bluuebunny/crossref_metadata_2025_split huggingface dataset:
855-P: PromarkerD Predicts Late-Stage Renal Function Decline in Type 2 Diabetes in the Canagliflozin Cardiovascular Assessment Study (CANVAS)
Authors: PETERS KIRSTEN E. , PRINZIO PATSY DI , BRINGANS SCOTT , DAVIS WENDY A. , DAVIS TIMOTHY , LIPSCOMBE RICHARD J. , HANSEN MICHAEL K. 
Published: May 2022

A third of people with type 2 diabetes (T2D) will develop chronic kidney disease (CKD) , the leading cause of end-stage renal disease (ESRD) . Current standard of care tests (urinary albumin:creatinine ratio (ACR) , estimated glomerular filtration rate (eGFR)) have limited ability to predict CKD progression. PromarkerD is a novel blood test that has prognostic value for the onset/progression of early-stage renal function decline in T2D. The ability of PromarkerD to predict later-stage renal decline in participants in the CANVAS trial was explored.
Concentrations of PromarkerD biomarkers (CD5L, ApoA4, IGFBP3) were measured by mass spectrometry at baseline in 3,525 CANVAS participants (n=1,179 placebo arm, n=2,346 canagliflozin arm) and combined with clinical data (age, serum HDL-cholesterol, eGFR) to provide PromarkerD scores (0 to 100%) for adverse renal outcomes. Cox regression was used to assess the ability of PromarkerD to predict three composites: i) ≥40% eGFR decline, ESRD, or renal death ii) outcome 1 or cardiovascular disease death and iii) outcome 2 or progression to macroalbuminuria.
At baseline, the participants (mean age 62.7 years, 67% males, median diabetes duration 12.5 years) had mean eGFR 77 mL/min/1.73m2, median ACR 11.6 mg/g and mean PromarkerD score 34.5%. During a mean 5.6 years of follow-up, 138 (3.9%) , 380 (10.8%) and 427 (12.1%) participants experienced composite outcomes 1 to 3, respectively. After adjusting for allocated treatment, each 10% increase in PromarkerD score was significantly associated with higher rates of adverse outcomes (outcome 1: HR 1.22 [1.to 1.38], outcome 2: HR 1.28 [1.to 1.37], outcome 3: HR 1.13 [1.to 1.21], all P≤0.001) with only modest attenuation after adjustment for both eGFR and ACR (all P≤0.013) .
This post-hoc analysis of CANVAS data shows that PromarkerD can be used to predict late as well as early-stage renal decline in people with T2D.

Disclosure
K.E.Peters: None. P.Di prinzio: None. S.Bringans: None. W.A.Davis: None. T.Davis: Advisory Panel; Merck Sharp & Dohme Corp., Novo Nordisk, Roche Diagnostics, Research Support; Novo Nordisk, Speaker's Bureau; Novo Nordisk. R.J.Lipscombe: Employee; Proteomics International, Stock/Shareholder; Proteomics International. M.K.Hansen: Employee; Janssen Research & Development, LLC.
869-P: Reductions in Traditional Risk Factors Explain Most of the Cardiovascular Benefit of SGLT2 Inhibitors and GLP-1 Receptor Agonists: An Analysis Using the BRAVO Risk Engine
Authors: NIU SHU , GUAN DAWEI , OSPINA NAYKKY SINGH , CUSI KENNETH , FONSECA VIVIAN , SHI LIZHENG , SHAO HUI 
Published: May 2022

