bluuebunny/crossref_metadata_2025_split huggingface dataset:
867-P: Cardiovascular Outcomes in Patients Initiating a Second Diabetes Medication after Metformin—The BESTMED Study
Authors: TURCHIN ALEXANDER , PETITO LUCIA , HEGERMILLER EMMA , CARNAHAN RYAN M. , KITZMAN HEATHER , CECILIA LANSANG M. , MCDONNELL MARIE E. , NAIR VINIT , PRIEST ELISA L. , WILLEY VINCENT , GOEL SATYENDER , KAUL ALAN F. , HERNAN MIGUEL 
Published: June 2024

Introduction: In patients with T2D at high cardiovascular (CV) risk, several classes of medications have been found to reduce incidence of CV events. However, long-term CV outcomes of T2D medications in lower risk patients are unknown.
Methods: We conducted a causal inference study by emulating a target trial using observational data from 12 health systems and insurance plans across the US. Eligible individuals were patients with T2D and hyperglycemia (HbA1c 7.0-11.0% or equivalent glucose levels) at moderate CV risk (no CV disease) on metformin monotherapy who initiated a second T2D medication between 01/01/13 and 09/01/21, with eGFR ≥ 45 ml/min/1.73m2 and with no contraindications to study medications. We compared patients initiating one of the following medication classes: DPP4s, GLP1s, SGLT2s and sulfonylureas (SUs). In each treatment arm we estimated the 5-year risk of a composite outcome (MI, ischemic CVA, HF hospitalization or CV death) after adjustment for demographics, comorbidities and laboratory values at baseline.
Results: We studied 55,441 patients followed for a median of 32 (IQR 18-54) months, with a median age of 60 (IQR 52-68) years and median baseline HbA1c of 7.8% (IQR 7.3-8.6%). Of these, 11,195 patients initiated a DPP4, 6,920 a GLP1, 7,911 an SGLT2 and 29,415 an SU; 40,673 (73.4)% of patients stopped the original study drug class before the end of follow-up after a median of 11 (IQR 3-22) months. A total of 2,566 (4.6%) of patients experienced the primary outcome endpoint. The estimated 5-year risk ratios (95% CI), compared to DPP4s, were 0.93 (0.73 - 1.13) for GLP1s, 0.96 (0.83 - 1.14) for SGLT2s and 1.08 (0.98 - 1.19) for SUs.
Conclusions: Among patients with T2D at moderate CV risk on metformin monotherapy, incidence of CV events was similar among four classes of most commonly used non-insulin T2D medications. Further research is needed to evaluate the risk of non-CV events to help patients and clinicians to make informed decisions on T2D therapy.

Disclosure
A. Turchin: Research Support; Eli Lilly and Company, Novo Nordisk. Consultant; Novo Nordisk, Proteomics International. Research Support; AstraZeneca. L. Petito: Research Support; Omron Healthcare Co., Ltd. E. Hegermiller: None. R.M. Carnahan: None. H. Kitzman: Advisory Panel; Novo Nordisk. M. Lansang: Research Support; Abbott, Dexcom, Inc. Consultant; Glooko, Inc. Research Support; Xeris Pharmaceuticals, Inc. M.E. McDonnell: None. V. Nair: None. E.L. Priest: Research Support; Boehringer-Ingelheim, AstraZeneca, Owkin. V. Willey: Other Relationship; Carelon Research. S. Goel: None. A.F. Kaul: None. M. Hernan: Consultant; ProPublica, Cytel. Other Relationship; ADIA Lab, Flatiron, Foundation Medicine.

Funding
PCORI (DB-2020C2-20308)
868-P: Efficacy and Safety of Crisugabalin with Acetyl-Levo-Carnitine in Chinese Patients with Diabetic Peripheral Neuropathic Pain—A Multicentre, Randomized, Open-Label, Positive-Controlled, Parallel-Group, Phase 2 Trial
Authors: JIANG HONGWEI , FU LIUJUN , XU NA , SHANG JUNJIE , YANG QIUWEI 
Published: June 2024

