Andrea Luk

Metabolic Syndrome Predicts New Onset of Chronic Kidney Disease in 5,829 Patients With Type 2 Diabetes: A 5-year prospective analysis of the Hong Kong Diabetes Registry

OBJECTIVE—Type 2 diabetes is the leading cause of end-stage renal disease worldwide. Aside from hyperglycemia and hypertension, other metabolic factors may determine renal outcome. We examined risk associations of metabolic syndrome with new onset of chronic kidney disease (CKD) in 5,829 Chinese patients with type 2 diabetes enrolled between 1995 and 2005. RESEARCH DESIGN AND METHODS—Metabolic syndrome was defined by National Cholesterol Education Program Adult Treatment Panel III criteria with the Asian definition of obesity. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease formula modified for the Chinese population. New onset of CKD was defined as eGFR <60 ml/min per 1.73 m2 at the time of censor. Subjects with CKD at baseline were excluded from the analysis. RESULTS—After a median follow-up duration of 4.6 years (interquartile range: 1.9–7.3 years), 741 patients developed CKD. The multivariable-adjusted hazard ratio (HR) of CKD was 1.31 (95% CI 1.12–1.54, P = 0.001) for subjects with metabolic syndrome compared with those without metabolic syndrome. Relative to subjects with no other components of metabolic syndrome except for diabetes, those with two, three, four, and five metabolic syndrome components had HRs of an increased risk of CKD of 1.15 (0.83–1.60, P = 0.407) 1.32 (0.94–1.86, P = 0.112), 1.64 (1.17–2.32, P = 0.004), and 2.34 (1.54–3.54, P < 0.001), respectively. The metabolic syndrome traits of central obesity, hypertriglyceridemia, hypertension, and low BMI were independent predictors for CKD. CONCLUSIONS—The presence of metabolic syndrome independently predicts the development of CKD in subjects with type 2 diabetes.

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.

Use of sulphonylurea and cancer in type 2 diabetes—The Hong Kong Diabetes Registry

BACKGROUND Hyperglycaemia is a risk factor for cancer and some sulphonylureas have anti-oxidant properties. This study examined associations between use of sulphonylureas and cancer. METHODS A consecutive cohort of 6103 Hong Kong Chinese patients with T2DM, free of cancer, was analysed using Cox models. Sulphonylurea usage was defined as use of the drugs at or within 2.5 years before enrolment and/or during follow-up periods. We adjusted for identified risk factors of cancer, use of other drugs, non-linear associations of lipids with cancer and probabilities of use of these drugs at different times and doses where appropriate. RESULTS During a median of 4.91 years of follow-up, 271 developed cancer. Glibenclamide, gliclazide and glipizide were ever used in 32.5% (n = 1983), 47.8% (n = 2920) and 13.5% (n = 823). After adjustment for covariates, use of gliclazide and glibenclamide was associated with reduced cancer risk in a dose-dependent manner. In addition, there were interactions between metformin and glibenclamide/glipizide use towards lower adjusted cancer risks. CONCLUSIONS In T2DM, use of glibenclamide and gliclazide may be associated with reduced cancer risk.

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.

Genetic Variants of the Protein Kinase C-β 1 Gene and Development of End-Stage Renal Disease in Patients With Type 2 Diabetes

CONTEXT Protein kinase C-beta (PKC-beta) is a cell-signaling intermediate implicated in development of diabetic complications. OBJECTIVE To examine the risk association of PKC-beta 1 gene (PRKCB1) polymorphisms and end-stage renal disease (ESRD) in an 8-year prospective cohort of Chinese patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS We genotyped 18 common tag single-nucleotide polymorphisms (SNPs) that span the PRKCB1 gene (r(2) = 0.80) in 1172 Chinese patients (recruited 1995-1998) without renal disease at baseline. A validation cohort included an additional 1049 patients with early-onset diabetes who were free of renal disease at baseline and were recruited after 1998. MAIN OUTCOME MEASURES Associations of PRKCB1 polymorphisms under additive, dominant, and recessive genetic models with new onset of ESRD (defined as estimated glomerular filtration rate <15 mL/min/1.73 m(2) or dialysis or renal-related death) were assessed by Cox proportional hazard regression, adjusted for all conventional risk factors including use of medications. RESULTS After a mean (SD) of 7.9 (1.9) years, 90 patients (7.7%) progressed to ESRD. Four common SNPs were associated with ESRD (P < .05). The closely linked T allele at rs3760106 and G allele rs2575390 (r(2) = 0.98) showed the strongest association with ESRD (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.31-3.87; P = .003, and HR, 2.26; 95% CI, 1.31-3.88; P = .003, respectively). Four common variants predicted ESRD in separate models. The HR for ESRD increased with increasing number of risk alleles (P < .001) in the joint effect analysis. The adjusted risk for ESRD was 6.04 (95% CI, 2.00-18.31) for patients with 4 risk alleles compared with patients with 0 or 1 risk allele. Incidence was 4.4 per 1000 person-years (95% CI, 0.5-8.2) among individuals with 0 or 1 risk allele compared with 20.0 per 1000 person-years (95% CI, 8.8-31.1) in those carrying 4 risk alleles (6.9% of the cohort). These results were validated in a separate prospective cohort of young-onset diabetic patients. Of 1049 patients in the validation cohort, 151 (14.3%) developed chronic kidney disease (CKD) during follow-up, and there were significant associations between both the T allele of rs3760106 and the G allele of rs2575390 and development of CKD (HR, 1.68; 95% CI, 1.10-2.57; P = .02, and HR, 1.62; 95% CI, 1.07-2.47; P = .02, respectively). CONCLUSION Genetic variants in the PRKCB1 gene were independently associated with development of ESRD in Chinese patients with type 2 diabetes.

