Despite therapeutic advances, diabetic ketoacidosis (DKA) hospitalizations continue to increase. The role of demographic factors, including age and sex in the outcomes of DKA remains underexplored. We aimed to investigate the interaction between age and sex on clinical outcomes, resource utilization and mortality in patients with type 1 diabetes hospitalized for DKA. We conducted a retrospective cohort study using the National Inpatient Sample from 2016 to 2021. We identified adult hospitalizations with DKA in patients with type 1 diabetes, stratified into three age groups: 18-44, 45-64 and ≥65 years. Multivariable logistic regression models were used to analyze the association between sex and the primary outcome of in-hospital mortality, and secondary outcomes including acute kidney injury (AKI) and sepsis, adjusting for patient and hospital characteristics. Across all age groups, female sex was independently associated with significantly lower odds of AKI (aOR 0.56 in ages 18-44; 0.71 in 45-64; 0.79 in ≥65) but higher odds of sepsis (aOR 1.66, 1.31 and 1.17, respectively; all p<0.05). In young adults (18-44), women had significantly lower adjusted odds of mortality (aOR 0.72, 95% CI 0.60 to 0.86). This mortality benefit was not observed in middle-aged or older adults. Prepandemic (2016-2019), mortality trends diverged by sex and age, with rates increasing for young men but decreasing for young women. The pandemic (2020-2021) precipitated a sharp mortality increase across all age-sex groups, most dramatically in young men (from 0.48% to 0.89%). Our study showed that age and sex were closely linked to acute complications and in-hospital death. Women had lower odds of AKI but higher odds of sepsis than men, with a survival advantage limited to young adults, and mortality rose during the COVID-19 years for both sexes, especially in young men.

There is growing interest in widening the use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) to all people with type 2 diabetes mellitus (T2DM). However, pivotal randomized controlled trials (RCTs) evaluated these drugs only in highly selected populations, often lacking generalizability to real-world populations. Understanding the effects of SGLT2i in populations where RCT evidence may be lacking is essential to help inform guideline development. To address this, we estimated the effect of empagliflozin in real-world users, many of whom would not have been eligible for the pivotal EMPA-REG RCT. We designed a trial emulation in UK primary care data, based on the EMPA-REG RCT, to assess the effect of empagliflozin in a more clinically relevant population. Adults with T2DM initiating empagliflozin (intervention) or dipeptidyl peptidase-4 inhibitors (active control) between January 1, 2014 and December 31, 2022 were included. Eligibility was extended to both RCT-eligible and RCT-ineligible individuals. The effect of empagliflozin on all-cause mortality was estimated using an adjusted Cox proportional hazards model, with stratified analyses by RCT eligibility. The majority of people prescribed empagliflozin would not have met the EMPA-REG RCT eligibility criteria (11,011/13,239, 83.2% RCT-ineligible). During follow-up, all-cause mortality occurred in 551 out of 13,239 (4.2%) in the empagliflozin group and 6,589 out of 49,264 (13.4%) in the active control group (adjusted HR 0.76, 95% CI 0.69 to 0.83). There was no evidence of differential treatment effect by RCT eligibility status (p-interaction=0.27). Patients prescribed empagliflozin in real-world settings differ substantially from those enrolled in the EMPA-REG RCT. Using electronic health records, we demonstrate that the mortality benefit observed in EMPA-REG extends to a broader, more diverse real-world population, including those excluded from the original RCT. These findings provide a novel source of real-world evidence supporting the wider use of empagliflozin in routine clinical practice.

IntroductionType 1 diabetes is an autoimmune disease with a strong genetic basis. The aim of this study was to identify additional single-nucleotide polymorphisms (SNPs) for type 1 diabetes age at diagnosis and to replicate previously identified loci.Research design and methodsMeta genome-wide association studies of age at diagnosis from eight cohorts (n=5910 in total) were performed in three models. Model 1 was age at diagnosis with no covariates. Model 2 was age at diagnosis adjusted for DR3/DR4 genotype categories. Model 3 was similar to model 2, including the most significant SNP from model 2 (coded additively). Models 1 and 2 were also performed for major histocompatibility complex (MHC) imputed data. In addition, we tested previously identified loci for age at diagnosis and type 1 diabetes risk for association with age at diagnosis in model 1.ResultsIn model 1, we identified a genome-wide significant locus (rs2856721, p=3.3×10−11) in the MHC region whose effect was attenuated in model 2 (p=0.03). In model 2, we identified another locus in the MHC region, rs76730244, p=4.9×10−9, which was associated with age at diagnosis adjusted for DR3/DR4 genotypes. Model 3 and analysis of the MHC region did not reveal novel loci. Among 14 previously identified SNPs for age at diagnosis, 6 were confirmed; in addition, 11 out of 78 non-HLA loci for type 1 diabetes risk were associated with age at diagnosis.ConclusionsWe identified rs76730244 in the MHC region for age at diagnosis of type 1 diabetes, which was independent of the HLA-DR3/DR4 genotype categories. We also confirmed 6 previously identified SNPs and showed that 11 non-HLA loci for type 1 diabetes risk are associated with age at diagnosis.

