bluuebunny/crossref_metadata_2025_split huggingface dataset:
150-LB: Software Modeling of Dorzagliatin for Artificial Intelligence Management of Type 2 Diabetes
Authors: ALLEN SYDNEY , BENNETT BRITTANY , EILERMAN BRADLEY , TESTA LEONARD J. 
Published: June 2019

Introduction: The use of Artificial Intelligence to make clinical decisions is a strategy of increasing interest to improve the cost and effectiveness of diabetes management. GlucosePATH is software which uses massively parallel processing to sort through millions of possible combinations to medications specified to patient specific variables. As new medicine classes become available, the baseline characteristic of the medication must be defined. As dorzagliatin enters phase 3 trials, modeling the pharmacologic properties of the molecule will represent the first example of the glucokinase activator class.
Methods: The first step in drug modeling defines the base characteristics of the molecule. Dorzagliatin is modeled mechanistically as a glucokinase activator which acts as a secretagog. This preventins mechanistic overlap and allows for modification of efficacy based on projected beta cell reserve. A dose of 75 mg daily was selected as it was the most efficacious dose in the phase 3 monotherapy trial.
The next step in drug modeling is defining the clinical characteristics of the drug. At the dose defined, dorzagliatin is modeled with a HgA1c reduction of 1.2. This is modeled on the phase 3 monotherapy Weight change and hypoglycemia were modeled as neutral. The only adverse event of significance which was modeled was a mild penalty for fatty infiltration of the liver. All of these characteristics were drawn from the composites of phases 1 through 3 available on literature review.
Results: Medications available in the market are described in terms of cost and insurance coverage. For the purpose of modeling dorzagilatin in a population, a cost of $300 monthly was entered as the low end of a new to market diabetes medication. Modeled on a population of 366 patients in the GlucosePATH database, the medicine was recommended in 4 patients. No significance difference between control and study population in mean HgA1c (both 7.3), cost ($629.99 vs. $629.79), or composite score out of 100 (82.65 vs. 82.64).

Disclosure
S. Allen: None. B. Bennett: None. B. Eilerman: Advisory Panel; Self; Dexcom, Inc., Medtronic. Speaker’s Bureau; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Corcept Therapeutics, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc. Stock/Shareholder; Self; PATH Decision Support Software LLC. L.J. Testa: Stock/Shareholder; Self; PATH Decision Support Software LLC.
1504-P: Low Normal Free Thyroxine Levels Are Associated with Prediabetes in Euthyroid Subjects
Authors: KIM SUNG-WOO , JEON EONJU , LEE JI-HYUN , SHON HO-SANG , PARK KEUN-GYU 
Published: June 2019

Background: Although the association between low-normal thyroid function and metabolic syndrome was well documented, little is known about the effect of thyroid hormone within the physiological range on carbohydrate metabolism. This study aimed to determine whether free thyroxine (FT4) influences serum glucose concentration and the prevalence of prediabetes in euthyroid subjects.
Methods: This was a cross-sectional survey derived from the Korea National Health and Nutrition Examination Survey, conducted between 2013 and 2015. We studied 4,767 participants of &gt;20 years of age who were euthyroid and nondiabetic.
Results: Prediabetic participants had lower FT4 concentrations than those without prediabetes, but thyrotropin concentrations were similar. We stratified the population into tertiles according to FT4 concentration. After adjusting for multiple confounding factors, HbA1c levels significantly decreased with FT4 tertile, whereas FBG was not associated with FT4 both in men and in women. The prevalence of prediabetes was significantly higher in T1 than in T3.
Conclusion: Subjects with low-normal serum FT4 had high HbA1c and were more likely to have the prediabetes. These results suggest that low FT4 concentration is a risk factor for prediabetes, even though thyroid function is within the normal range. Thus, screening for prediabetes in subjects with low-normal FT4 should involve the measurement of HbA1c.

