bluuebunny/crossref_metadata_2025 huggingface dataset:
797-P: Usability and Satisfaction of a New Affordable Insulin Pen for All: Positive Outcomes of Two Usability Studies
Authors: NIELSEN OLE K. , HUISMAN GEKE , QASEM JAMIL A. , ENG CHEE WEN , JØRGENSEN ANNE F. , TORRONE MARTINO , LARSEN BRIT S. , REDDY AMULYA
Published: May 2022

Globally, 13 million people (4 million in USA) inject insulin with single use disposable syringes daily. Compared to syringe and vials, pens are known to increase adherence and diabetes control and to reduce healthcare utilization costs. Yet, pens are largely unavailable to low-income groups, due to prohibitive cost. GO-Pen has designed a new affordable pen for use with vial insulin and conducted usability testing in collaboration with Médecins Sans Frontières (MSF) , an international medical humanitarian organization working to improve diabetes care for people living in difficult circumstances.

Here we report the results of two usability studies conducted among insulin pen users (n=19, f/m: 11/8, age: 23-64) and syringe users (n=20, f/m: 10/10, age: 24-70) in refugee populations in Malaysia and Jordan. A convenience sample of the first 20 to accept enrollment was set up after informed consent. After a short introduction, participants were asked to demonstrate the use of the insulin pen in front of a camera, without revealing their faces or any identifying information, while an interviewer noted their correct use and confidence level. Injection was simulated in a sponge. 100% (n=19) of pen users and 75% (n=15) of syringe users performed >90% of the tasks correctly. Among pen users, the most common failed tasks were priming the needle (n=4) . Among syringe users, the most common failed tasks were failing to check the vial label (n=9) and priming the needle (n=6) . 5% (n=1) of pen users preferred the new insulin pen over the pen they were already familiar with. 75% (n=15) of syringe users preferred the new insulin pen over syringes. The most common complaint among pen users was that there were too many steps in the process.

In conclusion, we find current pen users require little training and prefer the pen they are already familiar with. Syringe users who are unfamiliar with pen usage require more training than pen users, however, they have largely favorable attitudes towards this new insulin pen.

Disclosure

O.K.Nielsen: Stock/Shareholder; GO-Pen ApS. G.Huisman: None. J.A.Qasem: None. C.Eng: None. A.F.Jørgensen: None. M.Torrone: None. B.S.Larsen: None. A.Reddy: None.
8-LB: Glucagon—The Forgotten Hormone in Diabetes
Authors: MITCHELL BETH , NELSON DAVID R. , MEEKS ALEXANDRA , YAN YU
Published: May 2022

The ADA recommends that all people with diabetes at risk of level 2 or 3 hypoglycemia be prescribed glucagon. Studies of conventional reconstituted injectable glucagon showed low rates of successful delivery of a full dose and low prescription filling rates. Since July 2019, ready-to-use glucagon options have become commercially available. IBM® MarketScan® Research Database was used to study prescription patterns among people with T1D or T2D on insulin who had filled a glucagon prescription 2 years prior to July 2019 (pre-period) and/or 2 years after through July 2021 (post-period) . Logistic regression models (for feature selection of independent variables followed by two-way interaction identification from Multivariate Adaptive Regression Splines) were utilized to determine glucagon fills post-period based on variables pre-period (demographics, diabetes type, insurance, comorbidities, history of hypoglycemia, diabetes medications) . Classification trees were used to illustrate the effects of significant variables (variables added >1% accuracy from cross validation) . Of all insulin-treated people (n=138,826) over the 4-year period, 13.5% (T1D 48.4%, T2D 3.5%) had glucagon prescriptions filled. Of those who filled glucagon post-period (n=14,234) , 54.3% filled a ready-to-use glucagon. The primary drivers and % of glucagon fills post-period: overall included age <22 (63.3%) , T1D (37.4%) , and glucagon filled pre-period (62.2%) (each p<.001) ; among people with T1D, age <17 (81.6%) and glucagon filled pre-period (66.7%) (each p<.001) ; among people with T2D, glucagon filled pre-period (34.0%) , basal-bolus insulin filled in the 4-year period (4.4%) , and age <16 (58.6%) (each p<.001) . The results suggest that, despite guideline recommendations, glucagon prescription fills are low, and mostly by young people. Though at increased risk of hypoglycemia, fill was low in the elderly and people with T2D on basal-bolus insulin. After becoming available, ready-to-use glucagon represented over 50% of glucagon fills.

Disclosure

B. Mitchell: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. D. R. Nelson: Employee; Eli Lilly and Company. A. Meeks: Employee; Eli Lilly and Company. Y. Yan: Employee; Eli Lilly and Company.

Funding

Eli Lilly and Company
803-P: Serum Adiponectin Level Is Reduced after Short-Term Intensive Insulin Therapy in Patients with Newly Diagnosed Type 2 Diabetes
Authors: LIU LIEHUA , KE WEIJIAN , CHEN JIE , LI YANBING
Published: May 2022

Objective: Short-term intensive insulin therapy (SIIT) can induce remission of type 2 diabetes (T2D) , and the improvement of insulin sensitivity is considered essential. This study aimed to evaluate the role of adiponectin change during SIIT in patients with newly diagnosed T2D.

Methods: SIIT was given to 42 patients with newly diagnosed T2D to normalize blood glucose (4.4-6.0 mmol/L for fasting blood glucose [FBG], 4.4-8.0 mmol/L for 2h-postprandial blood glucose [2hBG]) for two weeks. Serum lipids, adiponectin, and high-sensitive C reactive protein levels, insulin resistance and β-cell function were evaluated before and after SIIT.

