Serial Transient Elastography Examinations to Monitor Patients With Type 2 Diabetes: A Prospective Cohort Study.

BACKGROUND AND AIMS: Type 2 diabetes is an important risk factor for nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis. Current international guidelines recommend the use of noninvasive tests as initial assessments for NAFLD, but the role of noninvasive tests as monitoring tools has not been established. We aimed to study the role of transient elastography as a monitoring tool in patients with type 2 diabetes. APPROACH AND RESULTS: We recruited patients with type 2 diabetes without viral hepatitis or excessive alcohol intake from a complication screening facility in Hong Kong in 2013-2014 and repeated the assessments in 2016-2018. The primary endpoint was an increase of liver stiffness measurement (LSM) to ≥10 kPa. The secondary endpoint was the change in the controlled attenuation parameter (CAP). A total of 611 patients with type 2 diabetes and a valid LSM (mean age, 57.7 ± 10.9 years; 342 men [56.0%]) were included in this study (568 also had a valid CAP). Overall, there was moderate correlation between the baseline and follow-up LSM (r = 0.689, P < 0.001). Among 487 patients with a baseline LSM <10 kPa, 21 (4.3%) had a follow-up LSM ≥10 kPa. Baseline body mass index, alanine aminotransferase (ALT), and ∆ALT were independent factors associated with LSM increase. Among 124 patients with a baseline LSM ≥10 kPa, 70 (56.5%) had a follow-up LSM <10 kPa. Among 198 patients with a CAP <248 dB/m at baseline, 103 (52.0%) had a CAP increased to ≥248 dB/m. CONCLUSIONS: The prevalence and incidence of NAFLD in patients with type 2 diabetes are high. Although advanced fibrosis is common in this population, few patients progress to advanced fibrosis in 3 years. Future studies should define the optimal surveillance interval in patients with diabetes.

Pharmacokinetic/pharmacodynamic and safety study of a single dose of evolocumab 140 mg in healthy Chinese subjects.

OBJECTIVE: Evolocumab, a human monoclonal antibody that binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), markedly reduces low-density lipoprotein cholesterol (LDL-C). Here we characterize the pharmacokinetics, pharmacodynamics, safety, and tolerability of evolocumab manufactured at a new site administered in healthy Chinese subjects. MATERIALS AND METHODS: This phase 1 study of a single subcutaneous 140-mg dose of evolocumab was conducted in healthy subjects of Chinese descent residing in Hong Kong. Subjects were followed through day 85. RESULTS: 20 subjects (all men) were enrolled. Mean (SD) age was 26.6 (8.5) years; baseline LDL-C was 2.4 (0.7) mmol/L. Mean (SD) evolocumab maximum serum concentration (Cmax) was 14.1 (5.0) µg/mL; area under the serum drug concentration-time curve from time 0 to time of last quantifiable concentration (AUClast) was 178 (80) day×µg/mL; AUC from time 0 to infinity (AUCinf) was 187 (80) day×µg/mL; terminal half-life was 5.95 (1.76) days; median time to reach Cmax (tmax) was 4.0 days. Maximum LDL-C decrease (-57.5%) was observed on day 15 and recovered to baseline by day 57. The most common adverse events (AEs) were nasal congestion (20%), oropharyngeal pain (15%), sneezing (15%), cough (10%), upper respiratory tract infection (10%), and diarrhea (10%). Most AEs were isolated incidences of mild severity, with no serious or treatment-related events. No anti-evolocumab antibodies were detected. CONCLUSION: A single 140-mg dose of evolocumab manufactured at the new site and administered in healthy Chinese subjects was associated with typical antibody pharmacokinetics, rapid and reversible decreases in LDL-C, and no new safety events.

