bluuebunny/crossref_metadata_2025 huggingface dataset:
1031-P: Comparison of Two Approaches to Basal Insulin Management for Adults with Type 1 Diabetes Flying across Multiple Time Zones
Authors: AXELROD CEARA , CASTORINO KRISTIN N. , BEVIER WENDY C. , HAROUSH GAL , FARFAN CHRISTIAN C. , MEFFORD MIKAYLA R. , NELSON KRISTEN , SPINK LISA A. , KERR DAVID
Published: June 2020

For people with type 1 diabetes (T1D) using multiple daily insulin injections (MDI), we previously reported that maintaining optimal glucose control whilst travelling across multiple time zones is challenging. The aim of this pilot study was to compare flexibly-dosed U100 insulin degludec (DEG) with a structured pre-flight dose algorithm for U100 insulin glargine (GLA) in adults with T1D flying >6 hours. Beginning in Honolulu (HI, UTC -10), subjects flew eastward non-stop for 9.5 hours to New York (NY, UTC -5). After 72 hours in NY, subjects returned to HI (11 hour flight) staying up to 72 hours. After 2 weeks, they switched to the other insulin and repeated the travel. The primary endpoint was inflight Time in Range (TIR, 70-140 mg/dl) using blinded continuous glucose monitoring (CGM-Abbott Freestyle Libre Pro) during eastward and westward travel. Secondary end-points included time above and below range and glycemic variability (coefficient of variation [CV]). Between insulin comparisons were made using Pearson N1 chi-square tests for proportions, mean glucose via two-tailed independent t-tests and glycemic variability via two-sample F-tests. Twenty subjects, (60% female, age 34.9 ± 15.2 [mean ±SD] years, HbA1c 7.5 ± 1.2%) completed the study. Insulin doses during travel were similar (23.0 ± 11.4 for GLA and 21.8 ± 12.0 units for DEG). Overall, mean glucose on GLA was 148.0 ± 73.8 mg/dL (CV 50%) versus 158.5 ± 76.7 mg/dL (CV 48%) on DEG, p=0.01. While aggregate TIR was greater on GLA (44% versus 38% with DEG), there was less hypoglycemia <70 mg/dL on DEG (p<0.01). Significantly less time was also spent below <60 (p<0.01) and >250 mg/dL (p<0.01) during eastward travel and <70 (p<0.01) during westward travel on DEG. Inflight CV on DEG was also less during both eastward (43% vs. 49%, p<0.01) and westward (38% vs. 51%, p<0.0001) travel.

In conclusion, for adults with T1D undertaking long-haul travel, DEG use was associated with less disruption to glucose control compared to GLA.

Disclosure

C. Axelrod: None. K.N. Castorino: Research Support; Self; Abbott, Dexcom, Inc., Medtronic, Mylan, Novo Nordisk Inc. W.C. Bevier: None. G. Haroush: None. C.C. Farfan: None. M.R. Mefford: None. K. Nelson: None. L.A. Spink: None. D. Kerr: Advisory Panel; Self; Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Eli Lilly and Company. Stock/Shareholder; Self; Glooko, Inc.

Funding

Novo Nordisk
1034-P: Efficacy and Safety of Fast-Acting Insulin Aspart According to Baseline HbA1c in Adults with Type 2 Diabetes Treated with a Basal-Bolus Regimen
Authors: FRANEK EDWARD , EKELUND MAGNUS , THÓRISDÓTTIR ÓLÖF , JANG HAK CHUL , LALIC KATARINA , RATHOR NAVEEN , ROSE LUDGER , GONZALEZ ALFONSO SOTO , SILVER ROBERT J. , LANE WENDY
Published: June 2020

The impact of baseline HbA1c on the efficacy and safety of fast-acting insulin aspart (FA) was assessed in a post-hoc analysis of a 16-week, treat-to-target trial in adults with type 2 diabetes (T2D) not optimally controlled with a basal-bolus regimen (onset 9). Participants (n=1091) were randomized to FA or insulin aspart (IAsp), each with insulin degludec with or without metformin. In this analysis, participants were separated by baseline HbA1c (<7.0%, [n=476] and ≥7.0% [n=615]).

Change from baseline in HbA1c was similar between treatments in the <7.0% subgroup, and HbA1c improved with FA vs. IAsp in the ≥7.0% subgroup (Table). Change from baseline in 1-h postprandial glucose (PPG) increment (meal test) favored FA across subgroups. The rate of severe or blood glucose-confirmed hypoglycemia was statistically significantly lower for FA vs. IAsp in the <7.0% subgroup, and was similar between treatments in the ≥7.0% subgroup. In the ≥7.0% subgroup treated with IAsp, the insulin degludec dose decreased slightly during the trial.

FA provides effective overall glycemic control with improved PPG control vs. IAsp in adults with T2D. For individuals with HbA1c <7.0%, FA provides a similar reduction in HbA1c vs. IAsp, but with less hypoglycemia. For individuals with HbA1c ≥7.0%, FA may offer a greater reduction in HbA1c vs. IAsp without an increased risk of hypoglycemia.

Disclosure

E. Franek: Advisory Panel; Self; Novartis AG. Speaker’s Bureau; Self; AstraZeneca, Bioton, Eli Lilly and Company. Other Relationship; Self; Boehringer Ingelheim, Novo Nordisk. M. Ekelund: Employee; Self; Novo Nordisk. Stock/Shareholder; Self; Novo Nordisk. Stock/Shareholder; Spouse/Partner; Novo Nordisk. Ó. Thórisdóttir: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. H. Jang: Speaker’s Bureau; Self; Daiichi Sankyo, Handok, Pfizer Inc., Takeda Pharmaceutical Company Limited. K. Lalic: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi. N. Rathor: Employee; Self; Novo Nordisk. L. Rose: None. A. Soto Gonzalez: Advisory Panel; Self; Novartis, Novo Nordisk. Consultant; Self; Mundipharma International, Novartis, Novo Nordisk. Speaker’s Bureau; Self; Eli Lilly and Company, Janssen/Mundipharma, Novartis, Novo Nordisk, Sanofi. R.J. Silver: Advisory Panel; Self; Medtronic, Novo Nordisk. Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. W. Lane: Research Support; Self; AstraZeneca, Gilead, Mylan, Sanofi, Tolerion, vTv. Other Relationship; Self; Dexcom, Insulet, Novo Nordisk.