Results:After the therepy, FBG (11.8±2.9 mmol/L vs. 6.8±1.3mmol/L,P<0.001) and 2hPG (18.4mmol/L± 6.4mmol/L vs. 9.7±2.4mmol/L, P<0.001) were both significantly decreased, with β-cell function (measured by acute insulin response [AIR], HOM-B) and insulin sensitivity (measured by HOMA-IR) improved. Serum adiponectin raised from 2.9±1.2mg/L to 3.4±1.1mg/L (P<0.001) ,while serum triglyceride and LDL-C decreased significantly. Serum adiponectin after treatment was correlated with baseline triglyceride (r = -0.33, P = 0.04) , HDL-C (r = 0.34, P = 0.03) , LDL-C (r = -0.31, P = 0.05) and Hs-CRP (r = -0.33, P = 0.05) ; the change of adiponectin (Δadiponectin) after treatment were significantly correlated with the level of Δtriglyceride (r = 0.38, P = 0.03) . There was no notable correlation between adiponectin and β-cell function index or HOMA-IR. Adiponectin levels were similar between patients who obtained diabetes remission (defined as FBG< 7.0mmol/L, 2hBG<10.0mmol/L without hypoglycemic agents) and those who did not (baseline:3.0±1.5mg/L vs. 2.9±1.0 mg/L; after SIIT:3.4±1.0mg/L vs. 3.3±0.9 mg/L,both P>0.05) .

Conclusion: Adiponectin level was significantly increased after SIIT in patients with newly diagnosed T2D. The change of adiponectin is related to the improvement of lipid metabolism and reduced inflammation.

Disclosure

L.Liu: None. W.Ke: n/a. J.Chen: None. Y.Li: None.

Funding

The National Key R&D Program of China (2018YFC1314100) , the Key-Area Research and Development Program of Guangdong Province (2019B020230001) , the National Natural Science Fund of China (81800716) , the science and technology program of Guangzhou, 202002020053.
810-P: Real-World Performance of IDegAsp over Six Years in Asian-Indian Population
Authors: KESAVADEV JOTHYDEV , SABOO BANSHI D. , SHANKAR ARUN , KRISHNAN GOPIKA , BASANTH ANJANA , ASHIK ASHA , DAVID ASHWIN , JOTHYDEV SUNITHA
Published: May 2022

There is scarce data on the long-term safety and efficacy of IDegAsp in Asian Indians in a real-world (RW) setting. IDegAsp is a co-formulation of an ultra-long-acting insulin Degludec and a rapid acting insulin Aspart. A multi-centric, retrospective observational study was conducted to evaluate long-term efficacy and safety of IDegAsp in T2D on regular follow up for >5 years. Baseline clinical data of 535 T2D (78.7% males; avg. age= 53.41 ± 12.yrs; HbA1c= 8.88 ±1.96 %; avg. duration of diabetes: 11.34 ± 7.57yrs) , previously on treatment (90.1 %) which included various OADs±insulin regimen, or treatment-naive (9.9 %) , who were switched to or initiated on IDegAsp respectively, from December 2014 - 2021 were analyzed. Significant improvements (P<0.05) in clinical parameters were observed from baseline (Table 1) . The TDD was 15.45 ± 10.53 units/day (at 3 months) which increased (p<o.oo1) to 20.03 ± 11.units/day post-treatment (67 months) . 65.2 % continued twice daily IDegAsp and 3.9 % switched from twice daily to once daily IDegAsp during treatment. 30.9% continued once daily IDegAsp. A total of non-severe hypoglycemic episodes were observed. In this RW study involving T2D from Asia, IDegAsp significantly improved A1C and a range of clinical profiles, with negligible hypoglycemia. Unlike conventional premix/basal bolus regimen, IDegAsp offers a less complex, more physiological, safe and effective solution for glycemic control.

Disclosure

J.Kesavadev: None. B.D.Saboo: None. A.Shankar: None. G.Krishnan: None. A.Basanth: None. A.Ashik: None. A.David: None. S.Jothydev: None.
818-P: Chronic Oral Polymeric Duodenal Exclusion Therapy Has Profound Metabolic Benefits in a T2D Rat Model and Affects Duodenal Morphological Enteroplasticity Similar to RYGB surgery: Implications for T2D Therapy
Authors: NIMGAONKAR ASHISH , GUERINA FLORENCE , KELLEHER SHANNON L. , CARLSON TAYLOR , COLBERT KEVIN , POLOMOSCANIK STEVEN , PETERSEN JOHN S. , HABEGGER KIRK M. , PASRICHA PANKAJ J. , FINEMAN MARK , JOZEFIAK THOMAS H.
Published: May 2022

Background: RYGB surgery has significant weight loss and improvement in glycemia, attributed predominantly to duodenal exclusion. To mimic this effect non-invasively, we developed oral, gut-restricted, inert polymer (GLY-POL) that interacts with mucus in the proximal small intestine to form a dynamic barrier excluding the duodenal lining from luminal contents. We hypothesized that such treatment would result in significant metabolic improvement and affect morphologic enteroplasticity similar to RYGB.

Methods: Goto-kakizaki (GK) rats were gavaged with GLY-POL daily for 8-weeks (n=7 per group) . Metabolic responses were evaluated weekly (BW, food intake, oGTT, mMTT, HOMA-IR) . Duodenal morphometric analysis (villus height and crypt depth) was performed in excised duodenum after study completion.

Results: There was profound metabolic improvement with chronic GLY-POL therapy; oGTT (iAUC ↓ = 60 - 70%, p<0.0005) , mMTT (iAUC ↓ > 55%, p < 0.005) , HOMA-IR improvement (p<0.005) , 6% weight loss (p<0.005) . There was no difference in food intake between the groups. There was a significant reduction in the duodenal villus height (p<0.0001) and crypt depth (p<0.0001) in treated rats compared to controls.

Conclusion: Our results confirm a key role for chronic duodenal exclusion oral GLY-POL therapy in improving the systemic metabolic milieu with profound reduction in FPG, PPG, insulin resistance and weight loss. Duodenal villus morphological changes are likely due to nutritional depletion from the GLY-POL lining. Similar cellular structural changes have been reported in the bypassed portion of the small intestine after RYGB surgery. GLY-POL therapy offers the potential for a novel non-invasive approach for glycemic and weight control in T2D patients that mimics the effects of gastric bypass without the adverse effects associated with this surgery.

