Diabetes, Obesity and Metabolism

BackgroundGlucagon-like peptide-1 (GLP-1) receptor agonists, including liraglutide and semaglutide, are widely prescribed to treat type 2 diabetes mellitus and obesity. Recent anecdotal reports have suggested these agents might be associated with allodynia, a neuropathic pain syndrome, but large-scale epidemiologic evidence is lacking. MethodsTo investigate this potential link, a retrospective cohort study was conducted using the IQVIA PharMetrics(R) Plus database. Adults aged 18 and older who initiated liraglutide, semaglutide, or bupropion-naltrexone between 2006 and 2020 were included, excluding those with prior diabetes or antihyperglycemic therapy. Incident allodynia was identified via ICD-9/10 codes as the primary outcome. ResultsAmong 20,504 new users, those on GLP-1 receptor agonists had an allodynia incidence of 35 per 1,000 person-years, compared to 15 per 1,000 person-years for bupropion-naltrexone users. Adjusted analyses demonstrated over a twofold increased risk of allodynia with GLP-1 receptor agonists (aHR 2.15, 95% CI 1.57-2.96). ConclusionThese findings emphasize the need for heightened clinical vigilance and further research into mechanisms and management.

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.

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.

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.

Aims/HypothesisUnderstanding heterogeneous patient responses to various glucose-lowering therapies is crucial for advancing personalized treatment approaches and optimizing outcomes for type 2 diabetes mellitus. While average treatment effects are known for many drug classes, patient responses may differ by underlying clinical and demographic factors. We hypothesize that major glucose-lowering drug classes exhibit heterogeneous treatment effects (HTE) across patient subgroups defined by key clinical and demographic characteristics. MethodsThis is a large-scale observational cohort study replicated in six data-sources across the Observational Health Data Sciences and Informatics network. New-user, active-comparator cohorts were constructed for patients with type 2 diabetes mellitus initiating one of the nine antihyperglycemic drug classes. Large-scale propensity score adjustment for measured confounding, empirical calibration using negative control outcomes, and random-effects meta-analysis were employed to estimate calibrated hazard ratios (HRs). HTE was assessed by comparing differences in log HRs across 10 demographic and clinical subgroups. ResultsEvidence of HTE was observed across hyperlipidemia, hypertension, obesity, and sex subgroups. Biguanides (vs. DPP-4i) were protective against acute myocardial infarction in patients with hyperlipidemia, and against heart failure hospitalization in patients with obesity. SGLT-2 inhibitors (vs. GLP-1 receptor agonists) reduced stroke risk only in non-obese patients. Sex-specific patterns also emerged: women taking GLP-1 receptor agonists had a higher risk of diarrhea, and women taking SGLT-2 inhibitors had a lower risk of stroke compared with DPP-4 inhibitors; these associations were not seen for male patients. ConclusionsThis hypothesis-generating study identified several potential signals (blood pressure status, lipid status, obesity status, and sex) where there exists treatment effect heterogeneity for several classes of type 2 diabetes mellitus drugs. These preliminary findings highlight the potential for personalized type 2 diabetes mellitus treatment recommendations based on patient characteristics.

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).

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.

Background and aimsThe optimal eating window for time-restricted eating (TRE) remains unclear. We investigated the effects of 8-hour TRE combined with usual care (UC, a Mediterranean diet-based education program), versus UC alone over 12 weeks on hepatic fat fraction, liver health markers, and fecal microbiota in adults with overweight or obesity. MethodsIn this multicenter randomized trial, participants (50% women) were assigned to UC (n=49), early TRE (n=49), late TRE (n=52), or self-selected TRE (n=47). Hepatic fat fraction was assessed by MRI; liver markers included elastography-based parameters, liver enzymes, and circulating biomarkers. Fecal microbiota was analyzed by 16S rRNA gene sequencing. ResultsHepatic fat fraction decreased significantly within the three TRE groups (all P[&le;]0.02), but no between-group differences were observed when comparing early TRE (mean difference [MD]: -0.4%; P=0.95), late TRE (MD: -1.5%; P=0.15), and self-selected TRE groups (MD: -0.7%; P=0.77) with the UC group, or among the TRE groups themselves (all P[&ge;]0.41). Similarly, no between-group differences were found in liver health markers and fecal microbiota. Participants with metabolic dysfunction-associated steatotic liver disease at baseline as well as those achieving [&ge;]5% weight loss had greater reductions in hepatic fat fraction than those who did not (MD: -2.7 and -2.6%; respectively, both P<0.001). A higher proportion of participants in the TRE groups achieved [&ge;]5% weight loss compared with UC (41-44% vs 16%; P=0.001). ConclusionThese findings suggest that the timing of the eating window in TRE may not impact liver fat or microbiota composition beyond the effects of weight loss, though the study was not powered for secondary outcomes. The study was registered on ClinicalTrials.gov (identifier: NCT05310721)

