Diabetes, Obesity and Metabolism

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.

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.

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.

ObjectivesTo estimate potential launch prices of generic semaglutide following patent expiry from 2026 and to quantify the global obesity and type 2 diabetes (T2DM) burden in countries where generic access may become possible. MethodsWe used World Bank population data and World Obesity and Diabetes Atlas prevalence estimates to calculate obesity and T2DM burden in countries where semaglutide patents expire in 2026 or were not filed. Patent status was identified using MedsPaL and cross-checked with regional databases. We updated established cost-plus pricing methodologies using 2024-2025 Indian API shipment data to estimate production costs for oral and injectable semaglutide, incorporating formulation, packaging, taxation, and profit assumptions. ResultsTen countries with 2026 patent expiry represent 44% of the global population and 48% of the global obesity burden. No patent filings were identified in 150 additional countries. By the end of 2026, generic injectable semaglutide could be distributed in 160 countries where 69% of global T2DM and 84% of clinical obesity occurs. Estimated generic injectable costs ranged from $28-140 per person-year, while oral formulations ranged from $186-380 per person-year. Injection devices contributed disproportionately to total cost. ConclusionPatent expiry could substantially expand access to semaglutide at dramatically lower prices, particularly in high-burden settings. However, device costs, secondary patents, and health system constraints may limit equitable uptake without coordinated policy action. Study ImportanceO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LISemaglutide is highly effective for obesity and cardiometabolic disease but remains unaffordable in many low- and middle-income countries due to high branded prices and patent protections. C_LIO_LIPrevious cost-plus analyses show that generic competition can substantially reduce prices of essential medicines after patent expiry. C_LI What are the new findings in your manuscript?O_LIUsing 2024-2025 API shipment data, we estimate generic injectable semaglutide could be produced for $28-140 per person-year following 2026 patent expiry. C_LIO_LIBy 2026, generic semaglutide could be available in 160 countries comprising 69% of global T2DM and 84% of clinical obesity burden. C_LI How might your results change the direction of research or the focus of clinical practice?O_LIProvides an evidence base for procurement planning and price negotiations ahead of patent expiry. C_LIO_LIHighlights the importance of addressing device costs and secondary patents to ensure equitable global access. C_LI

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.

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.

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.

BackgroundDigital health self-monitoring tools are widely used to support weight management and metabolic health. Higher engagement with these tools is often associated with better clinical outcomes; however, real-world engagement-outcome relationships for consumer metabolic monitoring devices remain incompletely characterized, particularly in heterogeneous user populations. ObjectiveTo evaluate whether engagement with a portable breath-based metabolic device (Lumen; Metaflow Ltd.) is associated with greater weight loss and reduction in body fat among real-world glucagon-like peptide-1 receptor agonist (GLP-1RA) users. The study also explores correlations between engagement and a device-specific measure of metabolic flexibility (FLEX score). MethodsWe retrospectively analyzed 2,296 adult Lumen users who self-reported GLP-1RA use over 24 weeks. Engagement was quantified as total engagement days over a 24-week period and ordered engagement consistency groups defined by weekly use frequency thresholds. Weight and body fat percentage data were collected by a combination of connected devices and manual user input in the Lumen smartphone application. Associations with weight loss and reduction in body fat percentage were evaluated using linear regression and ANCOVA adjusted for age, baseline BMI, and sex, with HC3 robust standard errors. Body fat percentage data were available for only 490 of the 2,296 subjects. In addition, similar associations were evaluated for FLEX score. GLP-1RA exposure was self-reported at onboarding and not verified longitudinally. ResultsAt 24 weeks, low/medium/high engagement users lost 3.2%, 4.6%, and 5.2% of body weight (trend p=2.36x10-11). Engagement days were associated with percent weight change (slope -0.0214% per day; P(HC3)=7.9x10- 18). Engagement days showed modest association with body fat percentage change (n=490; slope -0.0105% per day; P(HC3)=.010). The adjusted ANCOVA trend across engagement groups was not significant (P=.19). Engagement days and consistency both showed a highly significant trend in increase in FLEX score (slope +0.0185 per day; P(HC3)=2.0x10- 36). ConclusionsIn a real-world digital health dataset, higher engagement with a breath-based metabolic monitoring device and its smartphone application was associated with greater 24-week weight loss after adjustment for age, baseline BMI, and sex. The absolute difference between low and high engagement (2.0% body weight) is modest but clinically meaningful in real-world settings after 24 weeks of tracking. Associations with body fat percentage change were smaller and not consistently significant in adjusted analyses. Associations with metabolic flexibility were highly significant, but it remains unknown whether this parameter is predictive or reflective. Prospective controlled studies are needed to test causality and determine whether device-driven biofeedback and sustained engagement independently improve outcomes because GLP-1RA use was self-reported and unverified, and the present analysis was observational. These findings should be interpreted as engagement-outcome associations and reflect behavioral motivation and adherence rather than evidence of device efficacy.

