Diabetes, Obesity and Metabolism

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.

ImportanceGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are among the safest and most effective medications for diabetes and weight loss and are currently used by millions of individuals worldwide. While their cardiometabolic benefits are well established, emerging observational reports have raised concerns about a potential association between GLP-1 RA use and new-onset non-arteritic anterior ischemic optic neuropathy (NAION). ObjectiveTo emulate a target trial evaluating the risk of NAION associated with initiation of semaglutide, a GLP-1RA, compared with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) as second-line therapy for type 2 diabetes in a nationwide cohort of U.S. Veterans. DesignActive-comparator, new-user, target trial emulation. Marginal cause-specific hazard ratios (HRs) were estimated using overlap weighting to account for confounding. Data analysis was conducted from July 2025 to September 2025. SettingThe Veterans Health Administration (VHA) nationwide health care system between March 1, 2018 and March 1, 2025. ParticipantsU.S. Veterans with a diagnosis of type 2 diabetes who were current metformin users and had no prior exposure to GLP-1RAs or SGLT2is. ExposureInitiation of semaglutide or any SGLT2i. Main Outcome and MeasureIncident NAION, identified using ICD-10 and SNOMED diagnosis codes. ResultsA total of 102,361 Veterans met inclusion criteria, including 11,478 new initiators of semaglutide and 90,883 new initiators of an SGLT2i. Baseline characteristics were well balanced between treatment groups after overlap weighting (mean [SD] age, 60.1 [11.7] years; BMI, 37.8 [6.7] kg/m2; hemoglobin A1c, 7.0% [1.4]; 85.5% male; 61.9% non-Hispanic White; 20.7% Black; 8.1% Hispanic). Over a median follow-up of 2.1 years, 153 total incident NAION events occurred. The incidence rate of NAION was 123 per 100,000 person-years among semaglutide initiators and 67 per 100,000 person-years among SGLT2i initiators. Patients who initiated semaglutide had a 2.33-fold higher risk than patients who initiated SGLT2i (HR, 2.33; 95% CI, 1.54-3.54; P<.001). Conclusions and RelevanceIn this nationwide cohort of U.S. Veterans with type 2 diabetes, patients who initiated semaglutide had over a 2-fold increased risk of NAION compared to patients who initiated SGLT2i.

BackgroundParalytic ileus (PI), a condition characterized by reduced bowel motor activity without physical obstruction, can be affected by complications from type 2 diabetes (T2D) and anti-diabetic medications. It is unclear of the causal associations of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with the risk of PI in the context of T2D management. MethodsTo investigate the causal relationship of GLP-1RAs with PI, we conducted a 2-sample mendelian randomization (MR) study based on summary statistics from genome-wide association studies (GWAS). Genetic variants in the GLP1R were identified as genetical proxies of GLP-1RAs by the glycemic control therapy, based on genetic associations with glycated hemoglobin (GWAS n=344,182) and T2D (ncases/controls=228,499/1,178,783). The effects of GLP-1RAs were estimated for PI risk (ncases/controls=517/182,423) using GWAS data from the FinnGen project. ResultsBased on MR analysis, GLP-1RAs are causally associated with a decreased risk of PI (OR per 1 mmol/mol decrease in glycated hemoglobin: 0.21; 95% confidence interval [CI]=0.06-0.69). The magnitude of these benefit exceeded those expected from improved glycemic control more generally. ConclusionsOur studys findings show that GLP-1RAs are causally associated with a lower risk for PI, which provides information to guide clinicians in the selection of appropriate therapies for individuals with T2D while mitigating the risk of developing PI. Investigating the underlying mechanisms that contribute to the lower PI risk associated with GLP-1RAs is essential for a deeper understanding of these associations.

BackgroundThe American Diabetes Association recommends that metformin may be considered for patients with prediabetes. However, evidence on discontinuation and reinitiation patterns of metformin use in patients with prediabetes remains limited ObjectiveTo describe the rates and specific patient characteristics associated with metformin discontinuation and reinitiation in patients with prediabetes. MethodWe conducted a retrospective observational study using longitudinal electronic health record data from the Truveta database. We identified a total of 23,911 new metformin users with a baseline A1C between 5.7% and less than 6.5% in an incident cohort of prediabetes from January 1, 2019, to May 31, 2025. The pattern of metformin utilization was calculated using linked medication dispensing records within the Truveta network. Treatment discontinuation and reinitiation following the first discontinuation were estimated using the Kaplan-Meier model. Cox proportional hazards regression models were applied to evaluate the association between patient characteristics and treatment discontinuation. ResultIn this retrospective cohort, 14,857 patients (62.13%) discontinued metformin during a maximum follow-up of 6 years. Compared with those who continued treatment, patients who discontinued were more likely to be female (10,137 [68.23%] vs 5,642 [62.31%]), have baseline A1C <6% (5,455[36.72%] vs 2,892 [31.94%]), 60 years or younger (5,190 [57.32%] vs 5,190 [57.32%] ), have baseline class 3 obesity (4,434 [26.7%] vs 2,029 [20.6%]). The median time to discontinuation was 0.82 years (95% CI, 0.79-0.85), with 27.15% of patients discontinuing in 90 days after initiation. The cumulative proportion of discontinuation at 1 year and 2 years was 54.45% (95% CI, 53.77-55.13%) and 69.48% (95% CI, 68.77-70.91%), respectively. The proportion of patients reinitiating metformin after the first discontinuation at 1 year and 2 years was 32.44% (95% CI, 31.64-33.25%) and 41.81% (95% CI, 40.89-42.75%), respectively. The median time to reinitiation was 3.81 years (95% CI, 3.44-4.08) ConclusionMost patients with prediabetes discontinued metformin within the first year, and reinitiation was limited, highlighting gaps in adherence and the need for strategies to optimize metformin use in this population.

