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OBJECTIVE We examined the associations of GAD antibodies (GADA) and C-peptide (CP) with insulin initiation, glycemic responses, and severe hypoglycemia in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS In 5,230 Chinese patients (47.6% men) with T2D (mean ± SD age: 56.5 ± 13.9 years; median diabetes duration: 6 [interquartile range 1, 12] years), enrolled consecutively in 1996–2012 and prospectively observed until 2019, we retrospectively measured fasting CP and GADA in stored serum and examined their associations with aforementioned outcomes. RESULTS At baseline, 28.6% (n = 1,494) had low CP ( CONCLUSIONS There is considerable heterogeneity in autoimmunity and β-cell dysfunction in T2D with GADA+ and high CP associated with early insulin initiation, while GADA+ and low CP, increased the risk of severe hypoglycemia. Extended phenotyping is warranted to increase the precision of classification and treatment in T2D.

OBJECTIVE To evaluate the performance of a real-time continuous glucose monitor (CGM) in individuals with diabetes on peritoneal dialysis (PD). RESEARCH DESIGN AND METHODS Thirty participants with type 2 diabetes on continuous ambulatory PD wore a Guardian Sensor 3 on the upper arm paired with Guardian Connect for 14 days. We compared CGM readings against Yellow Springs Instrument (YSI) venous glucose during an 8-h in-clinic session with glucose challenge. RESULTS The mean absolute relative difference (MARD) was 10.4% (95% CI 9.6, 11.7) from 941 CGM-YSI matched pairs; 81.3% of readings were within %15/15 of YSI values in the full glycemic range. Consensus error grid analysis showed 99.9% of sensor values in zones A and B. There were no correlations between pH, uremia, hydration status, and MARD. CONCLUSIONS We showed satisfactory performance of a real-time CGM sensor in PD patients with diabetes, supporting future use to facilitate treatment decisions.

Objective: This study aims to unravel genetic determinants of coronary heart disease (CHD) in type 2 diabetes (T2D) and explore their applications. Research Design and Methods: We performed a two-stage genome-wide association studies for CHD in Chinese patients with T2D (3,596 cases and 8,898 controls), followed by replications in European patients with T2D (764 cases and 4,276 controls) and general populations (n=51,442-547,261). Each identified variant was examined for its association with a wide range of phenotypes, and its interactions with glycaemic, blood pressure (BP) and lipid controls on incident cardiovascular diseases. Results: We identified a novel variant (rs10171703) for CHD (OR [95% CI] = 1.21 [1.13–1.30]; P=2.4×10-8) and BP (β±SE = 0.130±0.017; P = 4.1×10-14) at PDE1A in Chinese T2D patients, but found only a modest association with CHD in general populations. This variant modulated the effects of BP goal attainment (130/80 mmHg) on CHD (Pinteraction = 0.0155) and myocardial infarction (MI) (Pinteraction = 5.1×10-4). Patients with CC-genotype of rs10171703 had >40% reduction in either cardiovascular events in response to BP control (2.9×10-8 < P < 3.6×10-5), those with CT-genotype had no difference (0.0726 < P < 0.2614), and those with TT-genotype had a threefold increase in MI risk (P = 6.7×10-3). Conclusions: We discovered a novel CHD- and BP-related variant at PDE1A which interacted with BP goal attainment with divergent effects on CHD risk in Chinese patients with T2D. Incorporating this information may facilitate individualized treatment strategies for precision care in diabetes only when our findings are validated.

Glycated hemoglobin A1c (HbA1c) has reduced reliability in advanced chronic kidney disease (CKD) owing to factors influencing red cell turnover. Recent guidelines support the use of continuous glucose monitoring (CGM) in glycemic assessment in these patients. We evaluated relationships between HbA1c and CGM metrics of average glycemia and glucose variability (GV) in moderate-to-advanced CKD.There were a total of 90 patients with diabetes in CKD stages G3b (Correlations between glucose management indicator (GMI) and HbA1c attenuated with advancing CKD (G3b [CGM-derived indices might serve as an adjunct to HbA1c monitoring to guide glycemic management, especially in those with eGFR 30 ml/min per 1.73 m

Objective We examined the associations of glutamic acid decarboxylase antibodies (GADA) and C-peptide (CP) with insulin initiation, glycemic responses and severe hypoglycemia in type 2 diabetes (T2D). Research Design and Methods In 5230 Chinese patients with T2D (mean±SD age: 56.5±13.9 years, diabetes duration (median, IQR): 6 (1-12) years, 47.6% men) enrolled consecutively in 1996-2012 and prospectively observed till 2019, we retrospectively measured fasting CP and GADA in stored serum and examined their associations with aforementioned outcomes. Results At baseline, 28.6% had low CP (p=0.002) for insulin initiation versus the GADA- group, while the low-CP group had an aHR of 0.88 (0.77-1.00, p=0.051) versus the high-CP group. Following insulin initiation, the GADA+ plus low-CP group had the largest decrements in HbA1c (-1.9% at month 6; -1.5% at month 12) versus -1% in the other 3 groups. The aHR of severe hypoglycemia was 1.29 [(95% CI 1.10-1.52), p=0.002] in the low-CP and 1.38 [(95% CI 1.04-1.83) p=0.024] in the GADA+ group. Conclusions There is considerable heterogeneity in autoimmunity and beta-cell dysfunction in T2D with GADA+ and high CP associated with early insulin initiation while GADA+ and low CP, increased risk of severe hypoglycemia. Extended phenotyping is warranted to increase the precision of classification and treatment in T2D.

OBJECTIVE Several studies support associations between relative leukocyte telomere length (rLTL), a biomarker of biological aging and type 2 diabetes. This study investigates the relationship between rLTL and the risk of glycemic progression in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In this cohort study, consecutive Chinese patients with type 2 diabetes (N = 5,506) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using quantitative PCR. Glycemic progression was defined as the new need for exogenous insulin. RESULTS The mean (SD) age of the 5,349 subjects was 57.0 (13.3) years, and mean (SD) follow-up was 8.8 (5.4) years. Baseline rLTL was significantly shorter in the 1,803 subjects who progressed to insulin requirement compared with the remaining subjects (4.43 ± 1.16 vs. 4.69 ± 1.20). Shorter rLTL was associated with a higher risk of glycemic progression (hazard ratio [95% CI] for each unit decrease [to ∼0.2 kilobases]: 1.10 [1.06–1.14]), which remained significant after adjusting for confounders. Baseline rLTL was independently associated with glycemic exposure during follow-up (β = −0.05 [−0.06 to −0.04]). Each 1-kilobase decrease in absolute LTL was on average associated with a 1.69-fold higher risk of diabetes progression (95% CI 1.35–2.11). Two-sample Mendelian randomization analysis showed per 1-unit genetically decreased rLTL was associated with a 1.38-fold higher risk of diabetes progression (95% CI 1.12–1.70). CONCLUSIONS Shorter rLTL was significantly associated with an increased risk of glycemic progression in individuals with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for glycemic progression in people with type 2 diabetes.

