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.

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.

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.

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.

Skin autofluorescence is associated with progression of kidney disease in type 2 diabetes: A prospective cohort study from the Hong Kong diabetes biobank.

BACKGROUND AND AIMS: Skin autofluorescence (SAF) can non-invasively assess the accumulation of tissue AGEs. We investigated the association between SAF and kidney dysfunction in participants with T2D. METHODS: Of 4030 participants consecutively measured SAF at baseline, 3725 participants free of end-stage kidney disease (ESKD) were included in the analyses. The association of SAF with incident ESKD or ≥30% reduction in estimated glomerular filtration rate (eGFR) was examined with Cox regression, linear mixed-effects model for the association with annual eGFR decline, and mediation analyses for the mediating roles of renal markers. RESULTS: During a median (IQR) 1.8 (1.1-3.1) years of follow-up, 411 participants developed the outcome. SAF was associated with progression of kidney disease (hazard ratio 1.15 per SD, 95% confidence interval [CI] [1.04, 1.28]) and annual decline in eGFR (ß -0.39 per SD, 95% CI [-0.71, -0.07]) after adjustment for risk factors, including baseline eGFR and urinary albumin-creatinine ratio (UACR). Decreased eGFR (12.9%) and increased UACR (25.8%) accounted for 38.7% of the effect of SAF on renal outcome. CONCLUSIONS: SAF is independently associated with progression of kidney disease. More than half of its effect is independent of renal markers. SAF is of potential to be a prognostic marker for kidney dysfunction.

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.

Age at diagnosis, glycemic trajectories, and responses to oral glucose-lowering drugs in type 2 diabetes in Hong Kong: A population-based observational study.

BACKGROUND: Lifetime glycemic exposure and its relationship with age at diagnosis in type 2 diabetes (T2D) are unknown. Pharmacologic glycemic management strategies for young-onset T2D (age at diagnosis <40 years) are poorly defined. We studied how age at diagnosis affects glycemic exposure, glycemic deterioration, and responses to oral glucose-lowering drugs (OGLDs). METHODS AND FINDINGS: In a population-based cohort (n = 328,199; 47.2% women; mean age 34.6 and 59.3 years, respectively, for young-onset and usual-onset [age at diagnosis ≥40 years] T2D; 2002-2016), we used linear mixed-effects models to estimate the association between age at diagnosis and A1C slope (glycemic deterioration) and tested for an interaction between age at diagnosis and responses to various combinations of OGLDs during the first decade after diagnosis. In a register-based cohort (n = 21,016; 47.1% women; mean age 43.8 and 58.9 years, respectively, for young- and usual-onset T2D; 2000-2015), we estimated the glycemic exposure from diagnosis until age 75 years. People with young-onset T2D had a higher mean A1C (8.0% [standard deviation 0.15%]) versus usual-onset T2D (7.6% [0.03%]) throughout the life span (p < 0.001). The cumulative glycemic exposure was >3 times higher for young-onset versus usual-onset T2D (41.0 [95% confidence interval 39.1-42.8] versus 12.1 [11.8-12.3] A1C-years [1 A1C-year = 1 year with 8% average A1C]). Younger age at diagnosis was associated with faster glycemic deterioration (A1C slope over time +0.08% [0.078-0.084%] per year for age at diagnosis 20 years versus +0.02% [0.016-0.018%] per year for age at diagnosis 50 years; p-value for interaction <0.001). Age at diagnosis ≥60 years was associated with glycemic improvement (-0.004% [-0.005 to -0.004%] and -0.02% [-0.027 to -0.0244%] per year for ages 60 and 70 years at diagnosis, respectively; p-value for interaction <0.001). Responses to OGLDs differed by age at diagnosis (p-value for interaction <0.001). Those with young-onset T2D had smaller A1C decrements for metformin-based combinations versus usual-onset T2D (metformin alone: young-onset -0.15% [-0.105 to -0.080%], usual-onset -0.17% [-0.179 to -0.169%]; metformin, sulfonylurea, and dipeptidyl peptidase-4 inhibitor: young-onset -0.44% [-0.476 to -0.405%], usual-onset -0.48% [-0.498 to -0.459%]; metformin and α-glucosidase inhibitor: young-onset -0.40% [-0.660 to -0.144%], usual-onset -0.25% [-0.420 to -0.077%]) but greater responses to other combinations containing sulfonylureas (sulfonylurea alone: young-onset -0.08% [-0.099 to -0.065%], usual-onset +0.06% [+0.059 to +0.072%]; sulfonylurea and α-glucosidase inhibitor: young-onset -0.10% [-0.266 to 0.064%], usual-onset: 0.25% [+0.196% to +0.312%]). Limitations include possible residual confounding and unknown generalizability outside Hong Kong. CONCLUSIONS: In this study, we observed excess glycemic exposure and rapid glycemic deterioration in young-onset T2D, indicating that improved treatment strategies are needed in this setting. The differential responses to OGLDs between young- and usual-onset T2D suggest that better disease classification could guide personalized therapy.