BackgroundGlucagon-like peptide 1 receptor agonists (GLP-1RAs) have emerged as breakthrough weight loss agents. However, discontinuation is common, and clinical trials have demonstrated significant weight regain following cessation. In this systematic review, we aimed to characterise the trajectory of weight regain after GLP-1RA cessation. MethodsThis systematic review and meta-regression analysis followed Cochrane and PRISMA guidelines. We searched MEDLINE, Embase, Cochrane Library, Scopus and Web of Science from inception to December 26, 2024 for randomised controlled trials and observational studies reporting weight outcomes after cessation of GLP-1RAs in adults with overweight or obesity. Weight regain was the primary outcome and was modelled using nonlinear regression. Secondary outcomes included HbA1c and systolic blood pressure. The study protocol is registered with PROSPERO (CRD420250631751). FindingsWe identified 44 relevant studies. Weight, HbA1c and systolic blood pressure consistently rebounded after cessation of GLP-1RAs. Six trials with 3,236 participants were included in the exponential recovery model. Weight regain was estimated to plateau at 75.6% (95% CI 68.5-82.7) of the weight lost on treatment. The rate constant was 0.0302 per week (95% CI 0.0204-0.0399), corresponding to a half-life of 23.0 weeks. At 1 year after cessation, an estimated 40.2% of the on-treatment weight loss remained. Most studies were assessed to have moderate risk of bias. InterpretationGLP-1RA cessation is associated with a predictable and decelerating pattern of weight regain, which appears to plateau below pre-treatment levels, suggesting that partial weight-loss benefit may persist long-term but is substantially attenuated. FundingNone.

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.

STRUCTURED ABSTRACTO_ST_ABSObjectivesC_ST_ABSTo expose the potential impact of residual confounding in common observational study designs investigating metformin using a type 2 diabetes cohort; to propose a more robust study design for future observational studies of metformin. DesignRetrospective cohort studies using a prevalent user design conducted in two distinct cohorts: individuals with type 2 diabetes and individuals with prediabetes. SettingInsurance claims database for Medicare Advantage beneficiaries in the United States, 2018-2019. An identical analysis of commercial insurance beneficiaries appears in the supplement. Participants404,765 individuals with type 2 diabetes, 81,791 individuals with prediabetes. Main outcome measuresTotal inpatient admission days in 2019, total medical spend (excluding prescription drugs) in 2019. Each of these measures is treated as a binary outcome: greater than zero inpatient days and top 10% medical spend. ResultsWe implement a common observational study design and observe a strong metformin effect estimate associated with reduced inpatient admissions and reduced medical expenditures; we also implement a more robust study design that suggests any estimated effect is attributable to residual confounding related to individuals overall health. ConclusionsCommon observational study designs examining metformin in a type 2 diabetes population are likely impacted by significant residual confounding. By additionally considering numerous negative control outcomes and a complementary prediabetes cohort, the study design proposed here demonstrates efficacy at exposing residual confounding related to overall health, nullifying the claim derived from a standard study design. Trial registrationPreregistration available at https://osf.io/qf49p.