Several hypotheses have been proposed that SGLT2 inhibitors and GLP-1 receptor agonists may have additional mechanisms to further reduce risks of cardiovascular complications unexplained by traditional risk factors control. This study aimed to examine and quantify the magnitude of additional protective effects of these two drugs on cardiovascular outcomes in individuals with type 2 diabetes (T2D) . Patient characteristics were extracted from four cardiovascular outcomes trials (CVOTs) of SGLT2 inhibitors and four CVOTs of GLP-1 receptor agonists completed before Nov 2021. We used the BRAVO simulation model to translate risk factors reductions from the newer drugs into risk reductions in cardiovascular complications, assuming the simulated risk reductions are only driven by traditional risk factors (i.e., A1c, SBP, LDL, and BMI) . We then derived the relative risk (RR) between observed risk reductions and simulated risk-factor-driven risk reductions in study outcomes to determine whether additional cardiovascular benefit of the newer drugs exist that can be explained by improvement of traditional risk factor control. Controlling for effect from traditional risk factors, SGLT2 inhibitor was associated with an additional risk reduction of hospitalization for heart failure (HHF) (RR: 0.74, 95% confidence interval (CI) : 0.59-0.94) , and a meaningful but not significant reduction in all-cause mortality (RR: 0.90, 95% CI: 0.77-1.03) , but an increased risk of stroke (RR: 1.29, 95% CI: 1.03-1.62) . No additional benefit was observed in preventing MI or CVD mortality from SGLT2 inhibitors. No additional benefit in preventing any study outcomes was associated with GLP-1 receptor agonists. Except for the benefit on HHF by SGLT2i, improvement in traditional CVD risk factors largely account for all the benefit associated with GLP-1 and SGLT2i to reduce CVD.

Disclosure
S.Niu: None. D.Guan: None. N.Singh ospina: None. K.Cusi: Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Fractyl Health, Inc., Genentech, Inc., Hanmi Pharm. Co., Ltd., Intercept Pharmaceuticals, Inc., Novo Nordisk. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. L.Shi: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.
871-P: Weight Change as Mediator for Cardiovascular Benefits of Novel Diabetes Medications: A Meta-Regression Analysis
Authors: RODRIGUEZ-VALADEZ JOSE M. , HUNINK MYRIAM , MASHARANI UMESH , YEBOAH JOSEPH , PARK MEYEON , LI LIHUA , WEBER ELLERIE , LI YAN , BERKALIEVA ASEM , MAX WENDY , FLEISCHMANN KIRSTEN , FERKET BART 
Published: May 2022

Background: Prior research suggests cardiovascular (CV) benefits of glucose-lowering interventions are mediated by bodyweight changes, either through changes in fluid retention or body fat mass. For example, a meta-regression analysis of 30 randomized trials on glucose lowering interventions showed a 1 kg weight decrease was associated with a 5.9% (95% CI 3.9 - 8.0) relative reduction of heart failure risk (Ghosh et al., 2020) . We evaluated heterogeneity of CV benefits by weight change for two novel diabetes medications that lower weight: sodium glucose transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) .
Methods: We performed meta-regression analyses of published CV outcome trials (6 on SGLT2i, 8 on GLP-1RAs) using reported hazard ratios (HRs) and bodyweight difference across study arms. Dependent variables included log HRs for 1) all-cause mortality, 2) major adverse cardiovascular events (MACE) , and 3) hospitalization for heart failure. We ran linear mixed models with weights equal to the inverse of the variance of each study’s log HR.
Results: The slopes from meta-regressions by pooling all trials and by drug type (Figure) were not significant and in some cases demonstrated an inverse relationship (SGLT2i for MACE, slope= -.102; p= .04) .
Conclusion: We could not reproduce findings of increased CV benefits with more weight loss for SGLT2i and GLP-1RAs.

Disclosure
J.M.Rodriguez-valadez: None. W.Max: None. K.Fleischmann: None. B.Ferket: None. M.Hunink: None. U.Masharani: Advisory Panel; Ryse Health, Research Support; Clementia Pharmaceuticals. J.Yeboah: None. M.Park: Advisory Panel; Otsuka America Pharmaceutical, Inc., Reata Pharmaceuticals, Inc., Other Relationship; Merck & Co., Inc. L.Li: None. E.Weber: None. Y.Li: None. A.Berkalieva: None.