Disclosure
S. Kim: None. E. Jeon: None. J. Lee: None. H. Shon: None. K. Park: None.
1507-P: Baseline Metabolite Profiles of Incident Type 2 Diabetes and Heterogeneity of Treatment Effect in the Diabetes Prevention Program (DPP)
Authors: CHEN ZSU-ZSU , LIU JINXI , MORNINGSTAR JORDAN , HECKMAN-STODDARD BRANDY M. , LEE CHRISTINE , DAGOGO-JACK SAMUEL , FERGUSON JANE F. , HAMMAN RICHARD F. , KNOWLER WILLIAM C. , MATHER KIEREN J. , PERREAULT LEIGH , FLOREZ JOSE C. , WANG THOMAS , CLISH CLARY B. , TEMPROSA MARINELLA , GERSZTEN ROBERT E. ,   DPP RESEARCH GROUP
Published: June 2019

Novel biomarkers of T2D and preventative treatment response could predict outcomes in high-risk individuals. We used Cox models to assess the association of 334 profiled metabolites in 2,019 baseline plasma samples with incident T2D after 3.2 years in a DPP substudy. We further assessed if associations out of the 334 metabolites differed by treatment (lifestyle (ILS), metformin (MET), and placebo (PLA)) and if, after stratification into concentration quartiles, the metabolite levels modified treatment effect in pair-wise treatment comparisons. We found 69 metabolites associated with incident T2D in the entire cohort (FDR-q&lt;0.05) including the novel association of cytosine, which had the lowest risk (HR of 0.77 per 1 SD, 95% CI 0.67-0.89, FDR-q 0.008). The associations of 35 metabolites differed across the three treatments (p for homogeneity &lt;0.05) and the quartiles of several of these metabolites modified treatment effects in pair-wise comparisons (Table 1). For example, individuals in higher quartiles of specific phospholipids had decreased T2D risk with ILS compared to PLA and MET, but not with MET when compared to PLA.
In conclusion, we identified baseline metabolites associated with T2D risk prediction and efficacy of prevention interventions. This motivates further studies to validate interactions between biomarkers and diabetes prevention strategies.

Disclosure
Z. Chen: None. J. Liu: None. J. Morningstar: None. B.M. Heckman-Stoddard: None. C. Lee: None. S. Dagogo-Jack: Board Member; Self; Jana Care Inc. Consultant; Self; Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi-Aventis. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Stock/Shareholder; Self; Dance Biopharm Holdings Inc. J.F. Ferguson: None. R.F. Hamman: None. W.C. Knowler: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. L. Perreault: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. J.C. Florez: None. T. Wang: None. C.B. Clish: None. M. Temprosa: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Other Relationship; Self; Merck KGaA. R.E. Gerszten: None. DPP Research Group: None.
1508-P: Trends in Treatment Initiation and Management of Type 2 Diabetes Mellitus: Analysis of 20 Years of Real-World Data
Authors: COHEN CHELI MELZER , SHALEV VARDA , CHODICK GABRIEL 
Published: June 2019

In the past 20 years, significant updates in diabetes management guidelines were performed. In this study we aimed to evaluate long-term trends in the treatment initiation and management of type 2 diabetes mellitus (T2DM). In this retrospective study, a computerized clinical database from Maccabi Healthcare Services, a 2.3 million member in Israel, was used. Included were adults T2DM patients who initiated antihyperglycemic medication between 1999 and 2018 (N=153,168). Fasting plasma glucose (FPG) and HbA1c levels were evaluated at treatment initiation and after 6, 12 and 24 months. In addition, first and second line treatment regimen were examined. Over twenty years of observation, FPG at therapy initiation decreased from 167.3±68.7 mg/dl (mean±SD) in 1999-2002 to 136.1±53.6 mg/dl in 2015-2018 (Figure). The respective decrement in HbA1c was from 7.8±2.1% to 6.8±1.8%. There was a tremendous difference in treatment regimen: In 1999-2002, metformin and sulfonylurea were the leading first line medications (63.5% and 37.0%, respectively) while in 2015-2018, the leading first line medications were metformin and DPP-4i (94.2% and 9.9% of patients, respectively). Study result indicate a clear trend of initiating antidiabetic treatment at lower FPG and HbA1c levels, and the fast disappearance of sulfonylurea from the clinical practice.

Disclosure
C. Melzer Cohen: None. V. Shalev: None. G. Chodick: None.
151-LB: High Risk of Krebs Von Den Lungen-6 (kL-6) Elevation when Dipeptidyl Peptidase-4 Inhibitors and Amiodarone Are Prescribed Simultaneously
Authors: OKADA JUNICHI , OKADA SHUICHI , YAMADA MASANOBU 
Published: June 2019