Disclosure

A.Nimgaonkar: Employee; Glyscend Inc. M.Fineman: None. T.H.Jozefiak: Employee; Glyscend Inc., Stock/Shareholder; Glycologix, LLC. F.Guerina: Employee; Glyscend Inc. S.L.Kelleher: Research Support; Glyscend Inc. T.Carlson: Employee; Glyscend Inc. K.Colbert: Stock/Shareholder; Glyscend Inc., LifeSprout. S.Polomoscanik: None. J.S.Petersen: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Stock/Shareholder; Glyscend Inc. P.J.Pasricha: Consultant; Vanda, Other Relationship; Teva Pharmaceutical Industries Ltd., Stock/Shareholder; Glyscend Inc., Neurogastrx, P4M.
82-LB: Improvement of Glycemic Control in People with Type 2 Diabetes Using Basal Insulin (PwT2D-BI) and Continuous Glucose Monitoring (CGM) —U.S. Study Using Machine Learning (ML)
Authors: CHINTHAMMIT CHANADDA , BRNABIC ALAN J.M. , PEREZ-NIEVES MAGALY
Published: May 2022

Background: CGM provide real-time glucose data that allows users to manage their diabetes holistically. This study aimed to assess the association between glycemic control and CGM use in PwT2D-BI.

Methods: This retrospective study used IBM MarketScan® 2015 - 2019 Databases to identify PwT2D-BI with (CGM) and without (control) use of CGM. CGM users were followed from first BI until CGM initiation, defined as index date (ID) . The ID of non-CGM controls were randomly assigned based on time between first BI and ID of CGM. . Comparison CGM use for 6 and 12 months were performed using Frequentist Model Averaging (FMA) in a ML framework adjusting for baseline characteristics. Model strategies were applied including matching, weighting, stratification and regression.

Results: A total of 5,934 PwT2D-BI (251 CGM; 5,683 control) were included in the study (Table 1) . Observed A1c reduction from baseline to 12 months was 0.87%, 0.95% for 6 and 12 months of CGM use, respectively vs. 0.32% for controls. FMA analyses found CGM users had a statistically significantly greater reduction in A1c both at 6 months (treatment difference 0.30 [0.13,0.48]) and 12 months (0.50 [0.37, 0.72]) .

Conclusion: Findings suggest that CGM use for at least 6 months in PwT2D-BI has clinical benefit as demonstrated by A1c reduction in the real-world setting.

Disclosure

C. Chinthammit: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A. J. M. Brnabic: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M. Perez-nieves: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
82-OR: Phase Angle of Bioelectrical Impedance Analysis Correlates with Multiple Parameters of Diabetic Polyneuropathy in Patients with Type 2 Diabetes
Authors: SCHIMPFLE LUKAS , MOOSHAGE CHRISTOPH , TSILINGIRIS DIMITRIOS , KENDER ZOLTAN , KURZ FELIX T. , JENDE JOHANN M.E. , SZENDROEDI JULIA M. , BENDSZUS MARTIN , KOPF STEFAN
Published: May 2022

Background and Aims: Sensorimotor polyneuropathy (DPN) is the most common diabetic complication and a major contributor to increased morbidity and mortality in diabetic patients. With diagnostic methods still being limited, we aimed to correlate the phase angle (PhA) , a marker derived from bioelectrical impedance analysis, with determinants of DPN. In particular we used magnetic resonance neurography (MRN) together with state-of-the-art clinical and electrophysiological measurements of DPN.

Materials and Methods: In this cross-sectional observational study we included 1healthy subjects and 2patients with type 2 diabetes (T2D) , amongst which 63 had DPN. The PhA was calculated using a multi-frequency bioelectrical impedance analyzer. Nerve conduction studies, quantitative sensory testing (QST) and diffusion weighted 3 Tesla MRN to determine the fractional anisotropy (FA) were performed.

Results: In the group comparison lower PhA values were found in T2D patients with DPN in contrast to T2D patients without DPN (5.71+/-0.vs. 6.07+/-0.08, p=0.007) and healthy controls (5.71+/-0.vs. 6.18+/-0.08, p<0.001) . Confounder-adjusted analysis among T2D patients showed positive correlations of the PhA with the FA of MRN (r=0.41, p=0.006) , with conduction velocities and action potentials of the peroneal (r=0.27, p<0.001; r=0.29, p<0.001) and tibial nerve (r=0.22, p=0.005; r=0.30, p<0.001) and with Z-scores of QST (thermal detection r=0.31, p<0.001; thermal pain r=0.20, p=0.010; mechanical pain r=0.19, p=0.015; mechanical detection r=0.19, p=0.013) .

Conclusion: The close association of the PhA with the FA, a marker of structural nerve integrity of MRN, might reflect the similar physics of current or diffusion respectively being impaired by altered nerve composition. Due to correlations of the PhA with classical diagnostics of DPN it could become a novel, easily accessible and powerful marker for a quick assessment of DPN.

Disclosure

L.Schimpfle: None. C.Mooshage: None. D.Tsilingiris: None. Z.Kender: None. F.T.Kurz: None. J.M.E.Jende: None. J.M.Szendroedi: Consultant; Boehringer Ingelheim International GmbH. M.Bendszus: None. S.Kopf: Board Member; Novo Nordisk, Speaker's Bureau; AstraZeneca, Recordati S.p.A.

Funding

The German Research Council (DFG, SFB 1158)
824-P: Dual Amylin and Calcitonin Receptor Agonists Improve Insulin Sensitivity and Increase Tissue-Specific Glucose Uptake Independent of Weight Loss
Authors: LARSEN ANNA T. , SONNE NINA , BREDTOFT EMMA-MARIE , KARSDAL MORTEN A. , HENRIKSEN KIM
Published: May 2022

Dual amylin and calcitonin receptor agonists (DACRAs) are known to induce a significant weight loss and improve glucose tolerance and glucose control in rats. However, it is unknown if DACRAs has an insulin sensitizing effect beyond that induced by weight loss and if DACRAs affect tissue specific glucose uptake. Additionally, clamp studies with DACRAs have not previously been performed in diabetic rats. Pre-diabetic ZDSD and diabetic ZDF rats were treated with the DACRA KBP-088 (1.5 nmol//kg, s.c.) for 12 days, and a hyperinsulinemic clamp was conducted on day 13, 24 h post-dosing. In ZDSD rats a hyperinsulinemic euglycemic clamp was carried out, while a hyperinsulinemic isoglycemic clamp was carried out in ZDF rats. In addition, specific glucose uptake was assessed during a hyperinsulinemic isoglycemic clamp in ZDF rats. In ZDSD rats, KBP-088 treatment resulted in a significant reduction in body weight and fasting blood glucose, and improved insulin sensitivity by increasing the glucose infusion rate (GIR) (vehicle: 8.6, KBP-088: 12 mg glucose/kg/min) . In ZDF rats, KBP-088 significantly reduced fasting blood glucose and improved insulin sensitivity (GIR, vehicle: 1.5, KBP-088: 16.5 mg glucose/kg/min) , independent on weight loss. In both studies, KBP-088 increased the rate of glucose clearance, likely be increasing glucose storage, but without altering the endogenous glucose production. Direct assessment of tissue specific glucose uptake showed, that KBP-088 significantly increased glucose uptake in both muscles and adipose tissues when compared to vehicle.

