Kyowa Hakko Research Articles

Hiroshi Shiku, MD, PhD: In Memoriam (1943–2022)

Hiroshi Shiku, MD, PhD: In Memoriam (1943–2022)

Itch-free state in patients with atopic dermatitis treated with ruxolitinib cream: A pooled analysis from two randomized phase 3 studies

Itch-free state in patients with atopic dermatitis treated with ruxolitinib cream: A pooled analysis from two randomized phase 3 studies

Monkeypox: Cutaneous clues to clinical diagnosis

Monkeypox: Cutaneous clues to clinical diagnosis

A2A Adenosine Receptor Antagonists and their Potential in Neurological Disorders.

Endogenous nucleoside adenosine modulates a number of physiological effects through interaction with P1 purinergic receptors. All of them are G protein-coupled receptors, and, to date, four subtypes have been characterized and named A1, A2A, A2B, and A3. In recent years, adenosine receptors, particularly the A2A subtype, have become attractive targets for the treatment of several neurodegenerative disorders, known to involve neuroinflammation, like Parkinson's and Alzheimer's diseases, multiple sclerosis, and neuropsychiatric conditions. In fact, it has been demonstrated that inhibition of A2A adenosine receptors exerts neuroprotective effects counteracting neuroinflammatory processes and astroglial and microglial activation. The A2A adenosine receptor antagonist istradefylline, developed by Kyowa Hakko Kirin Inc., was approved in Japan as adjunctive therapy for the treatment of Parkinson's disease, and very recently, it was also approved by the US Food and Drug Administration. These findings pave the way for new therapeutic opportunities, so, in this review, a summary of the most relevant and promising A2A adenosine receptor antagonists will be presented along with their preclinical and clinical studies in neuroinflammation related diseases.

6-OR: Vascular Endothelial ROCK2 Deficiency Promotes Browning and Burning of White Adipose Tissue

The accumulation of visceral fat is associated with multiple coronary risk factors such as glucose intolerance, dyslipidemia, and hypertension. We have previously demonstrated that Rho/Rho-associated protein kinase (ROCK) signaling is activated in animal models of diabetes and is involved in the pathogenesis of vascular complications. Specifically, ROCK is implicated in the molecular basis of inflammation- and ischemia-induced tissue damage through the actions on NF-κB dynamics. These findings support the hypothesis that ROCK signaling could be one of the important therapeutic targets for preventing cardiorenal events. However, isoform-specific roles of ROCKs have not been clarified yet. In this study, we aimed to determine the tissue-intrinsic roles of ROCK2 in the setting of obesity. To this end, we generated vascular endothelium-specific ROCK2 knockout mice (ER2KO) by crossing ROCK2 floxed mice with VE-Cadherin-Cre mice. ER2KO mice were fertile and had the same lifespan as wild type mice. Notably, ER2KO gained weight at a slower rate than wild type mice under high-fat diet feeding. Fat composition, as assessed by magnetic resonance imaging, was significantly lower in ER2KO, even though ER2KO displayed increased food intake. The gene expression analysis revealed increased expression of PPARα, a browning-inducing factor, and its downstream components, CIDEA, IL-4, and IL-10, in white adipose tissue obtained from ER2KO mice. ER2KO mice also showed an elevation in body temperature after fasting, suggesting that endothelial ROCK2 may negatively regulate fat browning. In summary, vascular endothelial ROCK2 negatively regulates fat accumulation through the mechanism of browning inhibition. Disclosure Y. Takeda: None. K. Matoba: None. R. Ukichi: None. Y. Nagai: None. Y. Kanazawa: None. K. Utsunomiya: None. R. Nishimura: Speaker's Bureau; Abbott Diabetes, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Terumo Corporation. Funding a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science, the MSD Life Science Foundation, the Takeda Science Foundation, the Suzuken Memorial Foundation, Sanofi KK, Tanabe Pharma, and Takeda Pharmaceutical., Kazunori Utsunomiya has received research support from Terumo, Novo Nordisk Pharma, Taisho Pharmaceutical, Böehringer Ingelheim, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, and OPharmaceutical as, Rimei Nishimura has received speaker honoraria from Astellas Pharma, Nippon Boehringer Ingelheim, Eli Lilly Japan KK, Kissei Pharmaceutical, Medtronic Japan, MSD, Novartis Pharma KK, Novo Nordisk Phar.

