bluuebunny/crossref_metadata_2025 huggingface dataset:
794-P: Effectiveness and Safety of iGlarLixi in People with Type 2 Diabetes (Pw2D), Not at Target on Basal Insulin (BI) and Oral Antidiabetic Therapy (BOT)—Results from the Observational, Prospective Study CHANCE
Authors: WIESNER TOBIAS , PFOHL MARTIN , PEGELOW KATRIN , MÜLLER JULIA , SEUFERT JOCHEN
Published: June 2023

iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide, is a once-daily treatment advancement option for Pw2D not at target on BOT. CHANCE investigated effectiveness and safety of switching the BI to iGlarLixi in daily clinical practice. Primary objective was to assess absolute change in HbA1c 24 weeks (W24) after switching to iGlarLixi. Secondary objectives included changes in fasting plasma glucose (FPG), bodyweight (BW), use of oral antidiabetic drugs (OADs), dose of previous BI, and hypoglycemia incidence. Overall, data from 70 Pw2D were analyzed. Mean BI dose was 38.9 units per day and individual target HbA1c was 6.9%. iGlarLixi was started with 30 dose steps per day (DS/d); at W24, mean dose was 41.6 DS/d. HbA1c decreased by -0.7% (P < 0.001), while FPG trended down by ~20 mg/dL. This was accompanied by a -3.0 kg decrease in BW (P = 0.442). Numbers of OADs used decreased markedly 24 weeks after switching to iGlarLixi (P < 0.05). Hypoglycemia incidence was low before and did not change significantly after switching to iGlarLixi. In conclusion, advancing BOT by switching the BI to iGlarLixi, improved glycemic control of Pw2D in daily clinical practice without BW gain and with low hypoglycemia incidence; however, titration was not sufficient to reach glycemic targets after 24 weeks.

Disclosure

T.Wiesner: Advisory Panel; Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Sanofi-Aventis Deutschland GmbH, Lilly Diabetes, Boehringer Ingelheim Inc., Abbott Diabetes, Novo Nordisk, Dexcom, Inc., Novartis. M.Pfohl: Advisory Panel; Boehringer Ingelheim and Eli Lilly Alliance, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Sanofi-Aventis Deutschland GmbH. K.Pegelow: Employee; Sanofi-Aventis Deutschland GmbH, Stock/Shareholder; Sanofi-Aventis Deutschland GmbH. J.Müller: Employee; Sanofi-Aventis Deutschland GmbH, Stock/Shareholder; Bayer Inc., Inmunebio Inc. J.Seufert: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim Pharma GmbH&Co.KG, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Abbott Diabetes, Bayer Inc., Boehringer Ingelheim Pharma GmbH&Co.KG, Merck Sharp & Dohme Corp., Sanofi-Aventis Deutschland GmbH, Novartis, Novo Nordisk.

Funding

Sanofi-Aventis Deutschland GmbH
798-P: Shift to a Lower BMI Category Is Associated with Improved Cardiometabolic Measures in Adults with T2D Treated with Tirzepatide
Authors: WIESE RUSSELL , DIB ANNE , NICOLAY CLAUDIA , ALLEN SHERYL , LEE CLARE
Published: June 2023

In the Phase 3 SURPASS studies of adults with T2D, the GIP/GLP-1 receptor agonist tirzepatide (TZP) provided clinically meaningful reductions in HbA1c levels and body weight. In this post-hoc analysis of TZP-treated participants in SURPASS 1-5 studies, we assessed whether those shifting to a lower BMI category would improve in cardiometabolic measures such as HbA1c, waist circumference (WC), systolic blood pressure (SBP), and lipid profiles. Changes in BMI category (<25 kg/m², 25- <30 kg/m², 30- <35 kg/m², 35- <40 kg/m², ≥40 kg/m²) from baseline to endpoint were assessed by study (N=3559), regardless of dose. BMI category shifts were grouped into “Improved” (shift to a lower BMI category, by at least one category), or “Stable/Worse” (no change/shift to a higher BMI category). At baseline, participants averaged 58 years, 93.36 kg, 53.6% were male, and 79.5% were white. While improvements in cardiometabolic measures were observed in both subsets of participants, numerically greater improvements in HbA1c, WC, SBP and lipid profile were observed for the 59% who improved their BMI category (Table 1). In the SURPASS studies, shifting to a lower and improved BMI category compared to a stable or worse BMI category was associated with greater improvement in cardiometabolic measures including HbA1c, WC, SBP, and lipid profile.

Disclosure

R.Wiese: Employee; Eli Lilly and Company. A.Dib: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. C.Nicolay: Employee; Eli Lilly and Company. S.Allen: None. C.Lee: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
815-P: Enhanced Disulphide Bond Stability Contributes to the Once Weekly PD Profile of Insulin Icodec
Authors: HUBALEK FRANTISEK , CRAMER CHRISTIAN , HELLEBERG HANS , JOHANSSON EVA , SCHLUCKEBIER GERD , STEENSGAARD DORTE B. , STURIS JEPPE , KJELDSEN THOMAS
Published: June 2023

Insulin icodec is a novel basal insulin analogue with a long half-life (196 hours) that is in clinical development for the treatment of diabetes with once weekly dosing. Insulin icodec was developed based on the hypothesis that lowering the insulin receptor affinity in the presence of a strong HSA-binding moiety would result in a long half-life, provided that non-receptor mediated clearance is diminished. The observation that insulin icodec retains its full potency over weeks has been attributed to low non-insulin receptor mediated clearance as well as to limited degradation in circulation, due to the amino acid modifications in insulin icodec that confer proteolytically-stabilization. Here, we report a previously undescribed insulin clearance mechanism, resulting in splitting insulin molecules into A- and B-chains by a thiol-disulfide exchange reaction. We found that the amino acid substitution of Tyr in A14 to Glu provided a major stabilization of insulin against such degradation while only minor improvements were introduced by the Tyr in B16 to His and Phe in B25 to His substitutions. These results correlate with improvements in the folding stability and likely reflect reduced exposure of insulin icodec's disulfide bonds to the thiol-disulfide exchange reaction. Even though insulin icodec's amino acid substitutions significantly limit its susceptibility to this new clearance mechanism, some free B-chain has been observed in plasma samples from minipigs and people with type 2 diabetes. In summary, we have identified thiol-disulfide exchange reactions as an additional insulin clearance mechanism and minimizing insulin icodec's susceptibility to this process has significantly contributed to its long PD, making it suitable for once weekly dosing.