In summary, KBP-088 significantly improved insulin sensitivity in both pre-diabetic and diabetic rats and markedly increased tissue specific glucose uptake. Importantly, KBP-088 has an insulin sensitizing effect independent of weight loss, highlighting DACRAs as promising agents for treatment of diabetes.

Disclosure

A.T.Larsen: Employee; Nordic Bioscience. N.Sonne: None. E.Bredtoft: None. M.A.Karsdal: Employee; Nordic Bioscience A/S, Nordic Bioscience A/S, Nordic Bioscience A/S. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S.
825-P: Composite Glucose and C-Peptide Endpoints Show Early Efficacy in Recent-Onset Type 1 Diabetes (T1D) Clinical Trials
Authors: JACOBSEN LAURA M. , CUTHBERTSON DAVID D. , HALLER MICHAEL J. , ISMAIL HEBA M. , SIMS EMILY K. , GITELMAN STEPHEN E. , WHERRETT DIANE K. , MORAN ANTOINETTE , ATKINSON MARK A. , PUGLIESE ALBERTO , GOTTLIEB PETER , SOSENKO JAY
Published: May 2022

C-peptide area under the curve (AUC) at ≥1 year, a standard endpoint of recent-onset T1D clinical trials, is derived from a 120-minute mixed meal tolerance test (MMTT) . We analyzed whether composite glucose and C-peptide endpoints, useful in post hoc analyses of prevention trials, could detect treatment effects as early as 3 months between the combined treated and placebo groups from 3 TrialNet recent-onset T1D trials that met their primary endpoint. Comparisons were made between treated and placebo groups after adjustments for age, sex, and BMI Z-score using AUC C-peptide (standard measure) , AUC C-peptide/AUC glucose (AUC ratio) , and a new measure, the centroid ratio. Centroids, geometric central points of shapes, were derived from MMTT shapes formed from mean glucose and C-peptide values at 30, 60, 90, and 120 minutes. The centroid ratio is the C-peptide coordinate/glucose coordinate of the centroid. A treatment effect at 3 months was evident for centroid and AUC ratios (p<0.0 and p=0.002, respectively) and not AUC C-peptide (p=0.056) . Similar results were seen when individual trials were compared. The difference between combined groups at 3, 6, and 12 months is demonstrated by vectors that start at baseline (Figure) .

In conclusion, composite glucose and C-peptide endpoints appear to identify early treatment efficacy and should be considered in future new-onset pilot studies and trials.

Disclosure

L.M.Jacobsen: None. A.Pugliese: Advisory Panel; Provention Bio, Inc., Consultant; Quell Tx. P.Gottlieb: Advisory Panel; Janssen Research & Development, LLC, ViaCyte, Inc., Other Relationship; IM Therapeutics, Research Support; Caladrius Biosciences, Inc., Immune Tolerance Network, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk, Precigen, Inc., Tolerion, Inc. J.Sosenko: None. D.D.Cuthbertson: None. M.J.Haller: Advisory Panel; SAB Biotherapeutics , Consultant; MannKind Corporation, Sanofi. H.M.Ismail: n/a. E.K.Sims: Other Relationship; Medscape, Patent. S.E.Gitelman: Advisory Panel; Abata Therapeutics, Avotres Inc., Biolojic Design, Ltd., Provention Bio, Inc., Rubius, SAB Biotherapeutics, Inc., Tolerion, Inc. D.K.Wherrett: n/a. A.Moran: Advisory Panel; Dompé, Other Relationship; Novo Nordisk, Research Support; Abbott Diabetes, Provention Bio, Inc. M.A.Atkinson: None.
831-P: Tocilizumab Is Effective in Reducing Inflammation in T2D–COVID-Organ-on-a-Chip Model
Authors: NEGI VINNY , GAVLOCK DILLON , LEE JEONGKYUNG , SHUN TONGYING , GOUGH ALBERT , MIEDEL MARK T. , TAYLOR D. LANSING L. , YECHOOR VIJAY
Published: May 2022

The COVID-pandemic has contributed to more than 5 million deaths worldwide in the last two years. Co-morbid conditions such as Type 2 Diabetes (T2D) , HTN, obesity, and CKD have been associated with increased mortality with COVID-19. In a large meta-analysis, the relative risk of mortality was 1.54 for patients with T2D and COVID-19. Thus, there is an imperative need to develop a platform for rapid and reliable drug screening/selection against COVID-related morbidity/mortality in T2D patients. With limited translatability of in vitro and small animal models to humans, human organ-on-a-chip models are an attractive platform to model in vivo disease conditions and test potential therapeutics. We seeded T2D or nondiabetes patient-derived macrophage and human liver sinusoidal endothelial cells along with normal hepatocytes and kupffer cells in the liver-on-a-chip (LAMPS - Liver Acinus MicroPhysiological System) developed by our group, perfused with media mimicking normal fasting or late metabolic syndrome (LMS - high levels of glucose, fatty acids, insulin, glucagon) states. We transduced both macrophage and endothelial cells to overexpress the SARS-CoV2-S (spike) protein and compared it with a control lentivirus transduction. We found that T2D cells overexpressing S-protein in LMS media (T2D chip) displayed an increased secretion of inflammatory cytokines compared to the nondiabetes chip over days. We then tested the effect of Tocilizumab (IL6-receptor antagonist) in T2D chips. Compared to vehicle control, Tocilizumab significantly decreased the S-protein induced inflammatory cytokine secretion in T2D chips but not in nondiabetes chips, indicating its higher efficacy in severe disease states only. This is consistent with what was observed in large clinical trials providing confirmatory evidence that the LAMPS T2D and nondiabetes chips serve as a relevant in vitro model system to replicate human in vivo pathophysiology of COVID and for screening potential therapeutics.