Background: Crisugabalin (HSK16149) was found to be a novel, potent treatment option for patients with diabetic peripheral neuropathic pain (DPNP); However, efficacy and safety data specifically for Chinese individuals were limited to several researches, and there was no comparative evidence on whether drugs should be combined. This study aimed to assess the efficacy and safety of Crisugabalin combined with acetyl-levo-carnitine (ALC) and lipoic acid (LA) combined with ALC for treatment of DPNP in China.
Methods: Adults (≥18 years) with DPNP, 40 mm≤VAS≤90 mm at screening were eligible for study participation. Subjects were randomized (1:1) to Crisugabalin (20mg, bid) combined with ALC (0.5g, tid), and LA (0.6g, qd, iv in 1 week, po in 2-12 week) combined with ALC (0.5g, tid) for 12 weeks. The primary endpoint was the change in average daily pain score (ADPS) from baseline to week 12. Key safety endpoints were the types and incidence of treatment-emergent adverse events (TEAEs) monitored throughout the trial.
Results: A total of 134 patients were randomized to receive Crisugabalin with ALC (n=68) or LA with ALC (n=65). Here we report initial results from interim analysis of the trial. At week 12, the mean ADPS change from baseline was -2.1 and -4.1 for LA (n=42) and Crisugabalin (n=44) group, showing statistical significance for Crisugabalin versus LA group (P&lt;0.0001). Most TEAEs in two groups were mild to moderate, and no investigational drugs-related TEAEs CTCAE≥3 happened throughout the study. The most frequent TEAEs in Crisugabalin group were dizziness (9/68, 13.2%) and somnolence (6/68, 8.8%).
Conclusion: These preliminary data demonstrated that Crisugabalin with ALC was superiority to LA with ALC in relieving pain and well tolerated in Chinese patients with DPNP.

Disclosure
H. Jiang: None. L. Fu: None. N. Xu: None. J. Shang: None. Q. Yang: None.
87-OR: A PKA to mTORC1 Signaling Axis Controls Metabolic Homeostasis via Phosphorylation of Raptor
Authors: SHI FUBIAO , LIU DIANXIN , ZHANG WEI , PATEL HARI U. , SHRESTHA SHRISTI , CARTAILLER JP , LI JIAN-LIANG , COLLINS SHEILA 
Published: June 2024

As critical mediators of cellular signaling, the second messenger cAMP and its associated protein kinase A (PKA) can function by regulating the activity of the mechanistic target of rapamycin complex 1 (mTORC1). However, the signaling mechanism and physiological significance underpinning this regulation have not been fully defined. Using the adipocyte as a model, we show that PKA phosphorylation of Ser791 in Raptor, the defining component of mTORC1, is required for mTORC1 activation by β3-adrenergic receptor (β3AR) stimulation. Mice with a phospho-resistant Raptor Ser791 to Ala (S791A) mutation specifically in adipocytes (adS791A) show impaired adipose browning after β3AR agonist CL-316,243 (CL) treatment. They develop adipose inflammation, fatty liver, and insulin resistance on high-fat diets. In follow-up hyperinsulinemic-euglycemic clamp studies, they manifest reduced glucose infusion rates, increased hepatic glucose production, and decreased skeletal muscle glucose uptake. Mechanistically, the adipocyte S791A mutation blunts CL-induced mTORC1 activity and leads to degradation of the PPARγ protein. In addition to PPARγ, the level of β3AR protein is also reduced in Raptor adS791A mice. We have identified PPARγ binding sites along with a known critical C/EBPα site in the β3AR promoter, suggesting PPARγ, with C/EBPα, could be a transcriptional regulator of β3AR expression. In contrast, expression of a constitutively active phospho-mimetic Raptor Ser791 to Asp (S791D) mutant in brown adipocytes results in transcriptomic changes indicative of greater PPARγ activity and enhanced adipocyte thermogenesis gene program. These data indicate that Raptor S791 phosphorylation might act through a PPARγ-dependent mechanism to control adipose tissue function. Taken together, our study reveals the functional consequence for the PKA phosphorylation of Raptor in adipocyte metabolism and presents a novel mechanism by which the cAMP-PKA pathway controls the mTORC1 signaling network.

Disclosure
F. Shi: None. D. Liu: None. W. Zhang: None. H.U. Patel: None. S. Shrestha: None. J. Cartailler: None. J. Li: None. S. Collins: None.