Progression of glucose intolerance and cardiometabolic risk factors over a decade in Chinese women with polycystic ovary syndrome: A case-control study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with increased metabolic risk, though data on long-term follow-up of cardiometabolic traits are limited. We postulated that Chinese women with PCOS would have higher risk of incident diabetes and cardiometabolic abnormalities than those without PCOS during long-term follow-up. METHODS AND FINDINGS: One hundred ninety-nine Chinese women with PCOS diagnosed by the Rotterdam criteria and with a mean age of 41.2 years (SD = 6.4) completed a follow-up evaluation after an average of 10.6 ± 1.3 years. Two hundred twenty-five women without PCOS (mean age: 54.1 ± 6.7 years) who underwent baseline and follow-up evaluation over the same period were used for comparison. Progression of glycaemic status of women both with and without PCOS was assessed by using 75-g oral glucose tolerance test (OGTT) screening with the adoption of 2009 American Diabetes Association diagnostic criteria. The frequency of impaired glucose regulation, hypertension, and hyperlipidaemia of women with PCOS at follow-up has increased from 31.7% (95% CI 25.2%-38.1%) to 47.2% (95% CI 40.3%-54.2%), 16.1% (95% CI 11.0%-21.2%) to 34.7% (95% CI 28.1%-41.3%), and 52.3% (95% CI 45.3%-59.2%) to 64.3% (95% CI 57.7%-71.0%), respectively. The cumulative incidence of diabetes mellitus (DM) in follow-up women with PCOS is 26.1% (95% CI 20.0%-32.2%), almost double that in the cohort of women without PCOS (p < 0.001). Age-standardised incidence of diabetes among women with PCOS was 22.12 per 1,000 person-years (95% CI 10.86-33.37) compared with the local female population incidence rate of 8.76 per 1,000 person-years (95% CI 8.72-8.80) and 10.09 per 1,000 person-years (95% CI 4.92-15.26, p < 0.001) for women without PCOS in our study. Incidence rate for women with PCOS aged 30-39 years was 20.56 per 1,000 person-years (95% CI 12.57-31.87), which is approximately 10-fold higher than that of the age-matched general female population in Hong Kong (1.88 per 1,000 person-years, [95% CI 1.85-1.92]). The incidence rate of type 2 DM (T2DM) of both normal-weight and overweight women with PCOS was around double that of corresponding control groups (normal weight: 8.96 [95% CI 3.92-17.72] versus 4.86 per 1,000 person-years [95% CI 2.13-9.62], p > 0.05; overweight/obese: 28.64 [95% CI 19.55-40.60] versus 14.1 per 1,000 person-years [95% CI 8.20-22.76], p < 0.05). Logistic regression analysis identified that baseline waist-to-hip ratio (odds ratio [OR] = 1.71 [95% CI 1.08-2.69], p < 0.05) and elevated triglyceride (OR = 6.63 [95% CI 1.23-35.69], p < 0.05) are associated with the progression to T2DM in PCOS. Limitations of this study include moderate sample size with limited number of incident diabetes during follow-up period and potential selection bias. CONCLUSIONS: High risk of diabetes and increased cardiovascular disease risk factors among Chinese women with PCOS are highlighted in this long-term follow-up study. Diabetes onset was, on average, 10 years earlier among women with PCOS than in women without PCOS.

Progression of diabetic kidney disease and trajectory of kidney function decline in Chinese patients with Type 2 diabetes.

Diabetes is a major cause of end stage renal disease (ESRD), yet the natural history of diabetic kidney disease is not well understood. We aimed to identify patterns of estimated GFR (eGFR) trajectory and to determine the clinical and genetic factors and their associations of these different patterns with all-cause mortality in patients with type 2 diabetes. Among 6330 patients with baseline eGFR >60 ml/min per 1.73 m2 in the Hong Kong Diabetes Register, a total of 456 patients (7.2%) developed Stage 5 chronic kidney disease or ESRD over a median follow-up of 13 years (incidence rate 5.6 per 1000 person-years). Joint latent class modeling was used to identify different patterns of eGFR trajectory. Four distinct and non-linear trajectories of eGFR were identified: slow decline (84.3% of patients), curvilinear decline (6.5%), progressive decline (6.1%) and accelerated decline (3.1%). Microalbuminuria and retinopathy were associated with accelerated eGFR decline, which was itself associated with all-cause mortality (odds ratio [OR] 6.9; 95% confidence interval [CI]: 5.6-8.4 for comparison with slow eGFR decline). Of 68 candidate genetic loci evaluated, the inclusion of five loci (rs11803049, rs911119, rs1933182, rs11123170, and rs889472) improved the prediction of eGFR trajectories (net reclassification improvement 0.232; 95% CI: 0.057--0.406). Our study highlights substantial heterogeneity in the patterns of eGFR decline among patients with diabetic kidney disease, and identifies associated clinical and genetic factors that may help to identify those who are more likely to experience an accelerated decline in kidney function.

