Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank.

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.

1-year weight change after diabetes diagnosis and long-term incidence and sustainability of remission of type 2 diabetes in real-world settings in Hong Kong: An observational cohort study.

BACKGROUND: Clinical trials have demonstrated that remission of type 2 diabetes can be achieved following sustained weight loss. However, the feasibility of achieving diabetes remission through weight management in real-world settings remains unclear. In this study, we aimed to examine the association of weight change at 1 year after diabetes diagnosis with long-term incidence and sustainability of type 2 diabetes remission in real-world settings in Hong Kong. METHODS AND FINDINGS: This was a population-based observational cohort study. The territory-wide Risk Assessment and Management Programme for Diabetes Mellitus (RAMP-DM) provides regular comprehensive assessments of metabolic control and complication screening for people with diabetes in Hong Kong. We included 37,326 people with newly diagnosed type 2 diabetes who were enrolled in the RAMP-DM between 2000 and 2017, followed until 2019. Diabetes remission was defined as 2 consecutive HbA1c <6.5% measurements at least 6 months apart in the absence of glucose-lowering drugs (GLDs) and with no record of GLDs at least 3 months before these measurements. During a median follow-up of 7.9 years, 6.1% (2,279) of people achieved diabetes remission, with an incidence rate of 7.8 (95% CI: 7.5, 8.1) per 1,000 person-years. After adjusting for age at diabetes diagnosis, sex, assessment year, body mass index, other metabolic indices, smoking, alcohol drinking, and medication use, the hazard ratio (HR) for diabetes remission was 3.28 (95% CI: 2.75, 3.92; p < 0.001) for people with ≥10% weight loss within 1 year of diagnosis, 2.29 (95% CI: 2.03, 2.59; p < 0.001) for those with 5% to 9.9% weight loss, and 1.34 (95% CI: 1.22, 1.47; p < 0.001) for those with 0% to 4.9% weight loss compared to people with weight gain. During a median follow-up of 3.1 years, 67.2% (1,531) of people who had achieved diabetes remission returned to hyperglycaemia, with an incidence rate of 184.8 (95% CI: 175.5, 194.0) per 1,000 person-years. The adjusted HR for returning to hyperglycaemia was 0.52 (95% CI: 0.41, 0.65; p < 0.001) for people with ≥10% weight loss, 0.78 (95% CI: 0.68, 0.92; p = 0.002) for those with 5% to 9.9% weight loss, and 0.90 (95% CI: 0.80, 1.01; p = 0.073) for those with 0% to 4.9% weight loss compared to people with weight gain. Diabetes remission was associated with a 31% (HR: 0.69, 95% CI: 0.52, 0.93; p = 0.014) decreased risk of all-cause mortality. The main limitation of the study is that the reliability of HbA1c used to define diabetes remission can be affected by other medical conditions. Furthermore, we did not have data on bariatric surgery. CONCLUSIONS: In this study, greater weight loss within the first year of diabetes diagnosis was associated with an increased likelihood of achieving diabetes remission and a decreased risk of returning to hyperglycaemia among those who had achieved diabetes remission. However, both the incidence of diabetes remission and the probability of its long-term sustainability were low with conventional management in real-world settings, in an era when the importance of weight loss was not fully appreciated. Our study provides evidence for policymakers to design and implement early weight management interventions and diabetes remission initiatives.

A novel electronic health record-based, machine-learning model to predict severe hypoglycemia leading to hospitalizations in older adults with diabetes: A territory-wide cohort and modeling study.