Disclosure

V.Negi: None. D.Gavlock: None. J.Lee: None. T.Shun: None. A.Gough: None. M.T.Miedel: None. D.L.Taylor: None. V.Yechoor: n/a.
835-P: The Hepatoselective Glucokinase Activator (GKA) TTP399 Does Not Increase Risk of Ketoacidosis in Type 1 Diabetes (T1D)
Authors: KLEIN KLARA , BOEDER SCHAFER C. , FREEMAN JENNIFER L. , MADDURI SUPRADEEP , GIOVANNETTI ERIN R. , VALCARCE CARMEN , BUSE JOHN B. , PETTUS JEREMY
Published: May 2022

Identification of adjunctive, oral pharmacotherapies to treat T1D has been limited by risk of DKA. TTP399, an oral hepatoselective GKA, significantly improves glycemia in individuals with T1D compared to placebo. This double-blind, randomized, placebo-controlled, Phase 1 mechanistic study examined whether TTP399 decreases ketogenesis during insulin withdrawal.

Individuals with T1D (n=23) using insulin pump therapy were randomized to TTP399 or placebo for 7-days after which an insulin withdrawal test (IWT) was performed. Insulin pumps were disconnected for up to hours to induce ketogenesis.

TTP399 significantly reduced fasting glucose (-27.6 vs. -4.4 mg/dL, p = 0.03) . During the treatment period, adverse events were fewer in TTP399-treated subjects. No hypoglycemic events <54mg/dL were observed in the TTP399 group compared with 2 subjects in the placebo group. Following insulin withdrawal, no significant differences in mean duration of IWT or beta-hydroxybutyrate (BOHB) at termination were observed between treatment groups (Figure 1A) . Serum bicarbonate was numerically higher and urine acetoacetate was qualitatively lower in TTP399-treated subjects (Figure 1A) . No patients on TTP399 met prespecified criteria for DKA while 43% of subjects on placebo did (Figure 1B, p = 0.03) .

These data suggest that TTP399 treatment improves glucose control with no increased risk of DKA.

Disclosure

K.Klein: None. S.C.Boeder: Consultant; Cecelia Health, Research Support; Dexcom, Inc., Lilly. J.L.Freeman: Employee; vTv Therapeutics, Stock/Shareholder; vTv Therapeutics. S.Madduri: None. E.R.Giovannetti: None. C.Valcarce: Employee; vTv Therapeutics. J.B.Buse: Consultant; Alkahest, Anji, AstraZeneca, Boehringer Ingelheim International GmbH, Cirius Therapeutics, Inc., Eli Lilly and Company, Fortress biotech, GentiBio, Glycadia, Glyscend, Janssen Pharmaceuticals, Inc., Mellitus Health, Moderna, Inc., Pendulum Therapeutics, Praetego, LLC, Stability Health, Valo, Zealand Pharma A/S, Other Relationship; Adocia, AstraZeneca, Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation, Novo Nordisk, Sanofi, Senseonics, vTv Therapeutics, Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Stock/Shareholder; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. J.Pettus: Advisory Panel; Lilly, MannKind Corporation, Novo Nordisk, Sanofi, Consultant; Carmot Therapeutics, Inc., Diasome.

Funding

JDRF international
836-P: A Prebiotic Fiber Blend Improved Postprandial Glucose (PPG) and Time in Range (TIR) as Evaluated by Continuous Glucose Monitoring (CGM) in Healthy Subjects with Normal Glucose Tolerance
Authors: DAMMAN CHRISTOPHER J. , FRIAS JUAN PABLO , LEE MARTIN L. , RIKSE LARS , LAM WING SHUN , LAI REN-HAU , WASHINGTON MARC
Published: May 2022

This open-label, pre-post, pilot study evaluated the impact of a prebiotic fiber blend (including green banana resistant starch & oat beta-glucan) on PPG and TIR measured by CGM (Abbott Freestyle Libre Pro) . Five healthy subjects (3M/2F; 41±7y, fasting glucose 92.2±10.9 mg/dL, BMI 23.9±3.2 kg/m2, mean+/-SD) consumed high glycemic index foods (e.g. cornflakes & rice milk) as the first meal of the day for 6 consecutive days followed by identical meals for 6 consecutive days with 7.5 grams of the prebiotic fiber blend. Addition of the prebiotic blend resulted in a significant 26.4% reduction in the baseline-adjusted 2-hr PP interstitial glucose (IG) area-under-the curve (Fig. 1a; 4125.9 ± 2468.9 vs. 3038.1 ± 1701.8 mg/dL, p=0.043) . Pooled subject 6-day % TIR (IG = 70-140 mg/dL) , % time above range (TAR, IG>140 mg/dL) , and % time below range (TBR, IG<70 mg/dL) showed a significantly higher % TIR (p=0.043) and lower % TBR (p=0.043) with the prebiotic blend (Fig. 1b) . This exploratory pilot study suggests the potential impact of a prebiotic fiber supplement as a complement to other dietary and pharmaceutical interventions for glycemic control. A randomized placebo controlled trial is currently underway to evaluate the impact of a full nutrition meal replacement shake with and without a similar fiber blend in persons with type 2 diabetes.

