bluuebunny/crossref_metadata_2025 huggingface dataset:
891-P: 18F-FDG PET/CT Mapping Identifies Spleen as Dominant Site for Blood Glucose Uptake in BCG-Treated Patients with Type 1 Diabetes
Authors: DIAS HANS F. , FANGLU FU JESSIE , ZHENG HUI , KUHTREIBER WILLEM , PRICE JULIE , CATANA CIPRIAN , FAUSTMAN DENISE L.
Published: June 2024

Introduction & Objective: In randomized clinical trials in patients with type 1 diabetes (T1D), bacillus Calmette-Guérin (BCG) vaccinations gradually lower blood sugar to near-normal levels, which appears to be driven by a BCG-induced shift in lymphoid cells’ glucose metabolism from oxidative phosphorylation to aerobic glycolysis. Here we investigated whether the BCG bacterium establishes residence in organs and alters their glucose metabolism.

Methods: In an open-label clinical trial in patients with longstanding T1D (n=6; T1D duration >13 years at time of baseline BCG injection), we used positron emission tomography (PET) and x-ray computed tomography (CT) to map organs with increased uptake of the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) after BCG vaccinations (Tokyo 172 BCG strain, Japan BCG Laboratory, Tokyo, Japan). Patients received a total of 6 BCG doses over a 2-year period. The first PET/CT scan was performed prior to receipt of BCG; each patient’s subsequent scans were compared to their baseline scan. We also injected BALB/c mice with BCG to test for BCG’s presence in various organs.

Results: The human and murine studies identified the spleen as the dominant site for glucose uptake and BCG residence after vaccination. Overall, the spleen showed a 47% increase in glucose uptake compared to baseline (p-value=0.03; mixed linear effects model statistics), which correlated in time with a systemic drop in blood sugar. The spleen’s activity steadily and significantly increased over the course of 2-years of 18F-FDG mapping, and the microbe persisted there over a 20-week period in the mice.

Conclusion: These findings suggest that the spleen, triggered by BCG vaccinations, assumes a critical role in systemic glucose regulation in the absence of a functional pancreas. This data fits with surgical data wherein splenectomy can cause diabetes in patients due to glucose dysregulation.

Disclosure

H.F. Dias: None. J. Fu: None. H. Zheng: None. W. Kuhtreiber: None. J. Price: None. C. Catana: None. D.L. Faustman: None.
893-P: Real-World Effectiveness of Finerenone in Chinese Patients with Type 2 Diabetes Mellitus (T2MD) and Chronic Kidney Disease (CKD)
Authors: LI ANG , GAO YING , GUO XIAOHUI , ZHANG JUNQING
Published: June 2024

Background: Given the inconsistence of real-world treatment with randomized controlled trials (RCTs) and guidelines, the risk of cardiovascular-renal events remains in patients with T2DM and CKD. This study aimed to assess the real-world effectiveness of finerenone in patients with T2DM and CKD in Peking University First Hospital.

Methods: This retrospective study included patients with T2DM and CKD treated with finerenone. Urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and serum potassium were recorded at baseline and post-finerenone treatment.

Results: Of the 93 patients, mean age was 59.5±8.5 years, 55 (59.1%) were male, and mean duration of T2DM was 13.0±7.2 years. Of these patients, 83.9% were on sodium-glucose co-transporter type-2 inhibitors, 43.0% on glucagon-like peptide-1 receptor agonists, 48.4% on insulin and 85.3% on renin-angiotensin system inhibitors. Baseline UACR was 408.0±449.4 mg/g, and 66% of patients had microproteinuria (30-299 mg/g). With finerenone administered mean daily dose at 14.6 mg for averagely 3.4 months, UACR decreased by 22.3% to 317.3±294.5 mg/g. eGFR decreased from 83.7±11.4 to 74.4±12.9 mL/min/1.73 m2 in patients with baseline eGFR>60 mL/min/1.73 m2 (75.3% of the total population). In patients with baseline eGFR<60 mL/min/1.73 m2 (24.7% of the total population), eGFR remained stable (49.2±6.6 vs. 49.0±6.1 mL/min/1.73 m2). Serum potassium slightly increased from 4.3±0.4 to 4.5±0.6 mmol/L and no adverse event of hyperkaliemia occurred.

