Diabetes, Obesity and Metabolism

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 [≥]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.

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.

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.

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

BackgroundIndividuals with severe mental disorders represent a very high-risk population for diabetes and its complications. Physical inactivity and sedentary behavior are shared behavioral risk factors for type 2 diabetes (T2DM) comorbidity. However, whether the protective effect of physical activity (PA) on T2DM is modified by obesity and age, and its specific dose-response relationship, remain unclear. MethodsThis study utilized cross-sectional data from 5,042 adults in the 2017-2020 National Health and Nutrition Examination Survey (NHANES). Weighted multivariable logistic regression and restricted cubic splines (RCS) models were employed to analyze the association between PA and T2DM risk and to assess the potential effect modification by BMI and age. ResultsAfter adjusting for confounders, higher levels of PA were independently associated with a lower risk of diabetes. Dose-response analysis using RCS revealed significant effect modification: the protective effect of PA exhibited a distinct "BMI gradient," being strongest in normal-weight individuals, attenuated in those with overweight, and absent in those with obesity. Concurrently, an "age stratification" was observed, with the protective effect being strongest in middle-aged adults, showing a borderline significant trend in young adults, and demonstrating no significant association in older adults. ConclusionThis study confirms that the protective effect of PA against T2DM is jointly modified by obesity and age. Future prevention strategies should shift from universal recommendations towards precise, stratified guidance based on BMI and age, which holds significant implications for the integrated care of individuals with mental disorders.

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.

AimSGLT2 inhibitors provide multiple benefits to patients with type 2 diabetes - including improved glycemic control and decreased risks of cardiorenal disease. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. MethodsCanagliflozin (300 mg) was administered to 30 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including drug-induced increases in urinary excretion of glucose, sodium, and uric acid. ResultsThis pilot study confirmed that canagliflozin (300 mg) triggered acute changes in mean levels of several biomarkers: fasting plasma glucose (-4.1 mg/dL; p=6x10), serum creatinine (+0.05 mg/dL; p=8x10-4), and serum uric acid (-0.90 mg/dL; p=5x10-10). The effects of sex on glucosuria depended upon how data were normalized. Whereas males responses were [~]60% greater when data were normalized to body surface area, males and females exhibited similar responses when glucosuria was expressed as grams of urinary glucose per gram-creatinine. The magnitude of glucosuria was not significantly correlated with fasting plasma glucose, estimated GFR, or age in these healthy non-diabetic individuals with estimated GFR>60 mL/min/1.73m2. ConclusionsNormalizing data relative to creatinine excretion will facilitate including data from males and females in a single analysis. Furthermore, because our ongoing pharmacogenomic study (NCT02891954) is conducted in healthy individuals, this will facilitate detection of genetic associations with limited confounding by other factors such as age and renal function. RegistrationNCT02462421 (clinicaltrials.gov) FundingResearch grants from the National Institute of Diabetes and Digestive and Kidney Diseases: R21DK105401, R01DK108942, T32DK098107, and P30DK072488.

ObjectiveOlder adults are underrepresented in trials, meaning the benefits and risks of glucose lowering agents in this age group are unclear. We applied causal analysis to assess the safety and effectiveness of SGLT2-inhibitors in people with type 2 diabetes (T2D) over 70. Research Design and MethodsHospital-linked UK primary care data (Clinical Practice Research Datalink, 2013-2020) were used to compare adverse events and effectiveness in individuals initiating SGLT2-inhibitors compared to DPP4-inhibitors. Analysis was age-stratified: <70 years (SGLT2-inhibitors n=66810, DPP4-inhibitors n=76172), [&ge;]70 years (SGLT2-inhibitors n=10419, DPP4-inhibitors n=33434). Outcomes were assessed using the Instrumental Variable causal inference method and prescriber preference as instrument. ResultsRisk of DKA was increased with SGLT2-inhibitors in those aged [&ge;]70 (Incidence risk ratio compared to DPP4i: 3.82 [95%CI 1.12,13.03]), but not in those <70 (1.12 [95%CI 0.41,3.04]). However incidence rates with SGLT2-inhibitors in those [&ge;]70 was low (29.6 [95%CI 29.5,29.7]) per 10000 person-years. SGLT2-inhibitors were associated with similarly increased risk of genital infection in both age groups (IRR <70 2.27 [2.03,2.53]; [&ge;]70 2.16 [1.77,2.63]). There was no evidence of an increased risk of volume depletion, poor micturition control, urinary frequency, falls or amputation with SGLT2-inhibitors in either age group. In those [&ge;]70, HbA1c reduction was similar with SGLT2-inhibitors and DPP4-inhibitors (-0.3 mmol/mol [-1.6,1.1], -0.02% [0.1,0.1]), but in those <70 SGLT2-inhibitors were more effective (-4 mmol/mol [4.8,-3.1], -0.4% [-0.4,-0.3]). ConclusionsCausal analysis suggests SGLT2-inhibitors are effective in adults [&ge;]70, but increase risk for genital infections and DKA. Our study extends RCT evidence to older adults with T2D. Article HighlightsWhy did we undertake this study? - Current guidelines for type 2 diabetes recommend an individualised approach to treatment, but evidence for older adults is limited. What is the specific question(s) we wanted to answer? - To assess the safety and effectiveness of SGLT2-inhibitors in older adults by applying a causal inference framework to address potential confounding bias in observational data. What did we find? - SGLT2-inhibitors are effective in reducing HbA1c and weight and generally safe for older adults. Adverse events in this older group include genital infections and a small increase in DKA. What are the implications of our findings? - SGLT2-inhibitors are effective and safe for older adults, but clinicians should be aware of the risks for genital infections and DKA.

ObjectiveCombinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. To this end we investigated the metabolic effects of co-administration of previously reported peptide-based GIPR antagonists with the GLP-1 agonist liraglutide. MethodsTwo GIPR peptide antagonists, GIPA-1 (mouse GIP(3-30)NH2) and GIPA-2 (NAc-K10[{gamma}E{gamma}E-C16]-Arg18-hGIP(5-42)), were pharmacologically characterised in vitro in an assay measuring cAMP production in CHO-K1 cells overexpressing the mouse GIPR. These peptides were then characterised in vivo in lean mice for their effect on oral glucose tolerance, as well as their ability to antagonize exogenous GIP action. Finally, a mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of peptide-based GIPR antagonists, alone or in combination with liraglutide. ResultsIn vitro, both GIPR peptides exhibited potent antagonistic properties, with GIPA-2 being the more potent of the two. Acute in vivo administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and circulated insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels, with offsetting effects on glycemia noted with co-administration with exogenous mouse GIP, suggesting true antagonism via GIPA-2 at the GIP receptor. Chronic administration studies in a DIO mouse model showed expected effects of GLP-1 agonism (via liraglutide), lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy with the GIPR antagonists and GLP-1 showed separation from single intervention arms though augmented insulin sensitizing effects (modestly lowering insulin and HOMA-IR) and lowering plasmas triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2. ConclusionWe conclude that, in contrast to the well-documented effects of GLP-1R agonism, systemic administration of peptide-based GIPR antagonists demonstrate minimal benefit on metabolic parameters in DIO mice, exhibiting no major effects on body weight, food intake and glycaemic parameters. However, the co-administration of both a GIPR antagonist together with a GLP1 agonist uncovers interesting synergistic and beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism.

ImportanceSodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor analogues (GLP1ra) and dipeptidyl peptidase-4 inhibitors (DPP4i) improve hyperglycaemia and, in the case of SGLT2i and GLP1ra, reduce the risk of major adverse cardiovascular events (MACE) in type 2 diabetes. It is not clear whether efficacy varies by age or sex. ObjectiveAssess whether age or sex are associated with differences in efficacy of SGL2i, GLP1ra and DPP4i. Data sourcesMedline, Embase and clinical trial registries. Study selectionTwo independent reviewers screened for randomised controlled trials of SGLT2i/GLP1ra/DPP4i, compared to placebo/active comparator, in adults with type 2 diabetes. Data extraction and synthesisWe sought individual participant data (IPD) all eligible studies. Where IPD were available, we modelled age- and sex-treatment interactions for each trial. Otherwise, we assessed age- sex distributions along with results from aggregate trial data. IPD and aggregate findings were combined in a Bayesian network meta-analysis. Main outcome measuresHbA1c and MACE. ResultsWe identified 616 eligible trials (604 reporting HbA1c, 23 reporting MACE) and obtained IPD for 75 trials (6 reporting MACE). Mean age was 59.0 (10.7) years and 64.0 (8.6) in HbA1c and MACE trials, respectively. Proportions of female were 43.1% and 44.0% in HbA1c and MACE trials, respectively. SGLT2i reduced HbA1c by 0.5-1.0% overall compared to placebo. This reduction versus placebo was attenuated in older participants (change in HbA1c 0.25 percentage-points less for 75-year-olds compared to 45-year-olds). SGLT2i showed greater relative efficacy in MACE risk reduction among older than younger people. This finding was sensitive to the exclusion of one of the IPD MACE trials, however, in all sensitivity analyses, SGLT2i were either as efficacious or more efficacious in older participants. There was no consistently significant difference in efficacy by age for GLP1ra or DPP4i for HbA1c or MACE, nor were there consistent significant sex differences for any class. ConclusionNewer glucose-lowering drugs are efficacious across age and sex groups. SGLT2i are more cardioprotective in older than younger people despite smaller HbA1c reductions. Age alone should not be a barrier to treatments with proven cardiovascular benefit providing they are well tolerated align with patient priorities.