Disclosure

F.Hubalek: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. C.Cramer: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. H.Helleberg: Employee; Novo Nordisk A/S. E.Johansson: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. G.Schluckebier: Employee; Novo Nordisk. D.B.Steensgaard: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk. J.Sturis: Employee; Novo Nordisk A/S, Other Relationship; Novozymes, Stock/Shareholder; Novo Nordisk A/S. T.Kjeldsen: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk.
826-P: Treatment of MODY3 Disease by AAV-Hnf1a-Mediated Gene Therapy
Authors: CASANA LORENTE ESTEFANIA , JIMENEZ VERONICA , GARCIA MIQUEL , CASELLAS ALBA , MORRÓ MERITXELL , PUJOL ANNA , FERRÉ TURA , SACRISTÁN VÍCTOR , JAMBRINA CLAUDIA , LEON XAVIER , FRANCKHAUSER SYLVIE , BOSCH FATIMA
Published: June 2023

Maturity-onset diabetes of the young (MODY) are a group of monogenic diabetes characterized by onset of hyperglycemia at an early adult age, normally before 25 years. MODY3, the most common type of MODY, is caused by mutations in the gene encoding for the transcription factor hepatocyte nuclear factor 1A (HNF1A). MODY3 patients are usually treated with sulfonylureas, but they tend to become unresponsive to these drugs and adverse effects associated to chronic administration of sulfonylureas have been reported. Presently, there are no current treatments addressing the root cause of MODY3. Here, we have developed a new gene therapy approach to treat this disease. To this end, using the CRISPR/Cas9 technology, we first generated a novel MODY3 mouse model that showed pancreatic down-regulation of HNF1A protein production. These mice developed β-cell dysfunction and hyperglycemia, recapitulating the main alterations observed in human patients. Treatment of MODY3 mice by intra-pancreatic duct administration of adeno-associated viral vectors (AAVs) encoding Hnf1α, under control of β-cell-specific promoter, resulted in HNF1A expression in β-cells, which upregulated the expression of HNF1A main target genes, such as GLUT2 and L-PK. AAV-Hnf1α-mediated gene therapy counteracted hyperglycemia, increased insulinemia, improved glucose tolerance and enhanced insulin secretion by pancreatic β-cells, thus reverting the MODY3 disease. This study represents the first demonstration for the genetic counteraction of a monogenic diabetes and paves the way for the clinical translation of AAV-Hnf1α-based gene therapy to treat MODY 3 patients in the future. Moreover, these results may also contribute to the development of new gene therapy strategies for other monogenic forms of diabetes.

Disclosure

E.Casana lorente: None. X.Leon: None. S.Franckhauser: None. F.Bosch: None. V.Jimenez: None. M.Garcia: None. A.Casellas: None. M.Morró: None. A.Pujol: None. T.Ferré: None. V.Sacristán: None. C.Jambrina: None.

Funding

Fundació La Marató de TV3 (201603-31-32-33); Ministerio de Economía, Industria y Competitividad (SAF2017-86266R); Agencia Estatal de Investigación; Fondo Europeo de Desarrollo Regional; Programa Estatal de I+D+i Orientada a los Retos de la Sociedad; MCIN/AEI/10.13039/501100011033 (PID2020-113864RB-I00); Generalitat de Catalunya, Spain 2017 SGR 1508 (to F.B.)
830-P: Preclinical Development of ALN-KHK, an Investigational RNAi Therapeutic for Type 2 Diabetes Mellitus
Authors: NOETZLI LEILA , BORODOVSKY ANNA , YU CHUA XIEN , TYMON ROXANNE , DARCY JUSTIN , BELOZEROVA SABRINA , KEIBLER MARK , TU HO-CHOU , MARATOS-FLIER ELEFTHERIA
Published: June 2023

Fructose consumption is implicated in increased rates of metabolic syndrome and type 2 diabetes worldwide. In the liver, ketohexokinase (KHK) is required for fructose metabolism, phosphorylating fructose to fructose-1-phosphate (F1P), a substrate for synthesis of fatty acids, contributing to nonalcoholic fatty liver. Excess liver fat is associated with insulin resistance and loss of glycemic control. Lowering KHK expression should reduce fatty acid synthesis and thus reduce insulin resistance and improve glycemic control in obese individuals with T2DM. We developed a robust RNAi therapeutics platform for delivery of siRNAs to liver using GalNAc conjugates to specifically silence hepatocyte-expressed genes. Liver-directed silencing of KHK improved insulin sensitivity in pre-clinical models of T2DM. ALN-KHK was selected based on in vitro assessment of a large set of GalNAc-siRNAs targeting human and primate KHK. ALN-KHK demonstrated suppression of liver KHK mRNA and protein in cynomolgus macaques after a single subcutaneous (SC) injection with potent and durable reduction in KHK protein (94.1% lowering through day 85 at the 10 mg/kg dose) supporting evaluation of infrequent dosing in the clinic. To evaluate impact of KHK silencing on fructose metabolism and establish circulating biomarkers of pharmacology, cynomolgus macaques were administered an oral fructose bolus on Day 30 following SC injection of ALN-KHK of 0.3, 3 or 10 mg/kg. ALN-KHK treatment resulted in a dose-dependent increase in circulating fructose with a 4.6-fold increase and a 10.7-fold decrease in FGF21 (which is regulated by liver F1P), at 2 hr post fructose bolus, associated with 90.7% KHK liver protein reduction. These data suggest monitoring of circulating fructose and FGF21 to assess KHK silencing in the clinic. In IND-enabling rat and non-human primate toxicology studies ALN-KHK was safe and well tolerated, supporting the planned initiation of first-in-human studies in obese healthy volunteers.