BACKGROUNDCardiovascular disease (CVD) is a leading cause of diabetes-related mortality in Mexico. Although diabetes subgroups capture underlying disease heterogeneity, their association and utility for risk prediction for fatal CVD in Mexican adults remain unclear. METHODSWe analyzed 24,943 adults with diabetes from the Mexico City Prospective Study. Participants were classified into mild obesity-related (MOD), severe insulin-deficient (SIDD), severe insulin-resistant (SIRD), and mild age-related (MARD) diabetes using a self-normalizing neural network algorithm. Fatal CVD was defined as death from ischemic heart disease or stroke (ICD-10 I20-I25, I60-I69). SCORE2-Diabetes was recalibrated and validated overall and by diabetes subgroup. Cox proportional hazards models were used to estimate subgroup-specific risk, and sequential models evaluated the incremental predictive value of diabetes subgroups combined with SCORE2-Diabetes and traditional risk factors. RESULTSOver a median follow-up of 19.3 years (IQR 12.7-20.6), 2,223 fatal CVD events (8.9%) were recorded. SIDD was the most prevalent subgroup (50.6%), followed by SIRD (17.3%), MARD (16.8%), and MOD (15.4%). SIDD and MARD showed the highest adjusted risk of fatal CVD (RR 1.58 [95%CI 1.38-1.81] and 1.35 [1.13-1.60]), whereas MOD and SIRD had lower risk. Recalibrated SCORE2-Diabetes demonstrated adequate discrimination overall (c-statistic 0.759, 95%CI 0.745-0.773) and for most subgroups but underperformed in MARD, with recalibration improving risk assessment. The combination of diabetes subgroups and SCORE2-Diabetes improved prediction for fatal CVD outcomes. CONCLUSIONSDiabetes subgroups show heterogeneity in fatal CVD risk in Mexican adults. SIDD and MARD identify high-risk individuals and integration subgroup classification with SCORE2-Diabetes enhances risk prediction.

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

BackgroundThe diagnostic accuracy of HbA1C for prediabetes has been questioned due to its discordance with fasting plasma glucose (FPG) and 2 h oral glucose tolerance test (OGTT) glucose in non-white populations. This study aims to estimate concordance in the diagnosis of prediabetes using HbA1C FPG, and OGTT in a Filipino-American cohort. MethodsCross-sectional data from 149 Filipino-Americans without known diabetes living in the San Francisco Bay Area were used to compare prevalence of prediabetes as diagnosed by HbA1C, versus diagnosis by FPG and OGTT. ResultsThirty nine percent of subjects met the diagnosis of prediabetes using any one of the measures. Overall agreement between HbA1C, FPG and OGTT was low. Prevalence was 8.1% by FPG, 8.7% by OGTT and 35% by HbA1C. BMI, waist-hip ratio, insulin, HOMA-IR, blood pressure, and triglycerides were significantly higher in those with prediabetes by HbA1C versus normal HbA1C. ConclusionsThere is significant discordance between HbA1C, FPG, and OGTT in diagnosing prediabetes in a Filipino-American cohort. HbA1C detected four times as many individuals with prediabetes than FPG or OGTT. Individuals classified with prediabetes by HbA1C had indicators of more insulin resistance compared to individuals with normal HbA1C suggesting that HbA1C appears to detect true metabolic abnormalities on the path to diabetes as opposed to detecting false positives. These results have important implications for diabetes and prediabetes screening in Filipinos.