Conclusion: Despite the different treatment background and finerenone use between the real-word clinical practice and RCTs, similar UACR reduction was observed in this study compared to FIGARO-DKD trials. Finerenone might improve proteinuria control and could be a promising treatment option to reduce the risk of cardiovascular-renal events in patients with T2DM and CKD in the integrated management.

Disclosure

A. Li: None. Y. Gao: None. X. Guo: None. J. Zhang: None.
902-P: GlucoLo Plus, a Complementary and Alternative Medicine (CAM) Used in Type 2 Diabetes Management, Is Associated with Lipid Profile Improvement
Authors: ZARRUK ALEXANDRO R.
Published: June 2024

Introduction & Objective: Diabetes is a chronic disease associated with many comorbidities and a higher risk of all-cause and cardiovascular mortality. The GLEEN Study is a previously reported double-blind randomised placebo-controlled trial that evaluated the efficacy and safety of daily GlucoLo Plus, a Complementary and Alternative Medicine (CAM). The secondary outcome of lipid profile improvement will now be presented.

Methods: The GLEEN Study was composed of 60 individuals with type 2 diabetes with a mean HbA1c 6.98% [52.8 mmol/mol], mean age 67.3 years [SD 9.5], 26 [43%] women, mean diabetes duration was 3.2 years, and meanbody mass index 27.9 kg/m2. Participants were randomly assigned to GlucoLo Plus (n=32 [53%]), or placebo (n=28 [47%]). The primary outcome of a significant HbA1c reduction of 0.843% was previously reported. The lipid profile including Total Cholesterol, Triglycerides, High-Density Lipoprotein (HDL) and Low-Density Lipoprotein (LDL) were measured at randomization and at the end of the 3-month trial.

Results: At 12 weeks, GlucoLo Plus decreased Total Cholesterol by 4.47 % while placebo increased it by 0.62%. The active arm had a decrease in Triglycerides by 10.33 % while the placebo arm had a Triglycerides lowering of 12.44%. GlucoLo Plus further improved the lipid profile by reducing LDL by 7.45 % while placebo increased it by 2.70% and it increased HDL by 14.52% while placebo reduced it by 0.38%.

Conclusion: GlucoLo Plus showed favorable effect regarding lowering Total Cholesterol, lowering LDL cholesterol and increasing HDL cholesterol. These results suggest that GlucoLo Plus could be, in addition to its’s proven glucose lowering abilities, an alternative and/or an addition to type 2 diabetes management in people who are reluctant to initiate or add new antidiabetic agents while providing them with some lipid profile benefits at the same time.

Disclosure

A.R. Zarruk: Consultant; Sanofi. Speaker's Bureau; Sanofi. Consultant; Bausch Health. Speaker's Bureau; Bausch Health. Consultant; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Consultant; Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim, Abbott. Consultant; Abbott.

Funding

Groupe Nature Pharma
905-P: Increased GDF15 Levels Are Unrelated to Anterior Pituitary Hormone Shifts in Metformin Use
Authors: HEWLETT JENNIFER R. , YANNAMANI AISHWARYA , SREEKUMARAN NAIR K.
Published: June 2024

Metformin is a widely used medication in the management of type 2 diabetes, and its weight-lowering effects involve the central nervous system. Growth differentiation factor 15 (GDF15) acts on the mid-brain, is increased with metformin, and is positively correlated with weight loss. Pituitary hormones can also be altered by metformin and in states of stress. We sought to understand the relationship between GDF15 and pituitary function with metformin use. Data was collected from a randomized, double-blinded, cross-over study of 9 adult patients with prediabetes who received metformin or placebo for two weeks. GDF15, thyroid stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH), cortisol, free T3, total T3, and total T4 were collected at baseline and following metformin. In this small study, GDF15 levels were significantly increased with metformin, however there was no association between the blood level of metformin and the degree of GDF15 increase (R2=0.339, P=0.1). Metformin was associated with an isolated TSH increase (p=0.024) without a significant change in thyroid hormones. TSH was negatively correlated with free T3 values (R2=0.558, P=0.021). A similar correlation was noted with the change in total T3 and total T4 which did not reach significance (R2=0.374, P=0.08; R2=0.389, P=0.073). Metformin was associated with an isolated increase in cortisol (P=0.012) without a significant change in ACTH (P=0.664). There was no correlation between ACTH and cortisol (R2=0.064, P=0.511). There was no relationship identified between GDF15 and TSH (R2=0.171, P=0.17) or GDF15 and cortisol (R2=0.201, P=0.226). Short-term metformin use is associated with isolated increases in TSH, which is likely physiologic, and cortisol, which is unrelated to ACTH. It remains to be determined whether metformin's effect on cortisol is due to altered adrenal steroidogenesis. Our findings suggest that the changes in TSH and cortisol with metformin are not due to GDF15 or a direct effect on the pituitary.