Secular trends in incidence of type 1 and type 2 diabetes in Hong Kong: A retrospective cohort study.

BACKGROUND: There is very limited data on the time trend of diabetes incidence in Asia. Using population-level data, we report the secular trend of the incidence of type 1 and type 2 diabetes in Hong Kong between 2002 and 2015. METHODS AND FINDINGS: The Hong Kong Diabetes Surveillance Database hosts clinical information on people with diabetes receiving care under the Hong Kong Hospital Authority, a statutory body that governs all public hospitals and clinics. Sex-specific incidence rates were standardised to the age structure of the World Health Organization population. Joinpoint regression analysis was used to describe incidence trends. A total of 562,022 cases of incident diabetes (type 1 diabetes [n = 2,426]: mean age at diagnosis is 32.5 years, 48.4% men; type 2 diabetes [n = 559,596]: mean age at diagnosis is 61.8 years, 51.9% men) were included. Among people aged <20 years, incidence of both type 1 and type 2 diabetes increased. For type 1 diabetes, the incidence increased from 3.5 (95% CI 2.2-4.9) to 5.3 (95% CI 3.4-7.1) per 100,000 person-years (average annual percentage change [AAPC] 3.6% [95% CI 0.2-7.1], p < 0.05) in boys and from 4.3 (95% CI 2.7-5.8) to 6.4 (95% CI 4.3-8.4) per 100,000 person-years (AAPC 4.7% [95% CI 1.7-7.7], p < 0.05] in girls; for type 2 diabetes, the incidence increased from 4.6 (95% CI 3.2-6.0) to 7.5 (95% CI 5.5-9.6) per 100,000 person-years (AAPC 5.9% [95% CI 3.4-8.5], p < 0.05) in boys and from 5.9 (95% CI 4.3-7.6) to 8.5 (95% CI 6.2-10.8) per 100,000 person-years (AAPC 4.8% [95% CI 2.7-7.0], p < 0.05) in girls. In people aged 20 to <40 years, incidence of type 1 diabetes remained stable, but incidence of type 2 diabetes increased over time from 75.4 (95% CI 70.1-80.7) to 110.8 (95% CI 104.1-117.5) per 100,000 person-years (AAPC 4.2% [95% CI 3.1-5.3], p < 0.05) in men and from 45.0 (95% CI 41.4-48.6) to 62.1 (95% CI 57.8-66.3) per 100,000 person-years (AAPC 3.3% [95% CI 2.3-4.2], p < 0.05) in women. In people aged 40 to <60 years, incidence of type 2 diabetes increased until 2011/2012 and then flattened. In people aged ≥60 years, incidence was stable in men and declined in women after 2011. No trend was identified in the incidence of type 1 diabetes in people aged ≥20 years. The present study is limited by its reliance on electronic medical records for identification of people with diabetes, which may result in incomplete capture of diabetes cases. The differentiation of type 1 and type 2 diabetes was based on an algorithm subject to potential misclassification. CONCLUSIONS: There was an increase in incidence of type 2 diabetes in people aged <40 years and stabilisation in people aged ≥40 years. Incidence of type 1 diabetes continued to climb in people aged <20 years but remained constant in other age groups.