BACKGROUND: Older adults with diabetes are at high risk of severe hypoglycemia (SH). Many machine-learning (ML) models predict short-term hypoglycemia are not specific for older adults and show poor precision-recall. We aimed to develop a multidimensional, electronic health record (EHR)-based ML model to predict one-year risk of SH requiring hospitalization in older adults with diabetes. METHODS AND FINDINGS: We adopted a case-control design for a retrospective territory-wide cohort of 1,456,618 records from 364,863 unique older adults (age ≥65 years) with diabetes and at least 1 Hong Kong Hospital Authority attendance from 2013 to 2018. We used 258 predictors including demographics, admissions, diagnoses, medications, and routine laboratory tests in a one-year period to predict SH events requiring hospitalization in the following 12 months. The cohort was randomly split into training, testing, and internal validation sets in a 7:2:1 ratio. Six ML algorithms were evaluated including logistic-regression, random forest, gradient boost machine, deep neural network (DNN), XGBoost, and Rulefit. We tested our model in a temporal validation cohort in the Hong Kong Diabetes Register with predictors defined in 2018 and outcome events defined in 2019. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC) statistics, and positive predictive value (PPV). We identified 11,128 SH events requiring hospitalization during the observation periods. The XGBoost model yielded the best performance (AUROC = 0.978 [95% CI 0.972 to 0.984]; AUPRC = 0.670 [95% CI 0.652 to 0.688]; PPV = 0.721 [95% CI 0.703 to 0.739]). This was superior to an 11-variable conventional logistic-regression model comprised of age, sex, history of SH, hypertension, blood glucose, kidney function measurements, and use of oral glucose-lowering drugs (GLDs) (AUROC = 0.906; AUPRC = 0.085; PPV = 0.468). Top impactful predictors included non-use of lipid-regulating drugs, in-patient admission, urgent emergency triage, insulin use, and history of SH. External validation in the HKDR cohort yielded AUROC of 0.856 [95% CI 0.838 to 0.873]. Main limitations of this study included limited transportability of the model and lack of geographically independent validation. CONCLUSIONS: Our novel-ML model demonstrated good discrimination and high precision in predicting one-year risk of SH requiring hospitalization. This may be integrated into EHR decision support systems for preemptive intervention in older adults at highest risk.

Early treatment with dipeptidyl-peptidase 4 inhibitors reduces glycaemic variability and delays insulin initiation in type 2 diabetes: A propensity score-matched cohort study.

AIMS: To examine whether early treatment intensification using dipeptidyl-peptidase 4 inhibitors (DPP4i) delays insulin initiation in Chinese patients diagnosed with type 2 diabetes for less than 5 years. MATERIALS AND METHODS: In a territory-wide prospective cohort study, patients with type 2 diabetes initiating DPP4i at diabetes duration <2 years (early intensification) and 3-5 years (late intensification) were matched using 1:1 propensity-score matching (n = 908 in each arm). We used Cox regression to compare the risk of insulin initiation between the two groups. We explored the interactive and mediation effects of glycated haemoglobin (HbA1c) variability score (HVS), defined as the percentage of HbA1c varying by ≥0.5% compared with preceding values. RESULTS: Of 1816 patients (60.7% men, mean age 54.4 ± 11.9 years), 92.4% and 71.9% were treated with metformin and sulphonylureas respectively at DPP4i initiation. Early DPP4i intensification [hazard ratio (HR) 0.71, (95% CI 0.58-0.68)] and low HVS (<50%) (HR = 0.40, 0.33-0.50) were associated with delayed insulin initiation during a median 4.08 years of follow-up. Early intensification with low HVS had the lowest risk versus late intensification with high HVS (HR = 0.30, 0.22-0.40) (pinteraction  = 0.013). HVS mediated 19.5% of the total effect of early DPP4i intensification on delaying insulin initiation. The late and early intensification groups had similar HbA1c at month 0 (8.4 ± 1.3% vs. 8.4 ± 1.5%) and month 3 (7.6 ± 1.2% vs. 7.6 ± 1.3%) after DPP4i initiation. By month 12, HbA1c in the late intensification group deteriorated (7.9 ± 1.4%) but remained stable in the early intensification group (7.6 ± 1.4%, p = 0.001) with persistent between-group difference over 72 months (8.2 ± 1.7% vs. 7.7 ± 1.6%, p = 0.001). CONCLUSIONS: In type 2 diabetes, early DPP4i intensification delayed insulin initiation, partially explained by reduced glycaemic variability.