Disclosure

C.J.Damman: Advisory Panel; Evolve Biosystems, Employee; Uplifting Results Labs. J.Frias: Advisory Panel; Altimmune, Becton, Dickinson and Company, Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi, Consultant; 89bio, Inc., Akero Therapeutics, Inc., Altimmune, Becton, Dickinson and Company, Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Afimmune Limited, Akero Therapeutics, Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Carmot Therapeutics, Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Ionis Pharmaceuticals, Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Speaker's Bureau; Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. M.L.Lee: Consultant; UR Labs. L.Rikse: Employee; Uplifting Results Labs. W.Lam: Employee; UR Labs. R.Lai: Employee; UR Labs. M.Washington: Employee; UR Labs (Uplifting Results) .
837-P: Hypoxemic COVID-Pneumonia, Diabetes Mellitus: Combination of Tailored Prednisone, Colchicine, Antithrombotics, Diuretic Improves Prognosis (CocAA-CoLa PLUS Study)
Authors: KEVORKIAN JEAN-PHILIPPE , MÉGARBANE BRUNO , FÉRON FLORINE , RIVELINE JEAN-PIERRE , MAUVAIS-JARVIS FRANCK , GAUTIER JEAN-FRANÇOIS
Published: May 2022

In patients (pts) with diabetes mellitus (DM) , Covid-pneumonia mortality rate >20% has been reported. A low fixed dose of intravenous dexamethasone (Dx) for days (RECOVERY study, 6 mg/d, i.e 0.5 mg/kg/d prednisone equivalent) has been shown to effectively reduce Covid-pneumonia mortality. In an observational study, prognosis was improved with an oral combination of prednisone fixed dose (1mg/kg/d) , direct anticoagulant/aspirin/colchicine/furosemide (DOAACF) . We hypothesized prednisone tailored doses driven by clinical evolution (extra 1mg/kg/d for every increase of O2 flow) added-on DOAACF for days would decrease morbi-mortality. In our monocentric, retrospective study (03.2020-05.2021) , pts with Covid-pneumonia requiring O2 out of the Intensive Care Unit (ICU) were included. According to the Physicians discretionary caring decisions, a control group (no corticoid) , a Dx group, an oral tailored prednisone ≥1mg/kg/d-DOAACF group were compared. The primary endpoint was Day 28 ICU requirement or mortality. Out of 3pts included for hypoxemic Covid-pneumonia, 132 pts had DM (43%) (control n = 28; Dx n = 46; tailored prednisone-DOAACF n = 58) : median age 69y; Males/Females 2.8; BMI 28 kg/m2; cardiovascular history 40%; median SpO2 at room air 92%; median maximal O2 flow 4L/min. Pts characteristics were non statistically different. Prednisone median dose (1.5mg/kg/d) and aspirin-colchicine-furosemide use were significantly higher in the tailored prednisone-DOAACF group in which events rate (12%) was significantly lower (control 50%, p = 0.0003, Dx 37%, p = 0.004) . In the tailored group, no statistical difference observed with pts without DM (13.3%, p = 1) . Out of the ICU, in pts with DM, a five oral drugs combination made of tailored prednisone ≥1mg/kg/d, anti-inflammatory, antithrombotics, diuretic improves hypoxemic Covid-pneumonia prognosis. A randomized trial is needed.

Disclosure

J.Kevorkian: None. B.Mégarbane: None. F.Féron: None. J.Riveline: None. F.Mauvais-jarvis: Consultant; Mithra Pharmaceutical. J.Gautier: Other Relationship; Novo Nordisk, Sanofi, Speaker's Bureau; Eli Lilly and Company.
84-OR: Responders to Neuropathic Pain Treatment Have Greater Target Engagement of Opioid Receptor Systems: A Resting State Functional Magnetic Resonance Imaging Study in Painful Diabetic Neuropathy
Authors: TEH KEVIN , SLOAN GORDON P. , WILKINSON IAIN D. , TESFAYE SOLOMON , SELVARAJAH DINESH
Published: May 2022

Painful diabetic neuropathy (DN) is a common and distressing complication. New approaches are required to identify novel targets that will serve as a catalyst for future drug discovery programmes. We have demonstrated that responders to neuropathic pain treatment have greater functional connectivity between the insula cortex and the corticolimbic system compared to non-responders. Activity within these networks is mediated by endogenous opioid receptor systems and may hold clues to possible future treatment targets. Methods: 43 painful-DN subjects [responders (VAS<4; n=29) and non-responders (VAS≥4; n=14) ] underwent detailed clinical and neurophysiological assessment, and RS-fMRI. Data analysis was performed using the NITRC Functional ConnectivityToolbox and SPM8 in MatLab. RS-fMRI data was masked and binarised using an opioid receptor atlas to restrict the analysis to the voxels with high receptor density. Subject-specific spatial maps of responders and non-responders were compared. Results: Compared to painful-DN non-responders, responders had greater functional connectivity between the corticolimbic system with the opioid receptor networks [F (2) (41) =43.53;intensity=128.7; R-amygdala beta=0.48; p-FDR<0.0001; R-putamen beta=0.3; p-FDR<0.0001; dorsal lateral prefrontal cortex beta=0.25; p-FDR=0.0002 and the posterior parietal cortex networks beta0.25; p-FDR=0.0002]. Conclusion: Painful DN treatment responders have better target engagement of opioid receptors systems compared to non-responders. This indicates that a functioning/intact descending pain inhibition network is crucial for a better pain response. Interventions targeted at this network could provide better pain relief in non-responders to neuropathic pain treatment.

Disclosure

K.Teh: None. G.P.Sloan: None. I.D.Wilkinson: None. S.Tesfaye: Advisory Panel; Astellas Pharma Inc., Bayer AG, Grünenthal Group, Nevro Corp., Wörwag Pharma GmbH & Co. KG, Speaker's Bureau; Eva Pharma, Pfizer Inc., Viatris Inc. D.Selvarajah: None.

Funding

National Institute of Health Research EME grant; European Foundation for the Study of Diabetes
840-P: Proof of Concept of I.P. Administered Neo-Islet (NI) T1DM Biotherapy: Omentum Becomes the New Endocrine Pancreas by Spontaneous Redifferentiation of In Vitro Dedifferentiated Islet Cells
Authors: GOOCH ANNA , CHOWDHURY SABIHA S. , WESTENFELDER CHRISTOF
Published: May 2022

We published that treatment with allogeneic, species specific NIs, organoids of Mesenchymal Stromal Cells (MSCs) and culture expanded islet cells (ICs) functionally cured/improved the diabetic state in NOD mice, insulin dependent pet dogs, and NOD/SCID mice treated with dog or human NIs without requiring antirejection drugs or encapsulation devices (see also abstract this meeting) . Fig 1 summarizes the mode of action of NI therapy and experimental detail: Dedifferentiated ICs (∼ 6 PDLs) are incorporated into NIs and implanted into diabetic animals. They redifferentiate in vivo and normalize blood glucose levels as demonstrated by gene expression analysis on NIs retrieved from euglycemic diabetic mice at 21 weeks post administration. As seen in the right portion of the graph, gene expression levels of islet endocrine hormones in retrieved NIs are not significantly different from those of freshly isolated islets (log10 (RQ) < ± 2) . These data demonstrate that although culture expansion of islet cells decreases endocrine gene expression as a function of PDLs, incorporation of ICs into NIs and implantation into a diabetic subject results in redifferentiation of the ICs, reestablishment of euglycemia, and restoration of islet hormone gene expression.