Amiodarone-caused pulmonary toxicity including interstitial lung diseases is a well-known side effect and its incidence was reported as approximately 5.7%. Also, dipeptidyl peptidase-4 inhibitors (DPP-4is) recently attracted physicians’ attention as a cause of drug-induced interstitial lung diseases. On the other hand, there must be patients who are prescribed both DPP-4is and amiodarone simultaneously. In this case, they might have an increased risk for interstitial lung disease. Given the lack of clarity regarding the risk for drug induced interstitial lung disease under the combination therapy of DPP-4is and amiodarone, we estimated serum Krebs von den Lungen-6 (KL-6) levels in patients who were prescribed amiodarone without DPP-4is, DPP-4is without amiodarone, and both DPP-4is and amiodarone simultaneously. 47 patients were prescribed amiodarone without DPP-4is (amiodarone group). 44 patients were prescribed DPP-4is without amiodarone (DPP-4is group). 15 patients were prescribed both amiodarone and DPP-4is (DPP-4is and amiodarone group). Elevation in KL-6 levels beyond the upper limit of normal range (reference range; &lt;500 U/mL) was observed in 3 patients in the amiodarone group, 3 patients in DPP-4is group, and 3 patients in DPP-4is and amiodarone group respectively. Thus, the frequency of KL-6 levels beyond the upper limit of normal range in amiodarone group was 6.4%, 6.8% in DPP-4is group, but 20% in DPP-4is and amiodarone group respectively. We confirmed that KL-6 levels were in the normal range before initiating DPP-4is and/or amiodarone administration. Moreover, KL-6 levels were transiently elevated and normalized within one year after DPP-4is and/or amiodarone termination. All of participated patients showed normal study on chest X-ray examination through the observation period. Thus, when physicians prescribe DPP-4is, physicians should probably concern whether patients are prescribed amiodarone.

Disclosure
J. Okada: None. S. Okada: None. M. Yamada: None.
1516-P: A Comparison of the Contributions of Impaired Insulin Secretion and Insulin Resistance to the Development of Type 2 Diabetes in a Japanese Community: The Hisayama Study
Authors: YOSHINARI MASAHITO , HIRAKAWA YOICHIRO , HATA JUN , HIGASHIOKA MAYU , HONDA TAKANORI , YOSHIDA DAIGO , MUKAI NAOKO , NAKAMURA UDAI , KITAZONO TAKANARI , NINOMIYA TOSHIHARU 
Published: June 2019

Objective: Impaired insulin secretion (IIS) and insulin resistance (IR) are the two main mechanisms for type 2 diabetes (T2D), but IIS has been reported to contribute to incident T2D more than IR in Asian populations. However, we assumed that the impact of IR on the incident T2D was being greater in the recent Japanese population, because the burden of obesity increased. Herein, we addressed the magnitude of the contribution of IIS and IR to the development of T2D in a Japanese community.
Methods: In 2007, a total of 2,108 residents aged 40-79 years (participation rate 77.1%) without diabetes at baseline underwent health examination including 75g OGTT, insulinogenic index (IGI), and HOMA-IR. Subjects were divided into 4 groups according to the presence or absence of IIS (IGI ≤ 0.4) and IR (1.6 ≤ HOMA-IR) and were followed-up prospectively for a median of 6.9 years. A Cox’s proportional hazards model was used to estimate the hazard ratios and 95% confidential intervals (CIs) for incident T2D with adjustment for confounders. The population attributable fraction (PAF) for the development of diabetes due to IS, IR and their combination were calculated.
Result: At baseline, the proportions of subjects with neither of IIS nor IR, isolated IIS, isolated IR, and both IIS and IR were 45.5%, 21.0%, 28.7%, and 4.8%, respectively. During follow-up period, 273 subjects developed T2D. The risk of incident T2D was 5.3 (95% CI 3.6-7.9) times higher in subjects with isolated IIS, 4.1 (2.8-6.2) times higher in subjects with isolated IR, and 13.5 (8.5-21.5) times higher in subjects with both IIS and IR than subjects with neither of IIS nor IR. The PAFs on the excess risk of T2D among subjects with isolated IIS, isolated IR and both IIS and IR were 25.8%, 29.1%, and 15.9%, respectively.
Conclusion: Our finding suggests that IIS and IR contributed equally to the development of T2D in the recent general Japanese population.