Monogenic diabetes in a Chinese population with young-onset diabetes: A 17-year prospective follow-up study in Hong Kong.

AIMS: Asians have a high prevalence of young-onset diabetes, but the pattern of monogenic diabetes is unknown. We aimed to determine the prevalence of monogenic diabetes in Chinese patients with young-onset diabetes and compare the clinical characteristics and outcome between patients with and without monogenic diabetes. MATERIALS AND METHODS: We sequenced a targeted panel of 33 genes related to monogenic diabetes in 1021 Chinese patients with non-type 1 diabetes diagnosed at age ≤40 years. Incident complications including cardiovascular disease (CVD), end-stage kidney disease (ESKD) and all-cause death were captured since enrolment (1995-2012) until 2019. RESULTS: In this cohort (mean ± SD age at diagnosis: 33.0 ± 6.0 years, median[IQR] diabetes duration 7.0[1.0-15.0] years at baseline, 44.9% men), 22(2.2%, 95% confidence interval[CI] 1.4%-3.2%) had monogenic diabetes. Pathogenic (P) or likely pathogenic (LP) variants were detected in GCK (n = 6), HNF1A (n = 9), HNF4A (n = 1), PLIN1 (n = 1) and PPARG (n = 2), together with copy number variations in HNF1B (n = 3). Over a median follow-up of 17.1 years, 5(22.7%) patients with monogenic diabetes (incidence rate 12.3[95% CI 5.1-29.4] per 1000 person-years) versus 254(25.4%) without monogenic diabetes (incidence rate 16.7[95% CI 14.8-18.9] per 1000 person-years) developed the composite outcome of CVD, ESKD and/or death (p = 0.490). The multivariable Cox model did not show any difference in hazards for composite events between groups. CONCLUSIONS: In Chinese with young-onset non-type 1 diabetes, at least 2% of cases were contributed by monogenic diabetes, over 80% of which were accounted for by P/LP variants in common MODY genes. The incidence of diabetes complications was similar between patients with and without monogenic diabetes.

Association of dipeptidyl peptidase-4 inhibitor initiation at glycated haemoglobin <7.5% with reduced major clinical events mediated by low glycated haemoglobin variability.

AIM: Therapeutic inertia, hypoglycaemia and poor treatment persistence can lead to glycaemic fluctuation and poor outcomes in type 2 diabetes (T2D). We compared glycated haemoglobin (HbA1c) variability, insulin initiation, severe hypoglycaemia and clinical events in patients with T2D initiated dipeptidyl peptidase-4 inhibitors (DPP4is) at low versus high HbA1c thresholds. METHODS: Using territory-wide electronic medical records in Hong Kong, we curated a propensity score-matched cohort of patients initiated DPP4i at HbA1c <7.5% versus ≥7.5% in 2007-2019. We expressed the HbA1c variability score (HVS) as a proportion of HbA1c varied by ≥0.5% compared with preceding values. We used the Cox model to compare the risks of insulin initiation and clinical outcomes, adjusted for time-varying variables between the two groups. Mediation analysis estimated the effects of HbA1c variability on outcomes. RESULTS: Among 6874 insulin-naïve patients who initiated DPP4i, 88.7% were treated with metformin and 79.6% with sulphonylureas at baseline (54.9% men; mean age 65.2 ± 11.4 years). After a median follow-up of 4.6 years, compared with the high-threshold plus high-HVS group (≥50%), the low-threshold plus low-HVS (<50%) group had reduced hazard ratios (95% confidence interval) of insulin initiation (0.35, 0.31-0.40), severe hypoglycaemia (0.38, 0.34-0.44), major adverse cardiovascular endpoints (0.76, 0.66-0.88), heart failure (0.42, 0.36-0.49), end-stage kidney disease (0.65, 0.36-0.49) and mortality (0.45, 0.35-0.57). Reduced HbA1c variability explained 31.1%-81.2% of the effect size of DPP4i initiation at HbA1c <7.5% versus ≥7.5% on outcomes. CONCLUSIONS: In Chinese patients with T2D, avoiding therapeutic inertia with intensified glycaemic control at HbA1c <7.5% using drugs with low risk of hypoglycaemia and good tolerability, such as DPP4i, delayed insulin treatment, reduced HbA1c variability and improved clinical events.