Short-term association between ambient temperature and acute myocardial infarction hospitalizations for diabetes mellitus patients: A time series study.

BACKGROUND: Acute myocardial infarction (AMI) is the leading cause of death among people with diabetes mellitus (DM) and has been found to occur more frequently with extreme temperatures. With the increasing prevalence of DM and the rising global mean temperature, the number of heat-related AMI cases among DM patients may increase. This study compares excess risk of AMI during periods of extreme temperatures between patients with DM and without DM. METHODS: Distributed lag nonlinear models (DLNMs) were used to estimate the short-term association between daily mean temperature and AMI admissions (International Classification of Diseases 9th revision [ICD-9] code: 410.00-410.99), stratified by DM status (ICD-9: 250.00-250.99), to all public hospitals in Hong Kong from 2002 to 2011, adjusting for other meteorological variables and air pollutants. Analyses were also stratified by season, age group, gender, and admission type (first admissions and readmissions). The admissions data and meteorological data were obtained from the Hong Kong Hospital Authority (HA) and the Hong Kong Observatory (HKO). FINDINGS: A total of 53,769 AMI admissions were included in the study. AMI admissions among DM patients were linearly and negatively associated with temperature in the cold season (cumulative relative risk [cumRR] [95% confidence interval] in lag 0-22 days (12 °C versus 24 °C) = 2.10 [1.62-2.72]), while those among patients without DM only started increasing when temperatures dropped below 22 °C with a weaker association (cumRR = 1.43 [1.21-1.69]). In the hot season, AMI hospitalizations among DM patients started increasing when the temperature dropped below or rose above 28.8 °C (cumRR in lag 0-4 days [30.4 versus 28.8 °C] = 1.14 [1.00-1.31]), while those among patients without DM showed no association with temperature. The differences in sensitivity to temperature between patients with DM and without DM were most apparent in the group <75 years old and among first-admission cases in the cold season. The main limitation of this study was the unavailability of data on individual exposure to ambient temperature. CONCLUSIONS: DM patients had a higher increased risk of AMI admissions than non-DM patients during extreme temperatures. AMI admissions risks among DM patients rise sharply in both high and low temperatures, with a stronger effect in low temperatures, while AMI risk among non-DM patients only increased mildly in low temperatures. Targeted health protection guidelines should be provided to warn DM patients and physicians about the dangers of extreme temperatures. Further studies to project the impacts of AMI risks on DM patients by climate change are warranted.

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.

Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study.

OBJECTIVE: Type 2 diabetes is an important risk factor for non-alcoholic fatty liver disease (NAFLD), but current guidelines provide conflicting recommendations on whether diabetic patients should be screened for NAFLD. We therefore studied the strategy of screening diabetic patients by FibroScan. DESIGN: Liver fat and fibrosis were assessed by controlled attenuation parameter (CAP) and liver stiffness measurements (LSM) by FibroScan at a diabetic centre for patients from primary care and hospital clinics. Probe-specific LSM cut-offs were used to detect advanced fibrosis. RESULTS: Of 1918 patients examined, 1799 (93.8%) had valid CAP and 1884 (98.2%) had reliable LSM (1770 with the M probe and 114 with the XL probe). The proportion of patients with increased CAP and LSM was 72.8% (95% CI 70.7% to 74.8%) and 17.7% (95% CI 16.0% to 19.5%), respectively. By multivariable analysis, female gender, higher body mass index, triglycerides, fasting plasma glucose and alanine aminotransferase (ALT) and non-insulin use were associated with increased CAP. Longer duration of diabetes, higher body mass index, increased ALT and spot urine albumin:creatinine ratio and lower high-density lipoprotein-cholesterol were associated with increased LSM. Ninety-four patients (80% had increased LSM) underwent liver biopsy: 56% had steatohepatitis and 50% had F3-4 disease. CONCLUSIONS: Diabetic patients have a high prevalence of NAFLD and advanced fibrosis. Those with obesity and dyslipidaemia are at particularly high risk and may be the target for liver assessment. Our data support screening for NAFLD and/or advanced fibrosis in patients with type 2 diabetes.