Background and AimsThe glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide has demonstrated efficacy for the secondary prevention of cardiovascular disease among patients with overweight/obesity without diabetes mellitus. However, the comparative effectiveness of GLP-1 RA versus other antiobesity medications (e.g. phentermine-topiramate) not been evaluated. MethodsThis was a retrospective, observational, cohort study using target trial emulation methodology using the Truveta electronic health record database of more than 120 million patients. Adult patients with a body mass index (BMI) >=27 kg/m2, a history of cardiovascular disease (prior ischemic stroke, transient ischemic attack, or myocardial infarction, or known coronary artery disease, heart failure, or peripheral artery disease) without diabetes mellitus were included in the study. The primary endpoint was time to first major adverse cardiovascular or cerebrovascular event (MACCE, defined as stroke or myocardial infarction). ResultsIn total, 35,240 were included in the bupropion-naltrexone versus GLP-1 RA comparison, and 27,051 were included in the phentermine-topiramate versus GLP-1 RA comparison. In the pre-weighting cohort, GLP-1 RA use was associated with decreased hazard of MACCE compared to bupropion-naltrexone (HR 0.50 [95% confidence interval (CI) 0.36-0.69]) and phentermine-topiramate (HR 0.43 [95% CI 0.30-0.60]). In the propensity score-overlap weighted cohort, GLP-1 RA prescription was not associated with a lower hazard of MACCE than bupropion-naltrexone (aHR 0.69 [95% CI 0.47-1.00]) but was associated with a lower hazard compared to phentermine-topiramate (aHR 0.61 [95% CI 0.41-0.91]; adjusted absolute rate difference 0.98 per 1000 person-years). ConclusionsPrescription of a GLP-1 RA was associated with a lower risk of subsequent MACCE than phentermine-topiramate.

