Kyowa Hakko Research Articles

1414-P: Stalling of Trends in Glycemic and Risk Factors Control in People with Type 2 Diabetes in Hong Kong in 2000–2019

Background: We aimed to examine trends in diabetes control in Hong Kong between 2000 and 2019. Methods: We conducted a retrospective analysis of data from 360,202 people aged 20 years or older with type 2 diabetes who underwent a territory-wide Risk Assessment and Management Programme-Diabetes Mellitus (RAMP-DM) in primary and secondary settings in Hong Kong between 2000 and 2019. We examined trends in proportion of people with type 2 diabetes achieving target of glycemic control (hemoglobin A1c [HbA1c] <7.0%), blood-pressure control (systolic/diastolic blood pressures [SBP/DBP] <140/90 mm Hg), and lipid control (low-density lipoprotein cholesterol [LDL-C] <130 mg/dl). Results: The proportion of people with type 2 diabetes who achieved HbA1c <7.0% increased from 40.3% (95% CI: 35.6%, 50.0%) in 2000 to 55.2% (54.4%, 56.0%) in 2014 and then leveled off thereafter. After improvements in blood-pressure control from 2000 to 2014, the proportion of people in whom blood pressure was achieved to below 140/90 mm Hg declined from 71.0% (70.4%, 71.6%) in 2014 to 63.5% (62.8%, 64.2%) in 2019. From 2000 to 2019, the proportion of people with LDL-C <130 mg/dl continued to increase from 32.6% (27.6%, 37.6%) to 59.9% (59.2%, 60.6%). The proportion of people in whom all three targets were simultaneously achieved increased from 9.5% (3.8%, 15.3%) in 2000 to 23.1% (22.1%, 24.1%) in 2014 and plateaued from 2014 to 2019. Conclusions: After major improvements from 2000 to 2014, glycemic control stalled and blood-pressure control declined in people with type 2 diabetes in Hong Kong, while there was a continued encouraging trend in lipid control. Disclosure H.Wu: None. A.Luk: Research Support; Novo Nordisk, Boehringer-Ingelheim, Bayer Inc., Speaker's Bureau; Eli Lilly and Company. E.S.H.Lau: None. A.Yang: None. X.Zhang: None. B.Fan: None. R.C.Ma: Advisory Panel; AstraZeneca, Merck & Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Speaker's Bureau; Abbott, AstraZeneca, Lilly, Bayer Inc., Boehringer Ingelheim Inc. E.Chow: Research Support; Medtronic, Merck KGaA, Speaker's Bureau; Novartis, Bayer Inc., Sanofi. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer Inc., Celltrion, Boehringer Ingelheim and Eli Lilly Alliance, Sanofi, Research Support; AstraZeneca, Servier Laboratories, Viatris Inc., Hua Medicine, Merck KGaA, Applied Therapeutics Inc., Lee Powder, Pfizer Inc., Speaker's Bureau; Novartis, Stock/Shareholder; GemVCare Ltd.

551-P: Healthy Lifestyle Behaviors as Predictors of Initiation of Hemodialysis (HD) in People With and Without Diabetes Mellitus (DM)

Breslow’s Health Practice Index (HPI) includes recommendations for a healthy lifestyle and is composed of 7 simple lifestyle factors (never smoking, regular physical activity, moderate or no use of alcohol, 7-8 hours sleep regularly, maintaining proper weight, eating breakfast, and not eating between meals). Cardiovascular health metrics (CVHMs), defined by the American Heart Association are composed of lifestyle factors and clinical laboratory values (smoking, weight, physical activity, diet, cholesterol, blood pressure, and blood glucose). To clarify the impact of HPI or CVHMs on incident HD according to DM, we analyzed a nationwide claims-based database of 294,647 people included from 2008-16 (DM- 277,935, DM 16,712). Risk for HD were analyzed according to DM and HPI/CVHMs based on the number of unfavorable lifestyle factors in the HIP and unfavorable lifestyle factors and clinical values in the CVHM (Table). Multivariate Cox regression analysis showed that DM increased the risk of dialysis 5- to 6-fold and DM and CVHMs synergistically increased the risk of HD. Results indicated that factors similar to those used to predict cardiovascular disease would also be useful to predict HD. These approaches might be helpful in clinical practice and patient education. Disclosure T.Osawa: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. K.Fujihara: None. M.H.Yamada: None. Y.Yaguchi: None. T.Sato: None. M.Kitazawa: None. Y.Matsubayashi: None. T.Yamada: None. S.Kodama: None.

463-P: Risk Stratification of Coronary Artery Disease (CAD) according to LDL-C, HDL-C Levels, and Glucose Status

Whereas elevated LDL-C is a major risk factor for CAD, the inverse association between HDL-C levels and risk of CAD is well-known. Although insulin resistance, and glucose intolerance are associated with low HDL-C levels, it is not clear whether the association of LDL-C with CAD differs depending on glucose status and HDL-C values. We examined associations of LDL-C with the incidence of CAD according to HDL-C and glucose status using a nationwide claims database on 1,524,289 individuals during 2008-2019 with no history of CAD or familial hypercholesterolemia. Cox proportional hazards model identified risks of CAD events among combinations of 3 levels of HDL-C and 7 levels of LDL-C according to glucose status. During a mean follow-up period of 5.5 years, 8,301 CAD events occurred. CAD risk increased from lower LDL-C levels accompanied by lower HDL-C levels regardless of glucose status (Table). Even in people with LDL-C <80mg/dl, HDL-C <40mg/dl conferred 2.5-fold increased risk of CAD all glucose status. HDL-C and LDL-C values had a synergistic effect on the incidence of CAD in people with normoglycemia, whereas an addictive effect in people with prediabetes and diabetes. Although more strict LDL-C target need to be achieved as worsening of glucose status, results demonstrated that the necessity of modulating the LDL-C target according to HDL-C levels is not affected by glucose status. Disclosure M.H.Yamada: None. M.Iwanaga: None. T.Yamada: None. S.Kodama: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. K.Fujihara: None. T.Osawa: None. M.Kitazawa: None. Y.Yaguchi: None. T.Sato: None. Y.Mitsuma: None. M.Yamamoto: None. Y.Matsubayashi: None.