Disclosure

L. Noetzli: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. A. Borodovsky: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. X. Chua: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. R. Tymon: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. J. Darcy: None. S. Belozerova: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. M. Keibler: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. H. Tu: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. E. Maratos-Flier: Employee; Novartis, Alnylam Pharmaceuticals, Inc.
838-P: Reversion of Nonalcoholic Steatohepatitis by Skeletal-Muscle Directed FGF21 Gene Therapy
Authors: JIMENEZ VERONICA , SACRISTÁN VÍCTOR , JAMBRINA CLAUDIA , LUISA JAÉN MARIA , MUNOZ SERGIO A. , CASANA ESTEFANIA , GARCIA MIQUEL , GRASS IGNASI , LEON XAVIER , ELIAS IVET , RIBERA ALBERT , ELIAS GEMMA , SANCHEZ VICTOR , CASELLAS ALBA , FERRÉ TURA , MOLAS MARIA , BOSCH FATIMA
Published: June 2023

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease, which is driven by the global obesity and type 2 diabetes epidemic. NASH is characterized by liver inflammation and fibrosis that can progress to cirrhosis, liver failure, cancer and death. Currently, NASH is an unmet medical need. Recent studies revealed the therapeutic potential of fibroblast growth factor 21 (FGF21) analogues/mimetics against NASH in pre-clinical models and in human patients, although periodic administrations are required and immunological responses may raise due to the use of engineered, non-native, proteins. Here, we demonstrated that adeno-associated viral (AAV) vector-mediated-FGF21 genetic engineering of skeletal muscle of high-fat diet-fed obese and insulin-resistant mice resulted in increased circulating levels of native FGF21. AAV-FGF21-treatment normalized liver fat content, liver inflammatory and fibrotic markers and counteracted hepatocyte damage, consistent with NASH resolution. It also precluded progression from NASH to cirrhosis and hepato-cellular carcinoma. Moreover, circulating FGF21 reversed adipose tissue hypertrophy and inflammation, increased energy expenditure, normalized glycemia and insulinemia, and increased insulin sensitivity. Scale-up of muscular FGF21 gene transfer to large animals also successfully resulted in long-term secretion of biologically active FGF21 and therapeutic effects in key target tissues, in the absence of adverse events. All these results point out the potential of the AAV-FGF21-mediated gene therapy to treat NASH and support the clinical translation of the approach.

Disclosure

V. Jimenez: None. V. Sacristán: None. C. Jambrina: None. M. Jaén: None. S.A. Munoz: None. E. Casana: None. M. Garcia: None. I. Grass: None. X. Leon: None. I. Elias: None. A. Ribera: None. G. Elias: None. V. Sanchez: None. A. Casellas: None. T. Ferré: None. M. Molas: None. F. Bosch: None.
854-P: ENT-03, a Centrally Acting Endogenous Spermine Bile Acid with PTP1B Inhibitory Activity, Has Potent Effects on Metabolism and Weight in a Mouse Model of Diet-Induced Obesity (DIO)
Authors: BARBUT DENISE , BAUR JOSEPH A. , TITCHENELL PAUL M. , DAVIS JAMES G. , ZEMEL MICHAEL B. , ALEXANDER FLEMING G. , MOSES ALAN C. , ZASLOFF MICHAEL
Published: June 2023

Background: We have discovered ENT-03, a spermine-bile acid of unprecedented structure in the brain of neonatal mice. ENT-03 appears postnatally at a time when the maternal supply of milk is inadequate to support maximal growth and development. ENT-03 has PTP1B inhibitory activity and acts centrally to normalize glycemia and reverse obesity.

Methods: ENT-03 (25mg/kg), semaglutide (0.04mg/kg) or vehicle were administered subcutaneously twice weekly for 10 weeks to DIO mice (n=5/group).

Results: In ENT-03 treated mice on a high fat diet, non-fasting glucose rapidly fell to within normal range prior to any significant weight loss (p=2×10-5), remaining normal thereafter. In contrast, in semaglutide treated mice, glucose fell in proportion to weight loss, remaining elevated throughout (p=0.2). ENT-03 treated mice were restored to lean body weight. Body weight and glucose improved partially in semaglutide treated mice. Body fat decreased by 49% in ENT-03 (p=10-5) and by 19% in semaglutide treated mice (p=0.1). Basal glucose uptake in muscle was increased 3-fold in ENT-03 treated mice compared to controls.

Conclusion: ENT-03 is a novel endogenous, centrally acting mammalian steroid which rapidly normalizes glucose, independent of body weight and causes gradual but marked weight loss in DIO mice. Phase 1 studies will begin in Q2 2023.

Disclosure

D.Barbut: None. J.A.Baur: Consultant; Cytokinetics Inc., Pfizer Inc., Other Relationship; Elysium Health, Research Support; Pfizer Inc., Metro Biotech. P.M.Titchenell: Consultant; Alnylam, Guidepoint, AstraZeneca. J.G.Davis: None. M.B.Zemel: None. G.Fleming: Board Member; NuSirt, Consultant; Amolyt, Oramed Pharmaceuticals, Adocia, Aerami, TixiMed, Biocon, Hagar, CMC Magnetics, AdioPharm. A.C.Moses: Advisory Panel; Enterin, ViaCyte, Inc., GentiBio, TixiMed, Consultant; Virta Health Corp., ARMI (Advanced Regenerative Manufacturing Institute), Stock/Shareholder; Minutia. M.Zasloff: None.
860-P: Evaluation of Efficacy and Safety of Glucokinase Activators—A Systematic Review and Meta-analysis
Authors: YANG WENJIA
Published: June 2023

Aims: Glucokinase activators (GKAs) promote the activity of glucokinase (GK) and is under development for the treatment of diabetes. The efficacy and safety of GKAs require evaluation.