Aims/hypothesisTo investigate the feasibility and preliminary efficacy of a 12-week remotely-delivered exercise snacks (ES) intervention in adults with type 2 diabetes. MethodsInsufficiently active adults with type 2 diabetes (N=69; 46 females; mean age {+/-} SD: 58{+/-}11 years) were randomized to an ES or mobility/stretching comparator group (CON), which involved 4 x 1-min bouts of either vigorous or low intensity exercise, respectively, on [&ge;]5 days/week. The primary outcome was feasibility based on adherence. Secondary outcomes included exercise enjoyment (1-7 scale), rating of perceived exertion (RPE; 0-10 scale), heart rate (HR), hemoglobin A1c (HbA1c), blood biomarkers of cardiometabolic health, 30-second sit-to-stand capacity, grip strength, estimated maximal oxygen uptake, and anthropometrics. ResultsWeekly adherence (estimated marginal mean [95% confidence interval]: 18 bouts [16 to 21] for both groups; P=0.99) and total enjoyment (ES: 4.5 [4.1 to 4.8] vs CON: 4.3 [4.0 to 4.7]; P=0.64) were high and not different between groups. Despite higher RPE (5.7 [5.4 to 6.1]) and peak HR (73 [70 to 77] % of age-predicted HR maximum) in ES vs CON (2.0 [1.7 to 2.4] and 61 [58 to 64] % of age-predicted HR maximum, respectively) (all P<0.001), there were no between-group differences in the change in any secondary outcome (all P>0.05) except for greater sit-to-stand capacity in ES after training (between-group effect estimate [95% confidence interval]: 1.9 repetitions [0.3 to 3.4]; P=0.02). Conclusions/interpretationExercise snacks were feasible to perform in the real-world and improved physical capacity to a greater extent than CON in adults living with type 2 diabetes. Trial registrationClinicalTrials.gov ID: NCT06407245 Research in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIExercise snacks ([&le;]1-min bouts of vigorous exercise spaced out across the day) are a time-efficient and practical approach to promote vigorous exercise and break up sedentary time. C_LIO_LIReal-world exercise snack interventions appear feasible for middle-aged and older adults. C_LI What is the key question?O_LIAre 12 weeks of exercise snacks performed in the real-world feasible for insufficiently active adults living with non-insulin treated type 2 diabetes? C_LI What are the new findings?O_LIExercise snacks are feasible for those living with type 2 diabetes to perform unsupervised in the real-world based on high adherence, enjoyment, and participant retention rates. C_LIO_LIExercise snacks improved 30-second sit-to-stand capacity and reduced waist circumference suggesting enhancements in physical capacity and body composition. C_LI How might this impact on clinical practice in the foreseeable future?O_LIExercise snacks could be utilized to help individuals living with type 2 diabetes build a routine or habit of incorporating small amounts of physical activity into their daily lives. C_LIO_LIThe improved physical capacity observed in the current study could contribute to lower fall risk and greater lower body strength in those with type 2 diabetes as they age. C_LI

Prediabetes and type 2 diabetes (T2D) are metabolic disorders characterized by insulin resistance and {beta}-cell dysfunction. To understand the molecular mechanisms driving the transition from prediabetes to T2D, we performed a longitudinal proteogenomic analysis on 458 participants from the Prediabetes Lifestyle Intervention Study (PLIS). We identified 185 plasma proteins to be differentially expressed between conditions, 36 of which predict future T2D-onset. Integrating genetic data from 321 individuals, we generated a genome-wide protein quantitative trait loci (pQTL) map, identifying 86 differential and 700 shared cis-pQTLs between prediabetes and T2D. Mediation analysis revealed 60 putative causal links connecting allele-driven plasma protein expression to clinical traits, identifying body fat distribution, insulin resistance, and {beta}-cell function as central drivers of pathogenesis. Collectively, these findings highlight specific proteins underlying disease progression and substantiate the view that prediabetes and T2D are not distinct conditions, but rather stages on a unified metabolic spectrum.

BackgroundDiabetes mellitus (DM) remains a major global health challenge and is associated with vision-threatening complications, including diabetic macular edema (DME), a leading cause of visual impairment. Dyslipidemia has been implicated in the development of macular edema through mechanisms involving vascular permeability, endothelial dysfunction, and chronic inflammation. However, evidence regarding the relationship between lipid abnormalities and macular edema remains inconsistent across studies. AimThis study aimed to evaluate the association between abnormal lipid profiles and diabetic macular edema among patients with type 2 diabetes mellitus attending Kilimanjaro Christian Medical Centre (KCMC). MethodsA hospital-based analytical cross-sectional study was conducted among 296 diabetic outpatients at KCMC. Participants underwent comprehensive ophthalmic evaluation including fundoscopy and imaging with optical coherence tomography (OCT) for assessment of macular edema. Blood samples were collected for biochemical lipid analysis. Data were cleaned and analyzed using STATA version 17. ResultsDiabetic macular edema was identified in 56.4% (167/296) of participants. Abnormal lipid parameters were common, with elevated total cholesterol observed in 48.6%, triglycerides in 43.6%, low-density lipoprotein (LDL) in 36.1%, and reduced high-density lipoprotein (HDL) in 38.9% of patients. Elevated total cholesterol, triglycerides, and LDL levels showed significant associations with macular edema (p < 0.05). After multivariable adjustment, serum triglycerides remained independently associated with macular edema (p = 0.002). ConclusionDyslipidemia demonstrated a significant association with diabetic macular edema, with serum triglycerides emerging as an independent predictor. These findings highlight the importance of lipid monitoring, lifestyle modification, and strengthened screening strategies in reducing the burden of vision-threatening diabetic complications.