AimThis study aimed to examine the burden of comorbidities and common geriatric syndromes in older adults with type 2 diabetes mellitus in Vietnam and their relationship with poor glycaemic control. MethodsThis is a cross-sectional study of patients aged 60 years or older diagnosed with type 2 diabetes who visited the cardio-metabolic clinics of two urban hospitals in Ho Chi Minh City, Vietnam, between November 2022 and June 2023. Poor glycaemic control was defined as HbA1c [&ge;] 7.0%. Comorbidity severity was assessed using the Charlson Comorbidity Index (CCI). Frailty was defined using Frieds criteria. Polypharmacy was defined as the use of five or more medications daily. Multiple-adjusted logistic regression models were applied to identify the factors associated with poor glycaemic control. ResultsThere were 576 participants. They had a mean age of 71.9 (SD 7.6) years, 46% were female, 30% were frail, 77% had polypharmacy. The mean duration of diabetes was 10.9 years (SD 7.4). The mean CCI was 2.5 (SD 1.1), and 34% of the participants had a CCI [&ge;]3. The most common comorbidities were dyslipidaemia (98%), hypertension (96%), followed by chronic kidney disease (17%), and peripheral artery disease (11%). The prevalence of poor glycaemic control (HbA1c [&ge;] 7%) was 47%. The factors significantly associated with poor glycaemic control were polypharmacy, frailty, and long duration of diabetes. ConclusionThere was a high prevalence of comorbidity, frailty, and polypharmacy among the participants; all were related to poor glycaemic control. Optimizing polypharmacy, frailty and comorbidity is essential in managing long-term diabetes.

BackgroundIndividual weight loss response to the GLP-1 receptor agonist semaglutide varies considerably, with many possible contributing factors. Leveraging multiple clinico-genomic cohorts, we analyzed differences in weight loss trajectories according to patient characteristics, including a polygenic score (PGS) and metabolic risk factors, in semaglutide initiators with BMI [&ge;]27 kg/m2. MethodsThis longitudinal study utilized clinical-grade exome sequencing and electronic health record data from six U.S. cohorts within the Helix Research Network (n=134,806). A BMI PGS was calculated using 26,941 variants. Twelve-month weight loss trajectories were modeled using mixed effects models, and associations with demographics, PGS, comorbidities, medications, and laboratory results were evaluated. FindingsAmong 1,923 semaglutide users, the mean pretreatment BMI was 38.4 kg/m2. For those on doses [&ge;]1.7 mg, the mean body weight reduction was 7.3% at 6 months and 9.9% at 12 months. Over 12 months, low PGS was associated with an adjusted 1.5% and 1.8% additional weight loss compared to intermediate and high PGS, respectively (both p<0.01). Male sex, type 2 diabetes, hypertension, obstructive sleep apnea, and non-alcoholic fatty liver disease were each associated with 1.2%-1.9% less weight loss (all p<0.05). In type 2 diabetes, each 1%-increase in pretreatment hemoglobin A1c was associated with 0.6% less weight loss (p=0.0019). InterpretationAmong adults with overweight or obesity, a lower genetic predisposition to obesity is linked to greater weight loss on semaglutide. Additionally, metabolic health significantly impacts the drugs effectiveness. These findings underscore the importance of precision medicine in obesity management. FundingRenown Health Foundation. Nevada Governors Office of Economic Development. HealthPartners.

BackgroundThe impact of common cardiovascular medications on sarcopenia in older persons is unclear. The aim of this population-based cohort study was to investigate the relationship between long-term intake of statins and renin-angiotensin-system inhibitors (RASi), i.e. angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), and established muscle mass and function parameters. MethodsCommunity dwelling older adults (n=1,083, 52% women, 68.3 {+/-} 3.5 years at baseline) from the Berlin Aging Study II (BASE-II) with a mean follow-up of 7.4 {+/-} 1.5 years were analyzed. Users of statins or RASi were compared to non-users. Appendicular lean mass (ALM) was measured via dual-energy X-ray absorptiometry and related to body mass index (ALM/BMI) and height2 (SMI). Hand grip strength (HGS) was assessed and related to arm muscle mass. The Timed "Up and Go" and Tinetti mobility test were used to evaluate physical performance. Adjusted linear regressions of drug use on muscle mass, strength, and function were conducted. ResultsIn linear regression analysis, statin use was neither associated with any of the muscle mass nor with function parameters. In contrast, RASi users had significantly lower ALM/BMI ({beta}= -0.036, p=0.004). When stratified by sex, the use of RASi was significantly associated with lower ALM/BMI in women ({beta}= -0.033, p=0.029) but not in men ({beta}= -0.037, p=0.072). ConclusionAlthough statins have been associated with adverse muscle events, their use in older adults was not significantly associated with muscle mass or function parameters. In contrast, use of RASi was associated with a lower muscle mass phenotype. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/25332603v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@3f6e5aorg.highwire.dtl.DTLVardef@660b27org.highwire.dtl.DTLVardef@16655a7org.highwire.dtl.DTLVardef@1814dd0_HPS_FORMAT_FIGEXP M_FIG C_FIG

