bluuebunny/crossref_metadata_2025_split huggingface dataset:
915-P: Head-to-Head Comparison of Dapagliflozin vs. Empagliflozin—Cardiovascular and Safety Events
Authors: SHIN HOJIN , PAIK JULIE M. , EVERETT BRENDAN M. , GLYNN ROBERT , WEXLER DEBORAH J. , PATORNO ELISABETTA 
Published: June 2024

Introduction: Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) are recommended for adults with type 2 diabetes (T2D) at high cardiovascular (CV) risk. However, the comparative effectiveness and safety of dapagliflozin and empagliflozin is unknown. We compared these two drugs for CV and safety events.
Methods: In three US claims databases (commercial and Medicare), we identified adults with T2D who initiated dapagliflozin or empagliflozin during 08/2014-06/2020. Endpoints evaluated were 2-point MACE (a composite of myocardial infarction (MI) or stroke), hospitalization for heart failure (HHF), MI, stroke, all-cause death, and safety outcomes (diabetic ketoacidosis, amputations, fractures, urinary tract infections, genital infections, acute kidney injury, and hypoglycemia). Database-specific models were weighted using propensity score matching-weights to adjust for confounding, and hazard ratios (HRs) were pooled across databases.
Results: We identified 107,602 dapagliflozin and 272,014 empagliflozin initiators. Compared with empagliflozin, dapagliflozin initiators were younger (mean age 56 vs 61 years) and had less CV disease at baseline (19% vs 31%). After adjusting for 129 confounders, compared with empagliflozin at both 10 mg and 25 mg doses, dapagliflozin showed similar risk for most CV outcomes, including MI/stroke (HR=0.96, 95% CI=0.88-1.03). However, dapagliflozin initiators had a higher risk of HHF (HR=1.17, 1.02-1.33), driven by the lower dose of dapagliflozin (HR5mg=1.23, 1.04-1.46 for dapagliflozin 5mg; HR10mg=1.08, 0.88-1.32 for dapagliflozin 10mg). Compared to those on empagliflozin, dapagliflozin initiators had a lower risk of genital infections (HR=0.93, 0.90-0.96) across all doses and a similar risk of the other safety outcomes.
Conclusion: Dapagliflozin has similar CV benefits at doses proven effective in cardiovascular outcome trials, i.e., dapagliflozin 10mg, but the 5 mg dose may not have similar CV effectiveness.

Disclosure
H. Shin: None. J.M. Paik: None. B.M. Everett: Consultant; Novo Nordisk. Research Support; Novo Nordisk. Consultant; Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Ipsen Pharmaceuticals, Provention Bio, Inc. R. Glynn: Research Support; Amarin Corporation, Kowa Pharmaceuticals America, Inc., Novartis AG, Pfizer Inc. D.J. Wexler: Other Relationship; Novo Nordisk. E. Patorno: Research Support; Boehringer-Ingelheim, Food and Drug Administration (FDA), National Institutes of Health, Patient-Centered Outcomes Research Institute.

Funding
Patient Centered Outcomes Research Institute (DB-2020C2-20326)
919-P: Identifying Clinical Phenotypes in Patients with Type 2 Diabetes Using Unsupervised Cluster Analysis—Insights from the CANVAS Program and CREDENCE Trial
Authors: RAZAGHIZAD AMIR , NI JIAYI , POSSIK ELITE , TSOUKAS MICHAEL , MAVRAKANAS THOMAS A. , HUYNH THAO , SWARDFAGER WALTER , MARQUES PEDRO , SHARMA ABHINAV 
Published: June 2024