Disclosure

A.Gooch: Board Member; SymbioCellTech, LLC., Employee; SymbioCellTech, LLC., Stock/Shareholder; SymbioCellTech, LLC. S.S.Chowdhury: Employee; SymbioCellTech, LLC. C.Westenfelder: None.
842-P: A Novel Drug to Modulate Autoinflammation and Promote Glucose Control in Type 1 Diabetes Mellitus
Authors: WAGNER DAVID H. , VAITAITIS GISELA M.
Published: May 2022

NOD mice are the accepted model for Type 1 Diabetes Mellitus (T1DM) Canine Diabetes (CD) demonstrates clinical outcomes identical to NOD and human T1DM. We described helper T cells that express the CD40 receptor, termed Th40 cells. In human T1DM Th40 cells expand significantly in number in peripheral blood prior to hyperglycemia; and respond to human islets. In NOD mice, Th40 cells increase first in the pancreatic lymph nodes, expand in number in the periphery prior to hyperglycemia, are the prominent T cell type detected in the pancreas during insulitis, and transfer diabetes to SCID recipients. Naturally occurring CD is insulin requiring and demonstrates the same clinical parameters as human disease. In a clinical pilot study using diabetic dogs we discovered significantly elevated Th40 cell numbers in PBMC compared to non-diabetic dogs (p < 0.0001) . Th40 cell numbers may help predict risk of development of T1DM as a subset of “at-risk” pre-T1DM human subjects who developed T1DM showed elevated Th40 numbers. Using a novel approach to target CD40-mediated inflammation we created a series of small peptides. The lead candidate, OPT101, has an approved IND and completed Phase 1a human clinical trials establishing human safety profiles. OPT501, a canine version caused a rapid reduction in Th40 cell numbers in diabetic dogs. Daily insulin requirements were reduced on average by 75% and in 2 cases by 90%. Fructosamine, the canine equivalent of HbA1c, was reduced 40.2% on average with 3 subjects achieving normal range. All participants had significantly reduced daily blood glucose averages, and 3 subjects maintained normal glucose levels and time-in-range (TIR) increased to greater than 50%, and in some cases greater than 90%, from a previous TIR of 10%. All participants demonstrated increased c-peptide levels, a measure of restored beta cell function, after 6 weeks of treatment. Equivalent clinical outcomes have not been reported for any other drug candidate in veterinary or human T1DM trials.

Disclosure

D.H.Wagner: Other Relationship; Op-T, LLC. G.M.Vaitaitis: None.

Funding

National Institutes of Health (AI131784; AI128592)
843-P: Fortnight Intensive Treatment Strategy for Type 2 Diabetes
Authors: RAMANARAYANAN SHIVAA MOHAN
Published: May 2022

According to ICMR IndiaB study, only 31% of Indians with type 2 diabetes (T2DM) have HbA1c ≤ 7 %. Hence, we strategize FIT (Fortnight intensive treatment) care to achieve an early Glycemic control that could effectively sustain over an extended period. In this study, individuals (N=107) with T2DM, aged >18 years with HbA1c >7% were subjected to a combination therapy of single or multiple OADs with or without insulin and short-term (14-days) insulinization. FBS (Fasting Blood sugar) and PPBS levels (Post prandial blood sugar) were measured on Day 0, 5, 14 and 90. Based on Day 0 estimates, individualized FIT care was initiated to achieve a target of FBS (100 – 130 mg/dL) and PPBS (180 – 190 mg/dL) . Treatment was intensified and optimized on Day 5 and 14, respectively. HbA1c between Day 0 and Day 90 was compared.On Day 0, mean FBS, PPBS and HbA1c values were 223.6 ± 69.2 mg/dL, 338± 68.5 and 10.1 ±1.9 %, respectively. Individuals using multiple (≥3) OADs and insulin therapy were 25% at enrolment and 75% during FIT care. After FIT care, there has been a significant reduction in FBS and PPBS (Figure 1) . By day 90, there is a significant (P<0.0001) reduction of 3.13 % in the mean HbA1c levels compared to the levels during enrolment. About 64.5% had a sustained HbA1c% of ≤7. Figure 1: Effect of FIT care across visits In T2DM, FIT care’s glycemic control as early as day 5 and day 14 is beneficial for sustained glycemic control and reduction of treatment failure.

Disclosure

S.Ramanarayanan: None.
847-P: Assessment of Intestinal Microbiota in African-Americans Diabetics Thriving on or Not Tolerating This Drug
Authors: FAYFMAN MAYA , SRINIVASAN SHANTHI , UMPIERREZ GUILLERMO E. , BLANCO GERARDO , GEWIRTZ ANDREW , CHASSAING BENOIT
Published: May 2022

Metformin is the broadly accepted the first-line medication for diabetes. Its use, however, is limited by gastrointestinal side effects, which occur in approximately 25% of patients. We performed a cross-sectional study assessing microbiota composition among African Americans (AA) with diabetes with or without metformin intolerance. Participants were stratified into three groups: 1) Intolerant (I) : history of metformin intolerance, not currently on metformin) ; 2) Partially intolerant (PI) : reporting GI symptoms and currently on metformin 3) Tolerant (T) : current metformin use with no GI symptoms. Rectal swab was collected and microbiota analyzed by amplification and sequencing of the V4 region of the 16s rRNA gene.Among 29 participants, mean age 59 ± 11, 58 % female, group I had greatest alpha diversity, followed by T and PI, although differences were not significant (I: 4.9; T: 4.2; PI: 3.9) . Mean difference in alpha diversity for I versus PI were 1.0 (95% CI -0.1, 2.1) and I versus T were 0.7 (95% CI -0.4, 1.8) . Phyla enrichment shown in figure.