Funding

Novo Nordisk
1042-P: Insulin Requirement during Total Parenteral Nutrition in Patients with Diabetes Mellitus
Authors: GARG RAJESH , ARUNACHALAM AMAR , BERMUDEZ LUIS E. , RAMIREZ MARIANA
Published: June 2020

Glycemic control in patients with diabetes mellitus receiving total parenteral nutrition (TPN) can be challenging due to multiple factors. These patients often have a high burden of illness and receive medications that raise blood glucose (BG) levels. Moreover, TPN delivers a large amount of glucose directly into the systemic circulation without the benefit of incretin effect. Therefore, relatively large amounts of insulin are expected to be required for glycemic control. However, there are no studies to guide insulin dosing in patients with diabetes being started on TPN. We conducted a retrospective study including all patients with diabetes admitted to our hospital over a 1-year period who received TPN for ≥ 3 days. The goal of this study was to estimate a safe starting dose of insulin for TPN. Patients receiving enteral nutrition along with TPN were excluded. Insulin doses and blood glucose levels on the last day of TPN were used for data analysis. We found 25 patients who fulfilled our inclusion/exclusion criteria. All patients had type 2 diabetes and were receiving antidiabetic drugs before hospitalization. Mean age was 68 ± 7 years, 56% were men, 80% were White, 44% had microvascular and 44% had macrovascular complications. Mean BMI was 26.7 ± 6.7 kg/m2, systolic BP 131 ± 27 mmHg, diastolic BP 65 ± 15 mmHg, HbA1c 7.7 ± 2.3% and serum creatinine 2.7 ± 3.3 mg/dl. The mean daily BG on TPN was 212 ± 47 mg/dl. Out of 171 BG values available on the last day of TPN, 116 (68%) were >180 mg/dl, 4 (2%) were <70 mg/dl and 0 were <40 mg/dl. Only two patients suffered mild hypoglycemic episodes while all others remained hyperglycemic. Average total daily insulin dose was 17 ± 20 units before starting TPN and 53 ± 54 units on the last day of TPN. Patients received an average of 0.7 Units/kg total daily dose of insulin on the last day of TPN. With this dose, they had minimal risk of hypoglycemia but the glucose levels were often high. Our study shows that the majority of patients with diabetes need more than 0.7 units/kg insulin when receiving TPN.

Disclosure

R. Garg: None. A. Arunachalam: None. L.E. Bermudez: None. M. Ramirez: None.
105-OR: Trends in Complications in Type 1 and Type 2 Diabetes in Denmark, 1996-2016
Authors: CARSTENSEN BENDIX , AMADID HANAN , JØRGENSEN MARIT E.
Published: June 2020

Background and aim: Both micro- and macro vascular complications represent major problems for diabetes patients and monitoring of the extent of these among diabetes patients is essential. Several studies have reported decreasing complications rates. We describe the burden and trend in 18 groups of complications in persons with diabetes in Denmark 1996-2016.

Methods: We compiled a diabetes register for the entire Danish population, including reliable classification of type of diabetes. From the National Patient Register we extracted dates of recorded complications in 18 classes. Binomial regression was used to describe the prevalence of complications at diagnosis and change in these over time. Rate models based on Poisson likelihood were used to describe the incidence rates and changes in these. Analyses were conducted separately for T1D and T2D, and controlled for sex, age, duration of diabetes and including a linear term to describe the calendar time effect (date of diagnosis).

Results: The prevalence at diagnosis of previous CVD was 10% in T1D and 37% in T2D, with annual relative changes of 3% in T1D and 5% in T2D. Retinopathy prevalence at diagnosis was 4.3% in T1D and 1.7% in T2D with no change in T1D, but a relative decrease of 6% in T2D. We found similar decreases in rates of complications in T1D and T2D; decrease of 2%/year in rates of CVD, 5%/year in amputations, while there were no changes in the incidence rates of retinopathy and renal disease over the period 1996-2016. For most complications we found a very high incidence during the first year after diagnosis, most likely reflecting a diagnostic catch-up and not any biological phenomenon.

Conclusions: A steady decrease in incidence rates of most complications was seen, but not for microvascular complications. The pattern of complications at diagnosis was more mixed, influenced by fluctuations in diagnostic activity over the period. In general an encouraging trend in complication occurrence was seen in Denmark in the period 1996-2016.

Disclosure

B. Carstensen: Stock/Shareholder; Self; Novo Nordisk A/S. H. Amadid: None. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S.
1050-P: Enhanced Release of Glucose into the Intraluminal Space of the Intestine Associated with Metformin Treatment as Revealed by 18F FDG-Based PET-MRI
Authors: SAKAGUCHI KAZUHIKO , MORITA YASUKO , NOGAMI MUNENOBU , OKADA YUKO , HIROTA YUSHI , SUGAWARA KENJI , TAMORI YOSHIKAZU , MURAKAMI TAKAMICHI , OGAWA WATARU
Published: June 2020

Objective: In addition to the inhibition of gluconeogenesis in the liver, metformin exerts various effects on the gut that likely contribute to the lowering of blood glucose levels. Positron emission tomography (PET)-computed tomography recently has revealed that metformin promotes the intestinal accumulation of [18F]fluorodeoxyglucose (FDG), a nonmetabolizable glucose derivative, indicating that the drug affects glucose handling in the intestine. It has remained unknown, however, whether this accumulation occurs in the wall or intraluminal space of the intestine. We here addressed this question with the use of [18F]FDG-based PET-magnetic resonance imaging (MRI), a recently developed imaging modality with increased accuracy of registration and high soft-tissue contrast.

Methods: Among 244 individuals with type 2 diabetes who underwent PET-MRI, we extracted 24 pairs of subjects matched for age, BMI, and HbA1c level who were (metformin group) or were not (control group) receiving treatment with metformin. We evaluated accumulation of [18F]FDG in different portions of the intestine with both a visual scale and measurement of maximum standardized uptake value (SUVmax), and such accumulation within the intestinal wall or lumen was discriminated on the basis of SUVmax.