631-P: Development of Noninvasive Diabetes Management Method Using Glycated Albumin in Tears

Aims/Background: Several clinical trials have demonstrated that strict glycemic control is important to minimize the risk of diabetic complications. Although frequent measurement of blood glucose levels by the invasive finger prick method is useful to achieve strict glycemic control, this method is invasive and burdensome to the patients. Glycated albumin (GA) is a biomarker which reflects the glycemic control status over the previous 2 weeks. We demonstrated GA levels in tears correlated those in blood. We hypothesized that regular GA tests in tears caused behavior change and improved glycemic control. Methods: Participants with type 2 diabetes were recruited and randomly divided to two groups. One group (intervention group) was performed tear GA tests every 2 weeks and reported the results, while the other group (control group) was not. After 8 weeks of intervention, the two groups were compared. GA levels in tears were measured by Liquid Chromatography / Mass Spectrometry. Results: We enrolled 56 participants to the study. Compared with the control group, the intervention group showed improvement in fasting blood glucose, HbA1c, GA, non-HDL cholesterol. Conclusions: Levels of GA, as a diabetes-related biomarker, in tears can be measured noninvasively. Regular measurement of the GA levels in tears could allow smoother management of diabetes mellitus and reduce the risk of complications noninvasively. Disclosure M.Aihara: None. N.Kubota: None. T.Yamauchi: Other Relationship; Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited, Novo Nordisk, Astellas Pharma Inc., AstraZeneca, Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim, Kyowa Kirin Co., Ltd., Kowa Company, Ltd., Merck & Co., Inc., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Daiichi Sankyo, Taiho Pharmaceutical Co. Ltd., Tosoh Corporation, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., NTT Docomo Inc., Aero Switch, Asahi Mutual Life Insurance Company, NIPRO Medical Corporation, Abbott Japan Co., Ltd., Bayer Inc., Kyorin Pharmaceutical Company, Limited.

1473-P: A Data-Driven Cluster Analysis of Renal Complications in Patients with Type 2 Diabetes—From Phenotypic Observation to Genetic Discovery

Diabetic kidney disease (DKD) has a strong genetic component. The marked phenotypic heterogeneity in type 2 diabetes (T2D) limits the power of cross-sectional genome-wide association studies (GWAS) on DKD. We performed a data-driven cluster analysis using the longitudinal electronic health records (EHR) of a prospective cohort to identify subgroups of patients with different patterns of progression of kidney functions. These included 29,416 Chinese patients with T2D recruited in 1995-2018 observed until 2019 (median [IQR] follow-up: 9 [5-12] years). We curated 211 variables including baseline data collected during structured assessment and follow-up EHR data. We applied generalized low rank models (GLRM) to resolve the inter-correlations among variables and reduce the high dimension of the raw dataset. We identified 6 clusters featured by distinct combinations of the 211 variables: 1) DKD-free characterized by stable estimated glomerular filtration rate (eGFR decline <1 ml/min per 1.73 m2 per year) and absence of macroalbuminuria (19.4%); 2) eGFR decline without macroalbuminuria and good glycemic and BP control (26.0%); 3) eGFR decline with albuminuria and high BP (20.1%); 4) eGFR decline with albuminuria and poor glycemic control (14.2%); 5) rapid eGFR decline, albuminuria, high BP and low glucose burden (10.5%); and 6) rapid eGFR decline, macroalbuminuria, high BP and high glucose burden (9.8%). We performed cluster-wise GWAS in 12,358 patients with available genotype data. We found diverse patterns of genetic associations for the 6 DKD clusters reaching genome-wide significance (P GWAS <5×10−8) for cluster 3 and 6. Polygenic risk scores (PRS) using top GWAS loci discriminated risk of end-stage kidney disease with AUC of 0.62 (PRS only) and 0.93 (PRS plus baseline clinical variables). Our novel cluster-GWAS using more precise phenotyping combining baseline and follow-up clinical variables had led to novel genetic discoveries. Disclosure M.Shi: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer Inc., Celltrion, Boehringer Ingelheim and Eli Lilly Alliance, Sanofi, Research Support; AstraZeneca, Servier Laboratories, Viatris Inc., Hua Medicine, Merck KGaA, Applied Therapeutics Inc., Lee Powder, Pfizer Inc., Speaker's Bureau; Novartis, Stock/Shareholder; GemVCare Ltd. R.C.Ma: Advisory Panel; AstraZeneca, Merck & Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk. C.H.Tam: None. E.S.H.Lau: None. A.Yang: None. H.Wu: None. B.Fan: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Speaker's Bureau; Abbott, AstraZeneca, Lilly, Bayer Inc., Boehringer Ingelheim Inc. A.Luk: Research Support; Novo Nordisk, Boehringer-Ingelheim, Bayer Inc., Speaker's Bureau; Eli Lilly and Company. E.Chow: Research Support; Medtronic, Merck KGaA, Speaker's Bureau; Novartis, Bayer Inc., Sanofi. Funding Research Grants Council of the Hong Kong Special Administrative Region (R4012-18); Theme-Based Research Scheme (T12–402/13N)