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.

ImportanceGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are fast-growing treatments for type 2 diabetes, obesity, and sleep apnea and are under investigation as potential treatments for many other conditions. The National Institutes of Healths (NIHs) All of Us Research Program offers a robust observational data source for studying questions related to GLP-1RA use in real-world settings. ObjectiveThis article describes key characteristics of All of Us participants who have been prescribed GLP-1RAs. The goals are to present the utility of the All of Us data and describe the strengths and limitations of using this resource for future research on GLP-1RAs. DesignUsing the All of Us Controlled Tier Curated Data Repository version 8 (CDRv8), we provide a descriptive analysis of the cohort with GLP-1RA records using cross-sectional surveys, longitudinal electronic health record (EHR) data, and longitudinal Fitbit data. SettingThe All of Us Research Program is a large, federally funded, longitudinal cohort study established in 2018 by NIH. Recruitment efforts are nationwide and target a range of populations to advance precision medicine for all. ParticipantsParticipants are U.S. residents, aged 18 or older at the time of study consent, who were enrolled between May 6, 2018, and October 1, 2023. ExposuresThe GLP-1RA cohort included participants with at least two GLP-1RA prescription records on different days at any time point based on their EHRs. Main OutcomesFrequencies and medians for a range of sociodemographic characteristics, health care utilization patterns, comorbid conditions, GLP-1RA prescription trends, laboratory and observation availability, and Fitbit data. ResultsThe All of Us GLP-1RA cohort is large (n=15 477), with high data availability across a range of relevant data types. These participants are older and have more comorbid conditions than the entire CDRv8 population. Prescription trends indicate rapid uptake of GLP-1RA drugs since 2014. Conclusions and RelevanceAll of Us CDRv8 is a valuable resource for research on GLP-1RAs across a large, heterogeneous cohort of participants. The variety and availability of data offer many possibilities for future observational, real-world research to address unanswered questions about GLP-1RA use and replicate recent findings generated from other datasets. Key pointsO_ST_ABSQuestionC_ST_ABSWhat data are available and what are the patterns of GLP-1 receptor agonist (GLP-1RA) prescriptions among participants in the All of Us Research Program? FindingsIn this descriptive cohort study of 633 534 All of Us participants, 15 477 participants had at least two records of GLP-1RA prescriptions. These participants tended to be older, have more comorbid conditions, and have higher health care utilization than the All of Us population as a whole. MeaningThe All of Us Research Program has a robust array of data to support observational studies of people receiving GLP-1RA prescriptions.

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.

BackgroundDrug suitability is determined by safety, efficacy, and pathological appropriateness. The pharmacogenomics of drug suitability can be assessed by analyzing drug response and drug choice in large population cohorts. MethodsWe investigated drug response and drug choice for dyslipidemia and hypertension using genetic, phenotypic, and prescribing data from the UK Biobank and the All of Us Research Program. Drug response was reassessed with rigorous biomarker scaling, while genome-wide association studies (GWAS) and polygenic scores were used to examine genetic factors influencing drug choice. ResultsConventional analyses showed that variants influencing baseline LDL cholesterol (LDL-C) were inversely associated with absolute LDL-C change but concordant with relative change following statin therapy; these signals disappeared after applying a variance-stabilizing Box-Cox transformation, indicating a methodological artifact in biomarker scaling. GWAS for drug choice identified several significant loci and unique genetic correlation patterns with cardiometabolic traits. Polygenic scores for drug choice yielded statistically significant predictive performance, which was enhanced by incorporating demographic factors, though prediction strength in clinical settings remains modest. ConclusionVariance-stabilizing transformation corrects spurious pharmacogenetic associations introduced by biomarker scaling. Genetic variation informs drug choice for dyslipidemia and hypertension, but current polygenic scores provide only modest benefits in clinical application.