Aims/hypothesis Few large-scale prospective studies have investigated associations between relative leucocyte telomere length (rLTL) and kidney dysfunction in individuals with type 2 diabetes. We examined relationships between rLTL and incident end-stage kidney disease (ESKD) and the slope of eGFR decline in Chinese individuals with type 2 diabetes. Methods We studied 4085 Chinese individuals with type 2 diabetes observed between 1995 and 2007 in the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data. rLTL was measured using quantitative PCR. ESKD was diagnosed based on the ICD-9 code and eGFR. Results In this cohort (mean ± SD age 54.3 ± 12.6 years) followed up for 14.1 ± 5.3 years, 564 individuals developed incident ESKD and had shorter rLTL at baseline (4.2 ± 1.2 vs 4.7 ± 1.2, p n = 3521). On Cox regression analysis, each ∆∆Ct decrease in rLTL was associated with an increased risk of incident ESKD (HR 1.21 [95% CI 1.13, 1.30], p 1c, lipids, renal function and other risk factors (HR 1.11 [95% CI 1.03, 1.19], p = 0.007). Shorter rLTL at baseline was associated with rapid decline in eGFR (>4% per year) during follow-up (unadjusted OR 1.22 [95% CI 1.15, 1.30], p p = 0.024). Conclusions/interpretation rLTL is independently associated with incident ESKD and rapid eGFR loss in individuals with type 2 diabetes. Telomere length may be a useful biomarker for the progression of kidney function and ESKD in type 2 diabetes. Graphical abstract

Intensive lifestyle modification showed variable success in the prevention of major clinical events and mortality among people with prediabetes. We propose that age may partly explain the heterogeneity and that health hazards related to prediabetes are age-specific.We conducted a retrospective analysis of a territory-wide diabetes surveillance dataset from the Hong Kong Hospital Authority between 2000 and 2019. Prediabetes was defined according to the American Diabetes Association criteria. Proportional Cox regression was performed, stratified by baseline age categories (20-39, 40-59, 60-79 and ≥80 years).1,630,942 individuals were included in the analysis. Compared with normoglycaemia, prediabetes was associated with greater hazards for cardiovascular disease (CVD) and all-cause mortality in most age groups but the effect size attenuated with ascending age (Prediabetes is associated with higher risk of major clinical events, even excluding subsequent development of diabetes and adjusting for metabolic factors. The risk relationships are stronger in young than older people.This study did not receive any specific funding.

To examine the association of initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) at lower glycemic threshold with decline in estimated-glomerular filtration rate (eGFR).We analyzed a prospective cohort of Chinese patients with type 2 diabetes from Hong Kong. Patients initiating SGLT2i at HbA1c 7.5 % (lower-HbA1c) versus ≥ 7.5 % (higher-HbA1c) were matched using 1:1 propensity score. We compared annual eGFR changes in the lower-HbA1c and higher-HbA1c groups using linear mixed-effect models. Binary logistic regression was used to explore associations of SGLT2i initiation at lower HbA1c with odds of rapid eGFR decline (4% per year).Among 3384 patients with a median follow-up of 1.9 years, the mean age was 60.2 ± 11.5 years and 62.1 % were male. The lower-HbA1c and higher-HbA1c groups had baseline HbA1c (%) of 6.9 ± 0.5 and 9.0 ± 1.3 respectively, with similar pre-index annual eGFR decline. The lower-HbA1c group had a slower post-index annual eGFR decline than the higher-HbA1c group (-0.99 versus -1.63 mL/min/1.73 mIn this real-world study, SGLT2i initiation at HbA1c 7.5 % was associated with slower eGFR decline especially in high risk patients, supporting the potential renal benefits of SGLT2i initiation at lower glycemic thresholds.

We postulated that the increased lifetime risk of chronic kidney disease (CKD) in young-onset diabetes is attributable to both long disease duration and more aggressive disease. We examined whether age at diabetes diagnosis modifies the effect of diabetes duration on risk of CKD. We included 436,744 people with incident type 2 diabetes in the Hong Kong Diabetes Surveillance Database (HKDSD) and 16,979 people with prevalent type 2 diabetes in the Hong Kong Diabetes Register (HKDR). We used Poisson models to describe joint effects of age at diabetes diagnosis, diabetes duration and attained age on incidence of CKD in HKDSD. We used Cox proportional hazards models to examine interaction effect of age at diabetes diagnosis and diabetes duration on risk of CKD with adjustment for confounders in HKDR. During a median follow-up of 5.3 years, 134,043 cases of CKD were recorded in the HKDSD. The incidence rate ratio for CKD comparing people of the same attained age but diagnosed with diabetes at ages 5 years apart was higher for people with a younger age at diabetes diagnosis, but decreased with increasing age at diabetes diagnosis. During a median follow-up of 6.3 years, 6500 people developed CKD in the HKDR. The increased risk of CKD with longer diabetes duration decreased with older age at diabetes diagnosis. The adjusted HR for CKD associated with 5 year increase in diabetes duration was 1.37 (95% CI 1.13, 1.65) in people with diabetes diagnosed at 20–29 years and 1.01 (95% CI 0.87, 1.18) in those diagnosed at ≥70 years. Young age at diabetes diagnosis amplified the effect of increasing diabetes duration on increased risk of CKD.