329-OR: Accuracy of Dietary Records (DR) Using a Smartphone App Is Greatly Improved by User’s Adjustments Compared with Artificial Intelligence (AI) Alone

Although DR are important in managing diabetes, the traditional method, such as weighing foods and calculating nutrients, is burdensome to both patients and medical care providers. Although photo DR with smartphones using AI to identify the dish and calculate nutrients can be expected to reduce this burden, accuracy not been clarified. Furthermore, it is not clear to what extent accuracy improves when users and dietitians adjust the name of the dish and the portion consumed compared with AI only. In this study, photo DR taken with the smartphone app were analyzed by AI only, then adjusted by the users followed by further adjustments by a dietitian. We compared the nutrients calculated by AI, users, and dietitians to those by the traditional weighing method. Analyzed were 180 participants (mean age 58.7 y, BMI 26.7 kg/m2, 94/86 women/men, 22 with diabetes, energy intake [EI] 1640 kcal/day) The EIs (kcal/day) were calculated as 1502, 1619, and 1674 for AI, users, and dietitians, respectively, those were lower than that with the weighing method Spearman's rank correlation coefficients compared to the weighing method were 0.48, 0.88, and 0.88 for AI, users and dietitians, respectively, showing a weak correlation for AI and a strong correlation for users and dietitians. The user's adjustments greatly improved accuracy without increasing the burden on the dietitians. Disclosure M.Kitazawa: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. C.Horikawa: None. I.Ikeda: None. Y.Takeda: None. E.D.Ferreira: None. M.Takeuchi: None. S.Y.Morikawa: None. K.Fujihara: None. S.Kodama: None. Funding Grants-in-Aid for Scientific Research (21K17637)

1251-P: Glycaemic Trajectory before Diabetes Diagnosis in People with Young-Onset and Usual-Onset Type 2 Diabetes—A Population-Based Retrospective Study in Hong Kong

Objectives: To identify distinct glycaemic trajectories before diabetes diagnosis in people with young-onset (<40 years) and usual-onset type 2 diabetes (≥40 years). Methods: Adult patients with incident type 2 diabetes diagnosed between 2002 and 2019 who had at least three HbA1c measurements before diabetes diagnosis in Hong Kong Hospital Authority electronic medical record system were included in this study. Latent class trajectory modelling was applied to identify distinct HbA1c trajectories before diabetes diagnosis, adjusted for sex and age. The shape and number of trajectory classes (one to five) were selected based on a combination of Bayesian Inclusion Criteria, model adequacy and proportion of people in each trajectory class (no less than 2% required). Results: A total of 2,252 people with young-onset type 2 diabetes (age [mean ± SD]: 34.1 ± 4.9 years; 40.0% male) and 77,892 people with usual-onset type 2 diabetes (age [mean ± SD]: 64.9 ± 11.0 years; 51.4% male) were included in this analysis. The 2-class solution and 1-class solution were chosen as the most appropriate models for young-onset and usual-onset type 2 diabetes respectively. A stable-increase trajectory with HbA1c rising gradually before diabetes diagnosis was identified in 96% of people with young-onset type 2 diabetes, while the other 4% had an accelerated-increase trajectory with HbA1c increasing rapidly within one year before diagnosis. People with usual-onset type 2 diabetes had HbA1c value increasing gradually before diabetes diagnosis. Conclusion: Blood glucose climbed gradually at a steady rate before diabetes diagnosis in most people with type 2 diabetes, while a small proportion of people with young-onset type 2 diabetes showed a rapid deterioration within a short period before disease onset. Disclosure Y.Fan: None. H.Wu: None. E.S.H.Lau: None. A.Yang: None. E.Chow: Research Support; Medtronic, Merck KGaA, Speaker's Bureau; Novartis, Bayer Inc., Sanofi. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Speaker's Bureau; Abbott, AstraZeneca, Lilly, Bayer Inc., Boehringer Ingelheim Inc. R.C.Ma: Advisory Panel; AstraZeneca, Merck & Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer Inc., Celltrion, Boehringer Ingelheim and Eli Lilly Alliance, Sanofi, Research Support; AstraZeneca, Servier Laboratories, Viatris Inc., Hua Medicine, Merck KGaA, Applied Therapeutics Inc., Lee Powder, Pfizer Inc., Speaker's Bureau; Novartis, Stock/Shareholder; GemVCare Ltd. A.Luk: Research Support; Novo Nordisk, Boehringer-Ingelheim, Bayer Inc., Speaker's Bureau; Eli Lilly and Company.