Methods: This meta-analysis included randomized controlled trials (RCTs) with a duration of at least 12 weeks conducted in patients with diabetes. The primary objective of this meta-analysis was the difference of hemoglobin A1c (HbA1c) change from baseline to study end between GKA groups and placebo groups. Risk of hypoglycemia and laboratory indicators were also evaluated. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated for the continuous outcomes, odd ratios (ORs) and 95% CI were calculated for the risk of hypoglycemia.

Results: Data from 13 RCTs with 2,748 participants treated with GKAs and 2,681 control participants were analyzed. Overall, the level of HbA1c decreased significantly in patients with GKA treatment compared with placebo (WMD=-0.316%, 95% CI -0.426 to -0.206%, P<0.001). The OR comparing GKA versus placebo was 1.88 for risk of hypoglycemia (95% CI 1.51 to 2.33, P<0.001). The WMD comparing GKA versus placebo was 0.308mmol/L for triglyceride (TG) levels (95% CI 0.153 to 0.464mmol/L, P<0.001). The sensitivity analysis demonstrated difference when stratified by drug type, selectivity, and study duration.

Conclusion: In patients with diabetes, GKA treatment was associated with a better glycemic control, but a significant increased risk of hypoglycemia and elevation in TG concentration in general. The efficacy and safety varied with drug type and selectivity.

Disclosure

W.Yang: None.

Funding

National Natural Science Foundation of China (81903711, 81970698, 81970708); Beijing Natural Science Foundation (7202216)
861-P: The Effect of Dual Amylin and Calcitonin Receptor Agonist Treatment on Spatial Memory in Rat Models of Metabolic Syndrome
Authors: ELHADY MOHAMED KHALED , LARSEN ANNA T. , MELANDER SIMONE A. , KARSDAL MORTEN A. , HENRIKSEN KIM
Published: June 2023

Obesity and metabolic-related complications, especially insulin resistance, have been linked to cognitive dysfunction. Dual amylin and calcitonin receptor agonists (DACRAs) elicit beneficial effects on body weight, glucose control, and insulin action, making them novel candidates for treating obesity and related comorbidities. Whether DACRAs affect cognition has yet to be addressed. With these studies, we evaluated the effect of DACRA treatment on spatial learning and memory in rat models of metabolic syndrome. Spatial learning and spatial memory retention were evaluated by Morris Water Maze in ZDSD rats treated with KBP-336 (4.5 nmol/kg Q3D) for 7 months and ZSF1 rats treated with KBP-336 (4.5 nmol/kg Q3D) for 2 months. In the ZDSD study, rats performed 8 training trials with a hidden platform in a constant position and a 60 s probe without the platform. At the study end, rats performed a 60 s probe followed by 4 re-training trials and another probe. At study end of the ZSF1 study, rats performed 6 training trials with a hidden platform in a constant position followed by a 60 s probe without the platform. In both studies, KBP-336 treatment improved the overall metabolic status, including glucose control and insulin action. In ZDSD rats, KBP-336-treated rats spent more time and traveled longer distances in Whishaw's corridor than vehicle-treated rats during the probes at the study end. Together indicating a possible treatment improvement in spatial memory on KBP-336. In ZSF1 rats, KBP-336 treatment resulted in increased time spent in the platform quadrant and Whishaw's corridor, as well as increased distance, traveled in Whishaw's corridor during the probe. In both studies, the treatment did not affect the spatial learning evaluated as latency to reach the hidden platform during the training trials. Altogether, we found that the improved metabolic status obtained with KBP-336 treatment might have a beneficial effect on spatial memory in diabetic and obese rat models.

Disclosure

K.Mohamed: Employee; Nordic Bioscience. A.T.Larsen: Employee; Nordic Bioscience A/S. S.A.Melander: None. M.A.Karsdal: Speaker's Bureau; Pfizer Inc. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S.

Funding

Danish Research Foundation; Innovation Fund Denmark; European Union’s Horizon 2020 Research and Innovation Program (814244)
866-P: Quantitative Analysis of Metformin-Induced Glucose Excretion in the Intestine
Authors: HOSOKAWA YUSEI , SAKAGUCHI KAZUHIKO , ITO JUN , SUGAWARA KENJI , MORITA YASUKO , OGAWA WATARU
Published: June 2023

The enhancement of the uptake of 18F-labeled fluorodeoxyglucose (FDG) during [18F]FDG PET is a recently found metformin action in the gut. Taking advantage of PET-MRI, which provides better tissue registration and soft-tissue contrast than conventional PET-CT, we revealed that metformin enhanced FDG accumulation in the intestinal lumen. We now quantitatively analyzed the phenomenon with a newly developed protocol of PET-MRI. We also analyzed the intestinal glucose dynamics using 13C-labeled glucose and mass spectrometry in mice.

We adopted imaging sequences of MR enterography to create 3D images of the intestinal tract, then superimposed the [18F]FDG PET images to obtain the 3D distribution of radioactivity. We conducted this test on type 2 diabetes subjects treated (N=5) or not (control, N=5) with metformin. Radioactivity was detected in the wall and lumen at similar extents in the control. However, in the metformin group, the radioactivity in the lumen, but not the wall, was three to four-fold greater than that in the control. We mathematically analyzed the data using a compartment model and calculated the glucose excretion rate (GER). GER of the control and metformin groups were 6.8 ± 1.2 mg/min and 26.1 ± 2.9 mg/min, respectively, the latter being comparable to glucose excretion into the urine induced by SGLT2 inhibitors.

For mouse experiments, we intravenously injected 13C-glucose into C57/B6 mice and analyzed the feces 1 hour after injection with a gas chromatography-quadrupole mass spectrometry. We could not detect 13C-glucose in the feces, possibly because gut microbiota metabolizes glucose in the intestine. However, the content of 13C in short-chain fatty acids (SCFAs) was increased by the injection of 13C-glucose, and metformin augmented the incorporation of 13C into SCFAs.

These results suggest that glucose in the circulation transfers to the intestinal lumen at a considerable rate and is metabolized by microbiota, at least partly, into SCFAs and that metformin augments the processes.