The long-term effects of metformin in individuals with type 2 diabetes who are at increased risk of severe respiratory infections are unknown. This study aimed to evaluate the effects of metformin use on the risk of first pneumonia hospitalisation and pneumonia-related death in a cohort of Chinese individuals with type 2 diabetes. We performed a retrospective analysis of a consecutive cohort of 22,638 individuals with type 2 diabetes in the Hong Kong Diabetes Register enrolled between 2001 and 2018, with follow-up until 31 December 2019. Overlap propensity-score weighting was performed to balance baseline characteristics. Of 22,638 individuals with type 2 diabetes, after excluding those who had not been prescribed any glucose-lowering drugs (GLDs) and/or with eGFR ≤30 ml min−1 [1.73 m]−2 or treated by dialysis and/or treated with insulin at baseline, we identified 15,784 either prevalent or incident metformin users and 917 users of other GLDs during a mean follow-up period of 7.5 years. Overlap-weighted analysis showed an HR of 0.63 (95% CI 0.52, 0.77) for first pneumonia hospitalisation and 0.49 (95% CI 0.33, 0.73) for pneumonia-related death in metformin users vs users of other GLDs; similar observations resulted following stratification by sex and kidney function. There was also a negative association between metformin exposure over time (proportion of duration of metformin prescriptions during the total follow-up time) and pneumonia events using the penalised spline analysis. Metformin users had a lower neutrophil/lymphocyte ratio at first pneumonia hospitalisation vs non-metformin users (mean [95% CI]: 12.8 [12.1, 13.5] vs 14.8 [12.3, 17.3], p = 0.032). The rate of metformin-associated lactic acidosis was 2.5 per 100,000 person-years. The lower risk of pneumonia events was also observed among incident metformin users vs other GLD users. Long-term use of metformin was associated with reduced risk of pneumonia and pneumonia-related death among Chinese individuals with diabetes. The relevance of these results to other respiratory infections merits further investigation.

Introduction Diabetes and bone health are closely related. We examined the incidence and risk factors of hip fractures in Chinese patients with type 2 diabetes (T2D). Materials and Methods In this prospective cohort, we consecutively enrolled 22,325 adults with T2D above the age of 40 years in the Hong Kong Diabetes Register between 1994 and 2015 with crude hip fracture incidence rate censored in 2017. Results At baseline, the mean age of this cohort was 60.9 ± 10.5 years (mean duration of diabetes 6 years, 52.4% male). During a mean ± standard deviation (SD) follow‐up period of 8.7 ± 5.2 years with 193,553 person‐years, 603 patients were hospitalized due to hip fractures with an incidence (95% confidence interval, CI) of 315.1 (290.4–341.3) per 100,000 person‐years. On multivariable analysis with competing death risk adjusted, the independent hazard ratios (95% CI) for hip fractures in T2D were 2.01 (1.61–2.51) for female sex, 1.08 (1.07–1.09) for age, 0.93 (0.90–0.95) for body mass index, 1.52 (1.25–1.85) for albuminuria and 1.12 (1.02–1.23) for low density lipoprotein‐cholesterol. In men, the 30‐day, 1‐year and 5‐year post‐hip fracture mortality rate (95% CI) were 5.8 (2.4–9.1) %, 29.2 (22.3–35.5) % and 65.9 (57.3–72.8) % respectively. The corresponding rates in women were 3.4 (1.6–5.1) %, 18.6 (14.7–22.4) %, and 46.8 (40.9–52.1) %. Conclusions Southern Chinese patients with T2D have a high risk of hip fracture associated with suboptimal cardiometabolic‐renal risk factors and a high post‐fracture mortality rate. The effects of improving modifiable risk factors on bone health warrants further evaluation., With prospective follow up of nearly 9 years, we identified several risk factors associated with increase hip fracture incidence in Southern Chinese patients with type 2 diabetes in the Hong Kong Diabetes Register. These include female sex, age, body mass index, albuminuria and low density lipoprotein.

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 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.

Background: Prediabetes is associated with increased risk of cardiovascular disease (CVD) , kidney disease and death but the extent to which the risk associations between prediabetes and clinical events are modified by age is not known. Methods: We conducted a retrospective analysis of a territory-wide diabetes surveillance dataset from the Hong Kong Hospital Authority including 2,692,880 individuals with at least one glycaemic measurement between 2000 and 2019. Prediabetes was defined according to the American Diabetes Association criteria. Proportional Cox regression was used to derive hazard ratios (HR) and 95% CI of prediabetes vs. normoglycaemic for incident CVD, end-stage kidney disease (ESKD) , all-site infection and all-cause death, stratified by baseline age categories (20-39, 40-59, 60-79 and ≥80 years) . Results: Compared with people with normoglycaemia, people with prediabetes had greater hazards for clinical events in all age groups but the effect size attenuated with ascending age. In the youngest and in the oldest age categories, the respective HRs (95% CI) of prediabetes vs. normoglycaemia were 1.93 (1.71-2.17) and 1. (1.01-1.12) for CVD, 1.72 (1.42-2.08) and 1. (1.03-1.17) for ESKD, 1.48 (1.36-1.62) and 1. (1.00-1.08) for all-site infection, and, 1.52 (1.33-1.73) and 1. (1.04-1.10) for all-cause death. The associations remained after excluding people who later developed diabetes and after adjusting for metabolic factors. Conclusion: Prediabetes increases the risk of major clinical events and death independent of subsequent development of diabetes and metabolic factors. The risk relationships between prediabetes and clinical events are stronger in young than older people. Disclosure X.Zhang: 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.Luk: None. H.Wu: None. E.S.H.Lau: None. M.Shi: None. B.Fan: None. A.Yang: None. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. 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. 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.

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

Background: In patients with type 2 diabetes (T2D) and non-ketotic presentation, low C-peptide (CP) and positivity for glutamic acid decarboxylase antibodies (GADA+) indicate early insulin requirement. In GADA- patients, the associations of CP with insulin use, glycemic response and severe hypoglycemia event (SHE) are unknown. Methods: We measured fasting CP and GADA in 4590 Chinese patients with T2D enrolled in the Hong Kong Diabetes Register in 1995-2012 followed up till 2019. The updated homeostasis model assessment (HOMA2) was derived from fasting CP and plasma glucose. We defined incident insulin use as the first insulin prescription of at least 28 days, glycemic response as HbA1c reduction at one year after insulin initiation, and SHE using ICD-9 codes. Linear and Cox regression models were applied for association analyses. Results: At enrolment, 32% had low CP ( Conclusions: In patients with T2D, CP interacted with GADA to influence disease progressions including early insulin therapy and SHE. C-peptide might be correlated with IR in patients with GADA-. These subphenotypes allowed more precise classification of beta cell function to guide personalized treatment. 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.P.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

Background: Few studies reported incidence rates of late-stage complications in people with youth-onset type 2 diabetes. We compared the clinical characteristics and incidence of cardiovascular disease (CVD) , end-stage kidney disease (ESKD) and death in a cohort of Chinese youth with type 2 and type 1 diabetes. Method: We performed a retrospective analysis of 1221 people with type 2 diabetes and 641 with type 1 diabetes diagnosed at age Result: At baseline, people with youth-onset type 2 diabetes were older at diagnosis (16 [14-18] vs. [8-15] years, p Conclusion: People with youth-onset type 2 diabetes had 2-fold increased risk of CVD and ESKD, in part driven by greater burden of obesity and other metabolic risk factors in this group. Disclosure Y.Fan: None. E.S.H.Lau: None. H.Wu: None. A.Yang: None. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. 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. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. 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. A.Luk: None.