1439-P: Association between Sleep Duration, Bedtime, and Hyperglycemia or Overweight/Obesity among Japanese Children

In adults, short sleep duration and late bedtime were associated with hyperglycemia and obesity, but these relationships in children are little known. We evaluated the association of bedtime and sleep duration with overweight/obesity or hyperglycemia in children by sex, considering the effects of diet, physical activity, and screen time. A cross-sectional study was conducted for 1139 Japanese children (553 boys) aged 10-y. Overweight was as defined by the International Obesity Task Force. Cutoff value for hyperglycemia was HbA1c ≥5.6%. Variables associated with hyperglycemia or overweight were based on logistic regression analysis. Multivariate logistic regression analysis showed that compared with an early bedtime (˜21:59) and long sleep duration (weekdays ≥8.67 h, weekends ≥9 h) , short sleep duration (weekdays <8.67 h, weekends <9 h) was associated with overweight in boys but not late bedtimes (22:00˜) . The significant association seen disappeared in girls when adjusted for screen time. For hyperglycemia, in both sexes wake time and sleep duration on weekends were significant in univariate analysis, but not in multivariate analysis adjusted for diet and physical activity. In Japanese boys, short sleep duration was significantly associated with overweight. Sleep ≥8.67 on weekdays and ≥9 h on weekends may be essential to prevent overweight. Table. Adjusted odds ratios for overweight Disclosure H. Shiozaki: None. K. Fujihara: None. M.H. Yamada: None. T. Osawa: None. M. Kitazawa: None. M. Yamamoto: None. T. Sato: None. T. Yamada: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Patient Centered Outcomes Research Institute

529-P: Impact of Medication Adherence (MA) to Oral Glycemic Agents (OHAs) on Initiation of Dialysis in Patients with Moderately Impaired Renal Function

Although we showed a significant association of poor adherence to OHAs with start of dialysis, this relationship according to the estimated glomerular filtration rate (eGFR) was not clarified. Patients with eGFR <60 mL/min/1.73m2 are at high risk for dialysis. To identify the impact of MA by eGFR categories, we analyzed a nationwide claims-based database of 7,862 people with DM and without prior dialysis from 2008-16 aged 18-72 y with available records for OHAs for at least 1 year (mean age 54 y, HbA1c 7.2%) . MA was evaluated by the proportion of days covered (PDC) , and PDC <80% indicated poor adherence. Other factors were also analyzed (Table) . Median follow-up was 5.1 years. Incidence of dialysis per 1000 person-years was 10.7 in the eGFR<60 group and 0.62 in the eGFR ≥60 group. By Cox regression analysis (Table) an increased risk of dialysis was associated with poor MA (HR 2.98[95% CI 1.69-5.23]) , high systolic blood pressure (SBP) (1.27[1.11-1.44]) ], or current smoking (1.98[1.11-3.51]) in the eGFR<60 group and with high SBP (1.41[1.10-1.80]) and high HbA1c (1.45[1.13-1.87]) in the eGFR ≥60 group. Other factors in addition to MA might lead to dialysis, but poor MA was a strong risk factor for dialysis in this short observation period, especially in patients with impaired renal function. Clinicians should pay special attention to MA in these patients to prevent dialysis. Disclosure Y.Yaguchi: None. H.Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. K.Fujihara: None. M.H.Yamada: None. Y.Matsubayashi: None. T.Yamada: None. M.Iwanaga: None. M.Kitazawa: None. M.Yamamoto: None. S.Kodama: None.

1159-P: Associations of HOMA2 with Clinical Outcomes in Type 2 Diabetes

Background: In patients with type 2 diabetes (T2D) negative for glutamic acid decarboxylase antibodies (GADA-) , the prognostic significance of insulin deficiency (ID) and insulin resistance (IR) remained uncertain. Methods: In 4590 patients with T2D consecutively enrolled to the Hong Kong Diabetes Register in 1995-2012 followed up till 2019, we measured GADA and fasting C peptide (CP) in stored samples at baseline. Using the updated homeostasis model assessment (HOMA2) , we defined below-median HOMA2-%B as ID and above-median HOMA2-IR as IR. We defined incident insulin use as the first insulin prescription of at least 28 days and used ICD-9 codes to define cardiovascular-renal diseases, severe hypoglycemia event (SHE) and all-cause mortality. We used Cox regression model to examine the associations between HOMA2 and clinical outcomes. Results: Amongst 3198 GADA- patients with available HOMA2 data, the median of HOMA2-%B was 52.4 (33.1, 60.9) and that of HOMA2-IR was 1.6 (1.1, 1.8) . The ID group was more likely to initiate insulin treatment [adjusted HR (95%CI) 1.26 (1.11-1.42) ] but less likely to progress to chronic kidney disease (CKD) , end-stage kidney disease (ESKD) and all-cause mortality than the non-ID group. The IR group had increased risks of incident insulin therapy [HR 1.13 (1.00-1.27) ], CKD, ESKD, and all-cause mortality than the non-IR group. Compared with the ID-/IR- group, the ID/IR group had the highest hazard of incident insulin use [HR 1.59 (1.30, 1.94) ], SHE and cardiovascular-renal diseases with HRs ranging from 1.45 to 2.09, although the associations for complications became insignificant after adjusting for metabolic factors and baseline treatments. Conclusions: In GADA- patients with T2D, ID and IR contributed differently to clinical outcomes with the co-existence of ID and IR associated with the highest risk of insulin requirement and adverse clinical outcomes. The assessment of ID and IR using HOMA2 improved risk stratification to identify high risk people for individualized intervention. Disclosure B.Fan: None. A.Luk: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.S.H.Lau: None. H.Wu: None. M.Shi: None. A.Yang: None. C.K.Lim: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. Funding The HKG Health Medical and Research Fund and RGC Research Impact Fund