Aims/hypothesisThe aim of this study was to evaluate the impact on metabolic control of the periodic use of a 5-day fasting-mimicking diet (FMD) program as an adjunct to usual care in people with type 2 diabetes under regular primary care surveillance. MethodsIn this randomised, controlled, assessor-blinded trial, people with type 2 diabetes using metformin only and/or diet alone for glycaemic control were randomised to receive 5-day cycles of FMD monthly as adjunct to regular care by their general practitioner or regular care only. Primary outcomes were changes in glucose-lowering medication and HbA1c levels after 12 months. Moreover, changes in use of glucose-lowering medication and/or HbA1c levels in individual participants were combined to yield a clinically relevant primary outcome measure ( glycaemic management), categorized as improved, stable or deteriorated after one year of follow-up. Results100 individuals with type 2 diabetes, age 18-75 years, and BMI > 27 kg/m2, were randomised to the FMD (n=51) or control group (n=49). Eight FMD participants and ten controls were lost to follow-up. In complete case intention-to-treat analyses, the mean medication effect score (MES) significantly declined in patients receiving FMD as compared to controls (FMD -0.2 {+/-} 0.3 vs controls +0.2 {+/-} 0.4, p<0.0001) in the face of similar changes of HbA1c adjusted for MES (FMD -0.4 {+/-} 0.8 % vs controls +0.2 {+/-} 0.8 %, p=0.0021). Glycaemic management improved in 53% of participants using FMD vs 8% of controls, remained stable in 23% vs 33%, and deteriorated in 23% vs 59% (p<0.0001). Conclusions/interpretationIntegration of a monthly FMD program in regular primary care for people with type 2 diabetes who use metformin only and/or diet alone for glycaemic control reduces the need for glucose-lowering medication and appears to be safe in routine clinical practice. Trial registrationClinicalTrials.gov: NCT03811587

IntroductionRecent clinical trials demonstrate that glucagon-like peptide-1 receptor agonists (GLP-1) elicit substantial reductions in glycemia and body weight in people with type 2 diabetes and obesity but must be continued indefinitely to maintain clinical improvements. Given the high cost and poor real-world persistence of GLP-1, an effective maintenance therapy that enables deprescription and sustained clinical improvements would be valuable. Thus, the purpose of this real-world study was to assess the effect of GLP-1 deprescription on glycemia and body weight following co-therapy with carbohydrate restricted nutrition therapy (CRNT) supported via telemedicine in a continuous remote care model among people with type 2 diabetes and excess body weight. Research Design and MethodsA retrospective, propensity score matched cohort study among patients with type 2 diabetes at a nationwide telemedicine clinic was conducted using medical record data. Patients in whom GLP-1 were deprescribed (DeRx; n=154) were matched 1:1 with patients in whom GLP-1 were continued (Rx) or never prescribed (NonGLP). Longitudinal and between matched cohort differences in HbA1c and weight were assessed at enrollment, deprescription/index date, and 6 and 12 months (m) post-deprescription/index date using a linear mixed effects model. ResultsHemoglobin A1c and body weight measured 6 and 12 months following deprescription/index date did not significantly differ between cohorts and improved at deprescription/index date and at follow up intervals compared to enrollment. HbA1c rose 6-and 12m post-deprescription/index in both DeRx and Rx and at 12m in NonGLP (p<0.001) but most patients maintained A1c<6.5%. No regression in body weight was observed with >70% maintaining [&ge;]5% body weight loss 12m post-deprescription/index date. ConclusionsThese results demonstrate that CRNT in a continuous remote care model provides an effective GLP-1 step-off and maintenance therapy, allowing patients to discontinue GLP-1 while maintaining body weight loss and glycemia below therapeutic targets. KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSGlucagon-like peptide-1 receptor agonists (GLP-1) have demonstrated in clinical trials significant reductions in glycemia and body weight among patients with type 2 diabetes and obesity with rapid regression of clinical improvements upon discontinuation of the medication even with persistent caloric restriction and exercise counseling, suggesting the drug must be continued indefinitely. Cost and poor persistence of the GLP-1 therapy pose real-world challenges to maintaining improved health outcomes long-term, so therapies that enable deprescription and maintenance of clinical improvements are needed. What this study addsThis study assessed the potential for utilization of carbohydrate restricted nutrition therapy (CRNT) supported via telemedicine in a continuous remote care model as a GLP-1 step-off and subsequent maintenance therapy. HbA1c and body weight up to 12 months following GLP-1 deprescription did not differ from matched cohorts in whom GLP-1 were continued or never utilized in this real-world study. How this study might affect research, practice or policyThis study informs clinical practice, showing that the CRNT supported by continuous remote care provides an effective GLP-1 step-off therapy, enabling maintenance of improved glycemia and weight loss following GLP-1 deprescription and mitigating the need for lifetime, continuous use of the pharmaceutical.