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 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 Results: Of 11,323 ACEi/ARBs users with new-onset eGFR 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.

We aimed to describe trends in rates of hospitalisation for lower extremity amputation (LEA) and 1 year mortality rates after LEA in people with diabetes in Hong Kong between 2001 and 2016.The Hong Kong Diabetes Surveillance Database is a territory-wide population-based diabetes cohort (N = 770,078) identified from the Hong Kong Hospital Authority electronic medical system. We identified LEA events using ICD-9 procedure codes and 1 year mortality after LEA from linkage to the Hong Kong Death Registry. Joinpoint regression models were used to describe the trends.Between 2001 and 2016, 6113 hospitalisations for LEAs in men and 4149 in women were recorded in the Hong Kong Diabetes Surveillance Database. The rates of minor LEAs declined by 48.6% (average annual per cent change [AAPC]: -3.8; 95% CI -5.7, -1.9) in men and by 59.5% (AAPC: -6.3; 95% CI -10.6, -1.8) in women. The rates of major LEAs declined by 77.9% (AAPC: -8.0; 95% CI -9.6, -6.5) in men and by 79.3% (AAPC: -10.4; 95% CI -13.1, -7.6) in women. The cumulative 1 year mortality rates after minor and major LEAs were 18.5% and 41.8% in men, and 21.3% and 42.0% in women, respectively, for the whole period. No change was detected in 1 year mortality rates during the surveillance in both sexes.Although hospitalisation rates for LEAs have declined overall in people with diabetes, there were no improvements in 1 year mortality rates after LEA. Continuous efforts are needed to further prevent LEAs and improve the survival rate of people undergoing LEAs. Graphical abstract.

Aims/hypothesis Infection is an under-recognised but important complication in people with diabetes. Studies on temporal trends in incidence of infection in this population are limited. We report the trends in infection-related hospitalisation in people with diabetes and compared hospitalisation rates between people with and without diabetes in Hong Kong. Methods Hospital admissions with infection, including pneumonia, influenza, tuberculosis, kidney infection, urinary tract infection, cellulitis, osteomyelitis, foot infection and sepsis, listed as principal diagnosis occurring between 2001 and 2016 were identified from people with diabetes in the electronic medical record system of the Hong Kong Hospital Authority. Data on hospitalisation for a subset of these infections in the general population between 2007 and 2016 were obtained from the Department of Health. The number of people with diabetes ranged between 117,322 in 2001 and 570,929 in 2016, and the number without diabetes ranged between 5,242,614 in 2007 and 5,593,153 in 2016. Joinpoint regression was used to describe the trends. Results In people with diabetes, over a period of 16 years, the age-standardised annual rates of hospitalisation decreased for tuberculosis but increased for influenza; rates of hospitalisation for pneumonia increased up until 2004/2005 and declined in men and stabilised in women. The rates of hospitalisation for most infection types were unchanged or increased in the 20–44 year and 45–64 year age groups and decreased in those aged 65 years or above. Trends for most of the infections were similar when comparing sexes. Between 2007 and 2016, the rate ratios of hospitalisation for most infection types between people with and without diabetes were stable, and the rate ratios remained higher in people with diabetes, ranging from 1.3–1.4 for pneumonia to 3.2–4.9 for kidney infections in 2016 compared with non-diabetic individuals. Conclusions/interpretation Despite advances in medical care, hospitalisation due to infections remains a major healthcare burden in people with diabetes. Graphical abstract Electronic supplementary material The online version of this article (10.1007/s00125-020-05286-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Background Nationwide studies on contemporary trends in incidence of diabetes-related complications in Asia are lacking. We describe trends in incident coronary heart disease (CHD), stroke, heart failure, hyperglycaemic crisis, and lower-extremity amputation (LEA) in people with diabetes in Hong Kong between 2001 and 2016. Methods The Hong Kong Diabetes Surveillance Database (HKDSD) is a territory-wide diabetes cohort identified from Hong Kong Hospital Authority electronic medical record system. We identified events of CHD, stroke, heart failure and hyperglycaemic crisis using hospital principal diagnosis codes at discharge and that of LEA using inpatient procedure codes. We used Joinpoint regression analysis to describe incidence trends by age and sex. Results Between 2001 and 2016, a total of 390,071 men and 380,007 women aged 20 years or older with diabetes were included in the HKDSD. Event rates of CHD, stroke, heart failure, hyperglycaemic crisis and LEA declined by 69.4% (average annual percent change: − 7.6, 95% CI − 10.2, − 5.0), 70.3% (− 8.7, 95% CI − 9.8, − 7.5), 63.6% (− 6.4, 95% CI − 8.0, − 4.7), 59.1% (− 6.6, 95% CI − 12.4, − 0.44), and 67.5% (− 5.8, 95% CI − 7.2, − 4.4), in men and by 77.5% (− 9.9, 95% CI − 11.8, − 7.9), 74.5% (− 9.0, 95% CI − 9.6, − 8.4), 65.8% (− 7.0, 95% CI − 8.0, − 6.0), 81.7% (− 8.5, 95% CI − 10.5, − 6.5), and 72.7% (− 9.1. 95% CI − 12.2, − 5.8) in women, respectively, over a 16-year period in people with diabetes in Hong Kong. Joinpoint analysis identified greater declines in event rates of the five diabetes-related complications in the earlier one-third of study period and slowed down but remained significant until 2016. Event rates decreased for all age groups above 45 years for both sexes. There was no significant change in event rates in the group aged 20–44 years except for decline in hyperglycaemic crisis. Conclusions The event rates of diabetes-related complications have declined substantially with no evidence of stabilization or increase in Hong Kong up to 2016. Improvements in outcome were observed for all age subgroups but not in young people with diabetes, calling for urgent action to improve quality of care to prevent complications in young people at risk.

Aims To explore the pattern of insulin use and glycaemic control in Asian people with type 2 diabetes, stratified by gender, young‐onset diabetes (YOD; diagnosed before age 40 years), and diabetic kidney disease (DKD; estimated glomerular filtration rate [eGFR]

To evaluate the effect of a team-based multi-component intervention care (MIC) program in obese patients with type 2 diabetes (T2D) and poor glycemic control.Patients with T2D and HbAOf 207 eligible patients [age (mean ± standard deviation): 56.9 ± 8.8 years, 47.4 % men, disease duration: 13.5 ± 8.2 years, HbATeam-based MIC for 1 year improved glycemic control in obese T2D which was sustained at 3-year.