Results: SUVmax of the jejunum, ileum, and right or left hemicolon was greater in the metformin group than in the control group. [18F]FDG accumulation in the ileum and right or left hemicolon as assessed with the visual scale was also greater in the metformin group. SUVmax for the intraluminal space of the ileum and right or left hemicolon, but not that for the intestinal wall, was greater in the metformin group than in the control group.

Conclusions: Metformin treatment was associated with increased accumulation of [18F]FDG in the intraluminal space of the intestine, suggesting that this drug promotes the transport of glucose from the circulation into stool.

Disclosure

K. Sakaguchi: Other Relationship; Self; AstraZeneca, Novartis AG, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Y. Morita: None. M. Nogami: None. Y. Okada: None. Y. Hirota: Other Relationship; Self; Sanofi. K. Sugawara: None. Y. Tamori: None. T. Murakami: None. W. Ogawa: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharma GmbH & Co.KG, Eli Lilly Japan K.K., Kowa Company, Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Other Relationship; Self; Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.
1051-P: Selective Targeting of Angiopoietin-Like 3 (ANGPTL3) via the Second-Generation Antisense Oligonucleotide (ASO) ISIS-703802 (AKCEA-ANGPTL3-LRx) in Subjects with Familial Partial Lipodystrophy (FPLD)
Authors: FOSS-FREITAS MARIA CRISTINA , AKINCI BARIS , NEIDERT ADAM H. , HENCH RITA P. , SWAIDAN MARIO , ORAL ELIF A.
Published: June 2020

FPLD is an extreme form of metabolic dyslipidemia and diabetes caused by selective loss of peripheral subcutaneous fat. Currently, there are no approved therapies for this rare cause of diabetes in the U.S. Reductions in circulating levels of the hepatokine ANGPTL3 either by mutations in humans or by targeted drugs in rodents are associated with reductions in triglyceride levels and provide protection from atherosclerosis, making it an attractive target for patients with FPLD and metabolic dyslipidemia. The objective of this proof-of concept, Phase 2, open-label study was to assess the early efficacy and safety of a strategy that targets ANGPTL3 via ISIS-703802 (AKCEA-ANGPTL3-LRx) in patients with FPLD. Four patients with FPLD (3F/1M; age range: 38-47; 1 with LMNA R482Q, 1 with LMNA R584H, and 2 with no causative genetic variant) with diabetes (HbA1c>6.5%) and hypertriglyceridemia (≥ 500 mg/dL or ≥ 200 mg/dL for patients meeting genetic or family history criteria) were included. Patients received the study drug at a subcutaneous dose of 20 mg weekly for 26 weeks. Primary endpoint was the percent change in serum triglycerides from baseline to week 27. All other endpoints were also analyzed at week 27. Treatment resulted in a 60±26 (mean±SD) % reduction in triglycerides from a baseline of 818±432 mg/dL. Consistent with antisense reduction of ANGPTL3 mRNA, circulating ANGPTL3 levels were lowered by 55±10%. Treatment was also associated with 51±27% reduction in circulating apoC3 levels, 64±24% reduction in total VLDL and chylomicron triglycerides, and 18±15% reduction in total cholesterol. In addition, HbA1c showed a modest mean absolute reduction of 0.2±1.0 % The drug was well tolerated and there were no new safety signals observed. Although a small study, these results suggest that targeting ANGPTL3 in patients with FPLD could successfully address metabolic dyslipidemia.

Disclosure

M. Foss-Freitas: None. B. Akinci: Advisory Panel; Self; Aegerion Pharmaceuticals, Regeneron Pharmaceuticals. Research Support; Self; Gemphire Therapeutics Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novartis AG, Novo Nordisk A/S, Sanofi-Aventis, Servier. A.H. Neidert: None. R.P. Hench: None. M. Swaidan: None. E.A. Oral: Consultant; Self; Aegerion Pharmaceuticals, Akcea Therapeutics, Regeneron Pharmaceuticals. Research Support; Self; Aegerion Pharmaceuticals, Akcea Therapeutics, Gemphire Therapeutics Inc., GI Dynamics Inc., Regeneron Pharmaceuticals.

Funding

Ionis Pharmaceuticals, Inc.; Akcea Therapeutics
1056-P: Effect of Dulaglutide on Glycemic Variability: Post Hoc Analysis of the AWARD Studies
Authors: JODAR ESTEBAN , WANG QIANQIAN , ROMERA IRENE , CAVEDA ELENA , GARCIA LUIS EMILIO
Published: June 2020

Glycemic variability (GV) may contribute to the development and progression of cardiovascular complications. This post-hoc analysis assessed GV in people with type 2 diabetes, treated with once-weekly dulaglutide (DU), and not receiving any concomitant insulin treatment. Analysis included pooled data from 5 randomized, parallel-arm, phase 3 studies (AWARD 1,2,3,6 and 8). The participants (N=1114, 48% male) received DU 1.5 mg without any concomitant insulin for 26 weeks and with evaluable GV measurements at baseline and study endpoint (week 26). The measurements included within-day and between-day GV calculated by standard deviation (SD) and coefficient of variation (CV) from self-monitored plasma glucose (SMPG), and between-day fasting self-monitored plasma glucose (FSMPG) values. At baseline, the mean (SD) age was 55.9 (9.7) years, BMI 32.7 (5.2) kg/m2, HbA1c 8.0 (0.9) % and fasting plasma glucose 166.5 (47.8) mg/dL. At 26 weeks, DU significantly reduced within-day and between-day GV from SMPG values (SD values, p<0.001, Figure) and between-day GV from FSMPG (p<0.001). SMPG GV changes were significant and consistent across studies. Analysis by CV gave consistent results (Figure). Overall, the analysis suggests that treatment with once-weekly DU 1.5 mg reduces within-day and between-day GV from SMPG and between-day GV from FSMPG.