391-P: Normalizing Glomerular Filtration Rate (GFR) Using Extracellular Volume (ECV) Instead of Body Surface Area (BSA) : Results from an Analysis of the Preventing Early Renal Loss (PERL) Trial

Standardization of GFR by BSA can underestimate kidney function in overweight individuals. Standardization of GFR by ECV, rather than BSA, may be a way to avoid measurement bias. Our aim was to compare the distribution and agreement of GFR measures in people with type 1 diabetes at risk of kidney disease, and to determine associations with clinical hemodynamic measures. In this exploratory analysis of the PERL clinical trial of allopurinol, the distribution and agreement of 4 measurements for GFR were compared in 542 participants with eligible data. GFR was measured using gold-standard iohexol plasma clearance procedures, and ECV was calculated using the Jødal-Bröchner-Mortensen method, which estimates ECV using results from clearance studies. GFR was standardized using ECV corrected for 14 L of fluid volume rather than 1.73 m2 of BSA. Agreement between measurements was assessed by Bland-Altman and Spearman correlation analyses. The trial primary outcome was re-analyzed using ECV-adjusted GFR. Mean age and BMI were 51±years and 29.5±6.0 kg/m2. The distribution of normalized GFR measures overlapped and agreement was strong; GFR/ECV overestimated GFR/BSA by 2.9 numerical units (mean 70.5 ml/min/14 L vs. 67.6 ml/min/1.73 m2) . Heart rate was associated with unstandardized GFR (r=-0.10, p=0.023) . Associations between diastolic blood pressure and all measures of GFR were observed (r ranged from 0.17-0.18; p-values<0.001) . Use of GFR/ECV did not change the main trial results. These data show that ECV calculation and GFR standardization by ECV are feasible, providing similar measure of GFR as compared to BSA adjustments, although PERL trial outcomes were not affected by the method used to normalize GFR. Future studies are needed to determine if ECV can be used as an outcome measure for renal interventions, including those that are affected by natriuresis and measures of circulating volume. Disclosure L.Lovblom: None. R.Pop-busui: Advisory Panel; Averitas Pharma, Inc., Boehringer Ingelheim International GmbH, Nevro Corp., Novo Nordisk, Reata Pharmaceuticals, Inc., Regenacy Pharmaceuticals, Inc. S.Polsky: Advisory Panel; Medtronic, Other Relationship; diaTribe, Research Support; Dexcom, Inc., Eli Lilly and Company, Leona M. and Harry B. Helmsley Charitable Trust, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Sanofi-Aventis U.S. A.B.Karger: Consultant; Roche Diagnostics, Research Support; Kyowa Kirin Co., Ltd., Siemens. A.Galecki: None. B.A.Perkins: Advisory Panel; Abbott Diabetes, Insulet Corporation, Sanofi, Board Member; Novo Nordisk, Other Relationship; Abbott Diabetes, Insulet Corporation, Medtronic, Novo Nordisk, Research Support; BMO Bank of Montreal, Novo Nordisk. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. S.O.Lanctot: Employee; Medtronic. D.M.Maahs: Advisory Panel; Abbott Diabetes, Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi, Consultant; Aditx Therapeutics, Inc., Biospex. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company. M.Mauer: None. L.Caramori: Advisory Panel; Bayer AG, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Research Support; Bayer AG, Novartis AG. S.Rosas: Advisory Panel; AstraZeneca, Teladoc Health, Other Relationship; Bayer AG, Research Support; AstraZeneca, Bayer AG. P.Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker's Bureau; Eli Lilly and Company. K.R.Tuttle: Advisory Panel; Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Consultant; AstraZeneca, Eli Lilly and Company, Research Support; Bayer AG, Goldfinch Bio, Inc., Novo Nordisk, Travere. Funding Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171