Funding
Research reported in this publication was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number R01HL153456. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
876-P: Empagliflozin-Induced Metabolic Changes and Cardiac Function in Patients with Type 2 Diabetes: A Randomized Crossover MRI Study with Insulin as Comparator
Authors: THIRUMATHYAM ROOPAMEERA , GOETZE JENS PETER , HOLST JENS J. , VEJLSTRUP NIELS , MADSBAD STEN , MADSEN PER L. , JØRGENSEN NILS B. 
Published: May 2022

Introduction: Empagliflozin reduces cardiovascular risk in type 2 diabetes, possibly through improved cardiac function associated with metabolic changes including lowered glucose and insulin concentrations and elevated free fatty acids (FFA) . We aimed to evaluate the influence of these metabolic changes on cardiac function in type 2 diabetes (T2D) .
Materials and Method: 17 subjects (13 males) with T2D, aged 58±3 years (mean±sem) , BMI 32.9±0.9 kg/m2, HbA1c 52.4±2.4 mmol/L, TD2 duration of 8.9±1.3 years were treated with empagliflozin (E) and NPH-insulin (I) for 5 weeks in a cross-over design with 3 weeks of washout between treatments. Insulin was titrated to produce similar glycemic control as during empagliflozin. Patients were studied before and at the end of each treatment period. Metabolic changes were evaluated with fasting glucose, FFAs and insulin concentrations, cardiac function with cardiac MRI during rest and chronotropic stress on two separate days without and with acute lowering of FFAs with acipimox. Cardiac endpoints were changes in left ventricular peak filling rate (∆LVPFR) and left ventricular ejection fraction (∆LVEF) .
Results: Fasting glucose was reduced from 8.7±0.5 mM during washouts to 7.6±0.3 mM on both treatments, while serum insulin was lower (E: 103±14 pM; I: 141±16 pM, p&lt;0.01) and FFAs higher (E: 0.60±0.03 mM; I: 0.50±0.mM, p=0.02) on empagliflozin compared with insulin treatment. Cardiac function did not differ between treatments in rest or during stress (rest: ∆LVPFR E: -2±19;I: -11±20 ml/s, p=1.0; ∆LVEF -1 ±1, -1±1%, p=0.8; stress: ∆LVPFR E:-32±20, I: -14±24 ml/s; ∆LVEF E: 1±2, I: 0±2%) . Acipimox reduced FFAs by ∼35% at all visits but did not reveal any cardiac effects of treatments.
Conclusion: Neither empagliflozin nor insulin treatment change cardiac function in patients with T2D. Treatment specific metabolic effects play no role for cardiac function under the studied conditions.

Disclosure
R.Thirumathyam: None. J.Goetze: Consultant; Novo Nordisk A/S. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. N.Vejlstrup: None. S.Madsbad: None. P.L.Madsen: None. N.B.Jørgensen: Advisory Panel; Novo Nordisk A/S, Research Support; Boehringer Ingelheim International GmbH, Speaker's Bureau; Novo Nordisk A/S, Stock/Shareholder; Eli Lilly and Company, Novo Nordisk A/S.

Funding
Boehringer Ingelheim Gmbh. Investigator initiated study grant.
890-P: Health Care Economic Burden and Resource Utilization in Adults with Type 2 Diabetes and Stroke
Authors: KING AARON A. , RAJPURA JIGAR J. , LIANG YUANJIE , PAPROCKI YUREK M. , UZOIGWE CHIOMA 
Published: May 2022