Liver is a major site for glucose metabolism. Patients with type 2 diabetes (T2D) and obesity have increased risk of liver cancer. We explored the association of glycemic burden (GB) and obesity with liver cancer in T2D in the prospective Hong Kong Diabetes Register (1995-2019). We calculated GB using the area under the curve above hemoglobin A1c (HbA1c) of 5.7% and defined obesity as body mass index (BMI) ≥ 25 kg/m

AIMS/HYPOTHESIS: The aim of the study was to describe trends in all-cause and cause-specific mortality rates in Hong Kong Chinese people with diabetes from 2001 to 2016.METHODS: The Hong Kong Diabetes Surveillance Database (HKDSD) is a territory-wide diabetes cohort identified from the Hong Kong Hospital Authority electronic medical record system. Deaths between 2001 and 2016 were identified from linkage to the Hong Kong Death Registry. We used Joinpoint regression analysis to describe mortality patterns among people with diabetes by age and sex, and standardised mortality ratios (SMRs) to compare all-cause mortality rates in people with and without diabetes.RESULTS: Between 2001 and 2016, a total of 390,071 men and 380,007 women aged 20 years or older with diabetes were included in the HKDSD. There were 96,645 deaths among men and 88,437 deaths among women. Mortality rates for all-cause, cardiovascular disease and cancer among people with diabetes declined by 52.3%, 72.2% and 65.1% in men, respectively, and by 53.5%, 78.5% and 59.6% in women, respectively. Pneumonia mortality rates remained stable. The leading cause of death in people with diabetes has shifted from cardiovascular disease to pneumonia in the oldest age group, with cancer remaining the most common cause of death in people aged 45-74 years. The all-cause SMRs for men declined from 2.82 (95% CI 2.72, 2.94) to 1.50 (95% CI 1.46, 1.54), and for women, they declined from 3.28 (95% CI 3.15, 3.41) to 1.67 (95% CI 1.62, 1.72). However, among people aged 20-44 years, the declines in all-cause mortality rates over the study period were not statistically significant for both men (average annual per cent change [AAPC]: -3.2% [95% CI -7.3%, 1.0%]) and women (AAPC: -1.2% [95% CI -6.5%, 4.4%]). The SMRs in people aged 20-44 years fluctuated over time, between 7.86 (95% CI 5.74, 10.5) in men and 6.10 (95% CI 3.68, 9.45) in women in 2001, and 4.95 (95% CI 3.72, 6.45) in men and 4.92 (95% CI 3.25, 7.12) in women in 2016.CONCLUSIONS/INTERPRETATION: Absolute and relative mortality has declined overall in people with diabetes in Hong Kong, with less marked improvements in people under 45 years of age, calling for urgent action to improve care in young people with diabetes.

This systematic review aims to assess the incidence of chronic kidney disease (CKD), cardiovascular disease (CVD) and mortality in people with type 2 diabetes diagnosed20 years.We searched MEDLINE, Embase and Cochrane Library for longitudinal studies published between 1 January 2000 and 31 November 2021.Seventeen studies (15 reporting CKD, 3 reporting CVD, 5 reporting mortality) from seven countries of sample size ranging between 96 and 4,141 were eligible. Most studies were conducted in North America and Europe (n = 14). Diabetes duration at enrolment varied from 0 to 8.3 years and follow-up duration from 1 to 12.6 years. The incidence rates (per 1,000 person-year) of albuminuria ranged between 12.4 and 114.8, macroalbuminuria or proteinuria between 10 and 35.0, end-stage kidney disease (ESKD) between 0.4 and 25.0, CVD between 3.7 and 19.5, and mortality between 1.0 and 18.6. The highest incidence rates of albuminuria, ESKD and mortality were recorded in Australian Aboriginal and Pima Indian populations. Youth-onset type 2 diabetes was associated with greater risk of developing CKD compared with type 1 diabetes in most studies.Studies reporting CVD in youth-onset type 2 diabetes are scarce. Estimated incidence rates of CKD and mortality in youth-onset type 2 diabetes varied across different study populations, potentially higher in indigenous people. Youth with type 2 diabetes are at higher risk of adverse kidney outcomes than their type 1 counterparts. More studies are needed in regions outside of North America and Europe.

Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing DKD phenotype. We compared the risks of adverse outcomes among patients with this phenotype compared with other DKD phenotypes.Multicenter prospective cohort study.19,025 Chinese adults with type 2 diabetes enrolled in the Hong Kong Diabetes Biobank.DKD phenotypes defined by baseline estimated glomerular filtration rate (eGFR) and albuminuria: no DKD (no decreased eGFR or albuminuria), albuminuria without decreased eGFR, decreased eGFR without albuminuria, and albuminuria with decreased eGFR.All-cause mortality, cardiovascular disease (CVD) events, hospitalization for heart failure (HF), and chronic kidney disease (CKD) progression (incident kidney failure or sustained eGFR reduction ≥40%).Multivariable Cox proportional or cause-specific hazards models to estimate the relative risks of death, CVD, hospitalization for HF, and CKD progression. Multiple imputation was used for missing covariates.Mean participant age was 61.1 years, 58.3% were male, and mean diabetes duration was 11.1 years. During 54,260 person-years of follow-up, 438 deaths, 1,076 CVD events, 298 hospitalizations for HF, and 1,161 episodes of CKD progression occurred. Compared with the no-DKD subgroup, the subgroup with decreased eGFR without albuminuria had higher risks of all-cause mortality (hazard ratio [HR], 1.59 [95% CI, 1.04-2.44]), hospitalization for HF (HR, 3.08 [95% CI, 1.82-5.21]), and CKD progression (HR, 2.37 [95% CI, 1.63-3.43]), but the risk of CVD was not significantly greater (HR, 1.14 [95% CI, 0.88-1.48]). The risks of death, CVD, hospitalization for HF, and CKD progression were higher in the setting of albuminuria with or without decreased eGFR. A sensitivity analysis that excluded participants with baseline eGFR 30 mL/min/1.73 mPotential misclassification because of drug use.Nonalbuminuric DKD was associated with higher risks of hospitalization for HF and of CKD progression than no DKD, regardless of baseline eGFR.