Funding
National Institutes of Health (R01DK116625 to SC), American Heart Association (23CDA1048341 to FS)
872-P: Tolerization Therapy for Treating Type 1 Diabetes Mellitus
Authors: DE HAAN PETER 
Published: June 2024

Introduction & Objective: Type 1 Diabetes Mellitus (T1DM) is an autoimmune disease in which T lymphocytes infiltrate pancreatic Langerhans islets and destroy insulin-producing β-cells. Amarna has developed a viral gene delivery vector platform named SVec that based on its safety, non-immunogenicity and tolerogenic properties may be effective in inducing/restoring immune tolerance to the primary self-antigens of autoimmune diseases to thereby halt or revert autoimmune disease progression. We wanted to test the feasibility of SVec for the development of an effective tolerization therapy for T1DM.
Methods: Two SVec vectors encoding the primary self-antigens of the disease e.g. proinsulin (SVPI) and preproinsulin (SVPPI) were generated and vector particles produced in our SuperVero packaging cells. To obtain hepatic transgene expression groups of ten female non obese diabetic (NOD) mice were administered intravenously with SVPI or SVPPI particles six weeks after birth at a dose of 2.5x107 IU/kg body weight and glycemia was monitored up to 30 weeks after birth.
Results: Ninety percent of the untreated NOD mice developed hyperglycemia within this time span, whereas only forty percent of the SVPI-treated mice became hyperglycemic. SVPPI did not protect female NOD mice from developing T1DM. Histological inspection of the pancreases revealed that the tolerized NOD mice with SVPI had healthy islets and islets partially infiltrated with T lymphocytes. On the contrary, the pancreases of untreated mice or those injected with SVPPI were completely or partially infiltrated with T lymphocytes. Conclusion: The induction of immune tolerance to proinsulin in the liver stops the autoimmune destruction of pancreatic β-cells and hence disease progression in mice that were on their way to develop T1DM. SVec is therefore highly promising for inducing antigen-specific immune tolerance and thus for developing effective and safe tolerization therapies for patients with an autoimmune disease including T1DM.

Disclosure
P. de Haan: None.
876-P: Imeglimin, a Novel, First-in-Class Glimin Helps in Maintaining ß-Cell Function in Patients with Recent-Onset Latent Autoimmune Diabetes in Adults—A Nine-Month Prospective Study
Authors: GADVE SHARVIL S. , GADVE SNEHA S. , GADVE SHRIYA , CHAVANDA KETKI S. , HANAMSHETTI SATISH 
Published: June 2024

Objective: Imeglimin is being used in T2DM. The effect of imeglimin on β-cell function in patients with latent autoimmune diabetes in adults (LADA) is not known, however, based on its mechanism of action, imeglimin could be expected to preserve pancreatic β-cell function in LADA patients. The objective of the study was to evaluate the effects of the imeglimin on β-cell function in patients with recent-onset LADA.
Research Design & Methods: This was an open-label, randomized-controlled trial conducted in a specialized diabetes care unit in India. Thirty Six recently diagnosed LADA patients were randomized to receive insulin therapy with 1000 mg twice a day imeglimin (n = 18) or without imeglimin (n = 18) for 9 months. Fasting and 2-hour postprandial blood samples were obtained at baseline and after 3, 6, and 9 months of treatment to determine blood glucose, glycosylated hemoglobin, and C-peptide levels.
Results: There were no significant differences in glucose and glycosylated hemoglobin levels between the two groups during 9 months of follow-up. At 9 months, fasting C-peptide, 2-hour postprandial C-peptide, and increment in C-peptide (delta CP) levels were not different in Insulin plus imeglimin group (P &gt; .05) compared with baseline, whereas in Insulin without imeglimin group the levels of fasting C-peptide, 2-hour postprandial C-peptide, and increment in C-peptide (delta CP) levels were significantly decreased compared with baseline (P &lt; .05). Levels of 2-hour postprandial C-peptide were higher in Insulin plus imeglimin group than Insulin without imeglimin group at 9 months (P &lt; .05).
Conclusions: Imeglimin helps in maintaining β-cell function in patients with recent-onset Latent Autoimmune Diabetes in Adults when given with insulin when compared to insulin given alone.