1438-P: Association between Screen Time, Including That for Smartphones, and Overweight/Obesity among Children in Japan

The association between screen time (ST) , including that for smartphones, and overweight/obesity (OW/OB) in children was examined separately for boys and girls, considering the influence of lifestyle factors including diet, physical activity, and sleep time. A cross-sectional study was conducted in 2242 Japanese children (1278 girls) aged 10-14 years. OW/OB was defined by the International Obesity Task Force. Logistic regression analysis showed that only for girls, total ST (≥4h) , smartphone ST (≥3h) and non-smartphone ST (≥2h) were all independently and significantly associated with overweight/obesity compared to <2h total ST, non-use of smartphones, and <1h non-smartphone ST. In girls with total ST ≥5h or <4h or smartphone ST <2h, the association between ST and OW/OB was not affected by physical activity or sleep time. On the other hand, when total ST was 4-5h or smartphone ST was ≥2h, the significant association with OW/OB disappeared when physical activity was ≥60 min/day and sleep time was ≥8.5h. In addition, none of these associations were significant in boys. In Japanese girls, smartphone ST, non-smartphone ST, and total ST were all significantly associated with OW/OB. To avoid OW/OB, it is suggested to keep smartphone ST, non-smartphone ST, and total ST to <3h, <2h, and <4h, respectively, and to engage in sufficient physical activity and sleep time. Disclosure K. Fujihara: None. S.Y. Morikawa: None. H. Ishiguro: None. M.H. Yamada: None. C. Horikawa: None. Y. Ogawa: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited.

378-P: Network Meta-analysis of Hypoglycemic Treatment Regimens with Potential Risk of Hypoglycemia in Terms of Glycemic Control and Severe Hypoglycemia

Insulin and its secretagogues are essential for some patients with type 2 diabetes (T2D) to maintain glycemic control (GC) . However, these drugs are inevitably accompanied by hypoglycemia. Avoiding severe hypoglycemia (SH) is essential considering its poor prognosis. This network meta-analysis aimed to find optimal hypoglycemic treatment regimens for T2D in terms of GC and SH. MEDLINE and EMBASE were used to identify trials comparing 2 or more treatments including insulins and/or SU/glinide and included both GC and SH in study outcomes. Treatment hierarchy was summarized as the surface under cumulative ranking probabilities (SUCRA) . There were 137 eligible trials from which 36 treatments were identified. Insulin plus (+) non-insulin drugs except for SU/glinide (others) had a higher SUCRA for changes in hemoglobin A1c (A1C) compared with only insulins (68.2±5.6% vs. 39.9±6.6%; P=0.01) although the difference in the SUCRA for SH was not significant (P=0.59) . Compared with only insulins, SU/glinide + others had a lower SUCRA for SH (42.4±5.8% vs. 58.5±3.4%, P=0.05) and comparable SUCRA for A1C change (P=1.00) . Cluster analysis indicated that premixed insulin + glucagon-like peptide-1 receptor agonist (Mix-ins+GLP1) consistently belonged to the high-efficacy group for A1C change and achievement of A1C<7.0% and ≤6.5% among the insulin + others therapies. Glinide + thiazolidinedione (TZD) was in groups with high efficacy in terms of A1C change and achievement of A1C<7.0% and high safety regarding SH among SU/glinide + others therapies. Results suggest that in T2D patients adjunctive use of non-insulin drugs (particularly, Mix-ins+GLP1) are recommended for further improving GC and that appropriate combinations of non-insulin hypoglycemic agents (particularly, glinide+TZD) are recommended to avoid SH and extend the time to treatment failure of non-insulin therapy. Disclosure S.Kodama: None. K.Kato: None. K.Watanabe: None. H.Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. T.Sato: None. M.H.Yamada: None. M.Yamamoto: None. Y.Matsubayashi: None. H.Ishiguro: None. M.Iwanaga: None. K.Fujihara: None. T.Yamada: None.