Disclosure

Y.Hosokawa: None. K.Sakaguchi: Research Support; Sumitomo Dainippon Pharma Co., Ltd. J.Ito: None. K.Sugawara: None. Y.Morita: None. W.Ogawa: Advisory Panel; Abbott Japan Co., Ltd., Research Support; Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Novo Nordisk, Teijin Pharma Limited, Kowa Company, Ltd., Sumitomo Dainippon Pharma Co., Ltd., Abbott Japan Co., Ltd., Speaker's Bureau; Sumitomo Dainippon Pharma Co., Ltd.

Funding

Japan Society for the Promotion of Science (21K08578, 22K18393)
89-OR: Immunoprivileged Hydrogels Extend Functionality of Islets in Immunocompetent Animals
Authors: STOVER HARALD
Published: June 2023

Background: Despite the promise of current islet cell transplantation, the need for systemic immune suppression significantly limits its utility for patients with diabetes. Until safe and immune-evasive cells are realized, physical immuno-protection offers an alternate route to allogeneic islet implants. Our proprietary synthetic hydrogels provide shape-agnostic, robust and retrievable Islet environments with anti-fouling and non-fibrotic properties.

Methods: Rat and human donor islets were encapsulated and implanted in the peritoneal space of streptozotocin (STZ)-induced diabetic immunocompetent mice and pigs to assess islet functionality over time through measurement of blood glucose, C-peptide, and HbA1c. Next generation shape-agnostic hydrogels were also tested for in-vitro and in-vivo function.

Results: Our hydrogels enabled rapid and persistent blood glucose control for 140+ days in immunocompetent mice with marginal loads of 1000 rat IEQ/mouse. Human donor islet function in mice was extended to day 45 (~8x longer than free human islets), with C-peptide detected at day 50, and corresponding HbA1c decreases. Our hydrogels showed minimal fibrosis when explanted after 45 days and showed robustness and integrity at day 340 post-implant in immunocompetent mice. Next-gen shape-agnostic hydrogels successfully excluded immune components including IgG and maintained good islet function in vitro. Our data also demonstrate function of human donor islets in immunocompetent pigs, based on C-peptide and cell viability data.

Conclusion: Our proprietary synthetic and retrievable hydrogels show strong immune protection in xenogenic transplants of donor islets into immune-competent animals. We are currently scaling to therapeutic doses in large animals, in pursuit of a curative therapy based on an optimal balance of Islet protection and functionality, without immunosuppression.

Disclosure

H.Stover: Employee; Allarta Life Science Inc.
90-OR: 3D Bioprinting of a Bionic Pancreas with a Vascular System—Results of Transplantation in Large Animals
Authors: WSZOLA MICHAL , BERMAN ANDRZEJ , KLAK MARTA , DOBRZANSKI TOMASZ , JANOWSKA OLIWIA , DOMANSKI SYLWESTER , PIATEK DOMINIKA , WEJMAN JAROSLAW , SZKOPEK DOMINIKA , ROSZKOWICZ-OSTROWSKA KATARZYNA I. , KOWNACKI LUKASZ , WOLINSKI JAROSLAW , DOBRZYN AGNIESZKA , KAMINSKI ARTUR
Published: June 2023

The transplantation of the pancreas is recommended in diabetes with complications. The combination of cell biology and 3D-bioprinting can create organs with vasculature which should be functional. There are issues to be solved: leakage, thrombosis, enhancement against high pressure, connecting organ to the recipient. The purpose of this study was to demonstrate 3D-bioprinting of bionic organs with use of dECM-derived biomaterials with stable flow through the organ in vitro and in large animal studies.

Materials and methods: Mathematical analysis in the designed bionic pancreas was performed. The bionic pancreas was 3D bioprinted with 2 types of bioinks. The first tests were carried out in a bioreactor then organs were subjected to magnetic resonance and X-ray with contrast. Pressure endurance tests were performed. 14 pigs received 3D-bioprinted bionic pancreas transplantation. DCL-VESS-Group (n=5) received decellularized vessels as anastomosis. 9 pigs received bionic pancreas with vascular prosthesis as anastomosis - Prosthesis-Group. Pigs were observed up to 14 days. Hist-pat analysis of removed pancreas was performed.

Results: The tests carried out in the bioreactor showed the stability of the bionic organ and vascular system in MRI and X-ray examination for 5 days. No leaks beyond the bionic pancreas were observed up to 400 mmHg. In all 14 cases of transplantation there was stable flow throughout the organ after release of vascular clamp. DCL-VESS-Group - In all cases vascular cloth was observed. Prosthesis-Group - In 5 cases there were no complications influencing blood flow through the organ. 4 died to postoperative complications. Stable flow within a transplanted bionic organ was observed till 2 weeks post - surgery within ultrasound examination and radiology intervention. Histopatological showed the presence of CD31 / PECAM-1 (new blood formation).

Conclusion: It is feasible to 3Dbioprint and transplant bionic organ in big animal model.

Disclosure

M.Wszola: Board Member; Polbionica Ltd., Stock/Shareholder; Polbionica Ltd.. K.I.Roszkowicz-ostrowska: None. L.Kownacki: None. J.Wolinski: None. A.Dobrzyn: None. A.Kaminski: None. A.Berman: Board Member; Polbionica Ltd., Stock/Shareholder; Polbionica Ltd. M.Klak: Employee; Polbionica Sp. z o.o., Stock/Shareholder; Polbionica Sp. z o.o. T.Dobrzanski: Employee; Polbionica. O.Janowska: Employee; POLBIONICA Sp. z o.o. S.Domanski: Employee; Polbionica. D.Piatek: None. J.Wejman: None. D.Szkopek: None.
92-LB: Safety, Tolerability, and Clinical Effects of ZP8396, a Novel Long-Acting Amylin Analog—A Single Ascending Dose Trial
Authors: OLSEN MINNA B. , HÖVELMANN ULRIKE , GRIFFIN JON , KNUDSEN KIM M. , JOHANSEN THUE , KENDALL DAVID , HEISE TIM
Published: June 2023