Background: Limited understanding exists regarding phenotypic heterogeneity in type 2 diabetes (T2D) patients and its therapeutic impact.
Methods: A pooled latent class analysis of the CANVAS Program and CREDENCE trial was conducted to identify T2D clinical phenotypes. The composite outcome of cardiovascular death (CVD) or hospitalization for heart failure (HHF) was analyzed and proportional hazards models assessed the effect of canagliflozin across phenotypes.
Results: Four phenotypes were identified: Phenotype 1 (n=966, 6.6%) with the lowest prevalence of heart failure, kidney dysfunction, and hypertension; Phenotype 2 (n=4169, 28.7%), primarily females with high atherosclerotic cardiovascular disease (ASCVD) prevalence; Phenotype 3 (n=7108, 48.9%), predominately men with high ASCVD prevalence; and Phenotype 4 (n=2300, 15.8%) with the highest prevalence of heart failure and renal dysfunction. Differential risk for CVD or HHF across phenotypes was observed, with the lowest risk in Phenotype 1 and the highest risk in Phenotype 4 (HR 5.21 [95% CI: 3.69-7.36]; Fig 1A and B). Canagliflozin significantly reduced CVD or HHF across phenotypes (P-interaction &gt; 0.05).
Conclusion: This study identified four distinct T2D phenotypes with differential CV risk. Canagliflozin significantly reduced the risk of CVD or HHF across phenotypes.

Disclosure
A. Razaghizad: None. J. Ni: None. E. Possik: None. M. Tsoukas: Speaker's Bureau; Novo Nordisk, Eli Lilly and Company, Boehringer-Ingelheim, Janssen Pharmaceuticals, Inc., AstraZeneca, Sanofi, Bausch Health, Abbott. T.A. Mavrakanas: Research Support; AstraZeneca. Other Relationship; AstraZeneca, Janssen Pharmaceuticals, Inc., Pfizer Inc. Advisory Panel; Bayer Inc. Other Relationship; Bayer Inc. Advisory Panel; Servier Laboratories. Other Relationship; Boehringer-Ingelheim. Advisory Panel; Boehringer-Ingelheim, GlaxoSmithKline plc. T. Huynh: Research Support; Pfizer Inc., Merck & Co., Inc., Bayer Inc. Speaker's Bureau; GlaxoSmithKline plc. W. Swardfager: None. P. Marques: Other Relationship; Janssen Pharmaceuticals, Inc. A. Sharma: Other Relationship; Boehringer-Ingelheim. Research Support; Janssen Pharmaceuticals, Inc. Other Relationship; Novo Nordisk. Advisory Panel; Novartis Canada. Other Relationship; AstraZeneca. Advisory Panel; Servier Laboratories, Takeda Pharmaceutical Company Limited. Research Support; Boston Scientific Corporation, Medtronic, Amgen Inc.
921-P: Real-World Study of the Efficacy of an Adjunctive Use of Ipragliflozin for Prevention of Chronic Kidney Disease in People with Type 1 Diabetes (IPRA-CKD)—A Multicenter Retrospective Study
Authors: NAKAMURA YUTA , HORIE ICHIRO , ABIRU NORIO , YANO HIROSHI , KAWAKAMI ATSUSHI , STUDY GROUP IPRA-CKD 
Published: June 2024

Introduction & Objective: SGLT2 inhibitors have been confirmed having renoprotective effects in type 2 diabetes, but their efficacy in type 1 diabetes (T1D) remains unclear. This study aimed to investigate the effects of adjunctive use of the SGLT2 inhibitor ipragliflozin (IPRA), which was approved for T1D since December 2018 in Japan, on kidney outcomes in people with T1D.
Methods: Medical records of people with T1D aged 20-74 years were retrospectively collected from 25 centers in Japan. As IPRA group, 159 cases treated with IPRA for more than 24 months from initiation (index date) were registered. As the Control (CTRL) group, 200 cases without IPRA use were registered. The kidney outcomes were compared between the two groups after randomly matching the index dates in CTRL group to those in IPRA group to exclude bias from COVID-19 pandemic period.
Results: At the index date, there were no significant differences between IPRA and CTRL groups in age (45.0 vs. 49.5 years), eGFR (81.1 vs. 81.0 mL/min/1.73 m2), and positive at microalbuminuria (29 vs. 17%), but IPRA group had significantly higher BMI, HbA1c, and insulin daily dose than Control group. In the primary endpoint, the median (range) of change in eGFR (mL/min/1.73m2) at 24 months after index date was -2.60 (-38.7 to 20.6) in IPRA group versus -2.80 (-34.0 to 22.9) in CTRL group, with no significant difference between the groups (p=0.96). In the secondary endpoints, the changes at 24 months after index date in HbA1c, body weight and insulin daily dose were significantly decreased in IPRA group than CTRL group, but those in proteinuria and were not. Incidents of severe hypoglycemia and ketoacidosis were not different between the groups.
Conclusion: This real-world study indicated that 24 months of adjunctive IPRA treatment might benefit glycemic control but did not significantly improve kidney function compared to insulin monotherapy in people with T1D.