126-OR: Metformin Discontinuation and Clinical Outcomes in Patients with Diabetes and Advanced Chronic Kidney Disease—A Prospective Cohort Study

Introduction: Metformin can now be used in patients with chronic kidney disease (CKD) up to estimated glomerular filtration rate [eGFR] ≥30 ml/min/1.73m2. However, surveys suggested its continuing use in some patients with eGFR<30 ml/min/1.73m2 in real world practice although the risk-benefit ratios remain uncertain. Methods: This was a prospective, population-based cohort of 36,940 patients with diabetes in Hong Kong stratified by continuation of metformin within 6 months after 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 death, major-adverse cardiovascular events (MACE), and end-stage kidney disease (ESKD) in a propensity-score overlap-weighted cohort of continued versus discontinued-metformin users. Results: Of 36,940 metformin users with new-onset eGFR<30 ml/min/1.73m2, 8400 (22.7%) discontinued metformin within 6 months whereas 28,540 (77.3%) continued with metformin. The median metformin daily dose was 1000 [interquartile range, IQR: 1000, 1000] mg in continued-metformin users. During a median follow-up of 3.5 (IQR:1.8-5.8) years, 15.3%, 16.6%, and 28.1% had incident MACE, heart failure, and ESKD respectively, and 41.5% died. Compared to continued-metformin use, discontinuation was associated with higher risk of MACE (weighted and adjusted HR=1.42, 95% CI: 1.31-1.54), heart failure (HR=1.70, 1.58-1.83), ESKD (HR=1.73, 1.63-1.83), and death (HR=1.24, 1.19-1.29). Results were consistent in patients with and without established cardiovascular diseases (CVD). Conclusions: Discontinuation of metformin was associated with increased risk of cardiovascular-renal events, regardless CVD status. Continuation of metformin below eGFR 30ml/min/1.73m2 may be associated with cardio-renal and mortality benefits that needs to be weighed against the risks of lactic acidosis. Disclosure A.Yang: None. R.C.Ma: Advisory Panel; AstraZeneca, Merck & Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer Inc., Celltrion, Boehringer Ingelheim and Eli Lilly Alliance, Sanofi, Research Support; AstraZeneca, Servier Laboratories, Viatris Inc., Hua Medicine, Merck KGaA, Applied Therapeutics Inc., Lee Powder, Pfizer Inc., Speaker's Bureau; Novartis, Stock/Shareholder; GemVCare Ltd. E.Chow: Research Support; Medtronic, Merck KGaA, Speaker's Bureau; Novartis, Bayer Inc., Sanofi. M.Shi: None. H.Wu: None. E.S.H.Lau: None. J.T.K.Cheung: None. X.Zhang: None. B.Fan: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Speaker's Bureau; Abbott, AstraZeneca, Lilly, Bayer Inc., Boehringer Ingelheim Inc. A.Luk: Research Support; Novo Nordisk, Boehringer-Ingelheim, Bayer Inc., Speaker's Bureau; Eli Lilly and Company. Funding Chinese University of Hong Kong

738-P: Lifestyle Intervention Program with Smartphone App Augmented by Intermittently Scanned Continuous Glucose Monitoring for People at High Risk of Diabetes—Randomized Controlled Trial

We examined the effects of a lifestyle intervention program with a smartphone app augmented by intermittently scanned continuous glucose monitoring (isCGM) of persons at high risk of developing diabetes in a 12-week randomized open-label trial (UMIN00004640). The program monitored blood glucose fluctuations and lifestyle habits and displayed them in an easy-to-understand interface as well as provided personalized lifestyle intervention messages. The primary endpoint was the change in time in range (TIR) of 70-140 mg/dL between intervention (App) and control (C) groups. Among 168 patients (mean age 48.1 y, mean BMI 26.6 kg/m2, and male 80.4%), 82 and 86 were assigned to the App group and C group, respectively. After 12 weeks, TIR of 70-140 mg/dL significantly improved in the App group compared to the C group (-2.6 min/day vs. +31.5 min/day, p=0.03). Changes in time above range (>140 mg/dL; -20.9 min/day vs. -22.6 min/day, p=0.86) did not differ, whereas time below range (<70 mg/dL; +23.5 min/day vs. -8.9 min/day, p=0.02) improved in App compared to C. BMI (-0.26 vs. -0.59, p=0.017) and carbohydrate intake (-4.4 kcal/day vs. -22.7 kcal/day, p=0.049) also improved in App compared to C. Intervention with a smartphone app and isCGM increased glycemic control with a decrease in carbohydrate intake and weight loss. Disclosure M.Kitazawa: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. H.Suzuki: None. C.Horikawa: None. Y.Takeda: None. I.Ikeda: None. M.Hatta: None. M.Iwanaga: None. T.Yamada: None. K.Fujihara: None.

1357-P: Conflicting Significance of High BMI as a Predictor of Individual Diabetic Complications

Although weight management plays a central role in diabetes treatment, the association between body weight and diabetic complications is not fully elucidated. Therefore, we investigated the relationship between BMI and risk of diabetic complications in patients with diabetes mellius (DM) using nationwide claims data. Analyzed were 91097 patients with DM without prior treatment-requiring diabetic eye disease (TRDED), initiation of dialysis (dialysis), coronary artery disease (CAD), cerebrovascular disease (CVD), heart failure (HF) or amputation (mean age 52 y, HbA1c 7.2%, median follow-up 4.5 y). Participants were divided into 6 groups according to BMI (BMI<20.0, 20.0-22.4, 22.5-24.9, 25.0-27.4, 27.5-29.0, ≥30.0). Risk of diabetic complications was examined by Cox regression analysis. There was an inverse correlation between the risk of dialysis and BMI; hazard ratio (HR) for dialysis in patients with BMI ≥30.0 was 0.46 (0.29-0.74). There was a U-shaped relationship between the risk of HF and BMI; HRs for HF in patients with BMI <20.0 and ≥30.0 were 1.97 (1.15-3.37) and 1.76 (1.27-2.45), respectively (Figure). High BMI was significantly associated with a higher risk of HF, but lower risks of TRDED and dialysis. The relationship between BMI and diabetic complications was inconsistent among complications, suggesting that the target weight should be individualized according to diabetic complications. Disclosure Y.Yaguchi: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. K.Fujihara: None. L.Khin: None. S.Wu: None. E.D.Ferreira: None. T.Sato: None. C.Horikawa: None. Y.Matsubayashi: None. K.Kato: None.