Disclosure
M. Yoshinari: None. Y. Hirakawa: None. J. Hata: None. M. Higashioka: None. T. Honda: None. D. Yoshida: None. N. Mukai: None. U. Nakamura: None. T. Kitazono: None. T. Ninomiya: Research Support; Self; Asahi Kasei Corporation, Denka Company Limited, DeSC Healthcare, Inc, Mochida Pharmaceutical Co., Ltd., Suntory Beverage & Food Limited, Sysmex Corporation.
1520-P: All-Cause Mortality in Chinese Adults with Diabetes in Association with New Indicator Generated by the 2-h Plasma Glucose Level Subtract Fasting Plasma Glucose Level
Authors: ZHAO ZHENPING , ZHANG MEI , QI JINLEI , ZHANG XIAO , LIU YUNNING , WANG LIJUN , ZHOU MAIGENG , WANG LIMIN ,   CCDRF WORKING GROUP
Published: June 2019

Background and Aims: Reducing the increased risk of death among diabetes patients is highly valued in regard to quality care of diabetes. We aim to identify practical indicator to estimate the hazard of all-cause mortality for Chinese population with diabetes.
Method: The Chinese Chronic Disease and Risk Factor Surveillance 2010 (CCDRF) selected a national representative sample of Chinese population aged ≥18 years using a multistage sampling design. CCDRF included a mortality follow-up by December 2018. A retrospective cohort of 10,388 Chinese subjects who diagnosed as diabetes was selected. Indicator ‘2hPG-FBG’ was created using 2-h Plasma Glucose Level (2hPG) of the OGTT subtract fasting plasma glucose (FBG) level for each individual. Subjects were classified into four groups (2hPG-FBG &lt;=0, 0-4, 4-10, and &gt;10 mmol/l). The Kaplan-Meier curve with log rank test and multivariate Cox proportional regression were employed to assess the group differences.
Results: A total of 10,388 participants were included, with 53.8% male and mean age 52.2 years. During the 8-year follow-up, 292 subject dead. Kaplan-Meier curves comparing the four groups showed significant differences (p &lt;.01). After adjusting for age, sex, smoking status, alcohol drinking and FBG, compared to group whose 2hPG≤ FBG, the hazard of the group (2hPG-FBG 0-4mmol/l) is similar but slight elevated (adjusted hazard ratio [AHR]=1.5; 95% CI, 0.9-2.4; p=0.11); the hazards are significantly higher for group (2hPG-FBG 4-10 mmol/l) (AHR= 2.0; 95% CI, 1.3-3.1; p&lt;0.01) and for group (2hPG-FBG &gt;10 mmol/l)(AHR=2.6; 95% CI, 1.6-4.3; p &lt;0.01).
Conclusions: The hazard of all-cause mortality doubled among Chinese population with diabetes whose 2hPG-FBG higher than 4 mmol/l, compared to those whose 2hPG≤ FBG.
Public health significant: Personalized target of 2hPG may be set based on patients’ FBG to reduce the increased risk of death among adults with diabetes.

Disclosure
Z. Zhao: None. M. Zhang: None. J. Qi: None. X. Zhang: None. Y. Liu: None. L. Wang: None. M. Zhou: None. L. Wang: None.
1529-P: Higher Rates of Disease Progression among Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH) Patients with Advanced Fibrosis (AF) and Diabetes Mellitus (DM)
Authors: YOUNOSSI ZOBAIR , KACHRU NANDITA , SHREAY SANATAN , LOOMBA ROHIT 
Published: June 2019

Objective: Prevalence of NAFLD/NASH is high in DM patients. Presence of DM has been suggested to potentially accelerate liver disease progression among these patients. The study aimed to assess the adverse events among NAFLD/NASH patients with AF (F3 and compensated cirrhosis/F4) stratified by DM status.
Methods: Adult NAFLD/NASH-AF patients with available lab results were identified from Optum Research claims data (2008-2016), to calculate their Fibrosis-4 (FIB-4) scores. Using the score, patients were categorized as F3 or F4 (first date of cut-off score as index date), and then stratified by DM. Events were measured as first date of FIB-4 score/diagnosis consistent with F4, or presence of decompensated cirrhosis (DCC) after initial diagnosis of NAFLD/NASH with F3 or F4.
Results: Among 91,122 NAFLD/NASH patients with FIB-4 scores, 2,482 (2.7%) had F3 and 939 (1.0%) had F4 stage of fibrosis. 36% of F3 and 35% of F4 patients had DM. Overall, incident event rates for patients with NAFLD/NASH - F3 and F4 with DM were higher than those without DM (Figure). Incident DCC rates were also higher in NAFLD/NASH with DM [F3 (33.9%) (p=0.19) and F4 (70.1%) (p=0.04)] than without DM.
Conclusions: NAFLD/NASH patients with AF and DM have higher rates of adverse events. These patients must be identified early for close monitoring and management.