ZP8396 is an amylin analog designed for once weekly dosing that has demonstrated the potential to reduce body weight and improve glycemia in animal models of obesity and diabetes. We performed a randomized, double-blind, placebo-controlled trial to assess safety, pharmacokinetics, and pharmacodynamics of a single subcutaneous injection of ZP8396 in healthy lean and overweight male subjects. A total of 56 subjects (mean age was 38.1 years; mean BMI of 25.6 kg/m2) were randomized to ZP8396 or placebo (6:2) within seven dose cohorts ranging from 0.04 mg to 2.4 mg. The mean half-life of ZP8396 was approximately 10 days. After 1 week of observation, mean body weight decreased by -0.6%, 2.6%, 3.6%, and 4.2% from baseline following a single dose of placebo, 0.7 mg, 1.4 mg and 2.4 mg, respectively (Figure 1). ZP8396 was well tolerated, with no serious or severe adverse events (AEs) and no withdrawals. The most frequent related AEs were decreased appetite, nausea and vomiting, most events were mild and transient. No anti-drug antibodies were detected.

In conclusion, administration of a single dose of ZP8396 resulted in dose-dependent and consistent reductions in body weight supporting the potential of ZP8396 as a treatment for obesity. Additional clinical studies of longer duration will be necessary to fully assess the clinical potential of ZP8396.

Disclosure

M. B. Olsen: Stock/Shareholder; Novo Nordisk A/S, Zealand Pharma A/S. U. Hövelmann: None. J. Griffin: Employee; Zealand Pharma A/S. K. M. Knudsen: Employee; Zealand Pharma A/S. T. Johansen: Employee; Zealand Pharma A/S. D. Kendall: Employee; Zealand Pharma A/S. Stock/Shareholder; Zealand Pharma A/S, MannKind Corporation. T. Heise: Research Support; Adocia, AstraZeneca, Biocon, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Consultant; Gan & Lee Pharmaceuticals. Research Support; Genova. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Research Support; Sanofi, Zealand Pharma A/S.
928-P: The Use of a Novel CGM-Informed Insulin Bolus Calculator Mobile Application by People with Type 1 and Type 2 Diabetes Improves Time in Range
Authors: SHOMALI MANSUR , KELLY COLLEEN , IYER ANAND K. , PARK JEAN Y. , ALEPPO GRAZIA
Published: June 2023

Background and Aims: People with diabetes on basal-bolus insulin regimens face challenges calculating bolus doses. Continuous glucose monitoring (CGM) systems can assist users with bolus dosing optimization through trend arrows. The purpose of this study was to demonstrate the safety and effectiveness of a CGM-informed insulin bolus calculator (IBC, Welldoc, Inc., Columbia, MD, U.S.A.) integrated into a mobile application that applies trend arrow and exercise adjustments to the bolus insulin dose recommendation. This investigational software also provided real-time coaching on CGM data to assist users in improving their time in range (TIR).

Methods: Fifty-four participants with diabetes using CGM (Dexcom G6, San Diego, CA, U.S.A.) were enrolled in a 30-day prospective study conducted at two research sites. Participants were asked to use the mobile application to monitor their CGM data and calculate their insulin doses. TIR during the prospective 30-day period was compared to that from 30 days of baseline data. Three populations were defined: 1) the intention-to-treat (ITT) group consisted of all enrolled subjects; 2) the complete cases (CC) group had ≥90% sensor wear time; and 3) the per-protocol (PP) group used the IBC at least 30 times during the study period.

Results: In the ITT group, the TIR improved from 68.4% to 71.8% (N=54, P=0.013). In the CC group, the TIR improved from 69.1% to 73.0% (N=49, P=0.005). In the PP group, the TIR improved from 69.2% to 73.0% (N=39, P=0.017). There was no increase in time with low glucose (<70 mg/dL) in all three populations. In a subgroup analysis, TIR increased from 74.7% to 81.4% in those with type 2 diabetes and from 64.4% to 65.2% in those with type 1 diabetes.

Conclusions: Use of a novel CGM-informed insulin bolus calculator with trend arrow and exercise dose adjustment by individuals with type 1 and type 2 diabetes was associated with significant improvement in TIR.

Disclosure

M.Shomali: Employee; WellDoc. C.Kelly: Consultant; WellDoc, Caladrius Biosciences, Inc., Epigenomics AG, Luna, Nevro Corp., Presidio Medical, Hitachi, Ltd., Resmed, Inc., Seaspine Hldgs, Inc., ViaCyte, Inc. A.K.Iyer: Employee; WellDoc. J.Y.Park: None. G.Aleppo: Advisory Panel; Medscape, Consultant; Bayer Inc., Insulet Corporation, Research Support; Dexcom, Inc., Eli Lilly and Company, Emmes, Insulet Corporation, Fractyl Health, Inc., WellDoc, Speaker's Bureau; Dexcom, Inc.

Funding

Welldoc Inc.
940-P: Real-World Concordance between Point-of-Care and Continuous Glucose Monitoring among Hospitalized Patients with Diabetes
Authors: SPIERLING BAGSIC SAMANTHA R. , FORTMANN ADDIE L. , BELASCO REBEKAH , RITKO ANNA , LOHNES SUZANNE , SANDOVAL HALEY , CHICHMARENKO MARIYA , SORIANO EMILY , BASTIAN ALESSANDRA , TALAVERA LAURA , PHILIS-TSIMIKAS ATHENA
Published: June 2023

Concordance between continuous glucose monitoring (CGM) and point-of-care testing (POCT) in research studies has been promising; however, the accuracy of using CGM for glucose management in real-world settings requires evaluation. Amid the COVID-19 pandemic, the CGM as “standard of care” (CGM as SOC) program was implemented at Scripps Mercy Hospital in San Diego, CA. In this real-world setting, concordance between the Dexcom G6 CGM system and POCT was evaluated among hospitalized adult patients with diabetes requiring insulin from May 2020-July 2022. For N=880 admissions, CGM readings over the first 24 hours of wear were analyzed relative to POCT conducted within 5 minutes. Patients had a median of 3 CGM-POCT data pairs, and the first CGM-POCT pair occurred a median of 2.75 hours after CGM device placement. Mean absolute relative difference (MARD) decreased over the first 24 hours of wear (B= -0.09%, p=0.0005; Figure 1A). Following the %20/20 rule, 62% of CGM readings were concordant upon the first measured POCT; 15.8% did not meet criteria at all during the first 24-hours. Using the Clarke Error Grid to describe concordance between CGM-POCT pairs (n=3015), only 0.7% (n=22) of CGM readings would have led to incorrect treatment decisions indicated by zones D/E (Figure 1B). These findings provide support for the accuracy of CGM for glucose management in the hospital.