Disclosure

E. Jodar: Other Relationship; Self; Elli Lilly & Co, Novo Nordisk, MSD, Lilly, Janssen, Pfizer, AstraZeneca, Sanofi, UCB, Amgen, FAES, Shire, Mundipharma, Novartis. Q. Wang: Employee; Self; Eli Lilly and Company. I. Romera: Employee; Self; Eli Lilly and Company. E. Caveda: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. L. Garcia: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

Funding

Eli Lilly and Company
1059-P: Additive Manufactured Macroencapsulation Devices for Islet Cell Replacement Therapy
Authors: LEVEY RUTH E. , COULTER FERGAL B. , ROBINSON SCOTT T. , MCDONOUGH LIAM , DEOTTI STEFANO , DOLAN EIMEAR B. , DOCKERY PETER , KELLY HELENA , OCEARBHAILL EOIN D. , DUFFY GARRY P.
Published: June 2020

Islet encapsulation devices can induce a Foreign Body Response (FBR) and the formation of a dense avascular fibrotic capsule. This FBR is heightened when the device has a smooth surface as fibrous tissue is unable to adhere, instigating a substantial immunological reaction, islet death and ultimately implant failure. In this study, we examine whether additive manufactured multiscale porous devices promote optimal tissue integration and vascularisation for long-term functional islet encapsulation. Furthermore, we examine the potential for this method to be scaled for functional use in a large diabetic animal model. Silicone devices exhibiting progressively more complex surface architectures (quantity of macro- and micro-pores), were implanted submuscularly in rodents. Upon explant, analysis of fibrous capsule, angiogenic and macrophage response were performed. To determine its potential as an encapsulation device, multiscale porosity devices were used for intra-peritoneal syngeneic islet transplantation in 8 diabetic rats. Circulating blood glucose levels were monitored for 8 weeks. To validate scalability and functionality, devices were implanted submuscularly in an STZ-induced diabetes pig model for 2 weeks before blood glucose levels were measured in response to the infusion of insulin through the device. Degree of tissue integration and vascularity in proximity to the implant was shown to increase 2.5 fold with precisely controlled multiscale device topography. Moreover, encapsulated islets maintain glucose responsiveness and function for 8 weeks. Bioavailability was equal when the same dose of insulin is delivered via the device vs. subcutaneously in diabetic pig model. The use of additive manufactured multiscale porous coatings on macroencapsulation devices can increase tissue integration and vascularity. These findings demonstrate functionality, scalability and could help to resolve the immunological and diffusion limitations of current encapsulation devices.

Disclosure

R.E. Levey: None. F.B. Coulter: None. S.T. Robinson: None. L. McDonough: None. S. Deotti: None. E.B. Dolan: None. P. Dockery: None. H. Kelly: None. E.D. OCearbhaill: None. G.P. Duffy: None.

Funding

European Union (645991)
106-LB: Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MK-1092 in Subjects with T1DM and T2DM
Authors: MORROW LINDA , GRIMM MICHAEL , BEYSEN CARINE , WALFORD GEOFFREY , DUNCAN KELLY , MITRA PRANAB K. , VADDADY PAVAN , HOMPESCH MARCUS
Published: June 2020

Background: MK-1092, a first-in-class insulin receptor partial agonist, is being developed as a novel basal insulin to treat diabetes. Primary objectives were to assess safety and tolerability of single subcutaneous (SC) doses of MK-1092 in T1DM and T2DM and to determine safe single SC doses of MK-1092 in T1DM with a maximum glucose infusion rate (GIRmax) between 1.5 and 4.5 mg/kg/min. Secondary objectives were to estimate PK profiles in T1DM and T2DM and to determine the GIRmax in T2DM.

Methods: All subjects received blinded treatments of MK-1092 or glargine and placebo matched to the alternative active treatment under euglycemic clamp conditions. T1DM: 2 cohorts (n=8/cohort) were each randomized (3:1) to receive MK-1092 (8 nmol/kg in cohort 1 or 32 nmol/kg in cohort 2) or glargine (3 nmol/kg [0.5 units/kg]). T2DM: 1 cohort (n=9) was randomized to receive either MK-1092 (n=6) or glargine (n=3). Each subject underwent 3 dosing periods. MK-1092 was dosed at 32, 16 and 64 nmol/kg in periods 1, 2, and 3, respectively and glargine was dosed at 3 nmol/kg in all periods.

Results: All doses tested were safe and well tolerated. There were no SAEs or discontinuations due to AEs. AEs were mild or moderate and resolved spontaneously. No anti-MK-1092 or anti-insulin antibodies were observed. In T1DM, the geometric mean of apparent terminal t1/2 was 8.54 and 6.70 hr; Tmax was 15.00 and 15.04 hr; AUC0-∞ was 21.5 and 74.9 nM*hr and Cmax was 0.79 and 3.43 nM for 8 and 32 nmol/kg MK-1092, respectively. PK parameters for 32 nmol/kg MK-1092 were comparable for T1DM and T2DM except for a ~40-50% lower AUC0-∞ and Cmax in T2DM. In T1DM, the mean GIRmax was 1.33 and 2.74 mg/kg/min for 8 and 32 nmol/kg MK-1092, respectively and 2.32 mg/kg/min for glargine. In T2DM, the mean GIRmax was 1.90, 1.40 and 2.83 mg/kg/min for 32, 16 and 64 nmol/kg MK-1092, respectively and ~ 1.2 mg/kg/min for glargine.

Conclusion: Single doses of MK-1092 are well-tolerated and lower glucose in patients with diabetes.