Disclosure
S.S. Gadve: None. S.S. Gadve: None. S. Gadve: None. K.S. Chavanda: None. S. Hanamshetti: None.
884-P: Duodenal Electroporation and Semaglutide Effectively Eliminate Need for Insulin in Type 2 Diabetes Patients
Authors: BUSCH CELINE B.E. , MEIRING SUZANNE , VAN BAAR ANNIEKE C.G. , HOLLEMAN FRITS , NIEUWDORP MAX , BERGMAN JACQUES 
Published: June 2024

Introduction: Re-Cellularization via Electroporation Therapy (ReCET™) is an endoscopic ablation technique which uses electroporation of cellular membranes to elicit apoptosis of the duodenal mucosa. We aimed to eliminate insulin therapy in T2D patients by combining a single ReCET procedure with a GLP-1 receptor agonist (GLP-1RA).
Methods: First-in-human study with 14 patients with T2D on basal insulin (BMI 24-40kg/m2; HbA1c≤8.0%; C-pep≥0.2nmol/l). All underwent ReCET after which semaglutide was titrated up to 1mg/week. Primary endpoints were feasibility (technical success, procedure time, GLP-1RA tolerance), safety ([S]AE, hypoglycemic events) and efficacy (off insulin at 6 months; HbA1c≤7.5%). Metabolic and glycemic data was collected throughout 24 months follow-up.
Results: ReCET showed 100% technical success rate. Procedure time was 58 min. Max semaglutide dosage was tolerated by 13 patients. No device related SAEs or severe hypoglycemic events were observed. At 6 months 12 patients (86%) were off insulin and remained off insulin at 9, 12 and 18 months (24mo data available Jan 2024). Despite being off insulin, glycemic and metabolic parameters improved significantly (Table 1).
Conclusion: ReCET appears to be safe and, when combined with semaglutide, can effectively eliminate the need for insulin up to 18 months in T2D patients, while improving glycemic control and metabolic health.

Disclosure
C.B.E. Busch: None. S. Meiring: None. A.C.G. van Baar: None. F. Holleman: None. M. Nieuwdorp: Stock/Shareholder; Caelus Health, AMI therapeutics. J. Bergman: Research Support; Fractyl Health, Inc. Consultant; Fractyl Health, Inc. Research Support; Endogenex. Consultant; Endogenex. Research Support; Digma. Consultant; Digma. Research Support; Aqua Medical. Consultant; Aqua Medical.

Funding
An unrestrided research grant by Endogenex.
9-PUB: Water Consumption Evaluation during a Short Weight Loss Program
Authors: CONSTANTIN CIPRIAN , CONSTANTIN GEORGIANA , LULIA STAICU M. , IJACU ANA M. , DRAGOICEA MIHAI , ZUGRAVU CORINA , GAGIU LAURA G. 
Published: June 2024

The aim of this study was to evaluate the water consumption during an interventional program using glucagon like peptide 1 receptor analog (aGLP1) or inhibitors of sodium glucose-cotransporter2 (iSGLT2) medication at type 2 diabetes mellitus (T2DM) patients. This was a retrospective study during the year 2023, using data from multiple centers. We included 45 T2DM patients (23women and 22men), age (mean±standard deviation) 61,12±6,13years, duration of T2DM 5,16±1,41years, BMI=34,4±3,15kg/m2, HbA1c=7,20±0,2%, divided in 3 similar lots (p&gt;0.05). All these groups were matched according to all important characteristics at the beginning. All patients were initially treated with metformin (met) 2g/day. After first evaluation we consider: lot A received iSGLT2 plus met, lot B received aGLP1 plus met and lot C with met. All patients received 10%calories reduction program in normal conditions. Targets were established using ADA23 guidelines. Observational parameters at baseline and after 1 and 3 months included water consumption (WaCo) liter/day, estimation in a 3 day-journal. Initially and in the end were determinate HbA1c and BMI. In our study it seems to be a significant clinical difference during a regular losing weight program considering water consumption (p&gt;0,05). Significant differences were observed comparing lot A vs. lot B and lot A vs. lot C when we kept the different antidiabetic medication used during this program (p&lt;0,05).

Disclosure
C. Constantin: None. G. Constantin: None. S.M. Lulia: None. A.M. Ijacu: None. M. Dragoicea: None. C. Zugravu: None. L.G. Gagiu: None.

Funding
Research Metabolism Center - Romania
906-P: Safety and Efficacy of Polmacoxib for Diabetes-Associated Frozen Shoulder—Prospective Randomized Control Trial
Authors: GAUTAM ASHISH , AGRAWAL PRABHAT K. , PURSNANI NIKHIL , YADAV SHAILENDRA K. , YADAV ALKA 
Published: June 2024

Introduction and Objective: Adhesive Capsulitis (AC) or frozen shoulder is a common complication of uncontrolled T2DM having prevalence of 10-39%. Shoulder pain and disability index(SPADI) is visual analogue scale tool to quantify disease severity in AC. Polmacoxib, a novel COX2 inhibitor is indicated for long term analgesia in osteoarthritis without CV side effects. Besides COX2 Inhibition it has high affinity to carbonic anhydrase (CA) enzyme. A preferential binding of Polmacoxib to CA reduces COX2 effects in cardiovascular system where it is present in abundance. Thus, preventing CV side effects. Prolonged effective analgesic, physiotherapy and strict glucose control are main stay treatment of AC. Objective was to study Polmacoxib as safe and effective analgesic in T2DM associated AC.
Methods: Eighty-six participants with T2DM and AC without CV disease were divided into 2 groups (43 cases and 43 comparators) after randomization. SPADI tool used before start of therapy and then weekly till 6 weeks in both groups. Increase in wight 5% and heart rate 10% above baseline, new onset pedal edema &/or right hypochondrial tenderness, easy fatigability &/or unexplained cough were measured signs of fluid accumulation and incipient CHF and considered early study termination. Standard diabetes care and physiotherapy given to both groups. Cases were given oral Polmacoxib 2 mg/day and Comparators oral tramadol sos for pain. A &gt;80% SPADI score reduction was considered cut-off for effective analgesia.
Results: one case lost follow up, so excluded. Thirty six out of 42 cases whereas 28 out of 43 comparators showed &gt;80% reduction in SPADI score at 2 wks. which was maintained till 6 wks. The proportion of participants who reported reduction in pain and disability above cutoff differ by use of Polmacoxib, X2 (1, N = 85) = 4.84, p &lt; .05. No participant showed any sign of CHF during study.
Conclusion: Polmacoxib was an effective and safe analgesic for prolong use in adhesive capsulitis due to T2DM

Disclosure
A. Gautam: None. P.K. Agrawal: None. N. Pursnani: None. S.K. Yadav: None. A. Yadav: None.
911-P: Effect of Dapagliflozin on Blood and Breath Ketones during Supervised Insulin Withdrawal in Adults with Type 1 Diabetes
Authors: PETERSEN MAX C. , JONES KAI E. , BOHNERT KATHRYN L. , MARKOV ALEXANDER M. , SALAM MAAMOUN , KRUTILOVA PETRA , MCKEE ALEXIS M. , ADAMSON SAMANTHA E. , MCGILL JANET B. 
Published: June 2024