Prescription of sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) among patients with guideline-directed indications remains limited with substantial inter-prescriber variability. In this prospective study of US adults, we used administrative claims database of individuals with type 2 diabetes and compelling indications for SGLT-2i and GLP-1RA to evaluate the impact of healthcare visits with certain specialty providers on the initiation of these medications. These specialties included family medicine, internal medicine, cardiology, endocrinology, and nephrology. Overall, 294,988 individuals eligible for SGLT-2i and 198,525 for GLP-1RA were identified. In 2019-2020, SGLT-2i and GLP-1RA were initiated in 10.4% and 16.7% of eligible individuals, respectively. After accounting for patient characteristics and comorbidities, healthcare visit with endocrinologists was associated with the highest rate of initiation of either drug across specialties (OR=2.16 [2.08-2.24] for SGLT-2i, and 2.76 [2.64-2.88] for GLP-1RA). Healthcare visits with cardiologists and with family medicine and internal medicine physicians were only modestly associated with initiation of SGLT-2i and GLP-1RA. The study highlights the need for broad education for expansion of the use of these medications rather than focus on dedicated specialty clinics.

ImportanceAdherence to GLP-1 RA is important for efficacy. Discontinuation and reinitiation patterns for patients with and without type 2 diabetes (T2D) are not well-understood. ObjectiveTo describe rates and factors associated with discontinuation and reinitiation of GLP-1 RA, for patients with and without T2D. DesignIn this retrospective cohort study, adults with overweight or obesity initiated on GLP-1 RA between January 2018 and December 2023 were identified using electronic health record (EHR) data from a collective of 30 US healthcare systems. Patients were followed for up to 2 years to assess discontinuation and for 2 additional years to assess reinitiation. SettingClinical and prescribing data from EHRs linked to dispensing information ParticipantsAdults newly initiated on GLP-1 RA between 2018 and 2023, with a baseline BMI [&ge;]27 and an available weight measurement within 60 days before initiation, and regular care in the year before initiation. Exposure/CovariatesPatients were stratified by presence of T2D at baseline. Associations with socio-demographics, health factors, weight changes, and gastrointestinal (GI) adverse events (AE) were modeled. Main Outcomes and MeasuresProportion of patients discontinuing and reinitiating GLP-1 RA were estimated from Kaplan-Meier models. Associations between covariates and discontinuation and reinitiation outcomes were modeled using time-varying Cox proportional hazards models. All analyses were conducted for patients with and without T2D. ResultsAmong 96,544 adults initiating GLP-1 RA, the mean (SD) age was 55.1 (13.3) years, 65.2% were female, 73.7% were white, and 61.3% had T2D. Individual income exceeded $50,000 for 49.7% of patients with and 57.2% of patients without T2D. One-year discontinuation was significantly higher for patients without T2D (65.1%), compared to those with T2D (45.8%). Higher weight loss, absence of GI AE, and higher income (T2D only) were significantly associated with higher discontinuation. Of 28,142 who discontinued and had a discontinuation weight available, one-year reinitiation was lower for those without T2D (34.7%), compared to those with T2D (51.0%). Weight re-gain was significantly associated with increased reinitiation. Conclusions and RelevanceMost patients with overweight or obesity discontinue GLP-1 RA within 1 year, but those without T2D discontinue at higher rates and reinitiate at lower rates. Inequities in access and adherence to effective treatments have the potential exacerbate disparities in obesity. Key pointsO_ST_ABSQuestionC_ST_ABSHow frequently do adults with overweight or obesity discontinue and subsequently reinitiate GLP-1 RA? What factors are associated with these outcomes? FindingsIn this study of 96,544 patients initiating GLP-1 RA, 46% of patients with and 65% without type 2 diabetes (T2D) discontinued within 1 year. Weight loss, income, gastrointestinal adverse events, and comorbidities were significantly associated with discontinuation. Following discontinuation, 51% of patients with and 35% without T2D reinitiated within a year. Weight re-gain since discontinuation was significantly associated with reinitiation. MeaningWhile most patients discontinue GLP-1 RA within a year, discontinuation is significantly higher and reinitiation is significantly lower for patients without T2D. Weight changes, tolerability, and proxies of access to care are significantly associated with sustained treatment.