Disclosure
Y. Nakamura: None. I. Horie: Research Support; Astellas Pharma Inc. N. Abiru: None. H. Yano: None. A. Kawakami: None.
93-OR: Clonal Expansion of Islet Reactive CD4 T-Cells with Early Disease Progression in Type 1 Diabetes
Authors: EDWARDS THOMAS H. , CHEN JANICE , DUFORT MATTHEW , HARTLEY RACHEL , SPEAKE CATE , GREENBAUM CARLA , LINSLEY PETER , CEROSALETTI KAREN 
Published: June 2024

Introduction & Objective: Islet antigen reactive (IAR) T cells play an important role in pancreatic β-cell destruction in type 1 diabetes (T1D) and are clonally expanded after T1D diagnosis, indicative of in vivo antigen exposure. The objective of this study was to determine if clonal expansion of IAR CD4 T cells occurs prior to T1D onset and is associated with risk for disease progression.
Methods: The study included prospective blood samples collected from islet autoantibody (Aab) positive individuals enrolled in the TrialNet Pathways to Prevention and Long Term Investigative Follow-up in TrialNet studies. IAR CD4 T cells were isolated using a CD154 activation assay from PBMC samples of a cross-sectional cohort of Aab negative (n=6), 1 Aab+ &gt;18y (n=6), 1 Aab+ &lt;14y (n=3), and &gt;1 Aab+ (n=6) donors with increasing risk for progression to T1D. Cells were analyzed by single-cell RNA-sequencing to identify T cell receptor α/β pairs and full transcript profiles. Clonal expansion was visualized using circos plots and analyzed using Simpson’s diversity. Transcript profiles were analyzed by unsupervised clustering and differential gene expression using Seurat v4.
Results: Clonal expansion of IAR CD4 T cells was observed primarily in the &gt;1 Aab+ at-risk group compared to the single Aab+ or Aab negative groups. The transcript profiles of IAR CD4 T cells formed clusters based on differentiation status from naïve to T effector memory phenotypes and revealed an enrichment of T effector memory cells in &gt;1 Aab+ at-risk subjects.
Conclusion: These results suggest that IAR CD4 T cell clonal expansion and enrichment of an effector memory transcript profile may accompany the progression to multiple Aab and increased risk for development of T1D. Further studies with longitudinal samples from subjects progressing from single to multiple Aab and T1D onset will validate and extend these findings to determine if IAR CD4 T cells are a biomarker of disease progression.

Disclosure
T.H. Edwards: Employee; Wavely Diagnostics, Inc. J. Chen: None. M. Dufort: None. R. Hartley: None. C. Speake: None. C. Greenbaum: Other Relationship; Sanofi, Takeda Pharmaceutical Company Limited, Bristol-Myers Squibb Company, Imcyse. P. Linsley: None. K. Cerosaletti: Research Support; GentiBio, Cour Pharmaceuticals.