1224-P: Glucagon Secretion Increases with Age in People with Type 2 Diabetes

It has been shown that the decline in the number of pancreatic beta cells and the insulin-secreting capacity of individual pancreatic beta cells progressively decreases with age, and this functional decline is accelerated by the addition of hyperglycemia. While, glucagon (GCG) is elevated in diabetes, and elevated GCG not only increases blood glucose levels (GLUs), but also decreases muscle mass due to protein metabolism leading to decrease in muscle glucose uptake, making blood glucose control more difficult. However, there are no reports yet regarding to age-related changes in GCG secretion. In this study, we analyze the age-related changes in GCG secretion in people with type 2 diabetes (T2D) after insulin treatment to remove glucose toxicity. A retrospective analysis was performed on people with T2D hospitalized for a period of 5 years from December 2017 in whom a test meal load (carbohydrate 75.5-70g, protein 8.5g, fat 28.5g) was performed before and after insulin treatment, and GLUs and GCG were measured. Insulin (IRI) and/or C-peptide (CPR) were also measured. A total of 121 patients (70 males, age 64.2 ± 11.6 years) were included in the analysis. After insulin treatment, GCG secretion was almost all lower than before treatment. GCG secretion increased with age (P=0.014). Insulinogenic Index decreased with age (R=-0.286 P=0.004), and IRI/GLU and CPR/GLU at 120 minutes after the test meal load also decreased with age (R=-0.314 P=0.001, R=-0.324 P=0.001). We confirmed that there is an increase in GCG secretion with aging in people with T2D. This might be one of the reasons for the decrease in muscle mass and physical activity in elderly people with T2D. Further studies are needed to expand the number including people with normal glucose and impaired glucose tolerance. Acknowledgments:The Cookie Testing Study Group provided support. Disclosure S.Kaneko: Advisory Panel; Lilly Diabetes, Speaker's Bureau; AstraZeneca, Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Lilly Diabetes, Bayer Inc., Kowa Company, Ltd., Kyowa Kirin Co., Ltd. K.Motohashi: None. Y.Ueba: None. S.Tokumoto: None. Funding Cookie Testing Study Group

686-P: Risk Associations between Patient Reported Depression, Cardiovascular-Renal Events, All-Cause Mortality, and Potential Single-Item Patient Health Questionnaire (PHQ) Screening for All-Cause Mortality in Asians—Six-Year Prospective Analysis of the Hong Kong Diabetes Register

Background: Asians are at higher risk of diabetes, though risk associations of depression and diabetes complications were reported mainly in the Western population. This is the first prospective study reporting association between depression and clinical outcomes in Asian patients with type 2 diabetes (T2D), adjusted for patient report outcomes (PRO) including lifestyle behaviours, self-care and health-related quality of life (HRQoL). Methods: We performed a retrospective analysis of 4525 Chinese patients with T2D utilizing the Hong Kong Diabetes Register medical records and PRO data collected between 2013 and 2019. Hazard ratios (HR) of depression for the following diabetes complications were estimated: cardiovascular disease (CVD) including ischemic heart disease (IHD), stroke, chronic kidney disease (CKD) and all-cause mortality adjusted for PRO with Cox regression models. Results: At baseline, 537 patients reported depressive symptoms with a PHQ-9 score≥7. Depression was significantly associated with CVD (HR 1.90 [1.20-3.01]) particularly for IHD (HR 2.21 [1.21-4.02]) after adjusting for conventional risk factors and PRO. Depression was significantly associated with all-cause mortality (HR 1.87 [1.16-3.03]) before adjusting for HRQoL. Patient Health Questionnaire (PHQ-9) Q4 (feeling tired or having little energy) was significantly associated with all-cause mortality (HR 1.76 [1.38-2.24]), indicating a potential single screening item for all-cause mortality in Asian patients with T2D. Conclusion: Depression is reported to have significant associations with diabetes complications considering PRO. PHQ-9 Q4 can be used as a single item tool in identifying patients with T2D who are at high risk of all-cause mortality, for early counselling and behaviour modifications. Disclosure J.N.M.Lui: None. H.Yeung: None. K.Loo: None. R.Ozaki: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer Inc., Celltrion, Boehringer Ingelheim and Eli Lilly Alliance, Sanofi, Research Support; AstraZeneca, Servier Laboratories, Viatris Inc., Hua Medicine, Merck KGaA, Applied Therapeutics Inc., Lee Powder, Pfizer Inc., Speaker's Bureau; Novartis, Stock/Shareholder; GemVCare Ltd. E.S.H.Lau: None. Y.Yeung: None. K.Lee: None. T.Yung: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Speaker's Bureau; Abbott, AstraZeneca, Lilly, Bayer Inc., Boehringer Ingelheim Inc. A.Luk: Research Support; Novo Nordisk, Boehringer-Ingelheim, Bayer Inc., Speaker's Bureau; Eli Lilly and Company. E.Chow: Research Support; Medtronic, Merck KGaA, Speaker's Bureau; Novartis, Bayer Inc., Sanofi. R.C.Ma: Advisory Panel; AstraZeneca, Merck & Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk.