One-hour post-load plasma glucose level predicts future type 2 diabetes in a community-based study of Hong Kong Chinese workforce.

BACKGROUND: We compared performance of high 1-hour PG level, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in predicting type 2 diabetes in a longitudinal community-based cohort of Hong Kong Chinese. METHODS: Between 2001 and 2003, 472 adults aged 18-55 years without diabetes underwent 75-gram oral glucose tolerance test (OGTT). Between 2012 and 2014, progression to diabetes was ascertained by reviewing medical records or repeating OGTT and HbA1c. We defined high 1-hour PG as PG ≥ 8.6 mmol/L at 1-hour. RESULTS: In this cohort, 23.5% had normal glucose tolerance and high 1-hour PG, 10.0% had isolated IGT, 4.2% had isolated IFG. Over 12-year follow-up, 9.3% developed type 2 diabetes. In logistic regression, high 1-hour PG was associated with progression to type 2 diabetes with adjusted odds ratio (95% CI) of 4.20 (1.60, 12.40), independent of IFG, IGT and other clinical variables. Areas under ROC (95% CI) for type 2 diabetes were similar between 1-hour (0.84 [0.78, 0.89], 2-hour (0.79 [0.72, 0.86]) and fasting PG (0.79 [0.71, 0.86]). CONCLUSION: High 1-hour PG identified young Chinese with 5-fold increased risk of type 2 diabetes independent of other intermediate hyperglycaemia status and clinical factors. 1-hour PG is similar to fasting and 2-hour PG in predicting type 2 diabetes.

A single ascending dose study of single-stranded oligodeoxyribonucleotide RO7062931 in Chinese healthy volunteers.

RO7062931 is an N-acetylgalactosamine (GalNAc)-conjugated single-stranded oligodeoxyribonucleotide complementary to hepatitis B virus RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This phase I single ascending dose (SAD) study evaluated the safety, tolerability, and pharmacokinetics of RO7062931 in Chinese healthy volunteers. There were four SAD cohorts (0.3, 1.0, 2.0, and 4.0 mg/kg), in each of which healthy volunteers were randomized to a single subcutaneous (s.c.) injection of RO7062931 or matching placebo in a 4:1 ratio. Placebo recipients were pooled as one treatment group for safety assessments. A total of 41 healthy Chinese men received one dose of RO7062931 (n = 33) or placebo (n = 8) and completed the study (85-day follow-up). Adverse events (AEs) were reported in 22 of 33 (66.6%) RO7062931 recipients (n = 80 treatment-related) and seven of eight (87.5%) placebo recipients (n = 1 treatment-related). Apart from two moderate-intensity AEs, all AEs were mild. The most frequently reported AEs were influenza, injection-related reactions, and headache. Dose-proportional increases in plasma RO7062931 exposure were observed between the 0.3 and 1.0 mg/kg doses, whereas a supra-dose-proportional increase occurred at doses greater than or equal to 2.0 mg/kg, along with a marked increase in urinary excretion. Single s.c. dose of RO7062931 up to 4.0 mg/kg were safe and well-tolerated in healthy Chinese volunteers. Pharmacokinetic data suggested that ASGPR saturation had commenced between doses of 2.0 and 4.0 mg/kg. Results were broadly consistent with observations in primarily White subjects in the global first-in-human study of RO7062931.

Advanced liver fibrosis predicts heart failure and hospitalizations in people with type 2 diabetes: A prospective cohort study from Hong Kong Diabetes Register.