Disclosure

L. Morrow: Employee; Spouse/Partner; Lilly Diabetes. Employee; Self; ProSciento. M. Grimm: None. C. Beysen: Employee; Self; ProSciento. G. Walford: Employee; Self; Merck & Co., Inc. K. Duncan: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. P.K. Mitra: Employee; Self; Merck Sharp & Dohme Corp. Stock/Shareholder; Self; Bristol-Myers Squibb. P. Vaddady: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. M. Hompesch: Board Member; Self; ProSciento. Employee; Self; ProSciento. Stock/Shareholder; Self; ProSciento.
106-OR: National Trends in Lower Extremity Amputation among U.S. Medicare Beneficiaries with Diabetes, 2000-2017
Authors: HARDING JESSICA , ANDES LINDA J. , ROLKA DEBORAH B. , IMPERATORE GIUSEPPINA , LI YANFENG , GREGG ED , ALBRIGHT ANN L.
Published: June 2020

Diabetes is the leading cause of non-traumatic lower extremity amputation (NLEA) in the United States. After a period of decline, some U.S. data show that diabetes-related NLEA has recently increased, particularly among young and middle-aged adults. However, the trend for older adults is less clear. To examine NLEA trends among older adults with diabetes (≥67 years), we used 100% Medicare claims for beneficiaries enrolled in Parts A and B during 2000-2017. NLEA was defined as the highest-level amputation per patient per calendar year. NLEA rates were stratified by sex, race and ethnicity, and NLEA level. All rates were age-sex standardized to the 2000 Medicare population. Trends over time were assessed using Joinpoint regression and annual percent change (APC) reported. NLEA rates (per 1,000 persons) halved from 8.5 in 2000 to 4.4 in 2009 (APC -7.9, p value<0.001). However, from 2009 to 2017 NLEA rates increased slightly to 4.8 (APC 1.2, p-value<0.001). Trends were similar across most sex and race/ethnic groups, however absolute rates were highest in blacks and men (Figure A). By NLEA level, overall increases were driven by increases in rates of toe and foot NLEAs. This study of the U.S. Medicare population shows that recent increases in diabetes-related NLEA are also occurring in the older population but at a less severe rate.

Disclosure

J. Harding: None. L.J. Andes: None. D.B. Rolka: None. G. Imperatore: None. Y. Li: None. E. Gregg: None. A.L. Albright: None.
1060-P: The Effect of FGF21/GLP-1 Fusion Protein on Glucose and Lipid Metabolism Using Diabetic Mice Models
Authors: GUO LIXIN , PAN QI , CHEN CHAO , LIN SHUSHAN , LI YU , LI XIAOPING , CHEN XIAOFENG , LIU LIANG , LI WENJIA , TANG XINFA
Published: June 2020

Objective: Fibroblast growth factor 21 (FGF-21) is an endocrine factor playing important role in energy metabolic pathways and might be a potential therapeutic target for metabolic disorders such as type 2 diabetes (T2D) and NASH. However, Wild type FGF-21’s clinical application is hindered due to its limited bio-activity. To enhance the medicinal properties, this study mutated FGF-21 to improve its bio-activity. And based on potential synergistic effect of GLP-1 and FGF-21, a FGF-21/GLP-1 fusion protein was constructed to develop a potential T2D/NASH effective drug.

Methods: FGF-21-Fc was mutated to enhance its receptor interaction and stability. FGF-21 mutants’ blood glucose reduction capability were compared on db/db mice. Moreover, by constructing a dual agonist from FGF-21 and GLP-1, the bio-activity was further enhanced. Using HFD ob/ob mice, the dual agonist was evaluated by measuring multiple indicators such as blood glucose level, body weight, liver function, and the NAS score.

Results: Results from db/db mice (n=9, single SC injection, 40nM/kg) show that the mutated FGF-21-Fc possesses significantly stronger blood glucose lowering effect than the wild type (P<0.01). Results from HFD ob/ob mice (n=8, SC injection, BIW, 4 weeks) show that the dual agonist reduces the blood glucose level by 60% or more (P <0.001), reduces ALT levels by more than 70%, and reduces NAS scores by more than 3 points. The dual agonist is more effective than dulaglutide on T2D and NASH (P<0.001).

Conclusions: According to this study, FGF-21 and GLP-1 can synergistically enhance the metabolic regulation through multiple mechanisms. The mutated dual agonist possesses optimized bio-activity and shows significant improvements for T2D and NASH. It is a very promising drug for both T2D and NASH treatment.

Disclosure

L. Guo: None. Q. Pan: None. C. Chen: None. S. Lin: None. Y. Li: None. X. Li: None. X. Chen: None. L. Liu: None. W. Li: None. X. Tang: None.
1061-P: Effects of Long-Term Vitamin D and Omega-3 Fatty Acid Supplementation on Inflammatory and Cardiac Biomarkers in Patients with Type 2 Diabetes
Authors: LIMONTE CHRISTINE , ZELNICK LEILA , HOOFNAGLE ANDY , THADHANI RAVI , MELAMED MICHAL , RUZINSKI JOHN , LEE I-MIN , SESSO HOWARD , BURING JULIE E. , MANSON JOANN E. , DE BOER IAN
Published: June 2020

Background: Immune system activation contributes to the development of microvascular and macrovascular complications in diabetes. Identifying interventions that reduce inflammation may delay progression of diabetes complications.

Methods: This study reports pre-specified secondary outcomes of the Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease, in which 1,312 adults with type 2 diabetes were randomized to vitamin D3 (2000 IU/d) versus placebo and omega-3 fatty acids (EPA+DHA;1g/d) versus placebo in a 2x2 factorial design. We measured serum interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and after two and five years, then used linear mixed models to test treatment effects.

Results: Participants were on average 67.6 years old (46% women). Overall, baseline geometric means of IL-6, hsCRP, and NT-proBNP were 1.2 pg/mL, 1.9 mg/L, and 262 pg/mL, respectively. After five years, mean IL-6 and hsCRP remained within 5% of their baseline values while mean NT-proBNP increased by 56% in the full population. Compared with placebo, participants assigned to vitamin D3 had a larger increase in NT-proBNP over time (ratio of change compared with placebo at five years 1.25; 95%CI 1.09-1.43; p=0.005), while there was no significant difference in change in IL-6 (ratio 0.97; 95%CI 0.80-1.18) or hsCRP (ratio 0.90; 95%CI 0.79-1.02). Comparing omega-3 fatty acids to placebo, there was no significant difference in change in IL-6 (ratio 1.11; 95%CI 0.92-1.34), hsCRP (ratio 0.88; 95%CI 0.77-1.00), or NT-proBNP (ratio 1.03; 95%CI 0.90-1.17) at five years. No heterogeneity was observed in subgroup analyses accounting for pre-specified clinical and demographic features.