IntroductionThis study analyzed the effects of the COVID-19 pandemic and body weight on islet and endocrine autoimmunity in children with type 1 diabetes (T1D).Research design and methodsData from 11 973 children and adolescents aged 0.5 to <18 years with new-onset T1D (2015–2023) from the Diabetes Prospective Follow-up Registry were evaluated. Rates of autoantibodies against beta cells (islet antigen 2 (IA2), zinc transporter 8 (ZnT8), glutamic acid decarboxylase (GAD), insulin), thyroid, transglutaminase (TGA), and adrenals were assessed. Logistic regression models adjusted for age and sex examined associations with COVID-19 and body mass index (BMI).Results6136 (51%) children were diagnosed with T1D before, and 5837 (49%) after the beginning of the COVID-19 pandemic. Beta-cell autoantibodies were present in 94.3%, thyroid autoantibodies in 7.7%, TGA autoantibodies in 8.3%, and adrenal autoantibodies in 5.6%. During versus before COVID-19, IA2 and GAD autoantibody positivity significantly increased (63.3% vs 60.5%, p=0.002, and 65.9% vs 64.0%, p=0.04, respectively), ZnT8 autoantibodies declined (68.0% vs 71.9%, p=0.002), while insulin autoantibodies remained unchanged (p=0.06). Prevalence of IA2, ZnT8, and insulin, but not GAD autoantibodies, showed positive associations with BMI. Thyroid and TGA autoantibodies were not related, while adrenal autoantibodies were negatively related to the pandemic.ConclusionsThe COVID-19 pandemic and body weight influenced autoimmunity in children with T1D. The rise in IA2 autoantibody positivity may suggest a faster progression from pre-existing autoimmunity to clinical disease. The pandemic did not appear to trigger associated endocrine autoimmunity.

Current studies have shown that the asialoglycoprotein receptor 1 (ASGR1) is involved in glycolipid metabolism and is associated with systemic insulin resistance. This study aims to explore the correlation between serum soluble ASGR1 (sASGR1) levels and metabolic dysfunction-associated steatotic liver disease (MASLD) by assessing the relationship between sASGR1 concentrations and various biomarker levels. The study included 148 patients diagnosed with MASLD from December 2021 to July 2024, and 98 control participants from the general population without MASLD. After collecting baseline clinical characteristics, ELISA kits were used to measure serum levels of sASGR1, fibroblast growth factor 21, and adiponectin. Compared with the control group, patients with MASLD had higher serum sASGR1 levels (p<0.05). Spearman correlation analysis showed that serum sASGR1 levels were significantly positively correlated with lipid metabolism indicators (triglycerides, total cholesterol, low-density lipoprotein cholesterol), glucose metabolism indicators (fasting plasma glucose, fasting insulin, glycosylated hemoglobin, homeostasis model assessment for insulin resistance), inflammatory markers (tumor necrosis factor α), liver function, and liver fibrosis. indicators (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase, procollagen type III, hyaluronic acid), and body mass index (p<0.05), and were significantly negatively correlated with high-density lipoprotein cholesterol (p<0.05). Further multiple linear regression analysis showed sASGR1 may be an independent risk factor for the occurrence of MASLD after adjusting for potential confounding factors (OR 2.644, 95% CI 1.138 to 6.143; p<0.05). The receiver operating characteristic curve revealed that the area under the curve for serum sASGR1 in predicting MASLD occurrence was 0.761 (95% CI 0.698 to 0.824), and its predictive performance increased to 0.863 (95% CI 0.813 to 0.913) when combined with AST and ALT. In this group of patients with MASLD, sASGR1 levels are higher and are associated with the occurrence of MASLD, suggesting that sASGR1 may be an independent risk factor for MASLD. The expression of organokines in serum and its relationship with inflammation, insulin resistance in obese patients, ChiCTR2200059056.