AIMS: We aimed to examine the impact of non-alcoholic fatty liver disease (NAFLD) on the clinical outcomes in patients with type 2 diabetes (T2D). METHODS: Between 2013 and 2014, 1,734 patients with T2D underwent transient elastography (TE) to assess liver status indicated by controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Liver steatosis was defined by CAP ≥ 248 dB/m and advanced liver fibrosis by LSM ≥ 10 kPa. In 2019, we assessed their clinical outcomes including hospitalizations and mortality. RESULTS: In this prospective cohort [56% men, mean (±standard deviation) age:60.8±11.5 years; glycated hemoglobin (HbA1c)7.8±1.6 %], 798 patients had liver steatosis, 296 patients had advanced liver fibrosis and 640 patients had normal liver at baseline. T2D with advanced liver fibrosis had higher body mass index, waist circumference, waist-hip ratio, fasting plasma glucose, HbA1c, blood pressure and lipid profiles than their counterparts with NAFLD or normal liver (all p < 0.05). After a median follow-up of 6.07 (interquartile range:5.84 to 6.30) years, there were 4,403 incident hospitalizations, 32,119 days of hospital stay, and 171 deaths. Using Cox regression analysis, advanced liver fibrosis was associated with increased risk of heart failure (hazard ratio [95% confidence interval] HR:3.07[1.08-8.68], p=0.035) and hospitalizations (HR:1.39[1.14-1.70], p=0.001) while liver steatosis was associated with reduced mortality (HR:0.60[0.41-0.87], p=0.007) compared to their counterparts with normal liver after adjustment for potential confounders. CONCLUSIONS: T2D comorbid with liver steatosis and advanced liver fibrosis are distinct clinical entities with differences in outcomes. Advanced liver fibrosis is an important predictor for worse outcomes including heart failure and hospitalizations in people with T2D.

Association of insomnia with incident chronic cognitive impairment in older adults with type 2 diabetes mellitus: A prospective study of the Hong Kong Diabetes Register.

AIMS: To examine the risk association of insomnia with incident chronic cognitive impairment in older adults with type 2 diabetes mellitus (T2D). METHODS: Between July 2010 and June 2015, patients with T2D aged ≥60 years enrolled in the Hong Kong Diabetes Register completed the Insomnia Severity Index (ISI) questionnaire. Patients were considered having insomnia if they had ISI score > 14. We prospectively followed up the cohort and censored outcome through reviewing diagnoses and clinical notes entered by attending physicians in electronic medical record to identify incident cases of mild cognitive impairment and dementia. RESULTS: After excluding shift workers and those with established chronic cognitive impairment at baseline, we included 986 patients with T2D in this study (58.3 % men, mean age ± standard deviation: 62.5 ± 2.6 years, disease duration of diabetes: 10.7 ± 8.2 years, HbA1c: 7.4 ± 1.3 %, insulin users: 28.7 %, insomnia: 9.1 %). After a median follow-up of 7.6 (interquartile range = 2.0) years, 41 (4.2 %) developed chronic cognitive impairment. Using Cox regression analysis, insomnia (hazard ratio, HR 2.909, p = 0.012) and HbA1c ≥ 7 % (HR 2.300, p = 0.038) were positively associated with incident chronic cognitive impairment while insulin use (HR 0.309, p = 0.028) showed negative association. CONCLUSIONS: Insomnia, suboptimal glycemic control and non-insulin use are independent risk factors for incident chronic cognitive impairment in older adults with T2D.

Effects of RAS inhibitors on all-site cancers and mortality in the Hong Kong diabetes surveillance database (2002-2019).

BACKGROUND: Cancer is replacing cardiovascular-disease as a leading cause of death in type 2 diabetes (T2D). The association of RAS-inhibitors (RASi) and cancer, including differences between angiotensin-converting-enzyme-inhibitor (ACEi) and angiotensin-receptor-blocker (ARBs) as well as their associations independent of blood pressure lowering, remains inconclusive in T2D. METHODS: We conducted a cohort study with new-user design in 253,491 patients in the Hong-Kong-Diabetes-Surveillance-Database (HKDSD) in 2002-2019. We evaluated the associations of time-varying RASi use (ACEi and ARBs) with all-site cancer, diabetes-related cancers, and cancer-specific mortality including comparison with new-users of calcium-channel-blockers (CCBs) as an active-comparator group. FINDINGS: Of 253,491, 133,730 (52.8%) were new-RASi and 119,761 (47.2%) were non-RASi users with a median follow-up period of 6.3 (interquartile ragne: 3.4-9.2) years (1,678,719 patient-years). After propensity-score weighting and adjustment for time-varying covariables, RASi use was associated with lower risk of all-site cancer (HR=0.76, 95%CI: 0.74-0.79), diabetes-related cancer (HR=0.79, 95%CI: 0.75-0.84), cancer-specific mortality (HR=0.50, 95%CI: 0.47-0.53), and diabetes-related cancer mortality (HR=0.49, 95%CI: 0.45-0.54) versus non-RASi. Amongst RASi users, ARBs use was associated with lower risk of cancer-specific mortality versus ACEi (HR=0.77, 95%CI: 0.66-0.91). Use of RASi was associated with an estimated-prevention of 2.6 (95%CI: 2.3-3.0) all-site cancer per-1000-person-years and 2.2 (95%CI: 2.0-2.5) cancer-related mortality per-1000-person-years. Lower risk of cancer-specific mortality was similarly observed in new-RASi compared with new-CCBs users. INTERPRETATION: RASi use was independently associated with lower cancer risk in T2D with stronger associations in users of ARBs than ACEi. The benefits of RASi in patients with diabetes might go beyond cardiovascular-renal protection if confirmed by other real-world studies and trials. FUNDING: Dr. Aimin Yang was supported by a CUHK Impact-Research-Fellowship Scheme.