Aims/HypothesisIt is important to address our use of cheaper generic therapies as the global prevalence of type 2 diabetes (T2DM) will surpass 600 million by 2035. Negative aspects of SU may be avoided by their use at low dose. We have previously shown that 20mg standard release gliclazide reduces plasma glucose through augmentation of the classical incretin effect, increased beta-cell glucose sensitivity and late-phase incretin potentiation. We hypothesised that there would be potential synergy between low dose SU when given in combination with a DPP4i, without increased hypoglycaemia risk, and aimed to assess this in a randomised clinical trial. Methods30 participants with T2DM (HbA1c <64 mmol/mol) treated with diet or metformin monotherapy were recruited to a single-centre, open-label, randomised crossover study. Participants completed four, 14-day study periods in a random order: control, gliclazide 20mg once daily (SU), sitagliptin 100mg (DPP4i), or combination (SUDPP4i). A 2-hour mixed meal tolerance test was conducted at the end of each block. Beta-cell function was assessed by modelling. The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary end points included frequency of blood glucose <3mmol/l on continuous glucose monitoring, sub analysis by genotype (KNCJ11 E23K), and analysis by gender and body mass index. ResultsLinear mixed model estimates showed a potent additive, glucose lowering effect of low dose SU combination with DPP4. Mean glucose AUC (mean 95% CI) (mmol/l) was: Control 11.5 (10.7 - 12.3), DPP4i 10.2 (9.4 - 11.1), SU 9.7 (8.9 - 10.5), SUDPP4i 8.7 (7.9 - 9.5) (p <0.001). Beta-cell glucose sensitivity (pmol min-1 m-2 mM-1) mirrored this additive effect: Control 71.5 (51.1 - 91.9), DPP4i 75.9 (55.7 - 96.0), SU 86.3 (66.1 - 106.4), SUDPP4i 94.1 (73.9 - 114.3) (p = 0.04). Glucose time in range <3mmol/l on CGM (%) was unaffected: Control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2 - 7) (p = 0.65). The increase in glucose sensitivity with sulphonylurea treatment was seen in men not women. ConclusionsCombination low dose gliclazide with a DPP4i has potent glucose lowering effect through augmentation of beta cell function. Glucose reduction was achieved at gliclazide concentrations far below those achieved with standard therapeutic doses. A double-blind randomised controlled trial is merited to formalise efficacy and safety of this combination, which may avoid negative aspects of SU and provide pharmacoeconomic benefit in diabetes care. Research in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABSPrevious isoglycaemic clamp studies in low dose sulphonylureas established that 20mg of gliclazide augments the classical incretin effect, increases glucose sensitivity by 50% and late phase incretin potentiation. What is the key question?What is the effect of low dose sulphonylureas as monotherapy or in combination with a DPP4i on parameters of beta cell function following a mixed meal? What are the new findings?Low dose sulphonylureas have potent glucose lowering potential which is further enhanced by the addition of a DPP4i, without increasing hypoglycaemia. Modelling of beta cell function demonstrates that low dose sulphonylureas heighten the beta cell dose response which is further augmented by the presence of a DPP4i. Phenotypic differences in response are noted, with male participants showing additional effect of glucose sensitivity in response to sulphonylureas. This effect is not seen in women. Gliclazide standard release at 20mg produces a similar pharmacokinetic profile during mixed meal tolerance test to 30mg of modified release gliclazide. How might this impact on clinical practice in the foreseeable future?These results suggest that it is possible to modernise the use of two cheap, effective second-line treatments of type 2 diabetes mellitus through future production of a combined preparation of low dose gliclazide and a DPP4i. This combination has real potential as a safe, efficacious treatment which could bring pharmacoeconomic benefit to low- and middle-income countries worldwide.