Disclosure

J.R. Hewlett: None. A. Yannamani: None. K. Nair: None.
908-P: Use of DPP4i/SGLT2i Fixed Dose Combinations in Indian Clinical Practice—A KAP Survey
Authors: SABOO BHARAT , PRAJAPATI CHARMY M. , SHETTY PARVAN A. , MURALIDHARAN PARTHASARATHY , QAMRA AMIT
Published: June 2024

Introduction & Objective: The Asian-Indian phenotype presents with increased insulin resistance, reduced Beta-Cell function, abdominal adiposity & clustering of CV risk factors. In India generic DPP4i/SGLT2i Fixed Drug Combinations (FDCs) are prescribed to enhance compliance amongst patients with T2DM. We aimed to study attitude & practice of Indian Physicians pertaining to patient populations benefitting from these FDCs.

Methods: We designed and utilized a 6-question survey during an Indian Medical Congress. Convenience Sampling was used to reach out to at least n=150 physicians. Descriptive Statistics was used to analyze data using MS-Excel 2019.

Results: Amongst 185 surveyed physicians, 48% respondents (n=89) reported over 40% of newly-diagnosed, treatment-naïve patients presenting with baseline HbA1c >8%. 52% (n=97) had more than 40% patients with HbA1c >8.5% despite Metformin monotherapy. Considering glycemic control in 3 clinical scenarios, 66% (n=122) physicians preferred DPP4i/SGLT2i FDCs for all scenarios namely (a) patients uncontrolled on Metformin monotherapy with HbA1c >8.5% (b) treatment-naive patients with contraindication/intolerance to Metformin & HbA1c >8% (c) add-on to insulin. Also 60.5% (n=112) physicians favored DPP4i/SGLT2i FDC for all 4 given reasons i.e. CV benefits, lower hypoglycemia risk, weight loss promotion & targeting multiple pathophysiological pathways. 85% (n=158) reported reduced Genito-Urinary Tract Infections (GUTI) with concurrent administration of DPP4i with SGLT2i or FDC. Most favored FDC was Sitagliptin/Dapagliflozin (36%, n=67).

Conclusion: In India there is significant burden of patients with T2DM who present with high HbA1c (newly diagnosed or despite metformin monotherapy). Generic DPP4i/SGLT2i FDCs are preferred in these patients also considering their extra-glycemic benefits. Most physicians (85%) noted reduction in SGLT2i associated GUTIs with use of DPP4i/SGLT2i FDCs. Further studies may validate these findings.

Disclosure

B. Saboo: None. C.M. Prajapati: Employee; Macleods Pharmaceuticals Ltd. P.A. Shetty: Employee; Macleods Pharmaceuticals Ltd., Eisai Inc. P. Muralidharan: Employee; Macleods Pharmaceuticals. A. Qamra: Employee; Macleods Pharmaceuticals Ltd.
91-OR: Selenite-Induced Glutathione Peroxidase 3 in the Control of Insulin Receptor Expression in Adipocytes
Authors: HAUFFE ROBERT , KLEINRIDDERS ANDRE
Published: June 2024

Selenoproteins are an important modulator of cellular redox homeostasis and metabolic processes. Previously we have demonstrated that mice fed a selenium rich HFD (SRHFD) are protected against diet-induced insulin resistance. Here, SRHFD-fed mice exhibited elevated white adipose tissue (WAT) insulin receptor (IR) expression and improved whole-body insulin sensitivity. This was due to a WAT-specific upregulation of the selenoprotein glutathione peroxidase 3 (GPx3), an important regulator of cellular redox states. Strikingly, we could demonstrate that this effect is blunted in mice with pre-existing obesity, where a failure to increase GPx3 in WAT associates with unaltered IR expression. However, the mechanism behind this interaction is unknown.