Disclosure
Z. Younossi: Consultant; Self; Gilead Sciences, Inc. N. Kachru: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. S. Shreay: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. R. Loomba: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc.
1533-P: Detecting Diabetes in Africans Is Improved by Both Modifying the A1C Threshold and Adding Glycated Albumin
Authors: MUGENI REGINE , BRIKER SARA M. , ADUWO JESSICA Y. , DUBOSE CHRISTOPHER , SUMNER ANNE E. , HORLYCK-ROMANOVSKY MARGRETHE F. 
Published: June 2019

A1C at the standard threshold of 6.5% has been a poor predictor of diabetes (DM) in Africans. Reasons for the poor performance of A1C are myriad and include hemoglobinopathies and anemia. To begin to address challenges with A1C as a diagnostic test for Africans, there needs to be a determination that the threshold for A1C of 6.5% is appropriate. In addition, there could be value in determining if glycated albumin (GA), a non-fasting marker of glycemia not affected by hemoglobinopathies and anemia, would improve detection of DM. Therefore, we tested in Africans (a) the ability of A1C and GA independently and combined to predict DM and (b) the optimal cut-points for A1C and GA. OGTT were performed in 366 African-born blacks (age 38±10 (mean± SD); BMI 27.5 ±4.4 kg/m2) who self-identified as healthy and currently living in the Washington, DC area. Diagnosis of DM was based on glucose criteria for the OGTT. Ability of A1C and GA to predict DM was estimated by area under the receiver operating characteristic curve (AROC). Youden index established optimal cut-points for A1C and GA. Diabetes was newly diagnosed in 6% (23/366). For the prediction of DM by A1C the AROC was 0.78 (95% CI 0.68-0.88), and the optimal cut point was ≥5.8%. For the prediction of DM by GA the AROC was 0.73 (95% CI 0.61-0.85), and the optimal cut point was ≥14.05%. At these cut-points, DM was identified by A1C in 61% (14/23) (sensitivity 61%, specificity of 82%), and by GA in 65% (15/23) (sensitivity 65%, specificity 72%). The combination of A1C and GA identified DM in 83% (19/23) (sensitivity 83%, specificity 60%). Overall, the combination of A1C ≥5.8% and GA ≥14.05% markedly improved the detection of undiagnosed diabetes in Africans. Combining two non-fasting markers of glycemia at African-specific thresholds may be an important innovation in healthcare delivery.

Disclosure
R. Mugeni: None. S.M. Briker: None. J.Y. Aduwo: None. C. DuBose: None. A.E. Sumner: None. M.F. Horlyck-Romanovsky: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Minority Health and Health Disparities
1538-P: Quality of Life Decrements for Complications of Type 2 Diabetes
Authors: NEUWAHL SIMON , HOERGER THOMAS J. 
Published: June 2019

To estimate the quality of life decrement associated with complications of type 2 diabetes, we combined public-use data on type 2 diabetes patients from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, its follow-on ACCORDION study, and the Action for Health in Diabetes (Look AHEAD) trial. The ACCORD trial administered the Health Utilities Index Mark 3 (HUI-3) instrument periodically, while the Look AHEAD trial administered the HUI-3 every 6 months. Measurements less than 1 year after a complication were associated with the complication event, and measurements more than 1 year after a complication were associated with a history of the complication. We used a fixed-effects model and included controls for BMI, duration of diabetes, and smoking. In total, there were 99,594 person-visit observations in our estimation sample, representing 14,899 unique persons with an average follow-up of 7.5 years. All complication events and complication history indicators negatively affected quality of life. The largest effects were observed for stroke (event year: 0.086; history: 0.056), congestive heart failure (event year: 0.043; history: 0.054), eGFR&lt;30 mg/g (event year: 0.059), and myocardial infarction (MI) (event year: 0.024) (p&lt;0.05). More modest effects were observed for revascularization (event year: 0.014), and eGFR&lt;60 mg/g (event year: 0.008; history: 0.010) (p&lt;0.05). Decrements for angina, history of angina, history of MI, history of revascularization, and history of eGFR&lt;30 mg/g were not statistically significant. This combined analysis of the ACCORD, ACCORDION, and Look AHEAD trials illustrates the negative health impacts of diabetes complications in the year they occur and in subsequent years. Some complications had a large and persistent negative impact on quality of life, such as stroke and eGFR&lt;30 mg/g. In some cases, the quality of life decrement was larger in subsequent years (CHF and angina), possibly because of the chronic and progressive nature of these complications.

Disclosure
S. Neuwahl: None. T.J. Hoerger: Research Support; Self; Sanofi.

Funding
Centers for Disease Control and Prevention