Age-specific population attributable risk factors for all-cause and cause-specific mortality in type 2 diabetes: An analysis of a 6-year prospective cohort study of over 360,000 people in Hong Kong.

BACKGROUND: The prevalence of type 2 diabetes has increased in both young and old people. We examined age-specific associations and population attributable fractions (PAFs) of risk factors for all-cause and cause-specific mortality in people with type 2 diabetes. METHODS AND FINDINGS: We analysed data from 360,202 Chinese with type 2 diabetes who participated in a territory-wide diabetes complication screening programme in Hong Kong between January 2000 and December 2019. We compared the hazard ratios and PAFs of eight risk factors, including three major comorbidities (cardiovascular disease [CVD], chronic kidney disease [CKD], all-site cancer) and five modifiable risk factors (suboptimal HbA1c, suboptimal blood pressure, suboptimal low-density lipoprotein cholesterol, smoking, and suboptimal weight), for mortality across four age groups (18 to 54, 55 to 64, 65 to 74, and ≥75 years). During a median 6.0 years of follow-up, 44,396 people died, with cancer, CVD, and pneumonia being the leading causes of death. Despite a higher absolute mortality risk in older people (crude all-cause mortality rate: 59.7 versus 596.2 per 10,000 person-years in people aged 18 to 54 years versus those aged ≥75 years), the relative risk of all-cause and cause-specific mortality associated with most risk factors was higher in younger than older people, after mutually adjusting for the eight risk factors and other potential confounders including sex, diabetes duration, lipid profile, and medication use. The eight risk factors explained a larger proportion of mortality events in the youngest (PAF: 51.6%, 95% confidence interval [CI] [39.1%, 64.0%], p < 0.001) than the oldest (PAF: 35.3%, 95% CI [27.2%, 43.4%], p < 0.001) age group. Suboptimal blood pressure (PAF: 16.9%, 95% CI [14.7%, 19.1%], p < 0.001) was the leading attributable risk factor for all-cause mortality in the youngest age group, while CKD (PAF: 15.2%, 95% CI [14.0%, 16.4%], p < 0.001) and CVD (PAF: 9.2%, 95% CI [8.3%, 10.1%], p < 0.001) were the leading attributable risk factors in the oldest age group. The analysis was restricted to Chinese, which might affect the generalisability to the global population with differences in risk profiles. Furthermore, PAFs were estimated under the assumption of a causal relationship between risk factors and mortality. However, reliable causality was difficult to establish in the observational study. CONCLUSIONS: Major comorbidities and modifiable risk factors were associated with a greater relative risk for mortality in younger than older people with type 2 diabetes and their associations with population mortality burden varied substantially by age. These findings highlight the importance of early control of blood pressure, which could reduce premature mortality in young people with type 2 diabetes and prevent the onset of later CKD and related mortality at older ages.

Age- and sex-specific hospital bed-day rates in people with and without type 2 diabetes: A territory-wide population-based cohort study of 1.5 million people in Hong Kong.