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.

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.

Glucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonists may provide greater weight loss than agonists targeting the GLP-1 receptor alone. We report results from three phase 1 trials investigating the glucagon/GLP-1 receptor co-agonist NNC9204-1177 (NN1177) for once-weekly subcutaneous use in adults with overweight or obesity. Our focus was a 12-week multiple ascending dose (MAD), placebo-controlled, double-blind trial in which adults (N=99) received NN1177 (dose-escalated to treatment doses of 200, 600, 1,300, 1,900, 2,800, 4,200, and 6,000 g) or placebo. Two other trials also contribute to the findings in this report: a first human dose (FHD) / single ascending dose (SAD), placebo-controlled, double-blind trial in which adults (N=49) received NN1177 (treatment doses of 10, 40, 120, 350, 700 and 1,100 g) or placebo, and a drug-drug interaction (DDI), open-label, single-sequence trial in which adults (N=45) received a 4,200 g dose of NN1177. Pharmacokinetic, safety and tolerability, and pharmacodynamic endpoints were assessed. For the MAD and FHD/SAD trials, baseline characteristics were generally balanced across groups. The half-life of NN1177 was estimated at between 77.3 and 111 hours. NN1177 appeared tolerable across trials; however, a number of safety concerns were observed, including an increase in heart rate (range 5-22 beats per minute) and decrease in reticulocyte count, which were both dose dependent, and increased markers of inflammation (fibrinogen and C-reactive protein), hepatic disturbances (increased aspartate aminotransferase and alanine aminotransferase), impaired glucose tolerance (dose groups 2,800-6,000 ug) and reduced blood levels of some amino acids. Clinically relevant weight loss was achieved (up to 12.6% at week 12; 4,200 ug in the MAD trial), but this was not accompanied by cardiometabolic improvements. In conclusion, although treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, unacceptable safety concerns precluded further clinical development.

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for obesity and type 2 diabetes, yet substantial variability in weight-loss response remains poorly understood. MethodsWe conducted a retrospective cohort study using de-identified electronic health records and performed 1:1 propensity matching on age, sex, type 2 diabetes status, baseline BMI and weight, index year, and follow-up duration. The matched cohorts included 10,339 tirzepatide-treated and 10,339 semaglutide-treated patients. Patients were categorized by maximum weight loss over two years into five response groups. Adverse events were identified through AI-enabled curation of clinical notes. Weight-loss trajectories, demographic patterns, adverse-event profiles, and pre- to post-treatment disease-prevalence changes were compared across drugs. ResultsPatients treated with tirzepatide lost more weight than those treated with semaglutide (mean reduction, 14.7% vs. 10.8%; p<0.001). High-response rates ([&ge;]15% weight loss in year 1) were nearly doubled with tirzepatide (42.6% vs. 21.6%; p<0.001), accompanied by faster monthly weight-loss velocity (2.54% vs. 2.18%). AI-enabled curation showed that tirzepatide was associated with lower prevalence of gastrointestinal and systemic adverse events. For both tirzepatide and semaglutide, women were more represented among high responders than the minimal weight-loss group (<5% weight loss) and White patients were more represented among high responders, whereas Black and Hispanic patients were more represented among the minimal weight loss group. ConclusionsIn this large, propensity-matched real-world cohort, tirzepatide was associated with greater and faster weight loss than semaglutide. Marked demographic disparities highlight the need for precision approaches to obesity treatment.