Objectives: To evaluate health care resource utilization and all-cause healthcare costs in adults with type 2 diabetes mellitus (T2DM) and stroke.
Methods: Patients ≥ 18 years of age with T2DM, with or without incident stroke, were identified between January 1, 2012 and December 31, 2020 using the Optum® Clinformatics® Data Mart database. Healthcare utilization and cost were measured for the 12 months after stroke (T2DM + stroke) or random ICD-9/ICD-code (T2DM only) . Stroke was defined as overnight hospitalization with a primary discharge code for hemorrhagic or ischemic stroke. We compared patient cohorts using an inverse probability of treatment weighting approach.
Results: The incidence rate of stroke in the year following T2DM diagnosis was 0.9% (n = 16,034) . Weighted analysis compared 11,021 patients with T2DM and incident stroke (mean age, 75.1; mean Charlson comorbidity index, [CCI] 4.6) and 11,1patients with T2DM alone (mean age, 75.2; mean CCI, 4.7) . Compared to patients with T2D alone, patients with T2DM and stroke were more likely to have an IP visit (adjusted rate ratio [ARR], 5.4; 95% CI, 5.3-5.6; p &lt; 0.01) , outpatient (OP) visit (ARR, 1.6; 95% CI, 1.6-1.6; p &lt; 0.01) , ER visit (ARR, 1.7; 95% CI, 1.6-1.7; p &lt; 0.01) , and longer hospital stay (ARR, 5.9; 95% CI, 5.8-5.9; p &lt; 0.01) . Pharmacy, IP, OP, and ER costs were higher in patients with T2DM and stroke compared to patients with T2DM alone (Total costs, $8,864 per patient per month [PPPM] vs. $2,902 PPPM; p &lt; 0.01) . IP visits (+$4,062) and OP visits (+$1,642) accounted for the biggest differences in healthcare costs. In a hypothetical population of one million patients with T2DM, we project an initial cost difference of +$615 million annually for patients with T2DM + stroke compared to T2DM alone.
Conclusions: In adults with T2DM, copresence of stroke was associated with higher healthcare utilization and cost compared to adults with T2DM alone. Treatments that lower risk of stroke in patients with T2DM should be considered in this population.

Disclosure
A.A.King: Advisory Panel; Novo Nordisk, Board Member; JDRF, Speaker's Bureau; Abbott, Dexcom, Inc., Lilly Diabetes, MannKind Corporation, Medtronic, Novo Nordisk. J.J.Rajpura: Employee; Novo Nordisk. Y.Liang: Employee; Novo Nordisk. Y.M.Paprocki: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. C.Uzoigwe: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk.
894-P: The Potential Value of Clustering-Based Type 2 Diabetes Subgroups for Guiding Intensive Treatment: A Maximum Cost-Based Comparison with Threshold-Based Classifications
Authors: LI XINYU , VAN GIESSEN ANOUKH , ALTUNKAYA JAMES , SLIEKER RODERICK , BEULENS JOLINE , PEARSON EWAN , ELDERS PETRA J.M. , FEENSTRA TALITHA , LEAL JOSE 
Published: May 2022

Aim: To quantify and compare the performance of setting priority for intensive treatment by novel clustering-based subgroups to threshold-based classifications using systematic coronary risk evaluation (SCORE) and HbA1c levels.
Methods: We divided 2,935 patients from the Hoorn diabetes care system cohort into five clustering-based subgroups: severe insulin-deficient (SIDD) , severe insulin-resistant (SIRD) , mild obesity-related (MOD) mild (MD) , and mild with high HDL-cholesterol (MDH) diabetes, and four risk threshold-based subgroups. The United Kingdom Prospective Diabetes Study Outcomes Model was used to simulate lifetime health outcomes in the U.S. and U.K. settings. Gains from hypothetical treatment scenarios based on clinical guidelines were compared to “care-as-usual” and expressed in incremental quality-adjusted life-expectancy (QALE) and complication costs.
Results: The SIRD and MOD subgroup had the lowest absolute and age-sex-standardized QALE, respectively (7.90; 9.07) . Threshold-based classifications better discriminated between patients with higher and lower absolute and standardized QALE than clustering-based subgroups. For MOD, hypothetical interventions costing up to $1973 (95%CI $1444-$2603) and £463 (95%CI £345-£603) per year would be cost-effective at $100,000 and £20,000 per QALY thresholds in the U.S. and U.K., respectively. The MOD, SIDD and SIRD subgroups had the best potential cost-effectiveness alongside the subgroup with high HbA1c and high SCORE.
Conclusions: Intensified treatment could be cost-effective at higher-than-average costs for three out of five of the clustering-based subgroups and two out of four of the threshold-based classifications. Both classification methods support priority setting for intensive treatment, but the threshold-based method may better identify those who have the most potential to benefit from intensified treatment.

