Eric S.H. Lau

Risk association of HbA1c variability with chronic kidney disease and cardiovascular disease in type 2 diabetes: prospective analysis of the Hong Kong Diabetes Registry

In type 2 diabetes, tight glycaemic control lowers the risk of diabetic complications, but it remains uncertain whether variability of glycaemia influences outcomes. We examined the association of glycated haemoglobin (HbA1c) variability with incident chronic kidney disease and cardiovascular disease in a prospective cohort of 8439 Chinese patients with type 2 diabetes recruited from 1994 to 2007.

Prospective Study on the Incidences of Cardiovascular-Renal Complications in Chinese Patients With Young-Onset Type 1 and Type 2 Diabetes

OBJECTIVE We examined metabolic profiles and cardiovascular-renal outcomes in a prospective cohort of Chinese patients with young-onset diabetes defined by diagnosis age <40 years. Patients with type 1 diabetes and normal-weight (BMI <23 kg/m2) and overweight (BMI ≥23 kg/m2) patients with type 2 diabetes were compared. RESEARCH DESIGN AND METHODS Between 1995 and 2004, 2,323 patients (type 1 diabetes, n = 209; normal-weight type 2 diabetes, n = 636; and overweight type 2 diabetes, n = 1,478) underwent detailed clinical assessment. Incident cardiovascular disease (CVD) including coronary heart disease, stroke, and peripheral vascular disease were identified using hospital discharge diagnoses. End-stage renal disease (ESRD) was defined by glomerular filtration rate <15 mL/min/1.73 m2 or dialysis. RESULTS Overweight patients with type 2 diabetes had the worst metabolic profile and highest prevalence of microvascular complications. Over a median follow-up of 9.3 years, incidences of CVD were 0.6, 5.1, and 9.6 per 1,000 person-years in patients with type 1 diabetes, normal-weight patients with type 2 diabetes, and overweight patients with type 2 diabetes. The respective figures for ESRD were 2.2, 6.4, and 8.4 per 1,000 person-years. Compared with type 1 diabetes, the overweight type 2 diabetes group had a greater hazard of progression to CVD (hazard ratio [HR] 15.3 [95% CI 2.1–112.4]) and ESRD (HR 5.4 [95% CI 1.8–15.9]), adjusted for age, sex, and disease duration. The association became nonsignificant upon additional adjustment for BMI, blood pressure, and lipid. CONCLUSIONS Young patients with type 2 diabetes had greater risks of developing cardiovascular-renal complications compared with patients with type 1 diabetes. The increased risk was driven primarily by accompanying metabolic risk factors.

Premature mortality and comorbidities in young-onset diabetes: a 7-year prospective analysis.

BACKGROUND There is an increasing prevalence of young-onset diabetes, especially in developing areas. We compared the clinical outcomes and predictors for cardiovascular-renal events between Chinese patients with type 2 diabetes with young- or late-onset of disease diagnosed before or after the age of 40 years, respectively. METHODS The Hong Kong Diabetes Registry was established in 1995 as an ongoing quality improvement initiative with consecutive enrollment of diabetic patients from ambulatory settings for documentation of risk factors, microvascular and macrovascular complications, and clinical outcomes using a structured protocol. RESULTS In 9509 Chinese patients with type 2 diabetes with a median (interquartile range) follow-up period of 7.5 (3.9-10.8) years, 21.3% (n = 2066) had young-onset diabetes. Despite 20 years difference in age, patients with young-onset diabetes (mean age, 41.3 years) had a similar or worse risk profile than those with late-onset disease (mean age, 61.9 years). Compared with the patients with late-onset diabetes, those with young-onset diabetes had lower rates of cardiovascular disease and chronic kidney disease for the same disease duration but a higher cumulative incidence of clinical events at any given age. With the use of stepwise Cox proportional hazard analysis, patients with young-onset diabetes had higher risks for cardiovascular and renal events when adjusted by age, but no difference in risks than in the patients with late-onset diabetes when further adjusted by disease duration. CONCLUSIONS Patients with young-onset diabetes had a similar or worse metabolic risk profile compared with those with late-onset disease. This group had higher risks for cardiovascular-renal complications at any given age, driven by longer disease duration.