BackgroundEffective interventions are needed to support co-creation of diabetes care plans that fit patients lives. We evaluated the QBSafe agenda-setting kit (14 conversation cards) for its impact on care fit and glycemic control when added to usual primary care. MethodsThis single-center, clinician-level cluster-randomized, open-label trial was conducted at a federally qualified health center in New Haven, Connecticut (ClinicalTrials.gov NCT05553912). Clinicians and their patients with type 2 diabetes and HbA1c >8% were randomized 1:1 to usual care with or without QBSafe cards. In the intervention arm, patients selected up to 3 cards highlighting concerns about life with diabetes prior to their visit. Primary outcomes were change at 6 months in care fit (Illness Intrusiveness Ratings Scale, IIRS) and HbA1c, analyzed by intention to treat. Secondary outcomes were treatment burden (Treatment Burden Questionnaire, TBQ) and diabetes distress (Diabetes Distress Scale, DDS), and satisfaction with visits. ResultsBetween February 2023 and July 2024, 143 participants (mean age 56 years; 61% female; 73% Hispanic; mean HbA1c 10%) were enrolled: 74 received usual care with QBSafe, 69 usual care alone. At 6 months, there were no significant between-arm differences in changes in IIRS (-3.9 [95% CI -10.4, 2.6]), HbA1c (-0.2% [95% CI -0.9, 0.5]), TBQ (1.0 [95% CI -16.6, 18.6]), or DDS (-0.1 [95% CI -0.4, 0.2]). Clinicians reported greater satisfaction when using QBSafe. Patient satisfaction was high and did not differ across arms. ConclusionsQBSafe cards improved clinician satisfaction but did not improve care fit or glycemic control. Future tools should focus on helping clinicians respond effectively to patient-identified challenges.

BackgroundThe role of adipokines in childhood glycemia is poorly understood. We investigate the longitudinal association between adipokines and glycemia in a cohort of children in Mexico City. MethodsChildren from the Programming Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) cohort (948 children, 52% male) were followed longitudinally from birth. Leptin, adiponectin, glucose, and HbA1c were measured at four, six, and eight years, and fasting insulin at eight years. Adiponectin to leptin ratio (ALR) and HOMA2 indices were computed. Longitudinal associations were examined by linear mixed models and cross-sectional associations were examined by multivariable linear regression. All models were adjusted for maternal and child covariates. FindingsBetween ages four and eight years, average levels of leptin increased from 3{middle dot}2 to 10{middle dot}8 ug/mL; adiponectin dropped from 15{middle dot}7 to 13{middle dot}7 ng/mL; and ALR dropped from 9{middle dot}1 to 3{middle dot}1 ug/ng. Longitudinally, across timepoints four, six, and eight years after birth, there was no association between adipokines and glycemia. However, the cross-sectional analysis at age 8 years found an association between leptin and insulin (1{middle dot}0, 95% CI: 1{middle dot}0; 1{middle dot}1), HOMA2-B (1{middle dot}0, 95% CI: 1{middle dot}0; 1{middle dot}0), HOMA2-IR (1{middle dot}0, 95% CI: 1{middle dot}0; 1{middle dot}1), and HOMA2-S (0{middle dot}9, 95% CI: 0{middle dot}9; 0{middle dot}9). InterpretationFurther investigation is needed to understand the role of adipokines in the development of T2DM in children and the factors that may alter adipokine metabolism.