934-P: Real-World Evidence of Glucose Lowering Drug Use, Glycemic Outcomes, and Severe Hypoglycemia in Hong Kong: Eighteen-Year Trends in 0.9 Million Adults with Diabetes

Introduction: Improvements in glycemic outcomes have stalled since 20in some international surveys. We examined the latest trends in drug use and glycemic outcomes following recent introduction of newer classes of glucose lowering drugs (GLDs) in a territory-wide analysis. Methods: Using data from the Hong Kong Diabetes Surveillance Database, we estimated age-specific trends in the proportion of patients reaching different glycemic targets, and rates of severe hypoglycemia (SH) in 963,612 patients between 2002-2019. We assessed patterns of GLDs use by age, sex, presence of atherosclerotic cardiovascular disease (ASCVD) and estimated glomerular filtration rate (eGFR) . Results: HbA1c improved most markedly between 2007-2014 but plateaued since 2014, with 53.1% patients achieving HbA1c <7% in 2019. The 20-44 age group had the highest proportion with HbA1c ≥9% (22.1% in 2002 and 16.8% in 2019) compared with the ≥75 age-group (14.9% in 2002 and 5.5% in 2019) . SH rates declined between 2002-20 and further in 2010-2014. Between 2002-2019, metformin use increased steadily from 41.1% to 58.7%, sulfonylurea use decreased from 52.2% to 31.1% while insulin use remained static. Use of dipeptidyl-peptidase 4 inhibitors (DPP4i) experienced rapid growth between 2007-20equally in all age groups, with a slower rise between 2011-2019. DPP4i remains the most widely prescribed newer oral GLDs (14.3%) compared with sodium glucose co-transporter 2 inhibitors (SGLT2is) (4.2%) and glucagon like peptide-1 receptor agonists (GLP1-RAs) (0.6%) in 2019. Compared with over 75s, higher proportions of the 20-44 age-group were treated with SGLT2is (6.4% versus 1.7%) and GLP-1RAs (1.5% versus 0.1%) and thiazolidinediones (8.1% versus 3.4%) in 2019, irrespective of ASCVD status. Conclusions: Following rapid improvement in 2007-2014, glycemic control and SH rates had plateaued despite the increasing use of SGLT2is and GLP-1RA in Hong Kong. Disclosure A.Yang: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. H.Wu: None. E.S.H.Lau: None. X.Zhang: None. M.Shi: None. B.Fan: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc.

18-OR: Discontinuation of Renin Angiotensin System Inhibitor and Cardiovascular-Renal Events in Advanced Diabetic Kidney Disease

Introduction: Whether angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) should be discontinued in advanced diabetic kidney disease (DKD) remains controversial. We examined the association of discontinuation of ACEi/ARBs when estimated glomerular filtration rate (eGFR) reached <30 ml/min/1.73m2 with risk of death, major adverse cardiovascular events (MACE) , and end-stage-kidney-disease (ESKD) defined as dialysis and/or eGFR <15/ml/min/1.73m2 in Chinese patients with type 2 diabetes (T2D) . Methods: We performed a prospective analysis of a register including 11,323 patients stratified by continuation of ACEi/ARBs within 6 months of reaching eGFR <30 ml/min/1.73m2 in 2002-2018 followed up until 2019. We used Cox model with time-dependent exposure and covariates to estimate the hazard ratio (HR) of outcomes in the overlap propensity score weighted cohort. Results: Of 11,323 ACEi/ARBs users with new-onset eGFR<30 ml/min/1.73m2, 2,055 (18.5%) discontinued ACEi/ARBs within 6 months whereas 9,268 (81.5%) had continuation of ACEi/ARBs. During a mean follow-up of 4.3 years, 13.5% and 28.4% had incident MACE and ESKD respectively, and 36.2% died. Compared to ACEi/ARBs continuation, discontinuation of ACEi/ARBs was associated with higher risk of MACE (HR=1.26, 95% CI: 1.15-1.39) and ESKD (HR=1.26, 95% CI: 1.14-1.40) , and neutral risk of death (HR=0.96, 95% CI: 0.89-1.04) . Results were consistent when modeling ACEi/ARBs as a time-dependent exposure using a marginal structural model. Conclusions: Discontinuation of ACEi/ARBs was associated with increased risk of cardiovascular-renal events in support of their continued use in patients with advanced DKD. Disclosure M.Shi: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. A.Yang: None. E.S.H.Lau: None. H.Wu: None. X.Zhang: None. B.Fan: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc.