ObjectiveBlue Cross and Blue Shield of Louisiana (BCBSLA) launched a zero-dollar co-pay (ZDC) pharmacy benefit on July 1, 2020, to reduce cost-related barriers to diabetes medications. This study evaluated the program’s effect on antidiabetic medication adherence and use patterns.Research Design and MethodsWe conducted a retrospective cohort study using BCBSLA medical and pharmacy claims from 2019–2021. The study included 7,603 continuously enrolled members with diabetes: 3,045 fully insured members with ZDC coverage (ZDC group) and 4,558 administrative-services-only members without ZDC coverage (control group). Follow-up was July 1, 2020, to December 31, 2021. Outcomes included monthly proportion of days covered (PDC), drug counts, and monthly medication use. We applied propensity score odds weights and estimated weighted difference-in-differences models with individual and time fixed effects, adjusting for demographics, comorbidities, healthcare utilization, and spending. Subgroup analyses examined pre-ZDC users, pre-ZDC non-users, and complex users.ResultsMean age was 48.8 (SD 12.5) years in the ZDC group and 52.9 (SD 11.3) years in controls; 57.4% and 55.6% were female, respectively. The ZDC program increased PDC by 4.4 percentage points (p<0.001), monthly medication use by 6.2 percentage points (p<0.001), and drug counts by 0.090 (p<0.001). For ZDC-eligible medications, increases were 5.4 percentage points for PDC, 7.6 percentage points for monthly use, and 0.074 for drug counts (all p<0.001). Improvements were observed among pre-ZDC users and complex users, but not among pre-ZDC non-users.ConclusionA zero-dollar co-pay pharmacy benefit improved antidiabetic medication adherence and increased medication use among BCBSLA members with diabetes.

Infections precede nearly all hospitalizations and amputations related to diabetes-related foot disease. Focusing on antibiotic management, we aimed to report the outcomes of people presenting with a new diabetes-related foot infection (DFI). In this prospective study conducted in Australian and New Zealand hospitals between 2018 and 2020, patients with diabetes, a foot ulcer and a newly diagnosed DFI were eligible for enrollment. DFI was categorized as mild or moderate/severe DFI, with the latter further categorized according to the presence of osteomyelitis. The primary outcome was healing of the index ulcer or amputation site at 6 months. Multivariable logistic regression analyses adjusted for potential confounders were undertaken to investigate the relationship between ulcer healing and infection severity, intravenous antibiotic duration and total antibiotic duration. Of 234 included patients presenting to 20 centers (mean age 61 years, 77% male), 15% had mild DFI, 31% moderate or severe DFI without osteomyelitis, and 54% moderate or severe DFI with osteomyelitis. Methicillin-resistant Staphylococcus aureus was identified in 7% (16/214) and Pseudomonas aeruginosa in 3% (7/214). Median (IQR) days of total antibiotic management were 18 (10, 22) for mild DFI, 20 (11, 40) for moderate or severe DFI without osteomyelitis and 34 (15, 51) for moderate or severe DFI with osteomyelitis. Healing at 6 months was 73% (22/30) in those with mild DFI, 68% (42/62) in moderate or severe infections without osteomyelitis and 62% (69/111) in moderate or severe DFI with osteomyelitis. After adjusting for confounders, none of infection severity, intravenous antibiotic duration or total antibiotic duration were associated with ulcer healing. Healing at 6 months following DFI does not appear to be associated with infection severity or antibiotic management. To plan clinical trials of antibiotic therapy for DFI, further work is required to define target subgroups and meaningful trial endpoints.