BackgroundThe clinical predictors and prognosis of heart failure (HF) by categories of left ventricular ejection fraction (LVEF) have not been well studied in people with diabetes. In a retrospective cohort of Chinese with type 2 diabetes, we examined 1) clinical factors associated with incident decompensated HF, and 2) mortality post-HF, stratified by LVEF.MethodsWe conducted a retrospective analysis of the Hong Kong Diabetes Register comprising 23,348 people with type 2 diabetes without history of HF enrolled between 1993–2015, followed for incident decompensated HF until 2017. Heart failure subtypes were defined according to LVEF on echocardiography. Multivariate Cox proportional hazards models were used to identify clinical factors associated with incident HF versus no HF, stratified by HF subtypes. All-cause mortality rates were compared by HF subtypes.ResultsOver median follow-up of 7.1 years from enrolment, 1,195 (5.1%) people developed decompensated HF. Among 611 (51.1%) people with echocardiography, 24.1% had HF with reduced LVEF (HFrEF) (LVEF vs 26.9%,p = 0.034) and HFrEF (vs 31.3%,p vs 71.0%,p = 0.38), but similar to HFrEF group (vs 55.8%,p = 0.651).ConclusionsIn Chinese with type 2 diabetes, HFpEF was the predominant HF subtype. One-year mortality following decompensated HF was lowest in HFpEF group but 10-year mortality was similar between HFpEF and HFrEF.

Sulfonylureas (SUs) are predominantly metabolized by cytochrome p450 2C9 (CYP2C9) and cytochrome p450 2C19 (CYP2C19) enzymes. CYP2C9 polymorphisms are associated with greater treatment response and hypoglycemic risk in SU users. However, there are no large scale pharmacogenetic studies investigating the effect of loss-of-function alleles CYP2C19*2 and CYP2C19*3, which occur frequently in East Asians. Retrospective pharmacogenetic analysis was performed in 11,495 genotyped patients who were enrolled in the Hong Kong Diabetes Register between 1995 and 2017, with follow-up to December 31, 2019. The associations of CYP2C19 polymorphisms with SU treatment failure, early HbA1c response, and severe hypoglycemia were analyzed by Cox regression or logistic regression assuming an additive genetic model. There were 2341 incident SU users that were identified (mean age 59 years, median diabetes duration 9 years), of which 324 were CYP2C19 poor metabolizers (CYP2C19 *2/*2 or *2/*3 or *3/*3). CYP2C19 poor metabolizers had lower risk of SU treatment failure (hazard ratio 0.83, 95% confidence interval (CI) 0.72-0.97, P = 0.018) and were more likely to reach the HbA1c treatment target

Aims To investigate association between skin autofluorescence (SAF) and cardiovascular events (CVE) and assess its predictive value in Chinese adults with type 2 diabetes (T2D). Materials and methods SAF was measured non-invasively in 3806 Chinese adults with T2D between 2016 and 2019 with CVE as primary endpoint and individual components as secondary endpoints. Cox proportional hazard models were used to examine associations between SAF and endpoints with adjustment for conventional risk factors. C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were performed to evaluate SAF's predictive value. Results During a median 1.8 (interquartile range, 1.2–3.1) years of follow-up, 172 individuals experienced CVE. Multivariate Cox model showed that SAF was independently associated with CVE (HR 1.18 per SD, 95% CI [1.02, 1.37]), coronary heart disease (HR 1.29 per SD, 95% CI [1.02, 1.63]), and congestive heart failure (HR 1.53 per SD, 95% CI [1.14, 2.05]). SAF yielded additional value on CVE risk stratification with enhanced IDI (95% CI) (0.023 [0.001, 0.057]) and continuous NRI (0.377 [0.002, 0.558]) over traditional risk factors. Conclusions Higher SAF was independently associated with CVE in Chinese adults with T2D and yielded incremental predictive information for CVE. SAF has potential as a prognostic maker for CVE.

Skin autofluorescence (SAF), a non-invasive measure of the accumulation of advanced glycation end products (AGEs) in skin collagen, is associated with baseline estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR). We aimed to investigate whether SAF can identify individuals with type 2 diabetes (T2D) at high-risk of renal function decline. A total of 3,806 Chinese with T2D had SAF measured between 2016 to 2019. The primary endpoint was incident end-stage kidney disease (ESKD) or ≥40% decline in eGFR relative to baseline. The secondary endpoint was the annual change in eGFR during follow-up. A Cox proportional hazard model was used for the primary endpoint, and linear mixed-effects model with random intercept and slope for eGFR slope and the association between SAF and rate of eGFR change. People with prevalent ESKD were excluded. Mean ± SD age was 60.4 ± 10.4 years, with mean ± SD eGFR 81.5 ± 22.9 ml/min/1.73 m2; median (interquartile range [IQR]) UACR was 2.2 (0.8-9.6) mg/mmol; and median eGFR slope was -2.18 ml/min/1.73 m2/year. During a median (IQR) 1.76 (1.13-3.13) years of follow-up, 219 experienced the primary endpoint. SAF was associated with increased risk of progression of kidney disease (adjusted hazard ratio 1.16 per SD, 95% CI [1.01, 1.33]), even after adjustment for established risk factors including eGFR and UACR. SAF was identified as an independent determinant of rate of eGFR decline (adjusted Beta coefficient -2.85 per SD, 95% CI [-3.82, -1.87]). Using the median eGFR slope as the cut-off, higher SAF was associated with faster eGFR decline (adjusted odds ratio 1.12 per SD, 95% CI [1.03, 1.22]) on multivariate logistic regression. This study demonstrates for the first time in a prospective setting that higher SAF is independently associated with increased risk of progression of kidney disease in individuals with T2D. Disclosure Q. Jin: None. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. A. Jenkins: Advisory Panel; Self; Abbott Diabetes, Sanofi-Aventis, Other Relationship; Self; Amgen Inc., Research Support; Self; Abbott, International Diabetes Federation, JDRF, Medtronic, Mylan N. V. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. E. S. Lau: None. A. Luk: None. R. Ozaki: None. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. T. So: None. H. Yeung: None. K. Loo: n/a. C. K. Lim: Stock/Shareholder; Self; GemVCare Ltd. Funding Research Grants Council of Hong Kong (R4012-18)