Association of technologically assisted integrated care with clinical outcomes in type 2 diabetes in Hong Kong using the prospective JADE Program: A retrospective cohort analysis.

BACKGROUND: Diabetes outcomes are influenced by host factors, settings, and care processes. We examined the association of data-driven integrated care assisted by information and communications technology (ICT) with clinical outcomes in type 2 diabetes in public and private healthcare settings. METHODS AND FINDINGS: The web-based Joint Asia Diabetes Evaluation (JADE) platform provides a protocol to guide data collection for issuing a personalized JADE report including risk categories (1-4, low-high), 5-year probabilities of cardiovascular-renal events, and trends and targets of 4 risk factors with tailored decision support. The JADE program is a prospective cohort study implemented in a naturalistic environment where patients underwent nurse-led structured evaluation (blood/urine/eye/feet) in public and private outpatient clinics and diabetes centers in Hong Kong. We retrospectively analyzed the data of 16,624 Han Chinese patients with type 2 diabetes who were enrolled in 2007-2015. In the public setting, the non-JADE group (n = 3,587) underwent structured evaluation for risk factors and complications only, while the JADE (n = 9,601) group received a JADE report with group empowerment by nurses. In a community-based, nurse-led, university-affiliated diabetes center (UDC), the JADE-Personalized (JADE-P) group (n = 3,436) received a JADE report, personalized empowerment, and annual telephone reminder for reevaluation and engagement. The primary composite outcome was time to the first occurrence of cardiovascular-renal diseases, all-site cancer, and/or death, based on hospitalization data censored on 30 June 2017. During 94,311 person-years of follow-up in 2007-2017, 7,779 primary events occurred. Compared with the JADE group (136.22 cases per 1,000 patient-years [95% CI 132.35-140.18]), the non-JADE group had higher (145.32 [95% CI 138.68-152.20]; P = 0.020) while the JADE-P group had lower event rates (70.94 [95% CI 67.12-74.91]; P < 0.001). The adjusted hazard ratios (aHRs) for the primary composite outcome were 1.22 (95% CI 1.15-1.30) and 0.70 (95% CI 0.66-0.75), respectively, independent of risk profiles, education levels, drug usage, self-care, and comorbidities at baseline. We reported consistent results in propensity-score-matched analyses and after accounting for loss to follow-up. Potential limitations include its nonrandomized design that precludes causal inference, residual confounding, and participation bias. CONCLUSIONS: ICT-assisted integrated care was associated with a reduction in clinical events, including death in type 2 diabetes in public and private healthcare settings.

Obesity, clinical, and genetic predictors for glycemic progression in Chinese patients with type 2 diabetes: A cohort study using the Hong Kong Diabetes Register and Hong Kong Diabetes Biobank.