ObjectiveWhile sodium-glucose co-transporter 2 (SGLT2) inhibitors offer a novel, insulin-independent approach to managing type 2 diabetes (T2DM), their overall benefit-risk profile, encompassing cardio-renal outcomes and long-term safety, requires a comprehensive synthesis of the evidence. This umbrella review aims to definitively evaluate the efficacy and safety of SGLT2 inhibitors in patients with T2DM. MethodsThis umbrella review systematically searched major databases for relevant systematic reviews and meta-analyses up to September 2025. The methodological quality and certainty of evidence were assessed using AMSTAR 2 and GRADE tools. ResultsSGLT2 inhibitors demonstrated significant benefits in glycemic control (HbA1c WMD: -0.52% to -0.56%), body weight (MD: -1.76 to -2.63 kg), and systolic blood pressure (WMD: -4.08 mmHg). They also showed marked cardio-renal protection, reducing risks of major adverse cardiovascular events (RR=0.85), hospitalization for heart failure (RR=0.67), cardiovascular death (RR=0.75), all-cause mortality (RR=0.79), and composite renal outcomes (RR=0.59-0.64). Additionally, they positively modulated inflammatory markers and adipokines. However, these benefits were counterbalanced by increased risks of genital infections (OR=3.57), urinary tract infections (OR=1.34), and diabetic ketoacidosis (OR=2.19). The overall quality of evidence was generally low to very low. ConclusionSGLT2 inhibitors offer a multi-faceted therapeutic option for T2DM, providing glycemic, cardiovascular, and renal benefits, which make them particularly valuable for high-risk patients. Clinicians should be aware of the associated adverse events. Future high-quality, long-term studies are warranted to strengthen these findings.

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

Background/AimsType 2 diabetes mellitus (T2DM) is an extremely prevalent disease with multisystem complications. We aim to compare the effects of two common glucose lowering medications; sodium glucose co-transporter 2 inhibitors (SGLT2I) and dipeptidyl peptidase-4 inhibitors (DPP4I), on the incidence of diabetic retinopathy and cataracts in T2DM patients in Hong Kong. MethodsRetrospective population-based cohort study of T2DM patients treated with SGLT2I or DPP4I between 1st January 2015 and 31st December 2020. Propensity score matching (1:1 ratio) between SGLT2I and DPP4I users was performed on demographics, past co-morbidities, number of prior hospitalizations, duration from T2DM diagnosis to intial drug exposure, non-SGLT2I/DPP4I medications (including other anti-diabetes drugs), abbreviated modification of diet in renal disease, HbA1c, fasting glucose, and their time-weighted means. Sensitivity analysis using a one-year lag time and competing risk analyses using cause-specific and sub-distribution hazard models were conducted. ResultsThis study cohort included 26 165 SGLT2I and 42 796 DPP4I users (total: N=68 961 patients; 56.43% males, median age: 62.0 years old (standard deviation (SD): 12.8)). Over a median follow-up of 5.56 years (IQR: 5.24-5.80) and after propensity score matching (SGLT2I: N=26 165; DPP4I: N=26 165), SGLT2I users had lower incidences of cataract (4.54% vs. 6.64%%, standardised mean difference [SMD]=0.09) and diabetic retinopathy (3.65 vs. 6.19, SMD=0.12) compared to DPP4I users. SGLT2I use was associated with lower risks of new onset cataract (HR: 0.67, 95% CI: [0.62- 0.72] P<0.0001) and diabetic retinopathy (hazard ratio [HR]: 0.57, 95% confidence interval [CI]: [0.53-0.62], P<0.0001). These associations remained significant on multivariable Cox regression ;cataract: HR: 0.69, 95% CI: 0.64-0.75 (P<0.0001); diabetic retinopathy: HR: 0.68, 95% CI: 0.63-0.75 (P<0.0001). ConclusionsAmongst T2DM patients in Hong Kong, SGLT2I use was associated with lower risks of new onset cataract or diabetic retinopathy compared to DPP4I use. Synopsis/PrecisSodium glucose cotransporter-2 inhibitor (SGLT2I) use was associated with lower rates of new onset diabetic retinopathy and cataracts compared to dipeptidyl peptidase-4 inhibitor (DPP4I) use in patients with type 2 diabetes melllitus (T2DM) from Hong Kong. What is already known on this topicVarious glucose lowering medications may have additional beneficial or aggravating properties for/against diabetic retinopathy and cataract formation in diabetic populations beyond their glucose lowering capabilities. What this study addsThis study showed that SGLT2I use was associated with significantly lower rates of new onset cataracts and diabetic retinopathy when compared to DPP4I use in a T2DM population in Hong Kong. Additionally, to the best of our knowledge, this is the first population-based study on the effects of SGLT2I and DPP4I use on the development of cataracts in individuals with T2DM. How this study might affect research, practice or policyThis study provides preliminary data for further evaluation of SGLT2I and DPP4I use in preventing the incidence and progression of cataracts and diabetic retinopathy in a T2DM individuals. This study may also aid clinicians in deciding between SGLT2 and DPP4I if microvascular retinal complications and cataracts are a concern in individual cases.