Disclosure

S.R.Spierling bagsic: None. L.Talavera: None. A.Philis-tsimikas: Advisory Panel; Dexcom, Inc., Novo Nordisk A/S, Sanofi, Other Relationship; Medtronic, Research Support; Novo Nordisk A/S, Lilly, Viking Therapeutics, NIH - National Institutes of Health. A.L.Fortmann: Employee; Dexcom, Inc. R.Belasco: None. A.Ritko: None. S.Lohnes: Consultant; Dexcom, Inc. H.Sandoval: None. M.Chichmarenko: None. E.Soriano: None. A.Bastian: None.
946-P: Impacts of MAGE and SD on the Relationship between TIR and Glucose Management Indicator in T2D Patients
Authors: CHEN DANRUI , LIU ZHIGU , LIN BEISI , YANG DAIZHI , YAN JINHUA , YANG YANLING , XU WEN
Published: June 2023

Aims: Previous studies proved that glucose coefficient of variation (CV), an index of glycemic variability (GV), affected the relationship between TIR and glucose management indicator (GMI) in patients with diabetes. This study aimed to explore whether other GV indexes, including MAGE and SD of glucose, affect the relationship between TIR and GMI in T2D patients.

Methods: Data were collected from T2D patients who received 48-h to 72-h CGM with iPro2 between January 2018 and October 2019. GV indexes, TIR, and GMI were derived from iPro2. A linear regression equation was generated with values of TIR and GMI. Patients were then divided into 3 subgroups according to the values of MAGE or SD. Predicted TIR in given GMI was calculated via the linear regression equations in the respective tertiles groups of MAGE or SD.

Results: A total of 118 T2D patients who were 57.2±11.6 years old, with a median diabetes duration of 6.0 years, HbA1c of 6.9±1.2%, and TIR of 87.5±12.9% were included. There was a strong negative correlation between TIR and GMI (r=-0.762, P<0.001). The linear regression equation was TIR%=-21.2× GMI%+224.6. Multiple linear regression analysis showed that both MAGE and SD have impacts on the relationship between TIR and GMI (P<0.001). The predicted TIR decreased when MAGE or SD increased with different given GMI (Table 1).

Conclusions: MAGE and SD influenced the relationship between TIR and GMI in T2D patients.

Disclosure

D.Chen: None. Z.Liu: None. B.Lin: None. D.Yang: None. J.Yan: None. Y.Yang: None. W.Xu: None.
95-LB: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Novel Oral Small Molecule GLP-1 Receptor Agonist (HRS-7535) in Healthy Subjects —A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Dose Study
Authors: WU JINGYING , HU WEI , DU YIJUN , ZHANG QIAN , ZHOU RENPENG , ZHANG QIN , QIN HUILING , YE ZI , XU YIMEI , FENG SHENG , SHU CHANG , SHEN YU , FAN YANG
Published: June 2023

Background: HRS-7535, a novel, oral small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist, has demonstrated no strict food restriction, and has been found to obviously improve glucose tolerance, promote insulin secretion, and reduce food consumption in preclinical studies. This study aimed to assess the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single and multiple ascending doses (SAD and MAD) of HRS-7535 in healthy subjects.

Methods: This was a randomized, double-blind, multi-part, phase 1 trial (NCT05347758). Overtly healthy adults 18-55 yrs were eligible, with the body mass index of 19.0-28.0 kg/m2 and the HbA1c of <6.2%. In the SAD, healthy subjects were randomized (6:2) to receive HRS-7535 (15, 60, and 120 mg) or placebo. In the MAD, healthy subjects were randomized (18:6) to receive daily HRS-7535 (120 mg [30/60/90/120 mg titration scheme]) or matching placebo for 4 wks.

Results: 24 subjects participated in SAD and 24 participated in MAD, respectively. Most common treatment-emergent adverse events in both SAD and MAD were nausea and vomiting; all TEAEs were mild in severity. PKs were approximately proportional; In SAD, the median Tmax was 5.98-5.99 h and geometric mean t1/2 was 5.28-9.08 h across the HRS-7535 dosing range. In MAD, the median Tmax was 5.98-10.98 h and geometric mean t1/2 was 6.48-8.42 h on Day 28 across the HRS-7535 dosing range. In MAD, the mean reduction in body weight from baseline on Day 29 was 4.38 kg in subjects with HRS-7535.

Conclusion: Both SAD and MAD of HRS-7535 showed acceptable safety profile and favorable PKs/PDs. The obvious reductions in body weight could be observed in healthy subjects. These finding support further clinical exploration of HRS-7535 in patients with metabolic syndromes.

Disclosure

J. Wu: None. S. Feng: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. C. Shu: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y. Shen: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y. Fan: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. W. Hu: None. Y. Du: None. Q. Zhang: None. R. Zhou: None. Q. Zhang: None. H. Qin: None. Z. Ye: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y. Xu: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Funding

Jiangsu Hengrui Pharmaceuticals Co., Ltd.
950-P: Factors Associated with Hyper-/Hypoglycemia Unawareness in People with Type 2 Diabetes
Authors: SUZUKI YUKA
Published: June 2023

Background: Hyper-/hypoglycemia unawareness harvours one of the major issues to hamper good clinical practice in people with type 2 diabetes (T2DM). To unveil risk factors of hyper-/hypoglycemia unawareness, we investigated its relationship with actual glucose variability in people with T2DM using continuous glucose monitoring (CGM).