A New Tool to Detect Kidney Disease in Chinese Type 2 Diabetes Patients—Comparison of EZSCAN with Standard Screening Methods

BACKGROUND EZSCAN(®) (Impeto Medical, Paris, France), a noninvasive device that assesses sweat gland dysfunction using reverse iontophoresis, also detects early dysglycemia. Given the interrelationships among dysglycemia, vasculopathy, and neuropathy, EZSCAN may detect kidney disease in diabetes (DKD). METHODS An EZSCAN score (0-100) was calculated using a proprietary algorithm based on the chronoamperometry analysis. We measured the score in 50 Chinese type 2 diabetes patients without DKD (urinary albumin-creatinine ratio [ACR] <2.5 mg/mmol in men or ACR <3.5 mg/mmol in women and estimated glomerular filtration rate [eGFR] >90 mL/min/1.73 m(2)) and 50 with DKD (ACR ≥25 mg/mmol and eGFR <60 mL/min/1.73 m(2)). We used spline analysis to determine the threshold value of the score in detecting DKD and its sensitivity and specificity. RESULTS EZSCAN scores were highly correlated with log values of eGFR (r=0.67, P<0.0001) and ACR (r=-0.66, P<0.0001). Using a cutoff value of 55, the score had 94% sensitivity, 78% specificity, and a likelihood ratio of 4.2 to detect DKD with a positive predictive value of 81% and a negative predictive value of 93%. On multivariable analysis, DKD was independently associated with EZSCAN score (β=-0.72, P=0.02), smoking status (1=never, 0=current/former) (β=-2.37, P=0.02), retinopathy (1=yes, 0=no) (β=3.019, P=0.01), triglycerides (β=2.56, P=0.013), and blood hemoglobin (β=-0.613, P=0.04). Patients without DKD but low EZSCAN score (n=10) had longer duration of disease (median [interquartile range], 13 [9-17] vs. 8 [4-16] years; P=0.017) and were more likely to have retinopathy (36.7% vs. 5.1%, P=0.02), lower eGFR (98 [95.00-103] vs. 106 [98.5-115], P=0.036), and treatment with renin-angiotensin system blockers (81.8% vs. 25.6%, P=0.002) than those with a normal score. CONCLUSION EZSCAN may detect high-risk subjects for DKD in Chinese populations.

Use of Net Reclassification Improvement (NRI) Method Confirms The Utility of Combined Genetic Risk Score to Predict Type 2 Diabetes

Background Recent genome-wide association studies (GWAS) identified more than 70 novel loci for type 2 diabetes (T2D), some of which have been widely replicated in Asian populations. In this study, we investigated their individual and combined effects on T2D in a Chinese population. Methodology We selected 14 single nucleotide polymorphisms (SNPs) in T2D genes relating to beta-cell function validated in Asian populations and genotyped them in 5882 Chinese T2D patients and 2569 healthy controls. A combined genetic score (CGS) was calculated by summing up the number of risk alleles or weighted by the effect size for each SNP under an additive genetic model. We tested for associations by either logistic or linear regression analysis for T2D and quantitative traits, respectively. The contribution of the CGS for predicting T2D risk was evaluated by receiver operating characteristic (ROC) analysis and net reclassification improvement (NRI). Results We observed consistent and significant associations of IGF2BP2, WFS1, CDKAL1, SLC30A8, CDKN2A/B, HHEX, TCF7L2 and KCNQ1 (8.5×10−18<P<8.5×10−3), as well as nominal associations of NOTCH2, JAZF1, KCNJ11 and HNF1B (0.05<P<0.1) with T2D risk, which yielded odds ratios ranging from 1.07 to 2.09. The 8 significant SNPs exhibited joint effect on increasing T2D risk, fasting plasma glucose and use of insulin therapy as well as reducing HOMA-β, BMI, waist circumference and younger age of diagnosis of T2D. The addition of CGS marginally increased AUC (2%) but significantly improved the predictive ability on T2D risk by 11.2% and 11.3% for unweighted and weighted CGS, respectively using the NRI approach (P<0.001). Conclusion In a Chinese population, the use of a CGS of 8 SNPs modestly but significantly improved its discriminative ability to predict T2D above and beyond that attributed to clinical risk factors (sex, age and BMI).