Highlighting the translational relevance, we use a human pre-adipocyte cell line to show that GPx3 expression increases IR protein levels, differentiation capacity, and protects against palmitate-induced insulin resistance.

In our current investigation using murine pre-adipocytes (3T3-L1), we show that GPx3 regulates IR expression via the transcription factor SP1, which is known to be susceptible to changes in the cellular redox state. Consequently, we demonstrate that an increase in selenite-induced GPx3 expression is associated with an increased binding of SP1 to the IR promoter. This mechanism involves a change in the oxidized glutathione pool by GPx3. Surprisingly, it is sufficient to provide cells with extracellular recombinant GPx3 to elicit this effect, suggesting either a receptor-mediated effect, or a reuptake of GPx3 into the cells. As a result, in vitro treatment with extracellular GPx3 increases IR expression and enhance mitochondrial function and differentiation capacity of 3T3-L1 cells.

In conclusion, we identify GPx3 as a novel modulator of WAT insulin receptor expression and insulin sensitivity, that potentially acts in a paracrine or autocrine manner, and is responsive to a dietary intervention.

Disclosure

R. Hauffe: None. A. Kleinridders: Speaker's Bureau; Novo Nordisk A/S, Daiichi Sankyo.
910-P: Novel Mechanism of Action Associated with SGLT2 Inhibition, Peripheral Energy Utilization, and CV Benefits in Subjects with Type 2 Diabetes Mellitus and HFrEF
Authors: QIN YUEJUAN , SANCHEZ NOAH D. , ACOSTA FRANCISCA M. , MOODY ALEXANDER , NEPPALA SIVARAM , TRIPLITT CURTIS L. , CLARKE GEOFFREY D. , CERSOSIMO EUGENIO , DEFRONZO RALPH A. , SOLIS-HERRERA CAROLINA
Published: June 2024

Background: SGLT2i is associated with CV benefits, but the mechanisms are not fully elucidated. We report a novel finding associated with improved CV Health in T2D & HFrEF. Elevated ketones, EF%, & heart remodeling have been reported with SGLT2i. This is likely, in part, due to a switch in cardiac metabolism to ketone oxidation. This switch might be present in peripheral tissues, including skeletal muscle (SkM).

Objective: To examine the effects of SGLT2i on SkM energy production, utilization, exercise recovery, lipid content, and cardiopulmonary function.

Methods n=10(Age= 61.6±3.5, BMI= 31.4±1.8, A1c=7.6%±0.4, EF 32.7%±2.7) were randomized to empagliflozin 25mg vs. placebo 2:1 for 12 wks. SkM 31P & 1H MRS was performed. Cardiopulmonary exercise testing (CPET) was done to assess functional capacity and determine CV prognosis.

Results: After SGLT2i, there was a significant improvement in SkM energy production, utilization at rest, and exercise recovery. The VE/VCO2 slope, significantly improved (p<0.05) (Fig.1)

Conclusion: We show for the first time that, in subjects with T2DM & HFrEF, SGLT2i significantly improve SkM bioenergetics and lipid content. This was associated with a significant improvement in CV prognostic markers. These findings may explain novel mechanisms of improvement in peripheral bioenergetics that translate into Global CV Health.

Disclosure

Y. Qin: None. N.D. Sanchez: None. F.M. Acosta: None. A. Moody: None. S. Neppala: None. C.L. Triplitt: Speaker's Bureau; Novo Nordisk. Consultant; Eli Lilly and Company. Other Relationship; American Diabetes Association. G.D. Clarke: None. E. Cersosimo: None. R.A. DeFronzo: Advisory Panel; AstraZeneca, Novo Nordisk, Boehringer-Ingelheim, Intarcia Therapeutics, Inc., Aardvark, Renalytix, Corcept Therapeutics, Alnylam Pharmaceuticals, Inc. Research Support; Boehringer-Ingelheim, AstraZeneca, 89bio, Inc., Amgen Inc., Medality, Corcept Therapeutics. Speaker's Bureau; AstraZeneca, Corcept Therapeutics, Renalytix. C. Solis-Herrera: Advisory Panel; Novo Nordisk, Bayer Inc.