A randomized clinical trial of genetic testing and personalized risk counselling in patients with type 2 diabetes receiving integrated care -The genetic testing and patient empowerment (GEM) trial.

AIMS: We evaluated the effect of personalized risk counseling incorporating clinical and genetic risk factors on patient empowerment and risk factor control in diabetes. METHODS: Patients with type 2 diabetes (T2D) with suboptimal glycaemic control (HbA1c ≥ 7.5%) were randomized to a genetic counselling (GC) or control group. All patients underwent genetic testing for alleles at three loci associated with diabetic complications. The GC group received additional explanation of the joint associations of genetic and modifiable risk factors on risk of complications. All patients were reassessed at 12 months including validated questionnaires for patient reported outcomes. The primary outcome was proportion of patients reaching ≥ 3 of 5 predefined treatment targets (HbA1c < 7%, BP < 130/80 mmHg, LDL-C < 2.6 mmol/L, Triglyceride < 2.0 mmol/L, use of renin-angiotensin system inhibitors). Secondary outcomes included new-onset chronic kidney disease or microalbuminuria and patient reported outcome measures. RESULTS: A total of 435 patients were randomized and 420 patients were included in the modified intention-to-treat analysis. At 12 months, the proportion of patients who attained ≥ 3 targets increased from 41.6% to 52.3% in the GC group (p = 0.007) versus 49.5% to 62.6% in the control group (p = 0.003), without between-group difference. Both groups had similar reduction in HbA1c, LDL-C and increased use of medications. In per protocol analysis, the GC group had higher diabetes empowerment, with reduced diabetes distress. In the GC group, the greatest improvement in positive attitude and self-care activities was observed in the intermediate to high genetic risk score (GRS) groups. CONCLUSIONS: In patients with T2D receiving integrated care, additional counselling on genetic risk of complications did not further improve risk factor control, although the improvement in self-efficacy warrants long-term evaluation.

Glucose-lowering drugs and outcome from COVID-19 among patients with type 2 diabetes mellitus: a population-wide analysis in Hong Kong.

OBJECTIVES: To investigate the association between baseline use of glucose-lowering drugs and serious clinical outcome among patients with type 2 diabetes. DESIGN: Territory-wide retrospective cohort of confirmed cases of COVID-19 between January 2020 and February 2021. SETTING: All public health facilities in Hong Kong. PARTICIPANTS: 1220 patients with diabetes who were admitted for confirmed COVID-19. PRIMARY AND SECONDARY OUTCOME MEASURES: Composite clinical endpoint of intensive care unit admission, requirement of invasive mechanical ventilation and/or in-hospital death. RESULTS: In this cohort (median age 65.3 years, 54.3% men), 737 (60.4%) patients were treated with metformin, 385 (31.6%) with sulphonylureas, 199 (16.3%) with dipeptidyl peptidase-4 (DPP-4) inhibitors and 273 (22.4%) with insulin prior to admission. In multivariate Cox regression, use of metformin and DPP-4 inhibitors was associated with reduced incidence of the composite endpoint relative to non-use, with respective HRs of 0.51 (95% CI 0.34 to 0.77, p=0.001) and 0.46 (95% CI 0.29 to 0.71, p<0.001), adjusted for age, sex, diabetes duration, glycated haemoglobin (HbA1c), smoking, comorbidities and drugs. Use of sulphonylureas (HR 1.55, 95% CI 1.07 to 2.24, p=0.022) and insulin (HR 6.34, 95% CI 3.72 to 10.78, p<0.001) were both associated with increased hazards of the composite endpoint. CONCLUSIONS: Users of metformin and DPP-4 inhibitors had fewer adverse outcomes from COVID-19 compared with non-users, whereas insulin and sulphonylurea might predict a worse prognosis.