High risk for cardiovascular disease in Chinese type 2 diabetic patients with major depression—A 7-year prospective analysis of the Hong Kong DiabetesRegistry

BACKGROUND Depression is known to be associated with premature mortality and cardiovascular disease (CVD) in type 2 diabetes, although there is a paucity of similar data in Chinese population. In this study, we examined the risk association of major depression with premature mortality and CVD in a hospital clinic-based cohort. METHODS In a prospective cohort of 7835 Hong Kong Chinese with type 2 diabetes but without CVD at baseline, 153 patients were diagnosed with major depression by psychiatrists in public hospitals. After a median follow-up period of 7.4 years, 827 patients died and 829 patients developed CVD mainly due to stroke (n=384). We used Cox proportional hazard regression to obtain the hazard ratio (HR, 95% confidence interval, CI) of depression for the risk of mortality and CVD. RESULTS Depressed patients were younger (51.6 versus 56.6 years, p<0.001), more likely to be female (78.4% versus 53.0%, p<0.001), had higher LDL-cholesterol (3.2 versus 3.0 mmol/L, p=0.038) at baseline and longer hospitalization stays per year (median:0.8 nights per 100-person-years versus 0.1 nights per 100-person-years, p<0.001). After adjusting for conventional risk factors, depression independently predicted CVD [HR=2.18(95% CI=1.45-3.27)], mainly due to stroke [HR=3.55(95% CI=2.15-5.84)]. LIMITATIONS The young age and small sample size of patients with depression did not give sufficient power to confirm risk association of depression with premature mortality and myocardial infarction. CONCLUSIONS In Chinese type 2 diabetic patients, depression was associated with a 2-3 fold increase in the risk of incident CVD, especially stroke.

Familial young-onset diabetes, pre-diabetes and cardiovascular disease are associated with genetic variants of DACH1 in Chinese.

In Asia, young-onset type 2 diabetes (YOD) is characterized by obesity and increased risk for cardiovascular disease (CVD). In a genome-wide association study (GWAS) of 99 Chinese obese subjects with familial YOD diagnosed before 40-year-old and 101 controls, the T allele of rs1408888 in intron 1 of DACH1(Dachshund homolog 1) was associated with an odds ratio (OR) of 2.49(95% confidence intervals:1.57–3.96, P = 8.4×10−5). Amongst these subjects, we found reduced expression of DACH1 in peripheral blood mononuclear cells (PBMC) from 63 cases compared to 65 controls (P = 0.02). In a random cohort of 1468 cases and 1485 controls, amongst top 19 SNPs from GWAS, rs1408888 was associated with type 2 diabetes with a global P value of 0.0176 and confirmation in a multiethnic Asian case-control cohort (7370/7802) with an OR of 1.07(1.02–1.12, Pmeta = 0.012). In 599 Chinese non-diabetic subjects, rs1408888 was linearly associated with systolic blood pressure and insulin resistance. In a case-control cohort (n = 953/953), rs1408888 was associated with an OR of 1.54(1.07–2.22, P = 0.019) for CVD in type 2 diabetes. In an autopsy series of 173 non-diabetic cases, TT genotype of rs1408888 was associated with an OR of 3.31(1.19–9.19, P = 0.0214) and 3.27(1.25–11.07, P = 0.0184) for coronary heart disease (CHD) and coronary arteriosclerosis. Bioinformatics analysis revealed that rs1408888 lies within regulatory elements of DACH1 implicated in islet development and insulin secretion. The T allele of rs1408888 of DACH1 was associated with YOD, prediabetes and CVD in Chinese.

Genetic and clinical variables identify predictors for chronic kidney disease in type 2 diabetes

Type 2 diabetes and chronic kidney disease (CKD) may share common risk factors. Here we used a 3-stage procedure to discover novel predictors of CKD by repeatedly applying a stepwise selection based on the Akaike information criterion to subsamples of a prospective complete-case cohort of 2755 patients. This cohort encompassed 25 clinical variables and 36 genetic variants associated with type 2 diabetes, obesity, or fasting plasma glucose. We compared the performance of the clinical, genetic, and clinico-genomic models and used net reclassification improvement to evaluate the impact of top selected genetic variants to the clinico-genomic model. Associations of selected genetic variants with CKD were validated in 2 independent cohorts followed by meta-analyses. Among the top 6 single-nucleotide polymorphisms selected from clinico-genomic data, three (rs478333 of G6PC2, rs7754840 and rs7756992 of CDKAL1) contributed toward the improvement of prediction performance. The variant rs478333 was associated with rapid decline (over 4% per year) in estimated glomerular filtration rate. In a meta-analysis of 2 replication cohorts, the variants rs478333 and rs7754840 showed significant associations with CKD after adjustment for conventional risk factors. Thus, this novel 3-stage approach to a clinico-genomic data set identified 3 novel genetic predictors of CKD in type 2 diabetes. This method can be applied to similar data sets containing clinical and genetic variables to select predictors for clinical outcomes.