Disclosure
X.Li: None. A.Van giessen: None. J.Altunkaya: None. R.Slieker: None. J.Beulens: None. E.Pearson: Speaker's Bureau; Sanofi. P.J.M.Elders: None. T.Feenstra: Research Support; Dutch Healthcare Institute (ZIN) , European Union/IMI Rhapsody. J.Leal: None.

Funding
RHAPSODY (115881)
9-LB: Increased Islet Expression of Somatostatin and Glucagon in Male Rats with Insulin-Dependent Type 2 Diabetes
Authors: HOFFMAN EMILY G. , ATHERLEY SARA C. , AKBARIAN NICKY , DSOUZA NINOSCHKA , LIGGINS RICHARD , RIDDELL MICHAEL 
Published: May 2022

Background: Pancreatic islet remodelling in type 1 diabetes increases somatostatin (SST) expression, which inhibits glucagon counterregulation to hypoglycemia. Here, we characterized islet morphology and hormone composition in a rodent model of insulin-deficient type 2 diabetes (T2D) .
Methods: Hypoinsulinemic T2D was induced in 8-9-week-old, male, Sprague-Dawley rats (n=4) via 3 weeks of high-fat feeding and a low-dose injection of streptozotocin (STZ; 35 mg/kg) . After 2 weeks of basal insulin treatment, pancreas tissue was extracted from T2D and healthy control (n=5) rats for immunohistochemical staining of representative islets.
Results: Fasted plasma C-peptide levels of hyperglycemic (24.8±3.3 mmol/l) T2D rats were reduced by ∼44% (624±64 vs. 1107±121 pmol/l; p&lt;0.001) , while glucagon was unchanged (75±31 vs. 98±39 pg/ml) . Fractional islet area of glucagon and SST were elevated by 40% (21±15 vs. 15±10%; p&lt;0.001) and 83% (11±8 vs. 6±5%; p&lt;0.001) , respectively, as compared to control rats (Figure) , which was most pronounced in small and medium-sized islets.
Conclusions: Fractional area expression of glucagon and SST increased per islet in insulin-treated rats with advanced T2D. These findings may help account for the increase in SST signaling that underscores defective glucagon counterregulation to hypoglycemia in insulin-deficient diabetic states.

Disclosure
E. G. Hoffman: None. S. C. Atherley: None. N. Akbarian: None. N. Dsouza: None. R. Liggins: Employee; Zucara Therapeutics, Stock/Shareholder; Zucara Therapeutics. M. Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Consultant; Eli Lilly and Company, Jaeb Center for Health Research, Speaker’s Bureau; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk.

Funding
GlycoNet
903-P: Health Care Economic Burden and Resource Utilization in Adults with Type 2 Diabetes and Peripheral Artery Disease
Authors: UZOIGWE CHIOMA , RAJPURA JIGAR J. , LIANG YUANJIE , PAPROCKI YUREK M. , KING AARON A. 
Published: May 2022