Conclusions: Among adults with type 2 diabetes, supplementation with vitamin D3 or omega-3 fatty acids did not reduce IL-6, hsCRP, or NT-proBNP long-term.

Disclosure

C. Limonte: None. L. Zelnick: None. A. Hoofnagle: None. R. Thadhani: None. M. Melamed: Other Relationship; Self; American Board of Internal Medicine, ICON plc. J. Ruzinski: None. I. Lee: None. H. Sesso: None. J.E. Buring: Advisory Panel; Spouse/Partner; Pharmavite. J.E. Manson: None. I. de Boer: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Consultant; Self; George Clinical, Goldfinch Bio, Ironwood Pharmaceuticals.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088762); National Institutes of Health (U01CA138962, R01CA138962)
1064-P: The Human Recombinant REG3A Protein ALF-5755 Restores Glucose Homeostasis and Insulin Sensitivity in High-Fat Fed Mice and in Ob/Ob Mice
Authors: DARNAUD MARION , CRUCIANI-GUGLIELMACCI CÉLINE , GONZALEZ PATRICK , AMOUYAL PAUL , AMOUYAL GILLES , JAMOT LAURE , MONIAUX NICOLAS , ANDREELLI FABRIZIO , BRÉCHOT CHRISTIAN B. , MAGNAN CHRISTOPHE , FAIVRE JAMILA
Published: June 2020

Introduction: REG3A (Regenerating islet-derived protein 3A) is a carbohydrate-binding protein belonging to the family of C-type lectins. REG3A has antioxidant and anti-inflammatory properties modulating glucose and lipid homeostasis. We report a study of the effects of the administration of the human recombinant REG3A protein ALF-5755 on glucose and lipid homeostasis in insulin-resistant mice.

Materials and Methods: 4-week-old C57Bl/6N male mice were fed HFD for 12 weeks. The control group received a standard chow diet. 12-week-old Ob/Ob mice were used. Mice were given ALF-5755 (43µg/day, ALF group) or a formulation buffer (buffer group) by subcutaneous infusion for 28 days. We measured: body weight, blood glucose, fasting insulin, glucose tolerance and insulin sensitivity, glucose turnover and uptake during hyperinsulinemic/euglycemic clamps and AMPK activity.

Results: In both models, ALF-5755 administration significantly decreased basal blood glucose with no change in basal insulin levels. The changes in blood glucose levels in response to an oral glucose load in the ALF and buffer groups were similar in HFD-fed mice but were lowered by ALF-5755 in Ob/Ob mice. Insulin secretion at 15 and 30 min was significantly reduced in the ALF group compared to Buffer group in both models. During clamp, glycolytic muscles exhibited an increase in glucose uptake in HFD-fed mice, and an increase in AMPK activity in both models treated with ALF-5755. Insulin sensitivity was increased in ALF group. The plasma TG was significantly decreased in the ALF compared to Buffer group. No difference in body weight was observed whatever the administered molecules.

Conclusion: Administration of ALF-5775 improves blood glucose and insulin sensitivity in insulin-resistant mice. This effect is mediated by an increase of skeletal muscle glucose uptake through AMPK activation. REG3A is a potential therapeutic drug for the management of insulin resistance syndrome.

Disclosure

M. Darnaud: None. C. Cruciani-Guglielmacci: Consultant; Self; The Healthy Aging Company. P. Gonzalez: None. P. Amouyal: None. G. Amouyal: None. L. Jamot: None. N. Moniaux: None. F. Andreelli: Consultant; Self; Lilly Diabetes, THAC. Speaker’s Bureau; Self; Lilly Diabetes. Other Relationship; Self; Lilly Diabetes. C.B. Bréchot: Consultant; Self; Romark. Employee; Self; The Healthy Aging Company. C. Magnan: None. J. Faivre: None.
1067-P: Development of Novel Modulators of the GABAA Receptor for Diabetes Therapy
Authors: HASSE BIRGIT , BELGARDT BENGT-FREDERIK , HECHT MARION , WÖRDENWEBER ROBIN , PIECHOT ALEXANDER , RODEN MICHAEL , ECKEL JÜRGEN
Published: June 2020

Accumulating data suggest that the GABAergic system may play a key role in beta-cell survival and regeneration in both type 1 and type 2 diabetes. Therefore, the development of new positive allosteric modulators of the GABAA receptors (GABAA-Rs) provides an interesting strategy for an antidiabetic therapy, although central nervous system side effects mediated by α1-GABAA-Rs are a potential concern. Here we synthesized and functionally analyzed a series of low molecular weight thioacrylamides (ThAcs), designed to both positively modulate GABAA-R signalling and show low blood brain barrier penetration. Beta-cell proliferation was increased by several ThAcs at nanomolar concentrations in a rat beta-cell line in vitro (i.e., ∼82% increased EdU incorporation after 24 hours treatment with ThAc HK-4 at 100 nM). The most effective candidate, HK-4, was further characterized. By using radio ligand competition assays and functional patch clamp experiments we analyzed the interaction between HK-4 and GABAA-Rs. In competition assays, we observed a dose-dependent affinity of HK-4 for GABAA-Rs in rat cortical neuron membranes. In electrophysiological patch clamp assays, we determined the modulating activity of HK-4 to individual human GABAA-Rs using HEK293 cells stably expressing different subunit combinations. HK-4 induced very strong potentiation of the current elicited by the natural ligand GABA on GABAA receptors containing combinations of α2β3γ2 (current ∼300% of GABA alone), α3β3γ2 (∼770%) and on α1β3γ2 (∼580%) subunits, respectively. Minimal blood brain barrier penetration of HK-4 was verified by mass spectrometry-based analyses of brain and plasma samples of rats. Additionally, HK-4 shows no major toxicological effects as determined in a 90-day toxicity study with daily dosing, has a favorable pharmacokinetic profile and demonstrates good oral bioavailability. Our data reveal the potential of HK-4 and other ThAcs for further development into antidiabetic drugs.

