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Objective: Associations between single nucleotide polymorphisms (SNPs) and aspirin resistance (AR) have been studied with variable results. The associations of genetic variants with AR may be helpful to explain why some individuals demonstrate aspirin insensitivity with this anti-platelet therapy. The purpose of this research was to investigate the effect of different genotypes in candidate genes on aspirin response in patients taking long-term aspirin therapy by measuring the serum thromboxane B2 (TXB2) and platelet function using the Multiplate® analyser. Methods: A total of 266 patients with stable coronary heart disease (CHD) taking low-dose aspirin for long periods of time and without any other anti-platelet drugs medications were enrolled into the study. They were required to take 80 mg of aspirin every morning for a week including the day before blood tests. Blood samples were collected 24 h after the last dose. The 80 mg dose of aspirin was taken orally and blood samples were collected again 1 h later. The serum TXB2 levels were measured in samples at 24 h post-dose and 1 h post-dose using the EIA kit and platelet activity was determined using the Multiplate® Impedance Platelet Aggregometry (ASPI) assay. Genotyping assays were performed by the TaqMan SNP genotyping technique. Results: Of the 266 patients, only 251 patients were enrolled in the present study. The PTGS1/COX1-1676 A > G (rs1330344) and the PTGS2/COX2-765 G > C (rs20417) SNPs showed significant associations with the ASPI measurements in samples taken at 24 h post-dose, but not with the values at 1 h post-dose or with the TXB2 levels (P < 0.05). Conclusions: Our results suggest that polymorphisms in the PTGS1/COX1 and the PTGS2/COX2 genes may be associated with reduced anti-aggregatory effects and increased the risk of AR, but future larger-scale cohort studies are necessary for further validation.
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Previously, no randomized controlled trials investigated the renoprotective effects of glucagon-like peptide-1 receptor agonists (GLP-1RA) as the primary endpoint in patients with diabetes and chronic kidney disease. In the FLOW trial, Perkovic et al. showed that once-weekly semaglutide reduced kidney failure, kidney-related death, and cardiovascular death by 24% as compared with placebo in patients with type 2 diabetes at high risk of renal progression.1.
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Diabetes Mellitus, Type 2 , Glucagon-Like Peptide-1 Receptor , Glucagon-Like Peptides , Renal Insufficiency, Chronic , Humans , Diabetes Mellitus, Type 2/drug therapy , Glucagon-Like Peptide-1 Receptor/agonists , Renal Insufficiency, Chronic/drug therapy , Glucagon-Like Peptides/therapeutic use , Glucagon-Like Peptides/pharmacology , Glucagon-Like Peptides/administration & dosage , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/pharmacology , Diabetic Nephropathies/drug therapyABSTRACT
Exploring the intricate crosstalk between dietary prebiotics and the specific intestinal microbiome (SIM) is intriguing in explaining the mechanisms of current successful dietary interventions, including the Mediterranean diet and high-fiber diet. This knowledge forms a robust basis for developing a new natural food therapy. The SIM diet can be measured and evaluated to establish a reliable basis for the management of metabolic diseases, such as diabetes, metabolic (dysfunction)-associated fatty liver disease (MAFLD), obesity, and metabolic cardiovascular disease. This review aims to delve into the existing body of research to shed light on the promising developments of possible dietary prebiotics in this field and explore the implications for clinical practice. The exciting part is the crosstalk of diet, microbiota, and gut-organ interactions facilitated by producing short-chain fatty acids, bile acids, and subsequent metabolite production. These metabolic-related microorganisms include Butyricicoccus, Akkermansia, and Phascolarctobacterium. The SIM diet, rather than supplementation, holds the promise of significant health consequences via the prolonged reaction with the gut microbiome. Most importantly, the literature consistently reports no adverse effects, providing a strong foundation for the safety of this dietary therapy.