Detection of increased serum miR-122-5p and miR-455-3p levels before the clinical diagnosis of liver cancer in people with type 2 diabetes.

People with type 2 diabetes (T2D) have increased cancer risk. Liver cancer (LC) has a high prevalence in East Asia and is one of the leading causes of cancer death globally. Diagnosis of LC at early stage carries good prognosis. We used stored serum from patients of Hong Kong Diabetes Register before cancer diagnosis to extract RNA to screen for microRNA markers for early detection of LC in T2D. After screening with Affymetrix GeneChip microarray with serum RNA from 19 incident T2D LC (T2D-LC), 20 T2D cancer free (T2D-CF) and 20 non-T2D non-cancer patients, top signals were validated in a 3-group comparison including 1888 T2D-CF, 127 T2D-LC, and 487 T2D patients with non-liver cancer patients using qPCR. We detected 2.55-fold increase in miR-122-5p and 9.21-fold increase in miR-455-3p in the T2D-LC group. Using ROC analysis, miR-122-5p and miR-455-3p jointly predicted LC with an area under the curve of 0.770. After adjustment for confounders, each unit increase of miR-455-3p increased the odds ratio for liver cancer by 1.022. Increased serum levels of miR-122-5p and miR-455-3p were independently associated with increased risk of incident LC in T2D and may serve as potential biomarkers for early detection of LC in T2D.

Gender differences in the associations between insomnia and glycemic control in patients with type 2 diabetes: a cross-sectional study.

STUDY OBJECTIVES: Insomnia is associated with insulin resistance and type 2 diabetes (T2D) in the general population. However, the associations between insomnia and glycemic control in T2D population are not consistently reported. In this study, we aimed to examine the associations between insomnia and glycemic control, and gender differences in these associations among Hong Kong Chinese patients with T2D. METHODS: This was a cross-sectional study involving T2D patients recruited from the Hong Kong Diabetes Registry between July 2010 and June 2015. Glycemic control was estimated by fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c). Participants with the Insomnia Severity Index score > 14 were considered as having insomnia. RESULTS: A total of 3753 patients were recruited. Compared with patients without insomnia, patients with insomnia had higher levels of FPG and HbA1c. After adjustment for potential confounding factors, insomnia was associated with higher FPG and HbA1c in the entire cohort. There were significant interactions between insomnia and gender for FPG (p = 0.001) and HbA1c (p = 0.025) in the full model. Subgroup analyses found that men with insomnia had higher FPG [8.23 (7.85-8.61) mmol/L versus 7.50 (7.39-7.61) mmol/L, p < 0.001] and HbA1c [7.79 (7.57-8.02)% versus 7.45 (7.39-7.52)%, p = 0.005] than men without insomnia after adjusted for confounding factors, whereas such difference was not observed in women. CONCLUSIONS: T2D patients with insomnia had worse glycemic control than the patients without insomnia. The associations were particularly pronounced in men.

MicroRNA and Diabetic Complications: A Clinical Perspective.