1208-P: Age-Specific Association between Risk Factors and All-Cause and Cause-Specific Mortality in People with Type 2 Diabetes

Background: We aimed to examine age-specific association and population attributable fraction (PAF) of risk factors for all-cause and cause-specific mortality in people with type 2 diabetes. Methods: We used data from 360,202 people with type 2 diabetes who underwent metabolic assessment in 2000-20in Hong Kong. We included eight risk factors, including three baseline comorbidities: cardiovascular disease (CVD) , chronic kidney disease (CKD) and cancer; and five modifiable risk factors: suboptimal HbA1c (≥7.0%) , suboptimal blood pressure (SBP/DBP ≥140/90 mmHg) , suboptimal LDL-C (≥2.6 mmol/L) , smoking and suboptimal weight (BMI <24.0 or ≥28.0 kg/m2) . We used Cox regression models to compare the hazard ratios and PAFs of the risk factors for mortality risk across age groups (18-54, 55-64, 65-74, and ≥75 years) . Findings: During a median 6.0 years of follow-up, 44,396 deaths were documented, with cancer, pneumonia, and CVD being the most common causes of death. When stratified by age group, the strength of the associations between most risk factors and all-cause and cause-specific mortality was strongest in the youngest age group and diminished with increasing age. The eight risk factors explained more population burden of mortality in the youngest (PAF: 51.6%) than the oldest (PAF: 35.3%) age group. In the youngest age group, the strongest population attributable risk factor for all-cause mortality was suboptimal control of blood pressure, followed by CKD. In the oldest age group, CKD and CVD were the largest contributors. CKD contributed most to mortality from CVD and pneumonia in the overall population, while cancer had the greatest PAF for cancer mortality across all age groups. Conclusions: The contribution of each risk factor to mortality in people with type 2 diabetes showed a different pattern across age groups. Age-stratified prevention strategies targeting the major risk factors may have the potential to reduce premature mortality. Disclosure H.Wu: None. A.Luk: None. E.S.H.Lau: None. A.Yang: None. X.Zhang: None. B.Fan: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd.

1179-P: Secular Trends in Dietary Intake Over a Five-Year Period in People with Type 2 Diabetes in Japan: Japan Diabetes Complications Study (JDCS)

To provide effective medical nutrition therapy (MNT) , it is necessary to consider dietary intake, which can change over time. This longitudinal study analyzed changes in the dietary intakes of Japanese patients with type 2 diabetes over a 5-year period. The JDCS is a nationwide study of Japanese patients with type 2 diabetes conducted in 1996. Participants were aged 40-70 years from outpatient clinics in 59 universities and general hospitals. Analyzed were 922 responders to a dietary survey assessed by the Food Frequency Questionnaire based on food groups at baseline and 5 years after registration. Paired samples t-test was used for analysis. Over a 5-year period, patients with type 2 diabetes maintained almost the same body mass index (BMI) (baseline: 22.9±3.0; 5 years later: 22.8±3.0 kg/m2) . Differences in energy intake, fat-to-energy ratio, and carbohydrate-to-energy ratio were small although significant. Neither the mean intake of fiber nor salt met the required intake for MNT for persons with diabetes both at baseline and after 5 years. As for food groups, there was a significant decrease in intakes of vegetables, seaweed, soybeans/soy products, and milk/dairy products. Details are shown in the Table. Results showed that Japanese patients with type 2 diabetes need to pay special attention to dietary fiber intake and salt intake on an ongoing basis. Disclosure C.Horikawa: None. R.Aida: None. C.Kamada: None. K.Fujihara: None. S.Tanaka: None. A.Araki: None. Y.Yoshimura: None. Y.Akanuma: None. H.Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Japan Society for the Promotion of Science (19H04028)

1098-P: Impact of Health Factors on Incident Cardiovascular Disease (CVD) According to Glucose Tolerance Status

Breslow’s Health Practice Index (HPI) includes recommendations for a healthy lifestyle and is composed of 7 simple lifestyle factors (sleep, breakfast, snacks, body mass index (BMI) , physical activity, drinking alcohol, and smoking status) . Cardiovascular health metrics (CVHMs) defined according to the American Heart Association are composed of lifestyle factors and clinical laboratory values (smoking status, BMI, physical activity, diet, systolic blood pressure <120 mmHg and diastolic blood pressure <80 mmHg, total cholesterol <200 mg/dl, and fasting blood glucose <100 mg/dl) . To clarify the impacts of HPI or CVHMs on incident CVD according to glucose tolerance status, we analyzed a nationwide claims-based database of 128,290 people included from 2008-aged 20-72 y in Japan (86,279 with normal glucose tolerance; 36,1with prediabetes; 5,9with diabetes) . HPI and CVHMs were divided into three categories (high, middle, and low) based on the number of ideal health factors present (Table) . Multivariate Cox regression analysis showed that people with prediabetes with an HPI of ≥5 or people with prediabetes and diabetes who had ≥5 CVHMs had no increased risks for CVD compared with those in the high HPI/CVHMs category for normal glucose tolerance (Table) . In summary, not only to follow a healthy lifestyle but to achieve laboratory treatment targets may be essential in people with diabetes. Disclosure T.Iijima: None. T.Yamada: None. S.Kodama: None. H.Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. K.Fujihara: None. M.H.Yamada: None. M.Yamamoto: None. T.Osawa: None. Y.Matsubayashi: None. T.Sato: None. Y.Yaguchi: None. M.Iwanaga: None.