AimsTo evaluate the effectiveness of the Oishi-kenko mobile cooking application in improving glycemic control, body weight, and dietary behaviors among individuals with type 2 diabetes without professional intervention. MethodsThis 12-week observational study was conducted entirely online. Participants were recruited via the Oishi-kenko website, internet advertisements, and Tsukuba City public relations channels. Of 24,671 website visitors, 214 installed the app, and 65 were included in the final analysis; HbA1c data were available for 24 participants. The app provided personalized, culturally tailored recipe suggestions based on user profiles and dietary standards. Body weight and HbA1c were assessed at baseline and every 4 weeks, and dietary habits were evaluated using the Brief-type Self-administered Diet History Questionnaire (BDHQ). ResultsMean HbA1c decreased from 6.40% at baseline to 6.12% after 12 weeks (-0.28%, P<0.05). Among participants with baseline HbA1c >7%, the reduction was -0.63%. BMI declined from 23.47 to 23.28 overall, with greater reduction among those with baseline BMI [&ge;]25. More frequent app-based cooking and higher baseline HbA1c predicted greater improvement. BDHQ analyses showed reduced intake of salty condiments, noodle soup, and fatty meats, alongside healthier eating behaviors. Over 80% of participants reported improved dietary habits. ConclusionsUse of the Oishi-kenko app was associated with improved glycemic control, modest weight loss, and healthier eating patterns in individuals with type 2 diabetes. These findings support the potential of culturally tailored, stand-alone dietary support applications as scalable tools for diabetes self-management. (The trial registry number: UMIN-CTR, ID: R000053861) HighlightsO_LIOishi-kenko app use significantly reduced HbA1c and BMI in individuals with type 2 diabetes. C_LIO_LIThe study was conducted fully online, from recruitment to data collection, without human intervention. C_LIO_LIParticipants adopted healthier dietary behaviors, including reduced intake of salty condiments, noodle soup, and fatty meats, along with more mindful eating practices. C_LIO_LIThe app shows promise as a stand-alone, culturally tailored digital tool for diabetes self-management without professional intervention. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/25342210v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@771eeborg.highwire.dtl.DTLVardef@8ed68aorg.highwire.dtl.DTLVardef@1a70476org.highwire.dtl.DTLVardef@161b52_HPS_FORMAT_FIGEXP M_FIG C_FIG

ImportanceAlcohol use is a leading cause of morbidity and mortality worldwide. Growing evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may represent a novel potential pharmacotherapeutic tool for alcohol use disorder (AUD). ObjectiveTo examine the association between GLP-1RA prescriptions and alcohol use. DesignThis cohort study used a cross-sectional measure of alcohol consumption and longitudinal electronic health record (EHR) data collected between 1981 and October 2023 from NIHs All of Us Research Program participants. SettingAll of Us is a large program to recruit and collect surveys, EHR, genomic, and wearable data from a wide array of Americans. The data presented here are from the All of Us Curated Data Repository version 8. Participants393,596 All of Us participants with EHR data recruited across the United States. ExposureAt least two GLP-1RA prescription records in the EHR. Main Outcomes and MeasuresAlcohol Use Disorders Identification Test (AUDIT-C) scores and responses to individual AUDIT-C questions. ResultsAmong 15,447 participants with at least two recorded GLP-1RA prescriptions on separate days, 3650 had active GLP-1RA prescriptions, 5642 would have future GLP-1RA prescriptions (primary comparison group), and 544 had former GLP-1RA prescriptions. Those with active GLP-1RA prescriptions had statistically significant but modestly lower AUDIT-C scores on average compared with those with future prescriptions (incidence rate ratio [IRR] of 0.95; 95% CI, 0.91-0.99; P = 0.01). Participants with a former GLP-1RA prescription had lower AUDIT-C scores compared with those with future prescriptions, but this difference was not statistically significant. Results were similar using a propensity-score matched comparison group with a lower average AUDIT-C score for the current GLP-1RA group (IRR = 0.89; 95% CI, 0.85-0.93; P = <0.001) and no significant difference for the former prescription group. Analysis of individual AUDIT-C questions shows a significant association with GLP-1RA prescriptions and frequency of drinking but not drinks per occasion or binge drinking. Conclusions and RelevanceThis studys findings indicate that GLP-1RAs may reduce alcohol consumption by decreasing use frequency. Experimental studies and randomized controlled trials are needed to test the mechanisms and potential efficacy of GLP-1RAs in people with AUD. KEY POINTSO_ST_ABSQuestionC_ST_ABSIs there an association between glucagon-like peptide-1 receptor agonist (GLP-1RA) prescriptions and alcohol consumption? FindingsIn this observational cohort study of 15 447 people with GLP-1RA prescriptions in NIHs All of Us cohort, active GLP-1RA prescriptions were associated with significantly lower Alcohol Use Disorders Identification Test (AUDIT-C) scores compared with scores of those who would have GLP-1RAs in the future and of a matched comparison group with no GLP-1RAs. People with former GLP-1RAs did not have lower AUDIT-C scores than these comparison groups. MeaningActive GLP-1RA use may be effective in reducing alcohol consumption.