BACKGROUND: Type 2 diabetes affects multiple systems. We aimed to compare age- and sex-specific rates of all-cause and cause-specific hospital bed-days between people with and without type 2 diabetes. METHODS AND FINDINGS: Data were provided by the Hong Kong Hospital Authority. We included 1,516,508 one-to-one matched people with incident type 2 diabetes (n = 758,254) and those without diabetes during the entire follow-up period (n = 758,254) between 2002 and 2018, followed until 2019. People with type 2 diabetes and controls were matched for age at index date (±2 years), sex, and index year (±2 years). We defined hospital bed-day rate as total inpatient bed-days divided by follow-up time. We constructed negative binominal regression models to estimate hospital bed-day rate ratios (RRs) by age at diabetes diagnosis and sex. All RRs were stratified by sex and adjusted for age and index year. During a median of 7.8 years of follow-up, 60.5% (n = 459,440) of people with type 2 diabetes and 56.5% (n = 428,296) of controls had a hospital admission for any cause, with a hospital bed-day rate of 3,359 bed-days and 2,350 bed-days per 1,000 person-years, respectively. All-cause hospital bed-day rate increased with increasing age in controls, but showed a J-shaped relationship with age in people with type 2 diabetes, with 38.4% of bed-days in those diagnosed <40 years caused by mental health disorders. Type 2 diabetes was associated with increased risks for a wide range of medical conditions, with an RR of 1.75 (95% CI [confidence interval] [1.73, 1.76]; p < 0.001) for all-cause hospital bed-days in men and 1.87 (95% CI [1.85, 1.89]; p < 0.001) in women. The RRs were greater in people with diabetes diagnosed at a younger than older age and varied by sex according to medical conditions. Sex differences were most notable for a higher RR for urinary tract infection and peptic ulcer, and a lower RR for chronic kidney disease and pancreatic disease in women than men. The main limitation of the study was that young people without diabetes in the database were unlikely to be representative of those in the Hong Kong general population with potential selection bias due to inclusion of individuals in need of medical care. CONCLUSIONS: In this study, we observed that type 2 diabetes was associated with increased risks of hospital bed-days for a wide range of medical conditions, with an excess burden of mental health disorders in people diagnosed at a young age. Age and sex differences should be considered in planning preventive and therapeutic strategies for type 2 diabetes. Effective control of risk factors with a focus on mental health disorders are urgently needed in young people with type 2 diabetes. Healthcare systems and policymakers should consider allocating adequate resources and developing strategies to meet the mental health needs of young people with type 2 diabetes, including integrating mental health services into diabetes care.

Real world evidence of clinical predictors of glycaemic response to glucose-lowering drugs among Chinese with type 2 diabetes.

AIMS: To examine whether simple clinical features can predict the 1-year glycaemic response to glucose-lowering drugs (GLDs) among Chinese with type 2 diabetes. MATERIALS AND METHODS: We used data from a diabetes risk assessment and complication screening programme and electronic medical records. We used linear regression models to examine the association between clinical features and 1-year glycaemic response to GLDs. RESULTS: Use of metformin (n = 15,433), sulphonylureas (SU) (n = 15,190), dipeptidyl peptidase-4 inhibitor (DPP-4i) (n = 7947), thiazolidinedione (TZD) (n = 4107), and sodium-glucose cotransporter 2 inhibitors (SGLT-2i) (n = 1883) were associated with a mean reduction of HbA1c ranging from 0.7% to 1.3% at one year. Men had a greater response to SU but a poorer response to metformin and TZD. Older age predicted a better response to all GLDs but not SGLT-2i, whereas increasing diabetes duration was associated with a poorer response to all GLDs except for DPP-4i. Obese patients responded greater to TZD and SGLT-2i but poorer to SU than those with normal weight. Patients with a higher level of triglycerides to high-density lipoprotein cholesterol ratio had a greater glycaemic response to TZD but a smaller response to SU and DPP-4i. CONCLUSIONS: Glycaemic response to GLDs differed considerably by clinical features among Chinese patients with type 2 diabetes.

Real-world usage of sulphonylureas in Asian patients with type 2 diabetes using the Joint Asia Diabetes Evaluation (JADE) register.