Funding
American Diabetes Association (1-19-ICTS-006)
930-P: Dapagliflozin Improves Glucose Metrics and Decreases Insulin Requirements in Adults with Type 1 Diabetes but Adds Ketosis Risk
Authors: MARKOV ALEXANDER M. , JONES KAI E. , PETERSEN MAX C. , KRUTILOVA PETRA , MCKEE ALEXIS M. , BOHNERT KATHRYN L. , ADAMSON SAMANTHA E. , SALAM MAAMOUN , MCGILL JANET B. 
Published: June 2024

Introduction: SGLT2 inhibitors slow CKD progression but none are approved in T1D due to risk of ketosis-related adverse events, including DKA. We evaluated the impact of dapagliflozin on glucose metrics, insulin requirements and BHOB.
Methods: After informed consent, 20 participants with T1D completed two weeks of outpatient care while monitoring capillary BOHB, both with and without open label dapagliflozin (10 mg) in a randomized crossover design. Glycemic metrics were monitored via CGM, and insulin use was recorded from pump download or self-reports in MDI users. BOHB (Precision Xtra®, Abbott) measurements were obtained up to 3X daily during the study periods.
Results: Participant age was 48 ± 18 years, 45% female, A1c 7.0 ± 0.9%, baseline TIR 61 ± 18% (mean ± SD). The baseline median insulin TDD was 57 (38 - 88). Sixteen patients used CSII and 4 MDI. SGTL2i use led to a 6.9% reduction in median TDD, 26.3% in basal doses. Participants averaged 36 cBHOB measurements in both usual care and SGLT-2 treatment phases. During usual care, there were 3 ketosis events (cBOHB &gt; 1.5 mmol/L) versus 10 during SGLT-2 treatment (P=0.11). Most ketosis events occurred in one individual over a 24hr period. No DKA occurred.
Conclusion: In adults with T1D, dapagliflozin use was associated with reduction in insulin doses and improvement in GMI. Ketosis events were concentrated in 1 participant.

Disclosure
A.M. Markov: None. K.E. Jones: None. M.C. Petersen: None. P. Krutilova: None. A.M. McKee: Advisory Panel; Medtronic, Novo Nordisk. Employee; Novo Nordisk. K.L. Bohnert: None. S.E. Adamson: None. M. Salam: None. J.B. McGill: Advisory Panel; Bayer Inc., Boehringer-Ingelheim, ClearNote Health, Lilly Diabetes, MannKind Corporation, Novo Nordisk. Research Support; Novo Nordisk.
94-OR: Pathogenic Action of GAD65 Autoantibodies on Islet Function in Type 1 Diabetes
Authors: KAMAT VARUN , HAMPE CHRISTIANE S. , SWEET IAN 
Published: June 2024

A hallmark of T1D is the appearance of autoantibodies directed against islet cell antigens including insulin and the 65kDa isoform of glutamate decarboxylase (GAD65). Based on unsuccessful attempts to trigger diabetes in mice using autoantibodies isolated from T1D patients, autoantibodies are widely viewed as having no role in the pathogenesis of T1D. However, beta cells in mice lack expression of GAD65. We revisited the issue of pathogenic effects of autoantibodies by testing the effects of GAD65 monoclonal autoantibodies (GAD65mAb) derived from blood of human T1D patients and subjects that were GAD65Ab-positive on rat and human islets. The paradigm-shifting results of our previous studies demonstrated the ability of one of the GAD65mAb idiotypes to penetrate and accumulate in beta cells and affect insulin secretory function. In the current study we have performed more detailed analyses of the effects of this GAD65mAb idiotype (b78) on rat, mouse and human islets. The results are summarized as 1. suppression of ISR by b78 in a time- and concentration-dependent fashion (half maximal effect &lt; 0.05 mg/mL, much less than physiological levels of blood IgG, and the maximal reduction in ISR (about 40%) was reached 3 days after exposure; 2. suppression of ISR by b78 paralleled decreases in ATP production, apparently mediated by a step in the electron transport chain or oxidative phosphorylation; 3. the effect of b78 was not toxic to islets as its effects on ISR and ATP was reversible within 4 hrs of its removal; 4. effects on islets are dependent on the presence of GAD65 as no effect on mouse islets was observed; effects of GAD65mAb on human and rat islets were similar. Finally, 3 days following IP injection of b78 into conscious rats resulted in elevated glucose levels during IP glucose tolerance tests. Thus, contrary to historical perspectives, an islet autoantibody can directly impair secretory function in islets in vitro and in vivo through a mechanism that appeared to involve inhibition of mitochondrial energetics.