Introduction: SGLT2 inhibitors increase DKA risk, limiting their use in T1D. To understand the effect of SGLT2i on ketone production, we measured glucose, beta-hydroxybutyrate (BOHB) and breath acetone (BrACE) with and without dapagliflozin during supervised insulin withdrawal in adults with T1D.
Methods: 20 adults with T1D underwent on-site supervised insulin withdrawal twice in a randomized crossover design: during usual care and after treatment with dapagliflozin (10 mg daily for 2 weeks plus the test day). After insulin withdrawal, capillary blood glucose, BOHB, and BrACE measurements were obtained at least hourly until stopping rules were met (glucose &gt;400 mg/dL, BOHB &gt;3 mmol/L, &gt;8 hours elapsed, or participant request).
Results: Mean (± SD) age was 48 ± 18 years, with baseline HbA1c 7.0 ± 0.9%. The maximal BOHB and BrACE values achieved during supervised insulin withdrawal were both greater with dapagliflozin than usual care (BOHB: 2.4 ± 1.2 vs. 1.6 ± 1.0 mmol/L, P &lt;0.001; BrACE: 13.7 ± 7.5 vs. 8.7 ± 5.7, P = 0.004). Adjusted for time from insulin withdrawal, dapagliflozin treatment was associated with significantly greater BOHB and BrACE concentration (both P &lt;0.001 by ANCOVA). The proportions of participants reaching BOHB &gt;1.5 mmol/L and &gt;2.5 mmol/L during supervised insulin withdrawal were greater in the dapagliflozin arm (74% vs. 37% with BOHB &gt;1.5 mmol/L; 53% vs. 16% with BOHB &gt;2.5 mmol/L; both P &lt;0.05 by McNemar’s test). Blood glucose reached a lower maximum (218 ± 53 vs. 302 ± 58 mg/dL, P &lt;0.001) in the dapagliflozin arm and did not significantly change during insulin withdrawal in the dapagliflozin arm (P for linear trend = 0.91).
Conclusion: In adults with T1D undergoing up to 8 hours of supervised insulin withdrawal after dapagliflozin treatment, blood and breath ketone concentrations were significantly greater compared to usual care and in the absence of significant hyperglycemia.

Disclosure
M.C. Petersen: None. K.E. Jones: None. K.L. Bohnert: None. A.M. Markov: None. M. Salam: None. P. Krutilova: None. A.M. McKee: Advisory Panel; Medtronic, Novo Nordisk. Employee; Novo Nordisk. S.E. Adamson: None. J.B. McGill: Advisory Panel; Bayer Inc., Boehringer-Ingelheim, ClearNote Health, Lilly Diabetes, MannKind Corporation, Novo Nordisk. Research Support; Novo Nordisk.

Funding
JDRF (2-SRA-2022-1190-M-B)
914-P: Association of Sodium–Glucose Cotransporter 2 Inhibitors with Risk of Diabetic Ketoacidosis among Hospitalized Patients—A Multicentre Cohort Study
Authors: SARMA SHOHINEE , HODZIC-SANTOR BENAZIR , COLACCI MICHAEL , VERMA AMOL A. , RAZAK FAHAD , RAISSI AFSANEH , LASSEN MATS C.H. , FRALICK MICHAEL 
Published: June 2024

Importance: Sodium glucose co-transporter-2 (SGLT-2) inhibitors are being used among hospitalized patients, but there is no real-world empiric data on the risk of diabetic ketoacidosis (DKA) in-hospital. Objective: To assess the risk of DKA with SGLT-2 inhibitor use during hospital stay.
Design, Setting, Participants: We conducted a multi-centre cohort study of hospitalized patients in 19 hospitals in Canada between January 1, 2015 and December 31, 2021. We included patients over age 18 years with type 2 diabetes mellitus who received an SGLT-2 inhibitor or a dipeptidyl peptidase-4 (DPP-4) inhibitor in hospital. Exposure: SGLT-2 inhibitor
Comparator: DPP4-inhibitor
Main Outcomes and Measures: The primary outcome was the risk of DKA defined using American Diabetes Association (ADA) DKA criteria (pH &lt;7.30, bicarbonate less than 18 mmol/l and positive ketones). Patients were followed from the date of admission to hospital to date of discharge or occurrence of DKA.
Results: We identified 11,098 patients who received an SGLT-2 inhibitor and 67,429 who received a DPP-4 inhibitor. The average age was 67.7 years (SD: 18.3 years), and 47.7% were women. In the matched population, the risk of DKA was 0.06% (N=6 events) over 5.2 hospital days with DPP-4 inhibitors and 0.19% (N=20 events) over 5.4 hospital days with SGLT-2 inhibitors. The relative risk was 3.33 (95% CI 1.33 - 8.30) for SGLT-2 inhibitors compared to DPP-4 inhibitors.
Conclusion and Relevance: Among hospitalized patients, the risk of DKA with use of SGLT-2 inhibitors was three-fold higher compared to DPP-4 inhibitors, but the absolute risk of DKA was low.

Disclosure
S. Sarma: None. B. Hodzic-Santor: None. M. Colacci: None. A.A. Verma: None. F. Razak: None. A. Raissi: None. M.C.H. Lassen: None. M. Fralick: Consultant; singal1, proofdx.