AIMS: To explore the patterns of use of oral glucose-lowering drugs (OGLDs) in Asian patients with type 2 diabetes (T2D), focusing on sulphonylureas (SUs), and to describe patient profiles according to treatment regimen. METHODS: We conducted a cross-sectional analysis of data from adults with T2D from 11 Asian countries/regions with structured assessment enrolled in the prospective Joint Asia Diabetes Evaluation (JADE) register between November 2007 and December 2019. Patients receiving insulin and/or injectable glucagon-like peptide-1 receptor agonists were excluded. RESULTS: Amongst 62 512 patients (mean ± standard deviation age: 57.3 ± 11.8 years; 53.6% men), 54 783 (87.6%) were treated with OGLDs at enrolment. Most received one (37.5%) or two (44.2%) OGLDs. In the entire cohort, 59.4% of treated patients received SU-based therapy with variations amongst countries/regions. Overall, 79.5% of SU regimens were based on SUs plus metformin, and 22.1% on SUs plus dipeptidyl peptidase-4 inhibitors. Among SU users, gliclazide was most commonly prescribed (46.7%), followed by glimepiride (40.0%) and glibenclamide (8.1%). More gliclazide users entered the cohort with glycated haemoglobin levels <53 mmol/mol (7%) than non-gliclazide SU users (odds ratio [OR] 1.09, 95% CI 1.02-1.17), with less frequent self-reported hypoglycaemia in the 3 months before registration (OR 0.81, 95% CI 0.72-0.92; adjusted for sociodemographic factors, cardiometabolic risk factors, complications, use of other OGLDs, country/region and year of registration). CONCLUSION: In Asia, SUs are a popular OGLD class, often combined with metformin. Good glycaemic control and safety profiles associated with the use of SUs, including gliclazide, support their position as a key treatment option in patients with T2D.

Relative leucocyte telomere length is associated with incident end-stage kidney disease and rapid decline of kidney function in type 2 diabetes: analysis from the Hong Kong Diabetes Register.

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 < 0.001) than the non-progressors (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 < 0.001); the association remained significant after adjusting for baseline age, sex, HbA1c, 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 < 0.001; adjusted OR 1.09 [95% CI 1.01, 1.17], 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.

Lifetime risk of developing diabetes in Chinese people with normoglycemia or prediabetes: A modeling study.

BACKGROUND: Little is known about the lifetime risk of progression to diabetes in the Asian population. We determined remaining lifetime risk of diabetes and life years spent with diabetes in Chinese people with normoglycemia and prediabetes. METHODS AND FINDINGS: Using territory-wide diabetes surveillance data curated from electronic medical records of Hong Kong Hospital Authority (HA), we conducted a population-based cohort study in 2,608,973 individuals followed from 2001 to 2019. Prediabetes and diabetes were identified based on laboratory measurements, diagnostic codes, and medication records. Remaining lifetime risk and life years spent with diabetes were estimated using Monte Carlo simulations with state transition probabilities based on a Markov chain model. Validations were performed using several sensitivity analyses and modified survival analysis. External replication was performed using the China Health and Retirement Longitudinal Survey (CHARLS) cohort (2010 to 2015). The expected remaining lifetime risk of developing diabetes was 88.0 (95% confidence intervals: 87.2, 88.7)% for people with prediabetes and 65.9 (65.8, 65.9)% for people with normoglycemia at age 20 years. A 20-year-old person with prediabetes would live with diabetes for 32.5 (32.0, 33.1) years or 51.6 (50.8, 52.3)% of remaining life years, whereas a person with normoglycemia at 20 years would live 12.7 (12.7, 12.7) years with diabetes or 18.4 (18.4, 18.5)% of remaining life years. Women had a higher expected remaining lifetime risk and longer life years with diabetes compared to men. Results are subjected to possible selection bias as only people who undertook routine or opportunistic screening were included. CONCLUSIONS: These findings suggest that Hong Kong, an economically developed city in Asia, is confronted with huge challenge of high lifetime risk of diabetes and long life years spent with diabetes, especially in people with prediabetes. Effective public health policies and targeted interventions for preventing progression to diabetes are urgently needed.

Nonalbuminuric Diabetic Kidney Disease and Risk of All-Cause Mortality and Cardiovascular and Kidney Outcomes in Type 2 Diabetes: Findings From the Hong Kong Diabetes Biobank.