Funding

Doris Duke Foundation
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 > 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+ >18y (n=6), 1 Aab+ <14y (n=3), and >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 >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 >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 > 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 < 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: <6 months, 6-12 months, & >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 <6 months, 2,509 for 6-12 months and 3,450 for >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 <6 months, 6-12 months, and >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 <6 months, 6-12 months, and >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<0.001) and 42.6% (MD 1.3%; p<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<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.
948-P: Glycemic and CGM Outcomes Are Nearly Independent of the Frequency of User Engagement with the Bionic Pancreas during 13 Weeks of Use in Adults and Children with Type 1 Diabetes
Authors: DAMIANO EDWARD , SELAGAMSETTY RAJENDRANATH , BRANDT RACHEL , RUSSELL STEVEN J.
Published: June 2024

It is well established that glycemic and continuous glucose monitoring (CGM) outcomes improve with increasing user engagement for both therapeutic devices (insulin pumps and pens) and diagnostic devices (CGMs, flash-glucose monitors, and blood-glucose monitors) used in the management of type 1 diabetes (T1D). Unlike any other insulin-delivery device, the iLet Bionic Pancreas (BP) determines and delivers 100% of all therapeutic insulin. Given this degree of autonomy, we hypothesized that glycemic and CGM outcomes obtained by the BP might be independent of the frequency of user engagement. To that end, data about user interactions with the BP were captured on the BP during the Bionic Pancreas Pivotal Trial (BPPT), and analyzed retrospectively. The average frequency of meal announcements initiated by each participant using the BP, and the average frequency of swipe gestures to unlock the lock screen of the BP, were analyzed and taken as proxies for user engagement with the device. Among 219 adults with T1D who used the BP for 13 weeks during the BPPT, the mean CGM glucose level was 156 ± 12 mg/dl. The average number of meal announcements and swipes to unlock the screen were 2.8/day and 9.9/day, respectively. The slope and intercept of the linear correlation between the mean CGM glucose level and the average number of daily swipes to unlock the screen were -0.08 and 157 mg/dl, respectively. The R2 correlation coefficient was 0.00. Similarly, the slope and intercept of the linear correlation between the mean CGM glucose level and the average number of daily meal announcements were -0.27 and 163 mg/dl, respectively, with an R2 of 0.06. Similar results to these are obtained when using 13-week HbA1c as an outcome. Unlike other therapeutic and diagnostic devices used in T1D management, glucose control achieved by the BP is nearly independent of the frequency of user engagement in terms of the metrics studied here.

Disclosure

E. Damiano: Board Member; Beta Bionics, Inc. Employee; Beta Bionics, Inc. Stock/Shareholder; Beta Bionics, Inc. R. Selagamsetty: Employee; Beta Bionics, Inc. Stock/Shareholder; Beta Bionics, Inc. R. Brandt: Employee; Beta Bionics, Inc. S.J. Russell: Employee; Beta Bionics, Inc. Stock/Shareholder; Beta Bionics, Inc. Other Relationship; Beta Bionics, Inc. Consultant; Beta Bionics, Inc. Research Support; Beta Bionics, Inc. Consultant; Novo Nordisk. Research Support; Novo Nordisk. Other Relationship; Novo Nordisk.
953-P: Changes in Time in Range (TIR) among Youth with Type 1 Diabetes (T1D) Initiating Different Automated Insulin Delivery (AID) Systems
Authors: GERA SONIA , REARSON ANDREW , BAKER GREY , DOUVAS JULIA L. , ALICEA-TRELLES NICOLE , GALLOP ROBERT J. , MEIGHAN SEEMA , MARKS BRYNN E.
Published: June 2024

Introduction & Objective: Glycemic outcomes in youth with T1D have not been compared between the two most commonly used AID systems in the United States, Insulet Omnipod 5 (OP5) and Tandem Control IQ (CIQ). Our aim is to perform the first head-to-head analysis of changes in TIR in youth initiating AID systems to further support clinical counseling and decision making.