The incidence of liver cancer and related mortality is increasing globally. Liver is a major site for glucose metabolism. People with type 2 diabetes (T2D) had increased risk of liver cancer. However, the association of glycemic burden (GB) with liver cancer in T2D remains unclear. We calculated GB using area under the curve above 5.7% of HbA1c (AUC_A1c) in patients with T2D enrolled in the prospective Hong Kong Diabetes Register established since 1995. Structured baseline data were linked to laboratory and hospitalization records in a territory-wide electronic medical record system with data censored in 2019. We performed Cox regression analysis to investigate the association of GB with incident liver cancer defined as first hospitalization with ICD9 code (155). We included 18,173 patients (50.93% male, age: 58.43±12.48 years, HbA1c: 7.58±1.66%, BMI: 25.51±4.06 kg/m2, disease duration: 20.68 ±7.63 years), who had ≥ 10 years of disease duration, > 3 years of observation, and ≥ 5 HbA1c measurements (21.98±12.33). During a median (IQR) follow up period of 10.62 (8.09, 15.88) years (218,381patient-years), 160 patients developed liver cancer with an incidence of 7.33 per 10,000 patient-years. We excluded 3 years of HbA1c values prior to incident liver cancer to avoid reverse causality. After adjusting for confounders, every 1 unit increase in AUC_A1c increased the hazard ratio (HR) of liver cancer by 1.22 (95% CI: 1.01-1.47), while AUC_A1c top quantile group had a HR of 1.78 (1.01-3.13) versus the lowest quantile group. In subgroup analysis, obese patients (BMI>25 kg/m2) had a HR of 1.34 (1.05-1.70) for liver cancer versus non-obese subjects. Amongst patients who developed liver cancer (n=1420) within 3 years of enrolment, one unit increase of AUC_A1c was associated with a HR of 1.49 (1.07-2.07) for liver cancer. GB and obesity independently increased the risk of liver cancer in T2D, emphasizing the importance of metabolic control for cancer risk reduction. Disclosure D. Mao: None. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. E. S. H. Lau: None. A. Yang: None. H. Wu: None. M. Shi: None. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. A. Luk: None.

Introduction: The overall evidence for the long-term exposure of metformin on cardiovascular-renal (CV) outcomes in patients with type 2 diabetes (T2D) at different stages of chronic kidney disease (CKD) remains controversial. Methods: We conducted a prospective analysis of 14,766 Chinese patients with T2D enrolled between 2000 and 2016 observed until 31 December 2019. We compared all-cause mortality and incidence of major adverse CV events (MACE) and end-stage kidney disease (ESKD) in prevalent and new metformin users versus other glucose lowering drugs (GLDs) users stratified by CKD stage. Results: During a mean follow-up of 9.6 years (141,310 person-years), we identified 1,798 deaths in metformin users (n=13,967) and 352 deaths in other-GLDs users (n=799). The mean daily dosage of metformin was 1,450 mg and duration of exposure was 7.8 years in CKD stage 1-2 (n=12,375). The respective figures were 1000 mg and 5.7 years in CKD stage 3-4 (n=1,592). Compared with other-GLDs, metformin exposure was associated with reduced risk of all-cause mortality (All: HR=0.48, 95% CI: 0.43-0.54; CKD stage 1-2: HR=0.38, 0.33-0.44; stage 3A: HR=0.53, 0.41-0.69); MACE (All: HR=0.85, 0.72-0.99; stage 1-2: HR=0.80, 0.65-0.99; stage 3-4: HR=0.97, 0.74-1.27) and ESKD (All: HR=0.65, 0.54-0.80; stage 1-2: HR=0.53, 0.33-0.85; stage 3-4: HR=0.80, 0.63-1.02). New users of metformin (n=4,013) had reduced risk of all-cause mortality across all CKD stages; MACE in stage 1-2 and ESKD in stage 1, 2 and 3 compared with users of other oral-GLDs (n=536). Increasing duration and dosage of metformin (up to 1500 mg/day) was associated with reduced or neutral risk of MACE, ESKD and all-cause mortality. The rate of metformin-associated lactic acidosis (MALA) was 5.39 per 100,000 patient-years in CKD stage 3-4. Conclusion: Long-term metformin use was associated with reduced or neutral risk of all-cause mortality, MACE and ESKD among Chinese patients with T2D at CKD stage 1-3 with low risk of MALA. Disclosure A. Yang: None. E. S. H. Lau: None. H. Wu: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. A. Luk: None. A. W. Fu: Research Support; Self; Merck KGaA. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. Funding Asia Diabetes Foundation; Merck Pharmaceutical (HK) Limited; Chinese University of Hong Kong (to A.Y.)

Background: The roles of insulin deficiency (ID) and resistance (IR) in young patients with type 2 diabetes (T2D) are uncertain. We explored the associations of HOMA2 IR and HOMA2 %B using fasting C peptide and plasma glucose (FPG) with incident T2D and insulin use in Chinese aged 18-50 years. Methods: Cohort 1 included subjects without T2D in 1998-2002 with glycemic status ascertained in 2012-2013. Cohort 2 included patients with T2D (1995-2014) with documentation of glycemic deterioration (continuous insulin use or failure of 2 oral drugs). Results: In cohort 1, 62 subjects developed (T2D-progressors) and 285 did not develop T2D (T2D-non-progressors) during 10-year follow-up. In cohort 2 (n=737), 293 (39.8%) required insulin after a median follow-up period of 8.6 years. At baseline, T2D-non-progressors had lower HOMA2 IR [median (IQR) 0.77 (0.60, 1.06)] vs. 1.06 (0.81, 1.38)] and similar HOMA2 %B [84.3 (72, 111.5) vs. 85.1 (75.6, 100.7)] compared with T2D-progressors. Non-insulin-requiring T2D patients had lower HOMA2 IR [1.47 (1.02, 2.11) vs. 1.76 (1.19, 2.42)] and higher HOMA2 %B [62.4 (39.4, 87.4) vs. 45.4 (25.8, 71.8)] than insulin-requiring patients. When stratified by median values and using low HOMA2 %B plus low HOMA2 IR as referent, subjects with high HOMA2 %B plus high HOMA2 IR had age and sex-adjusted odds ratio (95% CI) of 2.47 (1.28, 4.93) and those with low HOMA2% B plus high HOMA2 IR had 5.27 (2.27, 12.84) of incident T2D. In the T2D cohort, using high HOMA2 %B plus low HOMA2 IR as referent, the hazard ratio (95% CI) for insulin use increased with low HOMA2 %B [2.18 (1.47, 3.23)], high HOMA2 IR [2.45 (1.64, 3.64)] and low HOMA2 %B plus high HOMA2 IR [4.25 (2.82, 6.41)] adjusted for age, sex and disease duration. These associations were attenuated after adjusting for obesity, FPG, HbA1c and TG/HDL-C. Conclusions: In young to middle-aged Chinese, progressive worsening in IR and ID contribute to onset of T2D and insulin requirement, which can be attenuated by early control of metabolic factors. Disclosure B. Fan: None. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. A. Luk: None. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. H. Wu: None. M. Shi: None. A. Yang: None. C. H. Tam: None. E. S. H. Lau: None. D. Mao: None. C. K. P. Lim: Stock/Shareholder; Self; GemVCare Ltd. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum.