BackgroundAs prescribing of newer antihyperglycemic agents expands, there remains limited comparative safety data for older adults--a population particularly vulnerable to adverse drug events and underrepresented in clinical trials. We aimed to evaluate the real-world safety of second-line antihyperglycemic agents among older adults with type 2 diabetes. MethodsWe conducted a multinational cohort study using nine harmonized electronic health record and claims databases from the U.S. and Europe, applying a consistent analytical framework based on the LEGEND-T2DM initiative. Among adults aged [&ge;]65 years who initiated a second-line agent after metformin monotherapy, we compared safety outcomes across four drug classes: GLP-1 receptor agonists (GLP1RAs), SGLT2 inhibitors (SGLT2Is), DPP-4 inhibitors (DPP4Is), and sulfonylureas (SUs). We used propensity score adjustment, empirical calibration, and prespecified diagnostics to estimate hazard ratios (HRs) for 18 safety outcomes. ResultsIn a cohort of 1.8 million older adults, both GLP1RAs and SGLT2Is were linked to significantly lower risks of hypoglycemia (HR 0.21 [95% CI, 0.16-0.27] for GLP1RA vs SU; HR 0.21 [0.13- 0.33] for SGLT2I vs SU) and hyperkalemia (HR 0.63 [0.50-0.81] for GLP1RA vs SU; HR 0.75 [0.63-0.90] for SGLT2I vs SU) and peripheral edema (HR 0.81 [0.71-0.92] for GLP1RAs vs. DPP4Is; HR 0.62 [0.46-0.84] for SGLT2Is vs. SU). However, SGLT2Is were associated with a higher risk of diabetic ketoacidosis compared to both GLP1RAs (HR 2.03 [1.38-2.99]) and SUs (HR 1.64 [1.27-2.11]). GLP1RAs had significantly higher risks of nausea (HR 0.63 [0.55-0.72]) and vomiting (HR 0.63 [0.57-0.69]) relative to SGLT2Is. Results were consistent across both on-treatment and intent-to-treat sensitivity analyses. ConclusionIn older adults with type 2 diabetes, GLP1RAs and SGLT2Is demonstrated more favorable safety profiles than SUs and DPP4Is across multiple clinically relevant outcomes. These results support more informed, safety-conscious prescribing in a population underrepresented in clinical trials yet highly susceptible to adverse effects.

Background: GLP-1 receptor agonists (GLP1-RAs) are an established treatment for type 2 diabetes mellitus (T2DM) and obesity. Their widespread use is set to increase through both indication expansion and patent expiry. As well as efficacy, it is crucial to understand the safety of this drug class to enable optimal use. Here we demonstrate how a genetic approach can augment signal-detection and post-market authorization surveillance. Methods: We used single nucleotide polymorphisms (SNPs) in GLP1R to recapitulate the effect of agonism with GLP1RAs on circulating glucose, glycated hemoglobin (HbA1c), body mass index (BMI) and risk of type 2 diabetes (T2DM) using Mendelian randomisation. We then tested if the adverse effect highlighted by medicines regulators of pancreatitis and the emerging effect of sarcopenia were causally related to GLP1R agonism, using this approach. Analyses were conducted in UK biobank and replicated in FinnGen and All of Us, results being combined using meta-analysis. Analyses were further stratified by a priori risk factors of age and alcohol consumption. Results: Genetically proxied GLP-1R agonism was associated with a reduction in glucose (exp({beta}) = 0.95 95% CI [0.94, 0.97]), HbA1c (exp({beta}) = 0.94 95% CI [0.92, 0.95]), and BMI (exp({beta})=0.98 95% CI [0.97, 0.99]); and a reduced risk of T2DM (OR = 0.82 95% CI [0.79 to 0.86]). Risk of acute and chronic pancreatitis was however increased (OR = 1.10 95% CI [1.01 to 1.20] and OR = 1.05 95% CI [0.95, 1.17], respectively), which varied as a function of age with risk most pronounced in those aged 50-59 years-old (OR = 1.79 95% CI [1.43, 2.24], OR = 1.57 95% CI [1.16, 2.12]) and in drinkers (OR = 1.32 95% CI [1.12, 1.54], OR = 1.36 95% CI [1.12, 1.65]). Risk of sarcopenia also increased (OR 1.34; 95% CI 1.05,1,71). Conclusions: Genetically proxied agonism with GLP-1RAs recapitulated the pharmacological effects of GLP1-1RAs on glycaemic traits, BMI and T2DM risk. This approach supports a causal effect of GLP-1RAs on the well reported adverse effects of pancreatitis and further indicates age and alcohol consumption as risk modifying effects. The less well reported but emerging effect of sarcopenia appears to also be casually related to agonism at GLP-1R. These analyses suggest a genetic approach could be used as an adjunct to signal detection studies to enhance safety regulation as well as personalisation of the use of these drugs.