Disclosure
V. Kamat: None. C.S. Hampe: None. I. Sweet: Employee; EnTox Sciences, Inc. Advisory Panel; Regenerative Medical Solutions.

Funding
National Institutes of Health (R01 GM14874); National Institutes of Health (IIDP TRA2023); Helmsley Foundation (#FA218303).
941-P: Association of Incidence of Urinary Tract Infections (UTI) and Genitourinary Tract Infections (GTI) with Duration of SGLT2i in Type 2 Diabetes Mellitus Patients—A Pan-India Study
Authors: SINGH AKASHKUMAR N. , SINGH NAGENDRA K. , GUPTA ARVIND , PHATAK SANJEEV R. 
Published: June 2024

Introduction & Objective: The utilization of Sodium Glucose Co-transporter 2 inhibitors (SGLT-2i) in managing Type 2 Diabetes Mellitus (T2D) has been associated with an increased risk of developing genital & urinary tract infections (GTI & UTI). This study aims to determine the incidence of UTI and GTI occurring after the use of SGLT-2i in patients with T2D.
Methods: A real-world, cross-sectional study conducted across multiple centers involved the enrollment of patients from both primary & secondary care settings at 42 sites in India. The study focused on individuals diagnosed with T2D who visited the clinic between June 15, 2023 and September 30, 2023. The collected data encompassed demographic information, glycemic parameters, details regarding the use of SGLT2 inhibitors & DPP-4 inhibitors, and information on hygiene practices. For analysis, patients were categorized into 3 groups based on the duration of SGLT-2i use: &lt;6 months, 6-12 months, & &gt;12 months. The association between incidence and duration of SGLT2i groups was tested using Chi-square test.
Results: Out of the total sample of 9,312 patients, 5,469 were males, and 3,843 were females. The sample breakdown based on the duration of SGLTi use revealed that 3,353 patients used it for &lt;6 months, 2,509 for 6-12 months and 3,450 for &gt;12 months. The average age was 55 years. The incidence of UTI varied across the duration groups, with rates of 8%, 5.1%, and 2.7% for &lt;6 months, 6-12 months, and &gt;12 months, respectively. These findings suggest a higher occurrence of UTI in the initial months of SGLT2i drug initiation, followed by a subsequent reduction in incidence with prolonged drug use. Conversely, no significant differences were observed in the occurrence of GTI across the duration groups, with rates of 4.7%, 4.7%, and 4.1% for &lt;6 months, 6-12 months, and &gt;12 months, respectively.
Conclusion: As the duration of SGLT-2i treatment increases, there is a reduction in the incidence of UTI.

Disclosure
A.N. Singh: None. N.K. Singh: None. A. Gupta: None. S.R. Phatak: None.
943-P: Sodium–Glucose Cotransporter 2 Inhibitors (SGLT2i) and Polycythaemia—A Retrospective Analysis
Authors: PAVLOU PANAGIOTIS 
Published: June 2024