Cushings disease is caused by the overproduction of cortisol. The effects of this disease are well known in a general population, including high blood pressure, diabetes, and weight gain. Cushings disease causes both obesity and metabolic related symptoms, and it can be difficult to discern the obesity-dependent from the obesity-independent mechanisms of Cushings disease. To identify patients with Cushings disease, we identified 476 Michigan Medicine patients between January 1st 2000-2025 along with propensity-matched control cases. We stratified our participants by obesity status and into a Cushings disease group and a control group. As expected, the Cushings group had an elevated BMI compared to the control group (34 kg/m2 vs 29 kg/m2). We found a higher proportion of females diagnosed with Cushings compared to males (287 vs 72). Cushings disease was associated with an increase in the fasting glucose levels in both non-obese and obese patients. In both the obese, and non-obese patients, there was an increase in ALT and AST levels regardless of Cushings disease status, but the increase due to Cushings disease was much greater in the patients with obesity (73.4 vs 35.1 mg/dL). Cushings disease also had a moderating effect on blood pressure, with participants a BMI under 30 kg/m2 increasing by 12.6 mmHg and participants with obesity increasing by only 7.9 mmHg. These findings highlight the need to consider obesity status when evaluating the effects of Cushings disease.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSINTRODUCTIONC_ST_ABSTreatment response in Alzheimers disease (AD) varies substantially across patients, yet no validated frameworks exist to estimate heterogeneous treatment effects (HTE) from observational data while controlling for confounding bias. METHODSWe developed a causal machine learning framework integrating expert-guided causal graphs, complementary HTE estimators, sensitivity analyses, and policy learning. We applied it to cholinesterase inhibitors (ChEIs) in MCI due to AD to patients from the NACC and ADNI cohorts. RESULTSAnalysing 4,049 patients with 12-month and 2,223 with 36-month follow-up, all estimators indicated null or negative long-term ChEI effects on cognitive and functional outcomes, notably on functional measures. ChEIs showed slightly more deleterious effects among men than women. DISCUSSIONThis framework provides a methodology for estimating HTE from observational data. It revealed no beneficial responder subgroups, highlighting the challenge of detecting treatment heterogeneity in moderately sized cohorts. This approach can inform treatment selection for other AD therapies including memantine, anti-amyloid agents, and emerging treatments.

BACKGROUNDVisceral adipose tissue (VAT) has been associated with cardiovascular disease (CVD) mortality. However, the comparative performance of VAT-related clinical surrogates remains poorly characterized. OBJECTIVESTo evaluate the performance of seven VAT-related clinical surrogates for predicting CVD and cause-specific CVD mortality. METHODSWe analyzed data from the Mexico City Prospective Cohort, a population-based prospective cohort study, with baseline recruitmetn between 1998 - 2004 and ongoing mortality follow-up. CVD mortality included deaths from cardiac, stroke-related, and other vascular causes. Seven VAT-related surrogates (METS-VF, CVAI, EVA, DAAT, LAAP, VAI, and DAI) were estimated using clinical, biochemical, and anthropometric data at baseline. Associations with outcomes were evaluated using Cox regression models to estimate adjusted hazard ratios (aHRs). Discrimination was assessed with Harrells C-statistic (Cs) and fixed-point at 10-years receiver operating characteristic (ROC) curves, and calibration with slope plots. RESULTSIn a subsample of 102,385 participants (median age: 47 years; 67% female), 4,068 (3.97%) died from any CVD causes. METS-VF (Cs: 0.722; aHR: 1.17, 95% CI: 1.12-1.23), EVA (Cs: 0.72; 1.14, 1.12-1.23), CVAI (Cs: 0.70; 1.13, 1.09-1.18), and DAAT (Cs: 0.626; 1.13, 1.09- 1.18) were positively associated with CVD mortality and showed the highest predictive capacity among the surrogates. Adding METS-VF to a CVD risk score among individuals classified as intermediate risk improved discrimination for CVD mortality. CONCLUSIONSIn this large cohort of Mexican adults, four VAT-related clinical surrogates, particularly METS-VF, demonstrated good discriminatory performance for long-term CVD mortality. These indices could help to identify individuals with high VAT accumulation and high CVD risk in resource-limited settings.