SIGNIFICANCE: The rising global prevalence of diabetes and its debilitating complications give rise to significant disability and premature mortality. Due to the silent nature of diabetes and its vascular complications, and limitations in current methods for detection, there is a need for novel biomarkers for early detection and prognosis. Recent Advances: Metabolic memory and epigenetic factors are important in the pathogenesis of diabetic complications and interact with genetic variants, metabolic factors, and clinical risk factors. Micro(mi)RNAs interact with epigenetic mechanisms and pleiotropically mediate the effects of hyperglycemia on the vasculature. Utilizing mature profiling techniques and platforms, an increasing number of miRNA signatures and interaction networks have been identified for diabetes and its related cardiorenal complications. As a result, these short, single-stranded molecules are emerging as potential diagnostic and predictive tools in human studies, and may function as disease biomarkers, as well as treatment targets. CRITICAL ISSUES: However, there is complex interaction between the genome and epigenome. The regulation of miRNAs may differ across species and tissues. Most profiling studies to date lack validation, often requiring large, well-characterized cohorts and reliable normalization strategies. Furthermore, the incremental benefits of miRNAs as biomarkers, beyond prediction provided by traditional risk factors, are critical issues to consider, yet often neglected in published studies. FUTURE DIRECTIONS: All in all, the future for miRNA-based diagnostics and therapeutics for diabetic complications appears promising. Improved understanding of the complex mechanisms underlying miRNA dysregulation, and more well-designed studies utilizing prospective samples would facilitate the translation to clinical use.

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.

Association of self-reported recurrent mild hypoglycemia with incident cardiovascular disease and all-cause mortality in patients with type 2 diabetes: Prospective analysis of the Joint Asia Diabetes Evaluation Registry.

Severe hypoglycemia is an established risk marker for cardiovascular complications of diabetes, but whether mild hypoglycemia confers similar risks is unclear. We examined the association of self-reported recurrent mild hypoglycemic events with cardiovascular disease (CVD) and all-cause mortality in a prospective cohort of Chinese adults with type 2 diabetes.From June 2007 to May 2015, 19,019 patients in Hong Kong underwent comprehensive assessment of metabolic and complication status using the Joint Asia Diabetes Evaluation program. Recurrent mild hypoglycemic event was determined by self-report of mild-to-moderate hypoglycemic symptoms at least once monthly in previous 3 months. Incident cardiovascular events were identified using hospital discharge diagnosis codes and death using Hong Kong Death Registry.Patients reporting recurrent mild hypoglycemia (n = 1501, 8.1%) were younger, had longer disease duration, worse glycemic control, and higher frequencies of vascular complications at baseline. Over 3.9 years of follow-up, respective incidences of CVD and all-cause death were 18.1 and 10.3 per 1000 person-years and 15.4 and 9.9 per 1000 person-years in patients with and without recurrent mild hypoglycemia. Using multivariate Cox regression analysis, recurrent mild hypoglycemia was not associated with CVD or all-cause mortality. In subgroup analysis, mild hypoglycemia was related to CVD in patients with chronic kidney disease (hazard ratio 1.36, 95% confidence interval 1.01-1.84, P = 0.0435) and those on insulin (hazard ratio 1.37, 95% confidence interval 1.01-1.86, P = 0.0402) adjusted for confounders.Mild hypoglycemia by self-report was frequent in patients with type 2 diabetes and was associated with increased risk of CVD in susceptible groups.

Testosterone level in men with type 2 diabetes mellitus and related metabolic effects: A review of current evidence.

A significant proportion of patients with type 2 diabetes mellitus have a low testosterone level relative to reference ranges based on healthy young men. Only a small number of these patients suffer from classical hypogonadism as a result of recognizable hypothalamic-pituitary-gonadal axis pathology. The cut-off value of the serum testosterone level in men without obvious hypothalamic-pituitary-gonadal axis pathology is controversial. It is unclear to what extent a low serum testosterone level causally leads to type 2 diabetes and/or the metabolic syndrome. From a theoretical standpoint, there can be complex interactions among the hypothalamic-pituitary-gonadal axis, body composition and insulin resistance, which can be further influenced by intrinsic and extrinsic factors to give rise to metabolic syndrome, glucose intolerance, and low-grade inflammation to increase the risk of cardiovascular disease. Although a low serum testosterone level frequently coexists with cardiometabolic risk factors and might serve as a biomarker, more studies are required to clarify the causal, mediating or modifying roles of low serum testosterone level in the development of adverse clinical outcomes. Currently, there are insufficient randomized clinical trial data to evaluate the effects of testosterone replacement therapy on meaningful clinical outcomes. The risk-to-benefit ratio of testosterone therapy in high-risk subjects, such as those with type 2 diabetes, also requires elucidation. The present article aims to review the current evidence on low serum testosterone levels in patients with type 2 diabetes, and its implications on cardiovascular risk factors, metabolic syndrome and adverse clinical outcomes.