590-P: Assessment of a Comprehensive Physical Fitness Index to Predict Future Diabetes Mellitus (DM) and Metabolic Syndrome (MetS)

Impaired muscle strength, balance, and flexibility have been associated with the development of type 2 diabetes and atherosclerosis. A physical score (PS), which integrates these physical fitness indices, could be expected to better predict future metabolic diseases. We investigated the longitudinal relationship between the baseline PS and changes in PS and future DM and MetS. Analyzed were 5,718 persons (4,068 men) aged 30 to 69 y without DM who underwent physical fitness tests. Principal component analysis was performed on the correlation matrix of the physical fitness test results according to age and sex. The PS was defined as the first principal component score. Associations between PSs at the start of observation (year −2), change in the PS two years later (year 0) and the incidence of DM at the end of observation (until year 3) were examined by logistic regression analysis. The same analysis was performed for 5,304 persons (3,729 men) without MetS at baseline. Although no significant difference was found in the incidence of DM, a significant difference was found in the incidence of MetS; odds ratio was 1.39 (1.20, 1.61) for each decrease of 1 in the PS in year −2 and 1.51 (1.18, 1.92) for each decrease of 1 in the change in PS from year -2 to year 0. = Results showed that the PS was a simple and non-invasive predictor of MetS. Disclosure T.Sato: None. K.Kato: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. K.Fujihara: None. M.H.Yamada: None. Y.Yaguchi: None. M.Yamamoto: None. M.Kitazawa: None. H.Ishiguro: None. T.Osawa: None. T.Yamada: None. Funding Japan Society for the Promotion of Science; Japan Ministry of Health, Labour and Welfare (21K11569)

109-OR: Prior Cerebrovascular Disease Was Positively Associated with Severe Diabetic Retinopathy and Diabetic Macular Edema in Type 2 Diabetes

Background and Purpose: Although it is well established that diabetic retinopathy (DR) and diabetic macular edema (DME) are risk factors for incident cerebrovascular disease (CVD), whether the CVD history could be a predictor of severe DR or DME remains unknown among people with type 2 diabetes. Also, the effects of aging or systolic blood pressure on incident severe DR or DME in individuals with a history of CVD remains unknown. Methods: Severe DR and DME were defined as vision-threatening treatment-required diabetic eye diseases (TRDED). Enrolled were 31,638 Japanese patients with type 2 diabetes. We longitudinally explored the existence of such an association not only overall but also according to various factors. Results: The main outcome of TRDED was observed in 854 (2.7%) patients during a mean follow-up of 5.3 years (5.1/1,000 person-years). Prior CVD was present in 694 of 31,638 (2.2%) patients at baseline. In a multivariate adjusted Cox regression model, prior CVD was positively associated with incident TRDED in analysis of the study population (hazard ratio, 1.63 [95% confidence interval, 1.11-2.37] overall; 1.47 [0.54, 3.99] for age ≤49 y; 1.69 [1.12, 2.55] for age ≥50 y; 1.46 [0.89, 2.39] for SBP ≤139 mmHg; 1.97 [1.09, 3.58] for SBP ≥140 mmHg). All results, including several stratified analyses, correlated with visual inspection of the corresponding Kaplan-Meier analysis with log-rank tests indicating gaps between curves for those with and without prior CVD. Conclusions: These results indicate that CVD is a predictor of vision-threatening severe retinopathy, and suggested that they shared a common background pathophysiology. It also contributed to preventing severe visual impairment and further deterioration of the quality of life after stroke. Disclosure M.Yamamoto: None. M.Iwanaga: None. T.Yamada: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. K.Fujihara: None. H.Hasebe: None. H.Shiozaki: None. R.Kodera: None. T.Sato: None. Y.Yaguchi: None. T.Osawa: None. Y.Matsubayashi: None. Funding Japan Society for the Promotion of Science (JP21K11569, JP22K16212)

420-P: Longitudinal Trajectories of Tubular Biomarkers in Type 1 Diabetes

Background: Tubular biomarkers may provide insight into progression of kidney tubulointerstitial pathology that is complementary to traditional measures of glomerular function and damage. Methods: We examined longitudinal tubular biomarker trajectories in the DCCT/EDIC Study of T1D. For each of 220 randomly-selected participants, biomarkers were measured at up to 7 time points over 26 years. Measurements comprised KIM-1 and sTNFR1 in plasma, EGF and MCP1 in timed urine, and a composite tubular secretion score calculated from the urinary clearances of 8 small molecules secreted by the proximal tubule. Biomarker trends were described and associations with intensive diabetes therapy and glycemia changes over time were tested. Results: Mean age was 28 years at baseline, 45% were women, and 50% were assigned to intensive versus conventional therapy during DCCT. At baseline, participants had a mean estimated glomerular filtration rate (eGFR) of 125 ml/min/1.73m2, and 90% had a urinary albumin excretion rate (AER) < 30 mg/24h. Mean changes in biomarkers over time (in percent per decade) were: KIM-1 27.3% (95% CI 21.4, 33.5), sTNFR1 16.9% (95% CI 14.5, 19.3), MCP1 18.4% (95% CI 8.9, 28.8), EGF -13.5% (95% CI -16.7, -10.1), EGF/MCP1 -26.9% (95% CI -32.2, -21.3), and tubular secretion score -0.9% (95% CI -1.8, 0.0), compared with -12.0% (95% CI -12.9, -11.1) for eGFR and 10.9% (95% CI 2.5, 20.1) for AER. Intensive versus conventional therapy was associated with slower rise in sTNFR1 (relative difference in change 0.94; 95% CI 0.90, 0.98). Higher time-updated HbA1c was associated with faster rises in sTNFR1 (relative difference in change 1.06 per 1% higher HbA1c; 95% CI 1.05, 1.08) and KIM-1 (1.09; 95% CI 1.05, 1.14). Conclusion: Among people with T1D and normal eGFR at baseline, kidney tubular biomarkers changed significantly over long-term follow-up. Hyperglycemia was associated with larger increases in plasma sTNFR1 and KIM1 over time. Disclosure C.Limonte: None. I.Bebu: None. J.Seegmiller: None. M.Molitch: Consultant; Amryt Pharma Plc, Corcept Therapeutics, Janssen Pharmaceuticals, Inc., Sention, Takeda Pharmaceutical Co., Ltd. B.A.Perkins: Advisory Panel; Dexcom, Inc., Insulet Corporation, Novo Nordisk, Sanofi, Vertex Pharmaceuticals Incorporated, Other Relationship; Abbott, Medtronic, Sanofi, Research Support; Novo Nordisk, Bank of Montreal (BMO). A.B.Karger: Consultant; Roche Diagnostics, Research Support; Kyowa Kirin Co., Ltd., Siemens, Speaker's Bureau; Siemens, American Society of Nephrology, American Kidney Fund, National Kidney Foundation. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc. Dcct/edic writing group: n/a. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK094176, U01DK094157)