Disclosure

B. Hasse: Stock/Shareholder; Self; Algiax Pharmaceuticals GmbH. B. Belgardt: None. M. Hecht: None. R. Wördenweber: None. A. Piechot: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. J. Eckel: None.

Funding

EFRE; NRW; European Union
1077-P: De-escalation Treatment (DET): A Personalized Pharmacological Intervention to Stop Disease Progression in Patients with Type 2 Diabetes
Authors: PFÜTZNER ANDREAS , MANESSIS ANASTASIOS , DO LINDA , HANNA MINA
Published: June 2020

Type 2 diabetes is a chronic progressive disease with increasing drug demands. It is comprised of a hereditary ß-cell dysfunction, (ßCD), insulin resistance (IR), and chronic systemic inflammation (CSI), which can be present with different degrees of severity. We have tested an alternative approach to the common drug escalation programs. DET (De-Escalation Treatment), temporary, multi-drug intervention targets to improve ß-Cell function and reverse disease progression. A personalized drug combination for a three-month treatment is determined based on a biomarker panel consisting of classic and new biomarkers. 22 patients (8 women, 14 men, age: 62±8 yrs., disease duration: 12±7 yrs., HbA1c: 7.8 %, BMI: 33.2±2.4 kg/m², treatment with 1 or 2 oral drugs) were treated with follow-up periods of up to 12 years. DET consisted of low doses each of basal insulin to address ßCD, treatment of IR (exercise and/or pioglitazone), a drug to reduce CSI (diet, GLP-1, or SGLTII) and a hypoglycemic intervention (metformin, or DPP-IV). The DET approach was well tolerated (nausea: 4 cases, edema: 1 case). All patients experienced a normalization or pronounced improvement of glycemic control without report of hypoglycemia. Mean HbA1c after 3 months was 5.9±0.4 %. Intact proinsulin decreased from 9.3±2.1 pmol/L to 2.3±0.6 pmol/L, adiponectin improved from 3.4±1.2 to 8.6±2.4 mg/dL, and mean body weight decreased by 2.4±1.1 kg (all: p<0.01). After the DET, treatment was continued with lifestyle only or a drug monotherapy targeting the major component of their individual diabetes phenotype. This DET “honeymoon“ effect lasted in the mean for about 2 years (range until next DET: 6 months to >11 years). Regeneration of ß-cell function by means of DET resulted in a temporary stop of chronic disease progression. A formal prospective clinical study to investigate the practicability of this approach in routine clinical practice is currently ongoing.

Disclosure

A. Pfützner: Consultant; Self; LifeCare, Inc., Novo Nordisk A/S. Research Support; Self; CNOGA Medical, Esperion Therapeutics, Inc. Speaker’s Bureau; Self; Sanofi-Aventis. A. Manessis: Research Support; Self; Novo Nordisk Inc., Sciema GmbH. L. Do: Research Support; Self; Sciema GmbH. M. Hanna: None.

Funding

Diabetes Treatment Centers International
1079-P: Engineered Silica Particles Reduce HbA1c in Persons with Prediabetes
Authors: JOHNSTON ERIC V. , IQBAL MUHAMMAD N. , ROBERT-NICOUD GHISLAINE , LINDGREN MARIA Z. , WAARA ERIK R. , UDDEN ANNA , PIETILÄINEN KIRSI , BENGTSSON TORE
Published: June 2020

The standard of care for persons with prediabetes is lifestyle intervention, however in real-life less than 20% of people are able to adopt a healthier living. There is an unmet need for safe and effective treatment options for persons with prediabetes.

We have developed unique mesoporous silica particles (MSP) with tailored characteristics (SiPore15) that sequesters pancreatic amylase and lipase locally in the gut, resulting in decreased digestion of carbohydrates and fats. A first-in-man safety-trial in healthy and obese volunteers (clinicaltrials.org ID no. NCT03667430) showed a good safety profile for SiPore15 and an exploratory analysis revealed a reduction in HbA1c.

In the present efficacy-trial 43 subjects were enrolled, 33 persons with prediabetes (HbA1c 39 mmol/mol or above) and 10 persons newly diagnosed with diabetes type 2. All subjects were treated with SiPore15, 3 gm-TID with meals, for 12 weeks (clinicaltrials.org ID no. NCT03823027). A manufacturing error resulted in 26 subjects receiving the correct MSP for half of the treatment period and 9 subjects for the full period. An exploratory analysis revealed that the long-term blood glucose marker HbA1c was statistically reduced after 6 weeks (1 mmol/mol) and further reduced at 12 weeks (1.4 mmol/mol). Among the subjects who received the correct material, 0 subjects had a serious AE and the AEs reported were mild to moderate, indicating a favorable safety profile. The magnitude in HbA1c reduction was comparable to what has been observed with metformin in prediabetic clinical trials, translating to significant risk reduction in developing diabetes type 2.

SiPore15’s novel ingestible device concept, combined with the preliminary demonstration of efficacy and safety indicates that SiPore15 is an exciting approach for prevention and treatment of diabetes and merits further clinical investigation.

Disclosure

E.V. Johnston: None. M.N. Iqbal: None. G. Robert-Nicoud: Employee; Self; Sigrid Therapeutics. M.Z. Lindgren: None. E.R. Waara: None. A. Udden: None. K. Pietiläinen: None. T. Bengtsson: Board Member; Self; Atrogi, Sigrid Therapeutics.
1084-P: Postmarketing Real-World Effectiveness of Hydroxychloroquine (HCQ) in Treatment of Patients with T2D
Authors: PAREEK ANIL , DHARMADHIKARI SHRUTI , MEHTA RAVI T. , NAIDU KUMAR B.
Published: June 2020

Real-world data is important in providing evidence of treatment effectiveness in clinical practice. This real-world analysis included 1523 patients of T2D uncontrolled (A1c≥7%) on metformin-SU combination to additionally receive HCQ 400 mg/day for 24 weeks. Mean age of patients was 51.3 years and 53.25% were males. Of the 1523 enrolled patients, 1297 patients who completed 24 weeks of therapy were analyzed for effectiveness. Treatment with HCQ resulted in significant reduction in A1c (change from baseline at Week 12 and 24 was 1.10% and -1.41%, respectively; p<0.0001) and other glycemic and lipid parameters. At Week 24, 81% and 62% of patients reported a fall of ≥0.5% and ≥1% in A1c, respectively. Target A1c of <7% and <8% was achieved by 34% and 73% of patients, respectively at Week 24. Overall, HCQ was well tolerated. Majority of the 148 AEs were GI related (25%), mild in intensity (85%) and unlikely related (66%) to HCQ. Ten patients reported hypoglycemia; all were ADA Level 1. Nine NPDR cases were reported, all were mild and 8 were unlikely related to HCQ. Of 8 SAEs reported, 7 were not related to HCQ. Causality was assessed by investigator. Low-grade inflammation is a common feature in T2D. HCQ, an anti-inflammatory agent, significantly improved glycemic profile (comparable to other OHAs) with added benefits on lipids. Thus, HCQ could be an effective and well-tolerated therapeutic option for treatment of T2D.