ObjectiveTo examine whether the association between smoking status and cardiovascular (CV) mortality differs by arterial stiffness, assessed by pulse pressure index (PPI), among U.S. adults without baseline cardiovascular disease (CVD). MethodsUsing data from the National Health and Nutrition Examination Survey (NHANES) 2005-2016, we analyzed 16,605 adults aged 40-79 years without baseline CVD, with mortality follow-up through December 31, 2019. PPI was calculated as (systolic blood pressure [SBP] - diastolic blood pressure [DBP])/SBP and split at the cohort median (0.415) as low versus high. Smoking status was classified as never, former, or current, yielding six joint PPI-smoking groups. Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CV mortality, adjusting for demographics and cardiometabolic risk factors. ResultsOver a median follow-up of 8.4 years, 518 CV deaths (3.1%) occurred. Among individuals with low PPI, former smokers had CV mortality comparable to never smokers (HR 0.86, 95% CI 0.56-1.33), whereas current smokers remained at elevated risk (HR 2.51, 95% CI 1.65-3.81). This pattern was not observed in the high PPI stratum, where both former and current smokers had significantly higher CV mortality than never smokers. ConclusionFormer smokers with low PPI had CV mortality similar to never smokers, whereas former smokers with high PPI remained at elevated risk. These findings suggest that the CV benefit of smoking cessation may be greatest when arterial stiffness is minimal, supporting early cessation before substantial vascular aging occurs.

We performed a systematic review and meta-analysis of randomized controlled trials evaluating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus placebo in adults with heart failure (HF), searching PubMed, Cochrane CENTRAL, and ClinicalTrials.gov through February 2026. The primary outcome was the composite of cardiovascular death and first HF hospitalization. Random-effects meta-analysis used restricted maximum likelihood estimation with Hartung-Knapp-Sidik-Jonkman adjustment. We included 14 studies (6 dedicated HF trials and 8 cardiovascular outcomes trial HF subgroup analyses) encompassing 18,558 patients, of whom 2,499 were randomized in dedicated HF trials. The primary composite did not reach statistical significance (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.73-1.01; P=0.067; I2=47%). GLP-1 RAs significantly reduced all-cause mortality (HR 0.87, 95% CI 0.81-0.93; P<0.001; I2=0%), major adverse cardiovascular events (HR 0.83, 95% CI 0.73-0.95; P=0.019), and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (+7.4 points, 95% CI 6.3-8.5) and 6-minute walk distance (+17.6 m, 95% CI 13.4-21.7). Excluding the FIGHT trial (acute HFrEF) yielded a significant primary composite (HR 0.83, P=0.011). The mortality signal was driven primarily by CVOT subgroups; the largest dedicated HFpEF trial (SUMMIT) showed numerically higher mortality (HR 1.25). The strongest evidence supports GLP-1 RAs in HFpEF with obesity. HighlightsO_LIPrimary composite of CV death + HHF was not significant (HR 0.86, P=0.067) C_LIO_LIGLP-1 RAs reduced all-cause mortality (HR 0.87) with no heterogeneity C_LIO_LIKCCQ-CSS improved by 7.4 points and 6MWD by 17.6 m in HFpEF trials C_LIO_LIMortality benefit driven by CVOT subgroups, not dedicated HF trials C_LIO_LIStrongest evidence supports GLP-1 RAs in HFpEF with obesity C_LI