454-P: Risk Stratification of Cerebrocardiovascular Disease (CVD) according to HbA1c, Fasting Plasma Glucose (FPG), and Their Combinations in People with Prediabetes (preDM)

Association between preDM, defined by HbA1c or FPG alone, and CVD has remained controversial whereas impaired glucose tolerance (IGT) defined according to 2-h blood glucose level in the oral glucose tolerance test has been consistently associated with CVD. However, a glucose tolerance test is not practical in all persons. Thus, we attempted to identify a high-risk group for CVD in those with PreDM using HbA1c and FPG combinations. We analyzed data from a nationwide claims database on 1,140,096 Japanese with no CVD history or glucose abnormality from 2008 to 2022. Multivariate Cox regression analysis showed that compared with normal HbA1c (≤5.6%), CVD risk increased significantly and linearly from HbA1c 5.9% to HbA1c 6.8% in the diabetic range. Conversely, compared with normal FPG (70-99 mg/dl), CVD risk did not increase in the preDM range at each FPG level. Analysis of combinations of HbA1c and FPG showed that with FPG levels 70-99 mg/dl compared with HbA1c ≤5.6%, those with HbA1c 6.0-6.4% had an increased risk of CVD. Risk was higher than with HbA1c 6.5-6.8% (hazard ratio [HR] 1.30 [95% CI 1.11-1.52], 1.11 [0.63-1.96]) (Table). Results suggest that preDM with high HbA1c and normal FPG might have potential postprandial hyperglycemia or lack treatment interventions due to undiagnosed diabetes, which could increase risk of CVD. Disclosure K.Murai: None. M.Iwanaga: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. K.Fujihara: None. Y.Yaguchi: None. M.H.Yamada: None. Y.Matsubayashi: None. M.Kitazawa: None. M.Yamamoto: None. T.Yamada: None. S.Kodama: None.

1243-P: Usefulness of New Criteria for Metabolic Syndrome Optimized for Prediction of Cardiovascular Diseases in Japanese

The use of multiple diagnostic criteria for metabolic syndrome (MetS) may miss high-risk populations for cardiovascular disease. Moreover, since women are more likely to have subcutaneous fat deposits than men, the predictive ability of cardiovascular disease may be improved by optimizing the cut-off value of each component of criteria according to sex and considering whether to include waist circumference (WC) as a required component. In a nationwide cohort of 565,079 men and women from 2008 to 2016 in Japan, we analyzed the association between MetS and each component and the development of CAD, CVD, or CAD/CVD using multivariate Cox regression. Of these 3,934 men (1.19%) and 893 women (0.38%) developed CAD/CVD, with a 1.3- to 2.9-fold increased risk of CAD/CVD when current MetS components were met. The optimal thresholds for predicting CAD/CVD by ROC analysis in men and women were WC 83 and 77 cm, triglycerides 130 and 90 mg/dl, HDL-C 50 and 65 mg/dl, BP 130/80 and 120/80 mmHg, and FPG of 100 and 90 mg/dl, respectively. Although no significant difference was detected between the current MetS criteria and our modified criteria in the ability to predict CAD/CVD, using the new criteria increased prevalence of MetS and significantly improved sensitivity (Table). Optimizing MetS criteria could significantly reduce the number of high-risk individuals overlooked by the current criteria. Disclosure Y.Mitsuma: None. Y.Matsubayashi: None. M.Iwanaga: None. T.Yamada: None. K.Kato: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. K.Fujihara: None. K.Murai: None. T.Sato: None. Y.Yaguchi: None. M.H.Yamada: None. M.Yamamoto: None. T.Osawa: None. M.Kitazawa: None.