Conclusion: This pilot study evaluated the role of microbiota in metformin intolerance among African Americans. We identify differences in alpha diversity and microbiota. Prospective studies are needed to assess the role of microbial diversity and dysbiosis in metformin-related gastrointestinal symptoms.

Disclosure

M.Fayfman: None. S.Srinivasan: None. G.E.Umpierrez: Research Support; AstraZeneca, Dexcom, Inc., Novo Nordisk. G.Blanco: None. A.Gewirtz: None. B.Chassaing: Advisory Panel; Nestlé Health Science, Consultant; Procter & Gamble, Qiagen.

Funding

P30-DK-111024
860-P: A Territory-Wide Study of SGLT2 Inhibitor–Associated Postoperative Diabetic Ketoacidosis in Type 2 Diabetes Patients
Authors: LUI DAVID T.W. , WU TINGTING , LIU XIAODONG , AU CHI HO , LEE CHI HO , FUNG MAN HIM MATRIX , WOO YU CHO , TAN KATHRYN C. , WONG CARLOS K.
Published: May 2022

Objective: We aimed to characterize SGLT2 inhibitor (SGLT2i) -associated post-operative diabetic ketoacidosis (DKA) in type 2 diabetes patients.

Methods: We analyzed a territory-wide cohort of type 2 diabetes patients who underwent operations during 2015-2020. Patients who had SGLT2i prescriptions within 6 months before operations were assigned to SGLT2i group while others to control group. Inverse probability treatment weighting with propensity scores was used to balance the baseline covariates between two groups. Post-operative DKA was defined by DKA within 30 days post-operatively.

Results: In total, 151488 type 2 diabetes adults undergoing elective (3260 SGLT2i users; 105540 controls) and emergency operations (1087 SGLT2i users; 416controls) were included. SGLT2i users who underwent emergency operations had higher incidence of post-operative DKA (24.5/1000 person-years) than elective operations (1.0/1000 person-years; p<0.001) . SGLT2i exposure significantly elevated incidence of post-operative DKA (elective: incidence rate ratio [IRR]=5.57, p<0.001; emergency: IRR=5.37, p<0.001) . Among SGLT2i users, apart from emergency surgery, HbA1c>8% (64mmol/mol) and baseline insulin use increased the risk of post-operative DKA. SGLT2i users who developed post-operative DKA had worse outcomes (mechanical ventilation, intensive care and length of hospitalization; p<0.05) than those who did not. However, implementation of alert in Clinical Management System about perioperative precaution in SGLT2i users did not reduce the risk of post-operative DKA.

Conclusion: Preoperative SGLT2i use was associated with increased risks of post-operative DKA in type 2 diabetes, higher among patients who underwent emergency operations than elective ones. Clinicians should be vigilant regarding the high-risk group. Effective strategies to mitigate risks of SGLT2i-associated post-operative DKA are urgently needed given the associated morbidities.

Disclosure

D.T.W.Lui: None. T.Wu: None. X.Liu: None. C.Au: None. C.Lee: None. M.Fung: None. Y.Woo: None. K.C.Tan: None. C.K.Wong: None.
867-P: Favorable Kidney Outcomes Are Associated with Empagliflozin vs. DPP4i in Patients with Diabetes and Normal Kidney Function Real-World Evidence
Authors: SCHECHTER MEIR , COHEN CHELI MELZER , ROZENBERG ALIZA , YANUV ILAN , CHODICK GABRIEL , MOSENZON OFRI , KARASIK AVRAHAM
Published: May 2022

Kidney-protective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) are supported by both randomized control trials and real world evidence in high cardiorenal risk type 2 diabetes mellitus (T2DM) patients. However, long-term efficacy studies of T2DM patients with normal kidney function and low cardiorenal risk are lacking. Using a large Israeli database we studied kidney outcomes in patients with T2DM with low baseline KDIGO risk (eGFR≥60 ml/min/1.73, UACR<30 mg/g) and no cardiovascular history. Patients who initiated empagliflozin or any SGLT2i during 2015-2021 were propensity score matched to DPP4i initiators by 120 baseline characteristics and followed until an event or end of study period. The primary outcome included a composite of ≥40% sustained eGFR decline, end-stage kidney disease (ESKD) , or all cause death. Risk was calculated using cox-proportional hazard models adjusted to baseline eGFR. At baseline, 5195 matched pairs of empagliflozin or DPP4i initiators had a mean age of 60 Y, mean eGFR of 93 mL/min/1.73 m2 and were followed for a median of 35.2 months. Number of events for composite kidney outcomes was 172 (11.0 events per 1000 patient-years [PY]) in the empagliflozin group and 215 (13.7 events per 1000 PY) in the DPP4i group, HR 0.79 (95% CI 0.65-0.97; p=0.02) . Similar trends were observed for composite of ≥40% sustained eGFR decline or ESKD. Comparing all SGLT2 to DPP4i initiators (n= 6477, median FU time 37.6 months) number of events was 2 (9.9 events per 1000 PY) for SGLT2i and 266 (13.0 events per 1000 PY) in DPP4i, HR 0.77 (95% CI 0.64-0.92) .

In conclusion the benefits of empagliflozin and any SGLT2 inhibitors on kidney function are observed in T2DM patients with low cardiorenal risk. The finding supports use of empagliflozin independent of glycemic control in low cardiorenal T2DM patients.

Disclosure

M.Schechter: None. C.Melzer cohen: None. A.Rozenberg: None. I.Yanuv: None. G.Chodick: None. O.Mosenzon: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, BOL Pharma, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, Research Support; AstraZeneca, Novo Nordisk, Speaker's Bureau; AstraZeneca, Bayer AG, Eli Lilly and Company, Novo Nordisk, Sanofi. A.Karasik: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Vifor Pharma Management Ltd., Speaker's Bureau; Boehringer Ingelheim International GmbH, Novo Nordisk A/S.

Funding

Boeheringer Ingelheim