Objectives: To evaluate health care utilization and cost in adults with type 2 diabetes mellitus (T2DM) and peripheral artery disease (PAD) .
Methods: Patients ≥ 18 years of age with T2DM, with or without PAD, were identified between January 1, 2012 and December 31, 2020 using the Optum® Clinformatics® Data Mart database. Healthcare utilization and cost was measured for the 12 months after PAD (T2DM + PAD) or random T2DM-related ICD-9/ICD-code (T2DM alone) . PAD was defined as ICD-9/ICD-code of atherosclerosis or artery thrombosis of the lower extremities from ≥ 1 hospitalization, ≥ 2 physician evaluations, or hospitalization or physician visit with relevant current procedural terminology codes. Patient cohorts were compared using an inverse probability of treatment weighting approach.
Results: PAD incidence was 4.1% (n = 68,479) in the year after T2DM diagnosis. The weighted analysis compared 54,080 patients with T2DM and incident PAD (mean age, 74.0; mean Charlson comorbidity index, [CCI] 3.9) and 54,758 patients with T2DM alone (mean age, 74.2; mean CCI, 4.0) . Compared to patients with T2DM alone, patients with T2DM and PAD were more likely to have an inpatient (IP) visit (adjusted rate ratio [ARR], 2.4; 95% CI, 2.4-2.4; p &lt; 0.01) , outpatient (OP) visit (ARR, 1.5; 95% CI, 1.5-1.5; p &lt; 0.01) , or emergency room (ER) visit (ARR, 1.5; 95% CI, 1.4-1.5; p &lt; 0.01) and a longer IP stay (ARR, 2.6; 95% CI, 2.6-2.7; p &lt; 0.01) . Compared to patients with T2DM alone, patients with T2DM and PAD had higher mean healthcare costs (Total costs, $5,068 per patient per month [PPPM] vs. $2,416 PPPM; p &lt; 0.01) . In a health plan covering one million patients with T2DM, we project annual costs +$1.3B higher for patients with T2DM and PAD compared to patients with T2DM alone.
Conclusions: Patients with T2DM and PAD had higher healthcare utilization and costs. Further research could investigate cost effectiveness of treatments for patients with T2DM that lower risk of PAD.

Disclosure
C.Uzoigwe: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. J.J.Rajpura: Employee; Novo Nordisk. Y.Liang: Employee; Novo Nordisk. Y.M.Paprocki: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. A.A.King: Advisory Panel; Novo Nordisk, Board Member; JDRF, Speaker's Bureau; Abbott, Dexcom, Inc., Lilly Diabetes, MannKind Corporation, Medtronic, Novo Nordisk.
904-P: Trends in Out-of-Pocket Cost for Glucagon 2010–2020
Authors: ZUPA MARGARET , FELDMAN ROBERT , LUO JING 
Published: May 2022

The ADA Standards of Care recommend that all patients with diabetes at risk of hypoglycemia have glucagon available for emergency use. However, glucagon prescriptions are filled by only a small minority of patients with type 1 and type 2 diabetes in the United States each year. While there are multiple barriers to glucagon use, the extent to which out-of-pocket medication costs contributes to low uptake is not clear.
Using administrative claims from Optum’s de-identified Clinformatics® Data Mart Database (2007-2019) for adults with commercial or Medicaid insurance from 2010-2020, we sought to describe the trends in out-of-pocket costs for glucagon over time. Analyzed claims included all fills of glucagon, based on National Drug Codes, from 20through 9/30/2020. Our primary outcome was total out-of-pocket costs defined as the sum of copays and deductibles. Costs were adjusted for inflation based on 2020 dollars and scaled per single-use kit. Insurance type was based on the primary payor at the time of the glucagon fill.
The median (IQR) out-of-pocket cost of unmixed glucagon was $27.42 (15.09-37.98) in 2010, $33.58 (5.60-41.97) in 2015, and $30.42 (15.21-40.56) in 2020 for commercially insured beneficiaries. For Medicare beneficiaries, cost for unmixed glucagon was $0 (0-25.35) in 2010, $0 (0-33.58) in 2015, and $0 (0-40.56) in 2020. After introduction in 2019, the 2020 out-of-pocket cost of intranasal glucagon was $15.21 (7.60-35.49) for commercially insured beneficiaries and $10.14 (0.99-23.83) for Medicare beneficiaries.
Out-of-pocket costs for unmixed glucagon was stable for most commercially insured patients, and $0 for most Medicare beneficiaries from 20through 2020; therefore, cost should not serve as the primary barrier to accessing glucagon for most patients. However, for the subset of patients (4th quartile) with the highest out-of-pocket costs in both insurance groups, the cost of unmixed glucagon has increased over time. Novel intranasal glucagon had lower out-of-pocket cost compared to unmixed glucagon for most commercially insured patients immediately after introduction.

Disclosure
M.Zupa: None. R.Feldman: None. J.Luo: None.

Funding
NCATS KL2 (TR001856)