Background: The benefits of SGLT2i in diabetes mellitus, heart failure and chronic kidney disease have increased their scope and led to widespread use. However, recent evidence linked SGLT2i to polycythaemia and erythrocytosis. Our aim is to study this effect and assess the safety of SGLT2i use.
Methods: We retrospectively analysed data from 230 patients with diabetes receiving treatment with SGLT2i and measured its effect on haematocrit. A cohort of patients within polycythaemia range was identified and studied for parameters including haemoglobin (Hb), Hct, renal function and incidence of diabetic ketoacidosis (DKA), major adverse cardiovascular events (MACE) and urinary tract infections (UTI). Data was also collected for potential confounders affecting Hct and Hb.
Results: Mean baseline Hct was 41.3% (n=230). This increased to 42.3% (MD 1%; p&lt;0.001) and 42.6% (MD 1.3%; p&lt;0.001) at 3 and 6-12 months. The prevalence of polycythaemia range Hct was 3.5% (n=8) with 62.5% (n=5) newly developed. In the high Hct cohort, mean baseline Hct was 48.6% (n=8). This increased to 49.5% (MD 0.9%; p=0.38) and 49.6% (MD 1%; p=0.34) at 12 and 18-24 months respectively. Mean Hb was 163.5, 166.9 (MD 3 g/L; p=0.31) and 166.9 g/L (MD 4.2 g/L; p=0.31) at baseline, 12 and 18-24 months respectively. Mean eGFR was 75.8, 71.9 (MD -3.9; p=0.17) and 76.3 ml/min/1.73m2 (MD 0.5; p=0.82) at baseline, 12 and 18-24 months respectively. Mean urea was 6.23, 7.83 (MD 1; p=0.009) and 5.45 mmol/L (MD -0.78; p=0.01) at baseline, 12 and 18-24 months respectively. DKA was observed in 25% (n=2), UTIs in 37.5% (n=3), MACE in 37.5% (n=3) and venesection was required for one (n=1) patient in the polycythaemia range cohort over the treatment period.
Conclusion: SGLT2i treatment led to small but statistically significant increase in Hct, which persisted over a 6-12 month period and 18-24 months in the high Hct cohort. The prevalence of polycythaemia range Hct was 3.5% and new in most cases. These patients had high incidence of MACE and DKA.

Disclosure
P. Pavlou: None.
946-P: Insulin Pump Therapy in Type 1 Diabetes—a Real-World Study of Mortality and Clinical Outcomes
Authors: HAUGHTON SOPHIE , RILEY DAVID , FAHAD ARSHAD MUHAMMAD , AZMI SHAZLI , MALIK RAYAZ A. , ALAM UAZMAN , IQBAL AHMED 
Published: June 2024

Introduction & Objective: Clinical trials have demonstrated benefits of insulin pumps in type 1 diabetes (T1D). However, data from real-world studies is limited. We investigated the real-world impact of insulin pumps on glycaemia, diabetes complications and mortality when compared to multiple daily injections of insulin (MDI).
Methods: We performed a retrospective cohort study of all patients aged 18 or over with T1D on the TriNetX platform, a global collaborative network providing access to real time, anonymized medical records. We captured data from Jan 2018 to Oct 2023 to ensure that the results reflect recent advances in pump therapy.
Results: We identified 112,801 patients with T1D. Of this, 18,228 (16.2%) were treated with insulin pumps (mean age 36.9 years [SD 19.2], 44.8% male) and were propensity score-matched (1:1) to patients on MDI. All-cause mortality was significantly lower in the pump group at year 5 (RR 0.804 [0.726-0.891], p=0.014). There was no clinically significant percentage change difference in mean HbA1c at 5 years (mean percentage change -5.807% on pumps vs. -5.989% on MDI). The incidence of DKA was greater in the pump group at year 1 (RR 1.089 [1.020-1.162], p=0.010), however there was no difference each year from 2 to 5 years. There was a higher incidence of stroke (RR 1.364 [1.103-1.687], p=0.004) and ischemic heart disease (RR 1.214 [1.071-1.375], p=0.002) in year 1 in the pump group but not thereafter. The incidence of diabetes related eye disease remained elevated in the pump group at year 5 (RR 1.742 [1.613-1.881], p&lt;0.001).
Conclusion: In a large real-world cohort of people with T1D, insulin pumps compared to MDI were associated with lower overall mortality. Clinically significant reductions in HbA1c were seen in both groups. The risk of DKA, stroke and ischemic heart disease was higher in the first year of pump use but with no difference compared to MDI at year 5. Increased diabetes related eye disease in the pump group may represent a legacy effect of prior sub-optimal control.

Disclosure
S. Haughton: None. D. Riley: None. M. Arshad: None. S. Azmi: None. R.A. Malik: Speaker's Bureau; Lilly Diabetes, Sanofi, Novo Nordisk, Viatris Inc. U. Alam: Other Relationship; Procter & Gamble. Speaker's Bureau; Sanofi-Aventis Deutschland GmbH, Eli Lilly and Company, Grunenthal. A. Iqbal: Advisory Panel; Abbott. Speaker's Bureau; AstraZeneca, Dexcom, Inc.