Severe Hypoglycemia Identifies Vulnerable Patients With Type 2 Diabetes at Risk for Premature Death and All-Site Cancer: The Hong Kong Diabetes Registry

OBJECTIVE We examined the associations of clinical profiles in type 2 diabetic patients who developed severe hypoglycemia and their clinical outcomes, including death and all-site cancer. RESEARCH DESIGN AND METHODS A consecutive cohort of 8,767 type 2 diabetic patients with and without severe hypoglycemia in the 12 months before enrollment were recruited between 1995 and 2007, with follow-up until 2009. Severe hypoglycemia was defined by ICD-9 codes as hospitalizations resulting from hypoglycemia. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% CIs of clinical factors collected at enrollment for severe hypoglycemia. RESULTS In this cohort, mean age was 57.4 (SD 13.2) years and median disease duration of diabetes was 5 (interquartile range [IQR] 1–11) years. During a median follow-up of 6.71 (IQR 3.47–10.38) years, 235 patients had severe hypoglycemia (incidence 3.96 [95% CI 3.45–4.46] per 1,000 patient-years). At enrollment, patients with and without severe hypoglycemia had similar cancer rates. During follow-up, patients with severe hypoglycemia had a higher incidence of all-site cancer (13.4 vs. 6.4%, P < 0.0001) and mortality (32.8 vs. 11.2%, P < 0.0001) than those without severe hypoglycemia. After adjusting for confounders, old age, low BMI, high glycated hemoglobin, low triglyceride (TG), low LDL cholesterol (LDL-C), albuminuria, and chronic kidney disease were independent predictors for severe hypoglycemia. CONCLUSIONS In type 2 diabetes, severe hypoglycemia is associated with advanced age, renal dysfunction, poor glycemic control, and cancer subphenotypes (low BMI, low LDL-C, and low TG).

Low LDL Cholesterol, Albuminuria, and Statins for the Risk of Cancer in Type 2 Diabetes: The Hong Kong Diabetes Registry

OBJECTIVE LDL cholesterol <2.80 mmol/l was associated with increased cancer risk in type 2 diabetes. We explored the 1) interaction between low LDL cholesterol and albuminuria and 2) interaction between copresence of these two risk factors and statin use for cancer in type 2 diabetes. RESEARCH DESIGN AND METHODS We analyzed prospective data for 3,793 Chinese type 2 diabetic patients who remained naive for statin treatment and 1,483 patients in whom statin treatment was initiated during a median follow-up period of 5.24 years. All patients were free of cancer at baseline. Biological interactions were estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S). RERI > 0, AP > 0, or S > 1 indicates biological interaction. RESULTS In 3,793 statin-naive type 2 diabetic patients, copresence of low LDL cholesterol and albuminuria increased cancer risk by 2.8-fold (hazard ratio 2.77 [95% CI 1.78–4.31]) with significant biological interactions (RERI 1.05 [0.04–2.06]; AP 0.38 [0.09–0.66]). In the whole cohort of 5,276 type 2 diabetic patients, there was interaction between nonuse of statins and copresence of low LDL cholesterol and albuminuria with increased cancer risk (RERI 2.87 [0.64–5.09] and AP 0.60 [0.29–0.90]). Statin nonusers with LDL cholesterol <2.80 mmol/l and albumunuria had a 4.9-fold risk of cancer compared with statin users with or without both risk factors. CONCLUSIONS In type 2 diabetes, there was interaction between low LDL cholesterol and albuminuria with increased cancer risks. The latter was attenuated in the presence of statin treatment.

Diabetic nephropathy—What are the unmet needs?

In this pandemic of diabetes and obesity, Asia will have the highest number of affected people with the greatest increase in the young-to-middle aged group. Asian patients have increased risk for diabetic kidney disease which may be compounded by low grade infection, obesity and genetic factors. In these subjects, the onset of albuminuria and diabetic kidney disease causes further perturbation of metabolic milieu with increased oxidative stress, anaemia and vascular calcification which interact to markedly increase the risk of cardiovascular disease. Despite receiving optimal care to control blood pressure and metabolic risk factors as well as inhibition of the renin-angiotensin system in a clinical trial setting, there is a considerable residual risk for cardio-renal complications in patients with diabetic kidney disease. Control of obesity and low grade inflammation as well as correction of anaemia may represent areas where novel strategies can be developed and tested to curb this rising global burden of cardio-renal complications.

Depression in Chinese patients with type 2 diabetes: associations with hyperglycemia, hypoglycemia, and poor treatment adherence

We hypothesize that depression in type 2 diabetes might be associated with poor glycemic control, in part due to suboptimal self‐care. We tested this hypothesis by examining the associations of depression with clinical and laboratory findings in a multicenter survey of Chinese type 2 diabetic patients.