IntroductionIn the USA, patients with diabetes and end-stage renal disease are less likely to undergo deceased donor kidney transplantation (DDKT) or living donor kidney transplantation (LDKT). We explored the survival benefit of DDKT and LDKT among patients with diabetes.Research design and methodsWe used the United Network for Organ Sharing Standard Transplant Analysis and Research file to identify adults placed on the kidney waiting list between January 2014 and January 2024. Waitlist failure was evaluated with Fine and Gray analysis; life-years from transplant, equal survival (ES), and equal risk (ER) were extrapolated using lognormal survival regression; and life-years gained was quantified via restricted mean survival over 10 years.ResultsPatients with diabetes were more likely to experience 10-year waitlist failure (subdistribution HR 2.27, 95% CI 2.23 to 2.32) and receive inferior DDKT grafts (Kidney Donor Profile Index 49% vs 35%, p<0.001) compared with patients without diabetes. For patients with diabetes, LDKT, compared with DDKT, offered more life-years from transplant (18.2 years vs 14.1 years), resulted in more life-years gained (29% vs 24% relative increase over 10 years, p<0.001) and decreased ES by 19 months and ER by 30 months.ConclusionsProceeding to transplantation offers significant survival benefit for end-stage renal disease patients with diabetes, with LDKT offering superior survival compared with DDKT. By reducing time on the waiting list and providing superior grafts, the benefit of LDKT is particularly enhanced among patients with diabetes, and targeted efforts should be made to expand living donor access for this population.

The increased use of HbA1c as a diagnostic criterion, novel methods to collect and store blood samples as well as the quality of national registers enable screening targeted individuals, who are not screened opportunistically. The study evaluates whether screening for type 2 diabetes using at-home self-sampling HbA1c tests, targeted people who have not had their HbA1c measured the last 2 years, is feasible and cost-effective. During a period of 9 months, the Danish Diabetes Association mailed free capillary at-home self-sampling HbA1c tests to 8,000 randomly selected individuals aged 50-75 years who had not had their HbA1c measured in the past 2 years. The screening costs per screen-detected derived from the pilot study and estimated cost savings across HbA1c levels derived from a Danish simulation study was used to estimate cost-effectiveness. About 38% returned a blood sample. The share of participants with HbA1c of 48 mmol/mol (6.5%) and above was 1.7% (50/2913). The screening costs were 1.207 per screen-detected with type 2 diabetes. A national screening program targeting individuals aged 50 to 75 years, who have not had their HbA1c measured within the previous 2 years, is estimated to reduce healthcare costs and productivity losses by €1514 per screen-detected, if diagnosis is moved forward by 3 years, as derived from a Danish simulation study. Hence, the total social return ratio of the screening program is estimated to €1514/ €1183=1.28. The study suggests that screening for type 2 diabetes using at-home self-sampling HbA1c tests, targeting individuals aged 50-75, who have not had their HbA1c measured the past 2 years, is feasible and cost-effective in Denmark.

IntroductionShunting of glycolytic intermediates into the pentose phosphate pathway via transketolase activation by benfotiamine has been suggested to protect from hyperglycemia-induced microvascular damage, but the long-term effects of benfotiamine on diabetic sensorimotor polyneuropathy (DSPN) remain unclear.Research design and methodsThis 1:1 randomized double-blind, placebo-controlled parallel group monocentric phase II trial compared the efficacy and safety of 1-year treatment with benfotiamine 300 mg two times per day versus placebo over 12 months in participants with type 2 diabetes and mild-to-moderate symptomatic DSPN. The primary endpoint was the change in corneal nerve fiber length (CNFL) assessed by corneal confocal microscopy (CCM) from baseline to 12 months. Secondary endpoints included three other CCM parameters, skin biopsy (four parameters), nerve conduction studies (13 measures), quantitative sensory testing (six parameters), cardiovascular autonomic function tests (17 indices), sudomotor function tests (five parameters), 15 clinical scores and scales for neuropathic symptoms and signs and 13 health-related quality of life and depression instruments. Pharmacokinetics included measurement of six thiamine analytes in blood.ResultsA total of 57 participants underwent randomization. The changes from baseline to 12 months in CNFL did not differ between the two groups. The corresponding changes in the secondary morphometric, functional and clinical neuropathic outcomes as well as quality of life were also similar in the two groups. Only the Neuropathy Symptom Score tended to improve after benfotiamine treatment (p=0.098 vs placebo). Benfotiamine treatment increased the concentrations of all six thiamine analytes studied (p≤0.003 vs placebo). Safety analysis showed no relevant differences between the groups in the rates of adverse events.ConclusionsIn type 2 diabetes individuals with mild-to-moderate symptomatic DSPN, treatment with benfotiamine for 12 months was well tolerated, but had no significant effects on multiple morphometric, neurophysiological and clinical measures of neuropathy.Trial registration numberEuropean Clinical Trials Database (EudraCT) 2017-003054-16 registered on April 10 (https://eudract.ema.europa.eu/), 2018 and German Register for Clinical Trials DRKS00014832 registered on August 3, 2018 (https://drks.de/search/de).