Methods: Data were obtained from our prospective observational study comprising Japanese people with T2DM who underwent blinded professional CGM and the Diabetes Treatment Satisfaction Questionnaire (DTSQ). People with a time above range (TAR; >180 mg/dL) ≥25% and those who answered 0 (“never”) or +1 (“almost never”) for the frequency of hyperglycemia in the DTSQ were defined as having hyperglycemia unawareness. People with a time below range (TBR; <70 mg/dL) ≥4% with an answer of 0 or +1 for the frequency of hypoglycemia were labelled as having hypoglycemia unawareness. We extracted various clinical characteristics associated with the discrepancies between hyper-/hypoglycemia unawareness and TAR ≥25% / TBR ≥4% on a multivariate logistic regression analysis.

Results: This analysis included 284 subjects. In subjects with a TAR ≥25% (n=115), 27 had hyperglycemia unawareness. The analysis showed that each of no insulin use, older age, and a history of stroke was correlated with hyperglycemia unawareness. Among subjects with a TBR ≥4% (n=45), 28 were unaware of their hypoglycemia. A low eGFR was an independent risk of hypoglycemia unawareness.

Conclusions: We newly identified some clinical characteristics that were significantly associated with hyper-/hypoglycemia unawareness. In people with those characteristics, careful and intensive information sharing regarding asymptomatic hyper-/hypoglycemia using CGM may lead to better glucose management.

Disclosure

Y.Suzuki: None.
957-P: Continuous Glucose Monitoring in Patients with End-Stage Kidney Disease and Burnt-Out Diabetes
Authors: KAMINSKI CANDICE , GALINDO RODOLFO J. , ZABALA ZOHYRA E. , MOAZZAMI BOBAK , GERGES AMANY Y.G. , MCCOY ROZALINA G. , PENG LIMIN , UMPIERREZ GUILLERMO
Published: June 2023

Patients with long-standing type 2 diabetes and end-stage kidney disease (ESKD) on dialysis may experience resolution of their hyperglycemia, as defined by an HbA1c < 6.5%, without antidiabetic therapy. This phenomenon is known as “burnt-out diabetes”. Because HbA1c may be falsely low in patients with ESKD/dialysis therapy, we conducted a prospective study to compare glycemic control as measured by Dexcom G6 CGM in patients with ESKD and burnt-out diabetes and those without history of diabetes. We hypothesize that the use of CGM may provide better assessment of glycemic control than HbA1c (standard-of-care) in these patients and clarify the glycemic characteristics of burnt-out diabetes. We included adults with ESKD on dialysis, with (n=20) and without (n=10) a known history of diabetes, and with HbA1c <6.5% without antidiabetic therapy for > 6 months. All subjects wore a blinded Dexcom G6 CGM for 10 days. Their clinical characteristics and CGM metrics are shown in Table 1. Conclusion: CGM provides better assessment of glycemic excursions, compared to HbA1c, in patients with ESKD and diabetes. Most patients with burnt-out diabetes (HbA1c <6.5%, off therapy) have frequent and significant hyperglycemic excursions as detected by CGM. Further research will need to examine whether these excursions require pharmacotherapy.

Disclosure

C.Kaminski: None. R.J.Galindo: Consultant; Novo Nordisk, Eli Lilly and Company, Sanofi, Pfizer Inc., Bayer Inc., WW (Weight Watchers), Research Support; Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. Z.E.Zabala: None. B.Moazzami: None. A.Y.G.Gerges: None. R.G.Mccoy: Consultant; Emmi. L.Peng: None. G.Umpierrez: Research Support; Abbott, Dexcom, Inc., Baxter.

Funding

Jacob's Fund for Education
963-P: Near-Infrared Device for Diabetes Screening—ANODE01 Study
Authors: CHOUDHARY PRATIK , LAZARO-PACHECO DANIELA , SALTER JOHN E. , PALDANIUS PAIVI M.
Published: June 2023

Background: Diabetes mellitus (DM) screening is currently complex, inefficient and requires resource-intensive, invasive sampling. Development of affordable, rapid, and precise mass-screening tools is valuable in identifying the millions with undiagnosed DM, especially in lower income countries.

Materials and Methods: Accuracy and safety of a novel miniaturized full-spectrum near-infrared (NIR) spectroscopy device intended for DM screening was assessed in a multi-ethnic population with (n=50) or without (n=50) DM. Thirty NIR spectra scans per each middle fingernail and hand were tested for detection of dichotomised DM status based on cut-off values (< HbA1c 6.5% or 6.0 ≥) and specificity (%) of chemometrics outcomes, in assessment of glycated nail keratin versus an HbA1c point-of-care assay as control.

Results: The cohort had mean age of 43.6 vs 64.4 years, 42 vs 76% females and 54 vs 68% Caucasians for non-DM and DM participants. Median (IQR) HbA1c % was 5.45 (5.2 - 5.6) and 6.8 (6.3-7.6), respectively. Clinical feasibility for NIR use was confirmed with no adverse device -related events reports for the over 6000 spectral measurements. The NIR-device demonstrated a specificity of 95.2% and 94.1% at HbA1c 6.5 and 6.0% cut-off levels, respectively (Table).

Conclusions: Our preliminary results indicate high specificity and potential for clinical implementation of non-invasive NIR technology in detection of those without immediate DM risk.

Disclosure

P.Choudhary: Advisory Panel; Medtronic, Novo Nordisk, Dexcom, Inc., MannKind Corporation, Insulet Corporation, Research Support; Abbott Diabetes, Speaker's Bureau; Sanofi, Lilly. D.Lazaro-pacheco: Consultant; Glyconics Ltd. J.E.Salter: None. P.M.Paldanius: Consultant; Glyconics Ltd, Speaker's Bureau; Novartis.

Funding

Glyconics