1390-P: Incidence and Predictors of Remission and Relapse of Type 2 Diabetes Mellitus (T2DM) in Japan—Analysis of Nationwide Patient Registry

To determine the incidence/one year relapse from remission and associated factors in patients with T2DM. A total of 48,320 Japanese patients with T2DM with HbA1c ≥6.5% and/or glucose-lowering drug prescription were identified from databases of specialists’ clinics from 1989 and followed until September 2022. Remission was diagnosed according HbA1c <6.5% at least 3 months after cessation of glucose-lowering drug and relapse as failing to maintain remission for 1 year. Factors associated with remission/relapse were evaluated by logistic regression analysis. The overall incidence of remissions per 1,000 person-years was 10.5. Such values for those with HbA1c 6.5-6.9%, taking no glucose-lowering drugs at baseline, and a ≥10% BMI reduction in one year were 27.8, 21.7, 48.2, respectively (Fig.). Shorter duration, lower baseline HbA1c, higher BMI at baseline, higher BMI reduction at one year, and no glucose-lowering drugs at baseline were significantly associated with remission. Among 3,677 persons with remission, approximately two-thirds (2,490) relapsed within one year. Longer duration, lower BMI at baseline, and lower BMI reduction at one year were significantly associated with relapse. Results showed that the incidence of remission and predictors of relapse, especially baseline BMI were greatly different in East Asians compared to reports in Western populations. Disclosure K.Fujihara: None. L.Khin: None. K.Murai: None. Y.Mitsuma: None. K.Yamazaki: None. H.Maegawa: None. S.Tanaka: Research Support; Novo Nordisk. S.Kodama: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. Funding Japan Society for the Promotion of Science (21K11569)

11-OR: Fetal Renal Hypoxia Response to Maternal Overnutrition

Currently, 50% of women of reproductive age are obese, and one in seven live births is affected by hyperglycemia in mothers with gestational diabetes. To examine the impact of intrauterine overnutrition on the kidneys of the offspring, we generated a novel mouse model by feeding female C57BL6J mice with either control diet (CD) or high-fat diet (HFD, 60% Lipid) during gestation and feeding the male offspring with CD after weaning, allocated to two groups of male offspring, CD and HFD. CD and HFD had similar body weights, blood pressure and urinary albumin levels, but lower serum creatinine levels in HFD (CD; n=17, HFD; n=11, p<0.001), which might be due to renal hyperfiltration. Histologically, HFD presented renal tubular vacuolation at 4 weeks of age and glomerulosclerosis and intrarenal arteriosclerotic lesions at 15 weeks of age. Moreover, perirenal beige fat phenotype was lost in HFD at 4 week of age, presenting white adipose cells unlike the small adipose cells in CD, suggesting that maternal overnutrition induced systemic metabolic abnormality in offspring. Synchrotron phase-contrast micro-CT showed that HFD at 14.5 dpc showed asignificant increase in total kidney volume (CD; n=4, HFD; n=6, p<0.001). On the contrary, no significant difference in renal artery diameter was observed (p=0.52). Blood flow is determined by the supplying vascular diameter due to Murrays’ minimum energy hypothesis. Therefore, we studied the ratio of blood flow as the 3rd power of the diameter of fetal renal artery per renal volume, indicating no significant difference between CD and HFD (p=0.42). Despite of preserved blood supply, the protein expression of HIF-1α, the key hypoxic transcription factor, was higher in HFD than that in CD, suggesting increased oxygen demand due to maternal overnutrition-induced renal metabolism. Maternal overnutrition induces supply-demand mismatch leading to renal hypoxia in the fetus, which persists into adulthood in the offspring, which might promote susceptibility to diabetic nephropathy. Disclosure T.Takiyama: None. Y.Takiyama: None. R.Bessho: None. H.Kitsunai: None. Y.Takiyama: Research Support; Boehringer Ingelheim Japan, Inc., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Abbott Japan Co., Ltd., Roche Diabetes Care, MSD Life Science Foundation, Japan Society for the Promotion of Science, Teijin Pharma Limited, Kyowa Kirin Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly Japan K.K.

1713-P: Dietary Manganese (Mn) Intake Is Independently Associated with a Lower BMI in Younger Japanese with Type 2 Diabetes Mellitus (T2DM)

We analyzed the association between dietary Mn intake and obesity measured by BMI after adjustment for intake of nutrients and food groups in people with T2DM in Japan. Participants were 1567 people, 63% male, aged 30 to 89 y who were in the Japan Diabetes Clinical Data Management Study Group (JDDM), one of the largest cohorts of Japanese with diabetes. Intake of food groups was determined by a validated self-administered food frequency questionnaire based on food groups. Obesity was defined as BMI ≥25 kg/m2. Multivariate logistic regression analysis assessed the relationship between quartiles of dietary Mn intake and obesity stratified by age. Participants aged 30 to 89 y were grouped according to the following quartiles for age: 30-54 y, 55-63 y, 64-71 y, and 72-89 y. Compared to the lowest quartile (Q1) for Mn, a significant negative association between Mn and BMI was found in males for all quartiles of Mn (OR [95%CI] of Q2= 0.643 [0.424 - 0.973], Q3= 0.607 [0.374 - 0.986], Q4= 0.398 [0.218 - 0.728], p trend = 0.028) with adjustment for characteristics such as age, sex, current smoking, drinking, insulin, oral hypoglycemic agents treatment, activity, energy intake and macronutrients intake. However, statistical significance disappeared after adding total fiber as a covariate. Compared to the lowest quartile for Mn, the highest quartile of Mn was inversely associated with BMI in the younger age group (30-54 y [OR= 0.296 [0.088 - 0.996]]) even after total fiber adjustment. Multivariate analysis of food groups (rice, vegetables, soy products) that were highly correlated with Mn as covariates showed that the relationships between Mn intake and obesity were maintained (p trend for rice, vegetables, soy = <0.001, 0.187, 0.010) in all participants. In summary, higher dietary Mn intake was independently associated with a lower BMI, especially in the younger group and males. Future prospective or intervention studies are expected to confirm this result. Disclosure L.Khin: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. Jddm study group: n/a. K.Fujihara: None. M.Hatta: None. Y.Takeda: None. S.Y.Morikawa: None. C.Horikawa: None. N.Kato: None. M.Kato: None. H.Maegawa: None.