide novel insights into CVD risk prevention among individuals without T2D.

IntroductionCardiovascular disease (CVD) is an important complication of type 2 diabetes (T2D). Current incident CVD-prediction models use single baseline measurements and achieve moderate performance in people with T2D, with C-indices around 0.7. Modern healthcare registries contain repeated measurements of HbA1c, LDL-cholesterol and eGFR, which could carry incremental predictive value. However, the added value of trajectory measures for CVD-risk prediction remains unclear. We aimed to investigate the utility of HbA1c, LDL-cholesterol and eGFR trajectory measures for incident CVD-risk prediction in people with T2D. MethodsWe studied 83,326 people with T2D from Danish nation-wide registers, who were without a CVD-history at baseline (January 1st 2015), and had [&ge;]2 recorded HbA1c, LDL-cholesterol and eGFR measurements between 2012-2014. Their last measurement was considered as baseline. Across 2012-2014, three types of paired trajectory measures were calculated for each participant (mean & standard deviation (SD), median & interquartile range (IQR), and intercept & slope from a fitted growth model), for HbA1c, LDL-cholesterol, and eGFR, respectively. Reference Cox-regression models for CVD-events (ICD-10 codes assessed prospectively from 2015- 2020) included only baseline measurements (age, sex , age at T2D onset, HbA1c, LDL-cholesterol, HDL-cholesterol, eGFR, and medication use). Next, the paired trajectory measures were sequentially added to the reference model, computing Hazard Ratios, C-indices and Net reclassification index (NRI) with 95% confidence intervals. Lastly, a combined model was fitted. ResultsAt baseline, mean age was 65 (SD{+/-}12), median HbA1c was 48 (mmol/mol, IQR43-56), and 48% were female. During a median 6 years of follow-up 11,280 (14%) people had a CVD-event (ischemic heart disease: 40%; stroke: 32%; heart failure: 24%; CVD-mortality: 5%). Accounting for the reference model, trajectory measures of dispersion and change were associated with CVD-events, with hazard ratios {approx} 1.1 for HbA1c and eGFR, and >1.4 for LDL-cholesterol. Measures centrality did not show an association with CVD events. Addition of trajectory measures produced minimal gains in discrimination (C-index {Delta} +0.001-+0.003) but modest improvements in net reclassification (continuous NRI {approx} +3- +9%). ConclusionsTrajectory dispersion or change measures for HbA1c, eGFR and especially LDL-cholesterol, easily obtained from routine data, might moderately enhance incident CVD-risk prediction in people with T2D.