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BACKGROUND: Glucokinase (GK) plays a key role in glucose metabolism. In the liver, GK is regulated by GK regulatory protein (GKRP) with nuclear sequestration at low plasma glucose level. Some GK activators (GKAs) disrupt GK-GKRP interaction which increases hepatic cytoplasmic GK level. Excess hepatic GK activity may exceed the capacity of glycogen synthesis with excess triglyceride formation. It remains uncertain whether hypertriglyceridemia associated with some GKAs in previous clinical trials was due to direct GK activation or impaired GK-GKRP interaction. METHODS: Using publicly available genome-wide association study summary statistics, we selected independent genetic variants of GCKR and GCK associated with fasting plasma glucose (FPG) as instrumental variables, to mimic the effects of impaired GK-GKRP interaction and direct GK activation, respectively. We applied two-sample Mendelian Randomization (MR) framework to assess their causal associations with lipid-related traits, risks of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular diseases. We verified these findings in one-sample MR analysis using individual-level statistics from the Hong Kong Diabetes Register (HKDR). RESULTS: Genetically-proxied impaired GK-GKRP interaction increased plasma triglycerides, low-density lipoprotein cholesterol and apolipoprotein B levels with increased odds ratio (OR) of 14.6 (95% CI 4.57-46.4) per 1 mmol/L lower FPG for MASLD and OR of 2.92 (95% CI 1.78-4.81) for coronary artery disease (CAD). Genetically-proxied GK activation was associated with decreased risk of CAD (OR 0.69, 95% CI 0.54-0.88) and not with dyslipidemia. One-sample MR validation in HKDR showed consistent results. CONCLUSIONS: Impaired GK-GKRP interaction, rather than direct GK activation, may worsen lipid profiles and increase risks of MASLD and CAD. Development of future GKAs should avoid interfering with GK-GKRP interaction.
Subject(s)
Adaptor Proteins, Signal Transducing , Blood Glucose , Genetic Predisposition to Disease , Genome-Wide Association Study , Glucokinase , Mendelian Randomization Analysis , Humans , Adaptor Proteins, Signal Transducing/genetics , Risk Factors , Risk Assessment , Blood Glucose/metabolism , Glucokinase/genetics , Glucokinase/metabolism , Biomarkers/blood , Lipids/blood , Phenotype , Carrier Proteins/genetics , Carrier Proteins/metabolism , Polymorphism, Single Nucleotide , Time Factors , Dyslipidemias/genetics , Dyslipidemias/blood , Dyslipidemias/diagnosis , Dyslipidemias/epidemiology , Dyslipidemias/enzymology , Fatty Liver/genetics , Fatty Liver/enzymology , Fatty Liver/bloodABSTRACT
Evidence-based guidelines provide the premise for the delivery of quality care to preserve health and prevent disabilities and premature death. The systematic gathering of observational, mechanistic and experimental data contributes to the hierarchy of evidence used to guide clinical practice. In the field of diabetes, metformin was discovered more than 100 years ago, and with 60 years of clinical use, it has stood the test of time regarding its value in the prevention and management of type 2 diabetes. Although some guidelines have challenged the role of metformin as the first-line glucose-lowering drug, it is important to point out that the cardiovascular-renal protective effects of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists were gathered from patients with type 2 diabetes, the majority of whom were treated with metformin. Most national, regional and international guidelines recommend metformin as a foundation therapy with emphasis on avoidance of therapeutic inertia and early attainment of multiple treatment goals. Moreover, real-world evidence has confirmed the glucose-lowering and cardiovascular-renal benefits of metformin accompanied by an extremely low risk of lactic acidosis. In patients with type 2 diabetes and advanced chronic kidney disease (estimated glomerular filtration rate 15-30 mL/min/1.73m2), metformin discontinuation was associated with an increased risk of cardiovascular-renal events compared with metformin persistence. Meanwhile, it is understood that microbiota, nutrients and metformin can interact through the gut-brain-kidney axis to modulate homeostasis of bioactive molecules, systemic inflammation and energy metabolism. While these biological changes contribute to the multisystem effects of metformin, they may also explain the gastrointestinal side effects and vitamin B12 deficiency associated with metformin intolerance. By understanding the interactions between metformin, foods and microbiota, healthcare professionals are in a better position to optimize the use of metformin and mitigate potential side effects. The United Kingdom Prospective Diabetes Study and the Da Qing Diabetes Prevention Program commenced 40 years ago provided the first evidence that type 2 diabetes is preventable and treatable. To drive real-world impact from this evidence, payors, practitioners and planners need to co-design and implement an integrated, data-driven, metformin-based programme to detect people with undiagnosed diabetes and prediabetes (intermediate hyperglycaemia), notably impaired glucose tolerance, for early intervention. The systematic data collection will create real-world evidence to bring out the best of metformin and make healthcare sustainable, affordable and accessible.