Methods: This single center, retrospective chart review included youth < 21 years who were prescribed OP5 or CIQ between 2022-2023. AID start dates, pump data, 14-day baseline and 90-day continuous glucose monitor data were obtained from proprietary cloud-based software. A multiple linear regression model assessed for differences in 90-day time in range (TIR) according to AID system initiated.

Results: Among 470 youth, 228 (48.5%) started OP5 and 242 (51.4%) initiated CIQ. OP5 users were more likely to identify as female (57.5% vs 47.1%, p=0.03) and non-Hispanic Black (15.4% vs 4.5%, p=<0.01). OP5 users had a shorter TID duration (1.7 [IQR 0.7, 4.4] vs. 5.9 [IQR 2.9, 5.9], p=<0.01) and were more likely to have transitioned to AID from multiple daily injections (76.8% vs 19%, p<0.01). Baseline TIR was similar between groups (OP5 51.0% [IQR 36.3, 67.4] vs CIQ 52.9% [IQR 39.3, 66.3], p=0.74). There was no difference in AID active time (OP5 89.6% vs CIQ 87.4%, p=0.10) or user-initiated boluses per day (OP5 5.0 vs CIQ 5.3, p=0.21). 90-day TIR increased in both groups (p<0.001), rising by 11.9%-points (95% CI [10.3,13.4]) in OP5 users and 9.9%-points (95% CI[8.4,11.5]) in CIQ users. After adjusting for sex, race/ethnicity, T1D duration and prior regimen, improvements in 90-day TIR did not differ between AID systems (p=0.11).

Conclusion: Improvements in 90-day TIR following AID initiation among youth with T1D are significant and do not differ between commonly prescribed systems. Further studies are required to understand patient-related factors that may lead to differential success with a particular AID system.

Disclosure

S. Gera: None. A. Rearson: None. G. Baker: None. J.L. Douvas: None. N. Alicea-Trelles: None. R.J. Gallop: None. S. Meighan: Speaker's Bureau; Dexcom, Inc. B.E. Marks: Research Support; Tandem Diabetes Care, Inc., Dexcom, Inc., Medtronic, Digostics. Advisory Panel; International Society for Pediatric and Adolescent Diabetes, American Diabetes Association, T1D Exchange. Board Member; Juvenile Diabetes Research Foundation (JDRF).
958-P: High User Satisfaction and Ease-of-Use Scores with Six Months Use of the Tandem t:connect Mobile Application
Authors: ASSADI KIMIA , MANNING MICHELLE L. , PINSKER JORDAN E. , MESSER LAUREL H.
Published: June 2024

Objective: People with diabetes who use the t:slim X2 with Control-IQ technology (CIQ, Tandem Diabetes Care) in the United States also have the option to use the smartphone app (t:connect mobile), which includes the ability to bolus from the app, and continuously upload data to the cloud. This study explores user satisfaction and perceptions of ease of use (EOU) of the smartphone app.

Methods: People with type 1 and type 2 diabetes using CIQ completed surveys on satisfaction and perceived EOU of the app after 6 months of use. Data collection occurred June 2023 through November 2023.

Results: 3,687 individuals completed surveys at 6 months (54% female, 88% type 1 diabetes, 25% previous MDI users). Of 2,695 who responded to the satisfaction metric, 79.6% were either satisfied or very satisfied with the smartphone app. Of the 2,433 who responded to the EOU metric, 83.6% considered the app “easy” or “very easy” to use. Individuals who use the bolus feature of the app had comparably higher satisfaction and EOU percentages (84% satisfied and 88% EOU) compared to individuals who did not use the bolus feature (69% satisfied, 71% EOU)

Conclusion: Users new to Tandem report high satisfaction and EOU for the t:connect mobile smartphone app. The consistently positive perceptions indicates that the CIQ system with the mobile app hold general appeal, potentially assuaging pump hesitancy fears in people not yet using a pump.

Disclosure

K. Assadi: Employee; Tandem Diabetes Care, Inc. Stock/Shareholder; Tandem Diabetes Care, Inc. M.L. Manning: Employee; Tandem Diabetes Care, Inc. J.E. Pinsker: Employee; Tandem Diabetes Care, Inc. L.H. Messer: Employee; Tandem Diabetes Care, Inc.

Funding

Tandem Diabetes Care