Context: Prader-Willi syndrome is a genetic neurodevelopmental disorder characterized by hyperphagia and early-onset obesity from hypothalamic dysfunction with endocrinopathies and learning disability. Management is challenging with strict control of the food environment needed. While newer glucagon-like peptide-1 receptor agonists, such as semaglutide, have efficacy in non-PWS obesity, there have been limited case reports in PWS. Objective/Design/Setting: Retrospective records review of 12 adults with PWS and overweight/obesity treated with semaglutide at a UK academic hospital centre specialist clinic. Patients: mean +/- SD age 28.3 +/- 10.1 years, 83% female, BMI 46.6 +/- 8.2kg/m2, 75% type 2 diabetes mellitus. Intervention: Median follow-up 17.2 months (range 8.7-36.1) with median semaglutide dose 2.4mg once weekly (1.0-2.4). Results: Although there was no significant weight loss on semaglutide, there was stabilisation of the weight gain prior to treatment over previous 12.4 months (7.6-23.0) (post -3.1 +/- 9.9% vs. pre +5.7 +/- 5.6%: d -0.72, P=0.037). There was a significant decrease in hyperphagia on semaglutide from hyperphagia questionnaire for clinical trials (n=11, -7.3 +/- 6.1 (max 36), d -1.19, P=0.003), having been stable before treatment. HbA1c improved in those with elevated baseline levels (n=6, -4.2 +/- 4.9%, d -0.74, P=0.13). Mild gastrointestinal side effects were seen in 25% but did not lead to discontinuation. Conclusions: In adults with PWS, semaglutide produced weight maintenance, reduced hyperphagia, and improved glycaemic control, with good tolerability. Larger placebo-controlled trials are needed to confirm these findings in adults and adolescents with PWS, especially in those without T2DM, where efficacy may be greater.

IntroductionEarly-onset type 2 diabetes (EOD), defined as type 2 diabetes diagnosed before age 45, is a growing public health problem. Adolescence is a critical period for prevention interventions because related health behaviors and biological processes are established during this time. Early screening for type 2 diabetes risk including prediabetes (preDM) could identify youth most in need of intervention but unlike for adults, no questionnaire-based youth risk screeners exist. In this study, we assessed the ability of adapted American Diabetes Association (ADA) screening guidelines in adolescence to predict EOD and prediabetes (preDM/EOD) in adulthood. MethodsWe used data from the National Longitudinal Study of Adolescent to Adult Health (Add Health). We applied ADA guidelines (modified to align with available data) in Waves I and II, when participants were 12-19, and assessed ability to predict preDM/EOD in Waves IV and V, when participants were 24-43. We then calculated screening performance measures with (N=13,530) and without (N=14,540) accounting for the survey design. ResultsIn weighted analyses, 40% of participants (5,383) had preDM/EOD based on biomarkers at Waves IV-V. Of these participants, 1,272 were considered at risk according to the ADA screening criteria in Waves I-II (sensitivity=23.6%). Of 8,147 participants without preDM/EOD, 7,218 were not considered at risk in Wave I-II (specificity=88.6%). The screening guidelines had a positive predictive value (PPV) of 57.8% and a negative predictive value (NPV) of 63.7%. The F+ and F- measures were 33.5% and 74.1%, respectively. Unweighted analyses produced similar results. ConclusionsAdapted ADA youth screening guidelines demonstrated poor ability to predict preDM/EOD before age 45. Although specificity was high, sensitivity was low: 76% of participants who developed preDM/EOD would not have been identified as at risk in adolescence using the adapted ADA guidelines. Given the high prevalence of preDM/EOD, there is a need for better screening tools to identify youth at risk and better target diabetes prevention interventions.

BackgroundTo evaluate the association between Glucagon-like peptide-1 receptor agonists (GLP-1RA) use and the risk of acute diabetes complications among adults with type 1 diabetes (T1D) who were eligible for anti-obesity medication (AOM) treatment. MethodsWe employed a target trial emulation using EHR data from the OneFlorida+ network (2014-2024) to investigate the association between GLP-1RA initiation and acute diabetes complications among adults with T1D. Eligible participants were adults with a diagnosis of T1D and who met clinical criteria for AOM treatment. GLP-1RA initiators were 1:1 matched to non-initiators using time-conditional propensity scores. The primary outcome was the occurrence of diabetic ketoacidosis (DKA). Secondary outcomes included severe hypoglycemia, all-cause hospitalizations, and emergency department (ED) visits. Cox proportional hazards models were utilized to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). We applied a causal learning approach to explore heterogeneous treatment effects. FindingsThe matched cohort included 651 GLP-1RA users and 651 non-users. For GLP-1RA users and non-users, the incidence rates were 13.5 vs. 21.8 per 1,000 person-years for DKA. Compared to non-users, GLP-1RA use was not significantly associated with incidence of DKA (HR 0.62 [95%CI 0.33-1.17]) or severe hypoglycemia (HR 0.52 [95%CI 0.17-1.55]); notably, GLP-1RA use was significantly associated with fewer hospitalizations (HR 0.74 [95%CI 0.62-0.90]) and ED visits (HR 0.73 [95%CI 0.57-0.92]). InterpretationAmong adults with T1D and obesity, GLP-1RA use was not associated with an increased risk of DKA or severe hypoglycemia but was linked to fewer ED visits and hospitalizations. FundingThe study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) R01DK133465.