Background: Diabetes predisposes to heart failure (HF). In a prospective cohort of Chinese with type 2 diabetes, we examined 1) clinical factors associated with incident HF, and 2) mortality post-HF, stratified by ejection fraction (EF). Methods: Between 1 Jun 1993 and 30 Jun 2015, 23348 patients with type 2 diabetes without history of HF were enrolled in the Hong Kong Diabetes Register, and followed for incident HF until 30 Jun 2017. HF subtypes were defined according to EF on echocardiogram: HF with reduced EF (HFrEF), EF =50%. Multivariate Cox regression was used to identify clinical factors associated with incident HF vs. no HF, by HF subtypes. 1-year and 5-year mortality rates were compared by HF subtypes. Results: Over a follow-up of 7.1 years from enrolment, 1195 patients developed HF, of whom 611 (51.1%) had an echocardiogram within 2 years of HF episode. Distribution of HF subtypes as follows: HFrEF 24.1%, HFmrEF 15.2%, HFpEF 60.7%. Old age, low GFR, albuminuria and history of coronary artery disease were associated with increased hazards for all HF subtypes. In addition, female sex, high BMI and history of neuropathy were associated with HFpEF, and low HDL cholesterol was associated with HFmrEF. Over a follow-up of 2.1 years post-HF, 760 patients (63.6%) died with a mortality rate of 189.4 per 1000 person-year. 1-year mortality rate was lower in HFpEF group (16.2%) than those with HFmrEF (vs. 26.9%, p=0.034) and HFrEF (vs. 31.3%, p Conclusions: HFpEF was the predominant HF subtype in Chinese with diabetes. Clinical factors predicting incident HF differed according to subtypes. 1-year mortality was lower in HFpEF group but mortality at 5 years were similar between HFpEF and HFrEF with a trend of higher mortality in HFmrEF group. Disclosure A. Luk: None. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. X. Zhang: None. E. Fung: None. H. Wu: None. E. S. Lau: None. A. Yang: None. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc.

Introduction: Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are renin angiotensin system inhibitors (RASi) which can reduce the proinflammatory-vasoconstricting activity of ACE/angiotensin II and enhance the anti-inflammatory-vasodilatory activity of ACE2/angiotensin 1-7. These drugs may be protective across a range of respiratory infections including bacterial and viral pneumonias. We examined long-term use of ACEi/ARBs on the risk of first pneumonia hospitalization and pneumonia-related death in Chinese patients with type 2 diabetes (T2D). Methods: Prospective analysis of 16,285 Chinese T2D patients with new RASi use observed between 2001 and 2019. Overlap weighting was performed to balance baseline characteristics. We used time-dependent Cox model to estimate the hazard ratio (HR) of outcomes while adjusting for the time-varying covariates. Results: There were 6,379 (39.2%) ACEi-users only, 4,065 (25.0%) ARBs-users and 5,841 (35.9%) non RASi-users. During a median observation of 7.6 years, 6.1% had first pneumonia hospitalization, 1.3% died during or within one month of pneumonia hospitalization and 17.6% died from other causes. No association was observed between RASi use and first pneumonia hospitalization. However, RASi-users had lower risk for pneumonia-related death (HR 0.51, 95% CI 0.35-0.76) than non-users [ACEi-users only: HR 0.53 (0.34-0.81); ARBs-users: HR 0.58 (0.32-1.04)]. We also noted reduced risk for all-cause death in RASi-users (HR 0.60, 95% CI 0.54-0.67) [ACEi-users only: HR 0.61 (0.54-0.69); ARBs-users: HR 0.67 (0.57-0.79)]. Conclusions: Long-term use of RASi was associated with reduced risk of pneumonia-related death and all-cause death, but not first pneumonia hospitalization, in Chinese patients with T2D. Relevance to other respiratory infections such as coronavirus-disease 2019 (COVID-19) merits further investigation. Disclosure M. Shi: None. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. A. Yang: None. E. S. H. Lau: None. H. Wu: None. B. Fan: None. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. A. Luk: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA.

Background There are limited population-wide trend data on kidney failure and kidney replacement therapy (KRT) in people with diabetes. We conducted a retrospective cohort study to report incidence trends of kidney failure and KRT and related mortality in people with diabetes in Hong Kong between 2002 and 2015. Methods We used territory-wide electronic medical records including laboratory, diagnostic and procedural data to identify people with kidney failure and KRT. We used Joinpoint regression models to estimate the average annual percent change (AAPC) of kidney failure and KRT incidence for entire study period, and annual percent change (APC) for each linear trend segment, along with 1-year and 5-year mortality rates. Findings During 4.9 million person-years of follow-up of 712,222 people with diabetes, 31,425 developed kidney failure, among whom 23.0% (n=7,233) received KRT. The incidence of kidney failure declined by 46.8% from 2002 to 2007 (APC: -11.6, 95% CI: -16.3, -6.7), then flattened from 2007 to 2015 (APC: -0.9, 95% CI: -3.1, 1.3). The incidence of KRT remained constant (AAPC: -1.6, 95% CI: -4.4, 1.2). The 1-year mortality rates declined statistically significantly after both kidney failure and KRT. The 5-year mortality rates declined after kidney failure but the decline was not statistically significant after KRT. Interpretation The findings of our study highlight the importance of developing new strategies to prevent a looming epidemic of kidney failure in people with diabetes in Hong Kong. Funding Asia Diabetes Foundation

Few studies have investigated the relationship between rLTL and mortality in patients with type 2 diabetes in a large prospective study, particularly in the Asian population. This study investigates the relationship between rLTL and the risk of death in Chinese patients with type 2 diabetes.Consecutive Chinese patients with type 2 diabetes (N = 5349) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using a quantitative polymerase chain reaction. Mortality and clinical outcomes were obtained based on ICD-9 codes.The mean (SD) age of the subjects was 57.5 (13.3) years and mean (SD) follow-up duration was 13.4 (5.5) years. Baseline rLTL was significantly shorter in the 1925 subjects who subsequently died compared with the remaining subjects (4.3 ± 1.2 vs. 4.7 ± 1.2, P 0.001). Shorter rLTL was associated with a higher risk of mortality (HR: 1.19 (1.14-1.23), P 0.001), which remained significant after adjusting for traditional risk factors.Shorter rLTL was significantly associated with an increased risk of all-cause and CVD mortality in patients with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for mortality risk in patients with type 2 diabetes.