126-OR: Long-Term Consequences of Diabetic Foot Infection: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Foot infections are a common complication of type 2 diabetes. However, the clinical sequelae of diabetic foot infection (DFI) in the general population remain poorly characterized. Methods: We conducted a prospective cohort analysis of 1,451 participants with diabetes (mean age, 63 years [SD: 5.6]; 33% black; 47% female) in the ARIC study (visit 4: 1996-1998) . DFI was ascertained using ICD-9/codes from Medicare claims and hospital discharge records. We used Kaplan-Meier analyses to estimate the 5-year cumulative incidence of nontraumatic lower-extremity amputation (NLEA) , major fall, cardiovascular disease (CVD) [coronary heart disease, stroke, or heart failure], and death following incident DFI. We evaluated the association between incident DFI (modeled as a time-varying exposure) and the subsequent risk of clinical outcomes with Cox models. Results: During over two decades of follow-up (1996-1998 to 2017) , there were 328 incident DFIs, 72 NLEAs, 502 major falls, 748 CVD events, and 915 deaths. Following incident DFI, the five-year cumulative incidence of major clinical outcomes ranged from 14.7% (NLEA) to 38.6% (death) (Fig 1a) . Incident DFI was significantly associated with all clinical outcomes after multivariable adjustment (Fig 1b) . Conclusion: DFI is a high-risk marker for major morbidity and mortality in the general population of adults with diabetes. Disclosure M.Fang: n/a. J.Hu: None. K.Matsushita: Consultant; Akebia Therapeutics, Inc., Mitsubishi Tanabe Pharma Corporation, Other Relationship; Fukuda Denshi, Research Support; Kyowa Kirin Co., Ltd. E.Selvin: Other Relationship; Wolters Kluwer. C.W.Hicks: None. Funding HHS (N268201700001I) , HHS (N268201700002I) , HHS (N268201700003I) , HHS (N268201700005I) , HHS (N268201700004I) , NHLBI (K24HL152440)

116-OR: Changes in Glucose Tolerance and Related Factors after Renal Transplantation in Recipients with Impaired Glucose Tolerance

Background and Aims: Our previous study revealed that more than half of patients with impaired glucose tolerance (IGT) before renal transplantation improved to normal glucose tolerance after transplantation. However, the mechanism was not clear. This study aimed to investigate whether changes in glucose tolerance were associated with insulin secretion and resistance in Japanese renal transplant recipients diagnosed with IGT before transplantation. Materials and Methods: We analyzed data for 179 patients ≥20 years of age who received their first renal transplantation in our hospital from April 2005-October 20 and had no history of diabetes before transplantation. A total of 54 recipients who received the oral glucose tolerance test (OGTT) before and 1 year after transplantation and were diagnosed with IGT before transplantation. Patients were divided into two groups according to negative or positive changes in area under the blood glucose curves from 0-120 min after ingestion: improved group and non-improved group, respectively. Insulin secretion was estimated by the insulin secretion sensitivity index-2 (ISSI-2) and insulin sensitivity was estimated by the Matsuda index (MI) and homeostasis model assessment of insulin resistance (HOMA-IR) . Results: Thirty and 24 patients were in the improved and non-improved groups, respectively. ISSI-2 significantly increased from 1.67±0.44 to 2.00±0.60 (P<0.01) after transplantation in the improved group, but not in the non-improved group. ΔISSI-2 was significantly associated with the 60-min blood glucose level of the OGTT and ISSI-2 level before transplantation (β=0.01, P<0. and β=−0.59, P<0.01, respectively) . There were no differences in MI or HOMA-IR before and after transplantation between these two groups. Conclusion: Improvement of glucose tolerance after renal transplantation in patients diagnosed with IGT before transplantation is related to improvement of insulin secretion. Disclosure M. Kusumi: None. A. Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. H. Nomoto: None. H. Kameda: None. K. Cho: None. H. Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. T. Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc. Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc.