Disclosure

A. Pareek: Employee; Self; Ipca Laboratories. S. Dharmadhikari: Employee; Self; Ipca Laboratories. R.T. Mehta: Employee; Self; Ipca Laboratories. K.B. Naidu: Employee; Self; Ipca Laboratories.

Funding

Ipca Laboratories Limited
1087-P: Hospital and Emergency Department Utilization in U.S. Veterans with Hyperkalemia
Authors: KOVESDY CSABA P. , GOSMANOVA ELVIRA , WOODS STEVEN D. , FOGLI JEANENE J. , ROWAN CHRISTOPHER G. , HANSEN JARED L. , SAUER BRIAN C.
Published: June 2020

Background: Patiromer (PAT) is a sodium-free, non-absorbed potassium (K+) binder (KB) approved for the treatment of hyperkalemia (HK). HK is common in older pts with cardiorenal comorbidities and often leads to increased Healthcare Resource Utilization (HRU). Here we aim to describe electrolyte-related HRU in Veterans with HK who initiated PAT or discontinued RAAS inhibitor (RAASi DC) therapy and were not receiving a KB (1/1/2016−8/30/2018).

Methods: Using retrospective, observational data, pts utilizing the hospital or ED during the 6 months (mos) prior to the index date were assessed at 1, 3, and 6 mos post-index. The index date was the date of PAT initiation or the date of RAASi DC in pts not receiving a KB (RAASi DC/no KB). All pts had a baseline serum K+ ≥5.1mEq/L and HF, DM, or non-dialysis CKD. Pts with continuous exposure (CE) to PAT and those who did not restart RAASi were analyzed.

Results: 288 and 26,543 pts were included in the PAT and RAASi DC/no KB groups, respectively. Following CE to PAT at 1, 3, and 6 mos post-index, no electrolyte related ED or hospital utilization was observed. In the RAASi DC group, 2-5% of pts reutilized the ED or hospital within 6 mos (Figure).

Conclusion: Of the pts who experienced an electrolyte-related hospitalization or ED visit within the 6 mos prior to PAT dispensing, no pts reutilized these services in the following 6 mos. Given the limited number of PAT users, additional investigation is warranted.

Disclosure

C.P. Kovesdy: Consultant; Self; Amgen, AstraZeneca, Bayer AG, Cara Therapeutics, Reata, Takeda Pharmaceutical Company Limited, Tricida. E. Gosmanova: None. S.D. Woods: Employee; Self; Relypsa, Inc. Stock/Shareholder; Self; Vifor Pharma Group. J.J. Fogli: Employee; Self; Relypsa, Inc. Stock/Shareholder; Self; Vifor Pharma Group. C.G. Rowan: Consultant; Self; AbbVie Inc., Covidia, Halozyme, Keryx, Relypsa, Inc., Vifor Pharma Group. Other Relationship; Self; COHRDATA. J.L. Hansen: Research Support; Self; COHRDATA. B.C. Sauer: Research Support; Self; COHRDATA.

Funding

Relypsa, Inc.
1092-P: Treatment Changes Post–Second-Line Medication Initiation, a Real-World Retrospective Cohort Study
Authors: PASRICHA SANYA , CHERUPALLY MANISHA , KOEP ELEENA , ACKERMANN RONALD T. , AIKMAN CASSANDRA , COOPER ANDREW J. , O’BRIEN MATTHEW , WALLIA AMISHA , LISS DAVID T. , PARKER EMILY D.
Published: June 2020

Objective: This study used real-world data to describe treatment patterns in second-line antidiabetic medication (ADM) regimen (Sulfonylureas, DPP-4 inhibitors, GLP-1 RAs, SGLT2 inhibitors, or TZDs) over a fixed 12 month follow-up period.

Methods: Medical and pharmacy claims were used to identify adult commercial and Medicare Advantage Part D health plan enrollees with T2DM initiating second-line ADMs between 2013-2016. The primary outcome was the first pharmacy claim indicating a change in regimen: switch to a new ADM class; treatment discontinuation (gap ≥30 days); or intensification (≥doubling of dose, adding a new ADM class, or switching to/adding insulin). Patients were classified as adherent if no change was observed.

Results: Of 73,290 study subjects with 2LADM, 53% were Sulfonylurea, 26% were DPP-4, 7% were GLP-1 RA, 9% SGLT2, and 5% TZD. Changes in treatment within 1 year were observed for over 70% of all patients (Table). There was little switching, about 50% discontinued their 2LADM with the highest rate of discontinuation among those receiving GLP-1 RAs and lowest among those receiving TZDs. About 20% of patients intensified medication regimen.

Discussion: The very high rate of observed treatment changes, in particular discontinuation, may indicate that patients face multiple barriers to treatment adherence. Real-world studies can inform patient-centered treatment selection.

Disclosure

S. Pasricha: None. M. Cherupally: None. E. Koep: Employee; Self; UnitedHealth Group. R.T. Ackermann: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, UnitedHealth Group. C. Aikman: None. A.J. Cooper: None. M. O’Brien: Research Support; Self; UnitedHealth Group. A. Wallia: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc., UnitedHealth Group. D.T. Liss: None. E.D. Parker: None.

Funding

UnitedHealth Services (SP0036847)