RATIONALE & OBJECTIVE: 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. STUDY DESIGN: Multicenter prospective cohort study. SETTINGS & PARTICIPANTS: 19,025 Chinese adults with type 2 diabetes enrolled in the Hong Kong Diabetes Biobank. EXPOSURES: 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. OUTCOMES: 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%). ANALYTICAL APPROACH: 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. RESULTS: 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 m2 yielded similar findings. LIMITATIONS: Potential misclassification because of drug use. CONCLUSIONS: Nonalbuminuric DKD was associated with higher risks of hospitalization for HF and of CKD progression than no DKD, regardless of baseline eGFR.

High-density lipoprotein subclasses and cardiovascular disease and mortality in type 2 diabetes: analysis from the Hong Kong Diabetes Biobank.

OBJECTIVE: High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility. RESEARCH DESIGN AND METHODS: HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value. RESULTS: Over median (IQR) 5.2 (5.0-5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate < 0.05). Very large HDL-P were positively associated with all-cause mortality [1.75 (1.19, 2.58)]. Small HDL-P improved prediction of mortality [C-statistic 0.034 (0.013, 0.055), IDI 0.052 (0.014, 0.103), categorical NRI 0.156 (0.006, 0.252), and continuous NRI 0.571 (0.246, 0.851)] and CVD [IDI 0.017 (0.003, 0.038) and continuous NRI 0.282 (0.088, 0.486)] over the RECODe model. CONCLUSION: Small HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D.

Associations of the HOMA2-%B and HOMA2-IR with progression to diabetes and glycaemic deterioration in young and middle-aged Chinese.

AIMS: Insulin deficiency (ID) and resistance (IR) contribute to progression from normal glucose tolerance to diabetes to insulin requirement although their relative contributions in young-onset diabetes is unknown. METHODS: We examined the associations of HOMA2 using fasting plasma glucose and C-peptide in Chinese aged 20-50 years with (1) progression to type 2 diabetes (T2D) in participants without diabetes in a community-based cohort (1998-2013) and (2) glycaemic deterioration in patients with T2D in a clinic-based cohort (1995-2014). We defined ID as HOMA2-%B below median and insulin IR as HOMA2-IR above median. RESULTS: During 10-year follow-up, 62 (17.9%) of 347 community-dwelling participants progressed to T2D. After 8.6 years, 291 (48.1%) of 609 patients with T2D had glycaemic deterioration. At baseline, progressors for T2D had higher HOMA2-IR, while in patients with T2D, progressors for glycaemic deterioration had higher HOMA2-IR and lower HOMA2-%B than non-progressors. The non-ID/IR group and the ID/IR group had an adjusted odds ratios of 2.47 (95% CI: 1.28, 4.94) and 5.36 (2.26, 12.79), respectively, for incident T2D versus the ID/non-IR group. In patients with T2D, 50% of the ID/IR group required insulin at 6.7 years versus around 11 years in the non-ID/IR or ID/non-IR, and more than 15 years in the non-ID/non-IR group. Compared with the latter group, the adjusted hazard ratios were 2.74 (1.80, 4.16) in the ID/non-IR, 2.73 (1.78, 4.19) in the non-ID/IR and 4.46 (2.87, 6.91) in the ID/IR group (p-interaction = 0.049). CONCLUSIONS: In young Chinese adults, IR and ID contributed to progression to T2D and glycaemic deterioration.

Temporal trends in rates of infection-related hospitalisations in Hong Kong people with and without diabetes, 2001-2016: a retrospective study.

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.

Long-term metformin use and risk of pneumonia and related death in type 2 diabetes: a registry-based cohort study.

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.

Young age at diabetes diagnosis amplifies the effect of diabetes duration on risk of chronic kidney disease: a prospective cohort study.

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: Young age at diabetes diagnosis amplified the effect of increasing diabetes duration on increased risk of CKD.

Secular trends in all-cause and cause-specific mortality rates in people with diabetes in Hong Kong, 2001-2016: a retrospective cohort study.

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.

Secular trends in rates of hospitalisation for lower extremity amputation and 1 year mortality in people with diabetes in Hong Kong, 2001-2016: a retrospective cohort study.

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.