Age-defined type 1 diabetes (T1D) endotypes, T1DE1 and T1DE2, are characterized by reproducible differences in pancreatic immunopathology and clinical course. In particular, these endotypes differ in the extent and composition of lymphocytic insulitis and in the extent of loss of insulin-producing {beta} cell mass, at diagnosis. However, blood-based biomarkers that may distinguish these endotypes and inform the underlying immune-islet biology axis at diagnosis remain limited. Here, we characterized the clinical features and profiled circulating microRNAs (miRNAs) in plasma from two independent INNODIA cohorts of individuals with newly diagnosed stage 3 T1D (discovery, n=115; replication, n=147), stratified into age-defined endotypes (T1DE1, <7 years; T1DE2, [&ge;]13 years; and intermediate T1DInt, 7-12 years). Differential-expression and age-adjusted models were coupled to orthogonal ddPCR validation. Putative miRNAs cellular sources were inferred using reference miRNA expression atlases. Biological context was explored via correlations of miRNAs with whole-blood transcriptomics. Clinically, T1DE1 was associated with lower {beta}-cell function and higher first-year C-peptide decline, alongside distinct islet autoantibody patterns, consistent with an immunologically aggressive endotype. Small RNA-seq analysis and ddPCR validation identified a reproducible signature in which miR-150-5p, a B-and T-lymphocyte related miRNA, and miR-375-3p, a {beta} cell enriched molecule, were consistently increased in T1DE1 compared with T1DE2 across both cohorts. MiR-150-5p retained robust association with T1DE1 even after age adjustment, and neither miRNA was associated with age in non-T1D pediatric datasets, supporting T1D endotype specificity. The increased circulating miR-150-5p signal was not explained by differences in peripheral blood B-or T-cell frequencies in high-parameter flow-cytometry subsets, and its levels correlated inversely with whole-blood expression of the immune-associated miR-150-5p target genes MPPE1 and RABGAP1L. Finally, applying a rule-based combined classifier (miR-150-5p and miR-375-3p "high") achieved re-stratification of T1D individuals, including those in the intermediate age group, into two miRNA-defined groups with distinct {beta} cell functional trajectories. Collectively, these data suggest circulating miR-150-5p and miR-375-3p as non-invasive biomarkers linked to endotype-associated biology at T1D diagnosis, with potential utility for endotype-centered stratification and trial enrichment.