OBJECTIVETo assess changes in insulin secretion and sensitivity in subgroups of adult-onset diabetes (derived from cluster analysis of GADA-positivity, BMI, age, HbA1c, HOMA2-B and HOMA2-IR), the stability of the subgroup assignment, and the association between steatotic liver disease (SLD), liver fibrosis (LF) and tissue insulin resistance. RESEARCH DESIGN AND METHODSParticipants registered in a regional diabetes register within three years from diagnosis, were restudied 2-10 years later with fasting laboratory tests and a questionnaire (n=547). A subset (n=194) participated in a clinical investigation including estimation of insulin secretion and sensitivity with i.v. glucagon-insulin tolerance test, and SLD/LF with elastography. RESULTSDifferences between subgroups attenuated during the follow-up. Obesity and age-related subgroups (MOD & MARD) were most stable with >76% assigned to the same cluster at registration and follow-up, whereas that hold for <25% in the groups characterized by insulin deficiency or resistance (SIDD & SIRD). Despite stable BMI, HOMA2-B and HOMA2-IR decreased significantly during follow-up but remained highest in the SIRD group. Prevalence of SLD/LF was highest in SIRD (70%/42%) and MOD (60%/41%). The differences between subgroups were mainly explained by BMI. However, LF was associated (OR [95% CI]) with insulin resistance in liver (3.90 [2.05-7.42]; p<0.001), adipose tissue (1.14 [1.06-1.22]; p<0.001]) and muscle (0.33 [0.17-0.64]; p<0.001), independently of BMI or SLD. CONCLUSIONSCluster assignment should be performed near diagnosis, as the more severe phenotypic features attenuate with time (or treatment). To assess the risk of LF in individuals with diabetes, the degree of insulin resistance should be evaluated, not only BMI. TWITTER SUMMARYDiabetes consists of heterogenous disease phenotypes, and disease stratification could improve targeting of interventions. Previously, we suggested dissecting adult-onset diabetes into five cluster-based subgroups using six easily accessible variables (GAD-antibodies, BMI, age, HbA1c, HOMA2-B and HOMA2-IR) measured at or near diagnosis. In this study, we assessed changes in insulin secretion and sensitivity, stability of subgroup assignment and association of steatotic liver disease (SLD) and liver fibrosis (LF) with tissue insulin resistance 2-10 years after diagnosis. Differences between subgroups attenuated during follow-up. In the obesity and age-related subgroups (MOD & MARD) >76% were assigned to the original cluster when classified at follow-up, whereas this was true for <25% of the groups characterized by insulin deficiency or resistance (SIDD & SIRD). HOMA2-B and HOMA2-IR decreased significantly but were still highest in the SIRD group at the follow-up visit. SLD/LF were most common in SIRD and MOD, with differences compared to other subgroups mainly explained by BMI. LF was also associated with insulin resistance in liver, adipose tissue and muscle, independently of BMI or SLD. Cluster assignment performed near diagnosis is thus preferred, as phenotypic features attenuate with time. Insulin resistance should be evaluated when assessing the risk of LF in individuals with diabetes. ARTICLE HIGHLIGHTSa) We investigated cluster-stability, liver health and changes in insulin resistance and insulin deficiency in cluster-based diabetes subgroups b) Are there differences between subgroups? Does insulin resistance associate with liver steatosis and fibrosis in subgroups of diabetes? c) We observed a major shift towards the more common obesity and age-related clusters after the follow-up. Liver fibrosis was mainly associated with insulin-resistant and obesity-related subgroups and, independently of BMI or liver steatosis, with insulin resistance of different tissues. d) The phenotypic features of the subgroups attenuate with time and treatment, indicating the need for clustering to be performed at diagnosis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/25340818v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1e608c2org.highwire.dtl.DTLVardef@1491e75org.highwire.dtl.DTLVardef@16ea258org.highwire.dtl.DTLVardef@6455ae_HPS_FORMAT_FIGEXP M_FIG C_FIG