1178-P: Current Situations in Dietary Intake and Physical Activity in Japanese Patients with Type 2 Diabetes: JDCP Study

Medical nutrition therapy and exercise therapy are the cornerstones of treatment for patients with type 2 diabetes; however, there has not been a nationwide study on the actual dietary intake and physical activity status of patients since the 2000s. We aimed to clarify this in Japanese patients with type 2 diabetes using data from the Japan Diabetes Complication and its Prevention prospective (JDCP) , a nationwide study launched in 2007. A total of 1,992 patients with type 2 diabetes, aged 40-75 years, completed either the Brief-type, self-administered Diet History Questionnaire (1,643 patients) or International Physical Activity Questionnaire (1,834 patients) , and their data were analyzed in this study. Mean daily energy intake for all participants was 1686.8 kcal/day, and the mean proportions of carbohydrate, protein, and fat comprising total energy intake were 60.2, 16.2, and 23.6%, respectively. The patients in this study had similar energy and nutrient intake status to patients in the 1996 Japan Diabetes Complications Study; however, Japanese patients still had higher carbohydrate and lower fat consumption than patients with diabetes in Western countries. Only 10.5 % of the patients had equal to or more than 20 g/day of dietary fiber and 7.5% consumed less than 6 g of salt. Weekly physical activities of male and female patients were 2344.5±2700.9 and 1948.3±2209.3 METs·min/week in women, respectively (p <0.001) . As for exercise, 31.0% of patients did not do it habitually; this was particularly noticeable in female patients and patients under the age of 65. BMI increased from 22.7 to 24.1 kg/m2 in men and 23.2 to 24.8 kg/m2 in women from 1996 to 2007, respectively. The reason for this increment is suggested to be due to energy intake remaining unchanged despite a decrease in physical activity level. The balance between dietary energy intake and energy expenditure based on physical activity has become more important in Japanese patients with type 2 diabetes in recent years. Disclosure C.Horikawa: None. K.Tsuda: None. J.Satoh: None. Y.Hayashino: None. N.Tajima: None. R.Nishimura: Speaker's Bureau; Abbott Diabetes, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Terumo Corporation. H.Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Japan Diabetes Society

556-P: The Relationship between Short-Chain Fermentable Carbohydrates (FODMAPs) , Gut Microbiome, and Glucose Intolerance: An Exploratory Analysis

Fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) are fermentable short-chain carbohydrates that include fructans, galactooligosaccharides (GOS) , lactose, excess fructose, mannitol and sorbitol. Low FODMAP diets in irritable bowel syndrome were associated with reductions in metabolically beneficial, short-chain fatty acids (SCFA) - producing bacteria. We examined the interactions between FODMAP, gut microbiota and glucose tolerance in this exploratory analysis. Twenty subjects underwent oral glucose tolerance tests (OGTT) with C peptide measurements. Ten were classified as normal glucose tolerant (mean ±SD 55±years, body mass index (BMI) 22.7­±2.5 kg/m2, 2-hour plasma glucose 5.7±1.0 mmol/L) and with impaired glucose tolerance (58±­5 years, BMI 23.5±2.9 kg/m2, 2-hour glucose 9.0±0.9 mmol/L) . FODMAPs and macronutrients were assessed from 3-day food diaries. Fecal samples were collected for microbiome analysis. Total FODMAPs were positively correlated to presence of Dorea (r=0.49, p=0.027) . For individual FODMAP items, lactose was positively correlated with Akkermansia (r=0.54, p=0.013) , Bifidobacterium (r=0.42, p=0.037) and negatively correlated with Shigella (r=0.35, p=0.031) in both groups. GOS were positively correlated with Lactobacillus (r= 0.21, p=0.006) and negatively with Shigella (r=0.28, p=0.043) . In the whole group, lower insulin resistance as shown by homeostasis model assessment HOMA2-IR was associated with higher abundance of Bifidobacterium logum (r=0.48, p=0.01) . HOMA2-beta showed correlation with Dorea (r=0.43, p=0.056) . FODMAPs increased the health-promoting microbiota (e.g. Dorea, Lactobacillus, Akkermansia, and Bifidobacterium) . These SCFA promoting microbiota were associated with lower insulin resistance and improved beta-cell function while suppressing the growth of opportunistic pathogens, such as Escherichia spp. Disclosure N. Chu: None. J. He: None. R.C. Ma: Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH. A.P. Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd. Research Support; Boehringer Ingelheim. Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi. Stock/Shareholder; Aptorum Group Limited. Other Relationship; AstraZeneca, Novo Nordisk. J.C. Chan: Board Member; Asia Diabetes Foundation. Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc. Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories. Stock/Shareholder; GemVCare Ltd. E. Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc. Speaker's Bureau; Novartis AG, Sanofi. Funding Health Medical Research Fund (17180431) Hong Kong College of Physicians Young Investigator's Research Grant