IntroductionAnti-vascular endothelial growth factor (anti-VEGF) therapies are standards of care for vision-threatening retinal diseases. This retrospective observational study describes demographics, utilization, best recorded visual acuity (BRVA), and safety among eyes with neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR), diabetic macular edema (DME), or retinal vein occlusion (RVO) treated with the biosimilar aflibercept-ayyh (PAVBLU(R)) in routine clinical practice. MethodsElectronic medical records from the Retina Consultants of America database of patients receiving aflibercept-ayyh (12/1/2024-10/31/2025) were analyzed, focusing on eyes with [&ge;]84 days of follow-up. The index date was the first documented aflibercept-ayyh injection. Postindex data were used to assess treatment patterns, BRVA (Wilcoxon signed rank test), and adverse events of special interest (AESIs). ResultsA total of 1,000 consecutive eyes from 989 patients received 3,730 injections of aflibercept-ayyh; most (91%) switched from prior anti-VEGF therapy and 9% were anti-VEGF treatment-naive. Disease distribution was 58% nAMD, 19% RVO, 16% DME, and 7% DR. Among switchers, median (IQR) number of prior injections was 21 (8-46). Median (IQR) follow-up was 6.0 months (4.6-7.1). Median (IQR) number of aflibercept-ayyh injections per eye was 4 (3-5). Among eyes with [&ge;]84 days of follow-up (n=889), mean BRVA expressed as logarithm of minimum angle of resolution (logMAR) remained stable for switchers (0.4 to 0.4; P=0.96) and improved from baseline in anti-VEGF-naive eyes (0.5 to 0.4; P<0.01). Confirmed AESIs included iritis (n=2; 0.05% of injections), with no events of vitreous cells, endophthalmitis, retinal detachment, retinal vasculitis, or vitreous hemorrhage. ConclusionIn this descriptive real-world analysis, aflibercept-ayyh was associated with stable visual acuity in previously treated eyes and vision improvement in treatment-naive eyes, with no new or unexpected safety findings, consistent with expectations for aflibercept. These findings add real-world experience to preexisting evidence demonstrating no clinically meaningful differences between aflibercept-ayyh (PAVBLU(R)) and reference aflibercept (EYLEA(R)). KEY SUMMARY POINTSO_ST_ABSWhy carry out this study?C_ST_ABSO_LIThe anti-vascular endothelial growth factor (VEGF) drug aflibercept, approved in 2011 and marketed in the United States as EYLEA(R),* has demonstrated efficacy in treating retinal diseases such as neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR), diabetic macular edema (DME), or retinal vein occlusion (RVO) and is a standard of care for these disorders. C_LIO_LIAflibercept-ayyh is a biosimilar to aflibercept that has demonstrated comparable efficacy and safety in the treatment of nAMD in a randomized controlled clinical trial. C_LIO_LIThis study describes the real-world use patterns, vision outcomes, and safety of aflibercept-ayyh in clinical settings in the United States for the treatment of nAMD, DR, DME, and RVO. C_LI What was learned from the study?O_LIIn this real-world study of 1,000 consecutive eyes treated with the biosimilar aflibercept-ayyh in patients with retinal diseases, we observed no new safety concerns and that aflibercept-ayyh maintained visual acuity in eyes switching anti-VEGF agents and improved vision in anti-VEGF-naive eyes, consistent with expected responses to aflibercept. C_LIO_LIThese findings support aflibercept-ayyh as a suitable treatment option when anti-VEGF therapy is indicated. *EYLEA(R) is a registered trademark of Regeneron Pharmaceuticals, Inc. PAVBLU(R) is a registered trademark of Amgen Inc. C_LI

Background and ObjectivesRecent large-scale studies have consistently linked healthy dietary patterns to improved cardiometabolic health; however, the underlying biological pathways remain largely unclear, especially in non-European populations. In this study, we leverage data from four population-based cohorts (UK Biobank, NEO study, GNHS, and 10K) to investigate both common and cohort-specific biological pathways linking healthy dietary patterns to cardiometabolic disease through multi-omics profiling. Material and methodsIn each cohort, we first assessed the associations between each of the five major dietary pattern scores (i.e., AMED, hPDI, DII, AHEI, and EDIH) and cardiometabolic disease risk using Cox or logistic regression models. To explore the potential mediating role, metabolomics and proteomics measurements were incorporated into the models. All models were adjusted for relevant confounders, and false discovery rate correction was applied to account for multiple testing. ResultsWith a total of 71,679 individuals without pre-existing cardiometabolic disease across four participating cohorts (UKB: 54,024, NEO: 4,838, GNHS: 3,201, and 10K: 9,616), we confirmed that adherence to healthy dietary patterns was associated with a 5-10% reduced risk of cardiometabolic disease. Three common biological pathways were identified: (1) mediation via large HDL particles and apolipoprotein F; (2) mediation via DNAJ/Hsp40 and triglyceride-rich lipoproteins; and (3) mediation via CRHBP-regulated HPA axis activity affecting triglyceride-rich lipoproteins. ConclusionsOur integrative multi-omics analysis across diverse populations identifies novel biomarkers that connect healthy dietary patterns with cardiometabolic risk. These findings deepen our understanding of the biological mechanisms underlying diet-related disease and hold promise for enhancing the development of precision nutrition interventions.