BACKGROUND: Type 2 diabetes (T2D) is a progressive disease whereby there is often deterioration in glucose control despite escalation in treatment. There is significant heterogeneity to this progression of glycemia after onset of diabetes, yet the factors that influence glycemic progression are not well understood. Given the tremendous burden of diabetes in the Chinese population, and limited knowledge on factors that influence glycemia, we aim to identify the clinical and genetic predictors for glycemic progression in Chinese patients with T2D. METHODS AND FINDINGS: In 1995-2007, 7,091 insulin-naïve Chinese patients (mean age 56.8 ± 13.3 [SD] years; mean age of T2D onset 51.1 ± 12.7 years; 47% men; 28.4% current or ex-smokers; median duration of diabetes 4 [IQR: 1-9] years; mean HbA1c 7.4% ± 1.7%; mean body mass index [BMI] 25.3 ± 4.0 kg/m2) were followed prospectively in the Hong Kong Diabetes Register. We examined associations of BMI and other clinical and genetic factors with glycemic progression defined as requirement of continuous insulin treatment, or 2 consecutive HbA1c ≥8.5% while on ≥2 oral glucose-lowering drugs (OGLDs), with validation in another multicenter cohort of Hong Kong Diabetes Biobank. During a median follow-up period of 8.8 (IQR: 4.8-13.3) years, incidence of glycemic progression was 48.0 (95% confidence interval [CI] 46.3-49.8) per 1,000 person-years with 2,519 patients started on insulin. Among the latter, 33.2% had a lag period of 1.3 years before insulin was initiated. Risk of progression was associated with extremes of BMI and high HbA1c. On multivariate Cox analysis, early age at diagnosis, microvascular complications, high triglyceride levels, and tobacco use were additional independent predictors for glycemic progression. A polygenic risk score (PRS) including 123 known risk variants for T2D also predicted rapid progression to insulin therapy (hazard ratio [HR]: 1.07 [95% CI 1.03-1.12] per SD; P = 0.001), with validation in the replication cohort (HR: 1.24 [95% CI 1.06-1.46] per SD; P = 0.008). A PRS using 63 BMI-related variants predicted BMI (beta [SE] = 0.312 [0.057] per SD; P = 5.84 × 10-8) but not glycemic progression (HR: 1.01 [95% CI 0.96-1.05] per SD; P = 0.747). Limitations of this study include potential misdiagnosis of T2D and lack of detailed data of drug use during follow-up in the replication cohort. CONCLUSIONS: Our results show that approximately 5% of patients with T2D failed OGLDs annually in this clinic-based cohort. The independent associations of modifiable and genetic risk factors allow more precise identification of high-risk patients for early intensive control of multiple risk factors to prevent glycemic progression.

Trends in diabetes-related complications in Hong Kong, 2001-2016: a retrospective cohort study.

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.

Development and validation of algorithms to classify type 1 and 2 diabetes according to age at diagnosis using electronic health records.

BACKGROUND: Validated algorithms to classify type 1 and 2 diabetes (T1D, T2D) are mostly limited to white pediatric populations. We conducted a large study in Hong Kong among children and adults with diabetes to develop and validate algorithms using electronic health records (EHRs) to classify diabetes type against clinical assessment as the reference standard, and to evaluate performance by age at diagnosis. METHODS: We included all people with diabetes (age at diagnosis 1.5-100 years during 2002-15) in the Hong Kong Diabetes Register and randomized them to derivation and validation cohorts. We developed candidate algorithms to identify diabetes types using encounter codes, prescriptions, and combinations of these criteria ("combination algorithms"). We identified 3 algorithms with the highest sensitivity, positive predictive value (PPV), and kappa coefficient, and evaluated performance by age at diagnosis in the validation cohort. RESULTS: There were 10,196 (T1D n = 60, T2D n = 10,136) and 5101 (T1D n = 43, T2D n = 5058) people in the derivation and validation cohorts (mean age at diagnosis 22.7, 55.9 years; 53.3, 43.9% female; for T1D and T2D respectively). Algorithms using codes or prescriptions classified T1D well for age at diagnosis < 20 years, but sensitivity and PPV dropped for older ages at diagnosis. Combination algorithms maximized sensitivity or PPV, but not both. The "high sensitivity for type 1" algorithm (ratio of type 1 to type 2 codes ≥ 4, or at least 1 insulin prescription within 90 days) had a sensitivity of 95.3% (95% confidence interval 84.2-99.4%; PPV 12.8%, 9.3-16.9%), while the "high PPV for type 1" algorithm (ratio of type 1 to type 2 codes ≥ 4, and multiple daily injections with no other glucose-lowering medication prescription) had a PPV of 100.0% (79.4-100.0%; sensitivity 37.2%, 23.0-53.3%), and the "optimized" algorithm (ratio of type 1 to type 2 codes ≥ 4, and at least 1 insulin prescription within 90 days) had a sensitivity of 65.1% (49.1-79.0%) and PPV of 75.7% (58.8-88.2%) across all ages. Accuracy of T2D classification was high for all algorithms. CONCLUSIONS: Our validated set of algorithms accurately classifies T1D and T2D using EHRs for Hong Kong residents enrolled in a diabetes register. The choice of algorithm should be tailored to the unique requirements of each study question.