Low testosterone and clinical outcomes in Chinese men with type 2 diabetes mellitus – Hong Kong Diabetes Registry

AIMS To assess the implications of low testosterone on cardiovascular risk factors, metabolic syndrome (MES) and clinical outcomes in Chinese men with Type 2 Diabetes (T2D). METHODS A prospective cohort study carried out in a university hospital involving a consecutive cohort of 1239 Chinese men with T2D and a median disease duration of 9years followed up for 4.8years. Clinical characteristics, frequency of MES, serum total testosterone and clinical events were analyzed. Multivariate logistic regression was performed to examine the independent association of low testosterone with MES after adjustment for confounding covariates. Cox proportional hazards regression analysis was used to derive hazard ratio for clinical outcomes. RESULTS More men with low testosterone had cardiovascular-renal disease and MES than those with normal testosterone. The adjusted odds ratio (OR) of low testosterone for MES was 2.63 (95% Confidence Interval [CI] 1.56-4.61). After a median follow-up of 4.8years, the hazard ratio (HR) of low testosterone was 2.22 (95% CI 1.23-4.01) for incident non-prostate cancer. In a multivariate Cox-regression model, the HRs were attenuated but remained significant with adjustment for MES and renal parameters. CONCLUSIONS Chinese men with low testosterone had high prevalence of cardiovascular disease and MES with high incidence non-prostate cancer.

Advanced liver fibrosis but not steatosis is independently associated with albuminuria in Chinese patients with type 2 diabetes

BACKGROUND & AIMS Increasing evidence suggests that non-alcoholic fatty liver disease (NAFLD) may be an independent risk factor for chronic kidney disease (CKD). Given the high prevalence of NAFLD among patients with diabetes who are also at risk of CKD, we aimed to investigate the association between NAFLD and albuminuria, a marker commonly found in diabetic nephropathy. METHODS This study included a cohort of Chinese patients with type 2 diabetes from the Hong Kong Diabetes Registry recruited between March 2013 and May 2014. Liver stiffness measurement (LSM), with probe-specific cut-offs, was used to detect advanced liver fibrosis. While controlled attenuation parameter (CAP) was used to assess liver steatosis using transient elastography. RESULTS A total of 1,763 Chinese patients with type 2 diabetes were recruited in this analysis. The mean (standard deviation) age and duration of diabetes were 60.7 (11.5) years and 10.8 (8.5) years, respectively. The prevalence of albuminuria was higher in diabetic patients with liver steatosis and those with advanced fibrosis (no NAFLD vs. liver steatosis vs. advanced fibrosis: 41.4% vs. 46.2% vs. 64.2%, p <0.001). After adjustment for potential confounders including glycated hemoglobin, hypertension and body mass index, advanced fibrosis, but not liver steatosis, was associated with increased risk of albuminuria (odds ratio [OR] 1.52; 95% confidence interval [CI] 1.02-2.28; p = 0.039) in patients with eGFR ≥60 ml/min/1.73 m2. The odds of albuminuria increased with greater severity of liver fibrosis in a dose dependent manner, with the highest odds observed in patients with LSM scores ≥11.5 kPa assessed by M probe or ≥11.0 kPa assessed by XL probe (adjusted OR 1.53; 95% CI 1.07-2.20; p = 0.021). CONCLUSIONS Advanced liver fibrosis, but not steatosis, is independently associated with albuminuria in Chinese patients with type 2 diabetes. Attention should be paid to liver fibrosis in patients with obesity and type 2 diabetes complicated with albuminuria. LAY SUMMARY In this study, we assessed the link between non-alcoholic fatty liver disease (NAFLD) and albuminuria in a cohort of 1,763 Chinese patients with type 2 diabetes. This study shows that advanced liver fibrosis, a severe form of NAFLD, was independently associated with increased risk of albuminuria. The risk of albuminuria increased with greater severity of liver fibrosis.