Background and AimA growing body of evidence shows that upon extensive weight loss returning to non-diabetic glucose control is possible in people with recent onset type 2 diabetes (T2D). However, the impact of diabetes duration and different intervention strategies on remission is not clear. Thus, we investigated the remission of T2D in response to three months of two very low-calorie diets (VLCDs) with different macronutrient profiles in individuals with short and long diabetes duration. MethodsParticipants with a BMI >27 kg/m2 and T2D duration of [&le;]4 years or [&ge;]8 years were studied before and after following a VLCD strategy (600-800 kcal/day) for three months including discontinuation of antidiabetic medication. Individuals were stratified by diabetes duration and randomly assigned to one of two VLCDs with slightly different macronutrient composition. Phenotyping included mixed meal tolerance test (MMTT), metabolic characterization and assessment of body composition. ResultsFifty-two (30 women, 22 men) participants were enrolled between September 2020 and November 2022 into the trial and 47 participants completed the intervention. Remission of T2D, defined as plasma fasting glucose levels <126 mg/dl, was achieved in 34 participants (72%). Despite similar weight loss of subjects with a diabetes duration [&le;]4 years and [&ge;]8 years (-15.2 {+/-} 5.8 kg vs. -13.9 {+/-} 4.8 kg; p = 0.473), subjects with diabetes duration [&ge;]8 years had a 32% lower remission rate (82% vs. 50%; p = 0.027). Remission rates also differed between the two formula diets and were found to be higher with the high-fiber, high-protein, and low-carb, low-fat formula diet (91% vs. 56%; p = 0.008). In addition, individuals that achieved a remission had significantly lower fasting plasma glucose and higher C-peptide levels at baseline. ConclusionsOur findings show that significant body weight loss through VLCDs can induce T2D remission in nearly three-quarters of participants. Fasting plasma glucose and C-peptide levels, diabetes duration, and used macronutrient profile emerged as important factors for the achievement of diabetes remission, although a considerable remission is still possible after a long duration of T2D.

Background. GLP-1 receptor agonist trials are tightly controlled: standardized titration, intensive dietary counseling, frequent in-person follow-up, and rigorous exclusion criteria. The real world is none of those things. In a U.S. telehealth GLP-1 program, diet engagement, exercise, medication choice, dose timing, and out-of-pocket cost vary substantially from patient to patient. Whether trial-level efficacy translates into the outcomes a patient and clinician will actually see is an open question, and the answer matters, because telehealth is now where most GLP-1 prescribing happens. Methods. We conducted a retrospective cohort study of 13,507 adults who used a single GLP-1 agent (tirzepatide or semaglutide) through the Mochi Health telehealth obesity program and had a documented six-month weight observation. The primary outcome was achievement of >=10% total body weight loss at six months. To address selection bias in the tirzepatide-semaglutide comparison, we used 1:1 nearest-neighbor propensity-score matching on age, sex, baseline BMI, baseline weight, and comorbid diabetes, hypertension, dyslipidemia, and prior bariatric surgery (recorded at intake), with a 0.25 SD caliper on the propensity logit. We drew a directed acyclic graph (DAG) with a clinical co-author to make the identifying assumptions explicit and to mark where unobserved variables (insurance, socioeconomic status, concomitant medications such as metformin) limit causal interpretation. We report multivariable predictors via logistic regression, compute an E-value for the matched contrast, and benchmark our point estimates against landmark RCT outcomes. Results. Overall, 59.1% of patients achieved >=10% loss at six months, with mean loss of 11.5% (median 11.3%). Threshold attainment was 86.6% at >=5%, 59.1% at >=10%, 27.5% at >=15%, and 9.1% at >=20%. The unadjusted tirzepatide-semaglutide response gap was +16.0 percentage points (68.8% vs 52.8%); after 1:1 propensity-score matching (3,480 pairs, all post-match |SMD| < 0.05) the gap was +18.1 percentage points (69.6% vs 51.6%, 95% CI +15.9 to +20.3). Matching on the measured covariates did not attenuate the advantage, indicating that selection on those characteristics does not explain it; the matched risk ratio was 1.35 (E-value 2.04). The gap was unchanged when a self-reported insurance indicator was added to the matching (+18.4 pp) and remained large (+14.2 pp) within patients who reached a therapeutic dose. Multivariable predictors of response were tirzepatide (OR 2.10, 1.95-2.26), female sex (OR 1.37, 1.20-1.56), and prior bariatric surgery (OR 1.36, 1.18-1.57); response was lower with comorbid diabetes (OR 0.84, 0.77-0.92) and, modestly, with higher baseline BMI per unit (OR 0.98, 0.97-0.99). Response varied by baseline BMI, from 58.0% in overweight patients (BMI <30) and a peak of 63.5% in Obese I to 52.4% in Obese III. Conclusions. Real-world response to GLP-1 therapy in a telehealth setting is meaningfully attenuated from RCT benchmarks but remains clinically substantial: roughly three in five patients reach the 10% threshold. The tirzepatide advantage over semaglutide is large and, notably, does not shrink under propensity-score matching on measured confounders, so it is not an artifact of the observed selection variables; an unmeasured confounder would need a risk-ratio association of about 2.0 with both drug choice and response to explain it away (E-value 2.04). The findings are observational, conditional on the DAG's identifying assumptions, and unmeasured confounders (insurance, socioeconomic status, concomitant medications) remain possible.