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Diabetes Mellitus, Type 2 , Hypoglycemic Agents , Metformin , Practice Guidelines as Topic , Precision Medicine , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Metformin/therapeutic use , Humans , Hypoglycemic Agents/therapeutic useABSTRACT
OBJECTIVES: There is relatively scarce data regarding the association between primary hyperparathyroidism (PHPT) and incident diabetes in large population-based longitudinal studies. We aimed to evaluate the risk of incident diabetes in individuals with and without PHPT and investigate the association between serum calcium concentrations and the risk of incident diabetes in patients with PHPT. METHODS: We included 2749 PHPT patients and 13,745 age, sex and index year matched non-PHPT individuals during 2000-2019. We used Cox regression models to compare the risk of incident diabetes in individuals with and without PHPT, and the risk of incident diabetes in PHPT patients with serum calcium concentration above and below the median value. The association between serum calcium concentrations and the risk of incident diabetes was examined by restricted cubic spline analyses in patients with PHPT. RESULTS: During a median follow-up time of 5.17 years (IQR 2.17, 9.58), 433 patients (15.75%) with PHPT and 2110 individuals (15.35%) without PHPT developed diabetes, respectively. Patients with PHPT had a higher incidence rate of diabetes compared to non-PHPT individuals (27.60 [95% CI 25.00, 30.30] vs. 23.90 [95% CI 22.80, 24.90] per 1000 person-years, log-rank test p = .007]. Crude Cox regression model showed PHPT was associated with a 15% higher risk of incident diabetes (HR 1.15, 95%CI 1.04, 1.28). In patients with PHPT, a 44% higher risk of incident diabetes was found in patients with serum calcium concentrations above the median value (2.63 mmol/L), compared to those below the median value (HR 1.44, 95%CI 1.08, 1.90). Restricted cubic spline analyses confirmed a positive linear association between serum calcium concentrations and the risk of incident diabetes in those with PHPT (p-value for nonlinear = .751) CONCLUSIONS: Patients with PHPT had a higher risk of incident diabetes compared to non-PHPT individuals. A positive linear association was found between serum calcium concentrations and the risk of incident diabetes in patients with PHPT.
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INTRODUCTION: We designed and implemented a patient-centered, data-driven, holistic care model with evaluation of its impacts on clinical outcomes in patients with young-onset type 2 diabetes (T2D) for which there is a lack of evidence-based practice guidelines. RESEARCH DESIGN AND METHODS: In this 3-year Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial, we evaluate the effects of a multicomponent care model integrating use of information and communication technology (Joint Asia Diabetes Evaluation (JADE) platform), biogenetic markers and patient-reported outcome measures in patients with T2D diagnosed at ≤40 years of age and aged ≤50 years. The JADE-PRISM group received 1 year of specialist-led team-based management using treatment algorithms guided by biogenetic markers (genome-wide single-nucleotide polymorphism arrays, exome-sequencing of 34 monogenic diabetes genes, C-peptide, autoantibodies) to achieve multiple treatment goals (glycated hemoglobin (HbA1c) <6.2%, blood pressure <120/75 mm Hg, low-density lipoprotein-cholesterol <1.2 mmol/L, waist circumference <80 cm (women) or <85 cm (men)) in a diabetes center setting versus usual care (JADE-only). The primary outcome is incidence of all diabetes-related complications. RESULTS: In 2020-2021, 884 patients (56.6% men, median (IQR) diabetes duration: 7 (3-12) years, current/ex-smokers: 32.5%, body mass index: 28.40±5.77 kg/m2, HbA1c: 7.52%±1.66%, insulin-treated: 27.7%) were assigned to JADE-only (n=443) or JADE-PRISM group (n=441). The profiles of the whole group included positive family history (74.7%), general obesity (51.4%), central obesity (79.2%), hypertension (66.7%), dyslipidemia (76.4%), albuminuria (35.4%), estimated glomerular filtration rate <60 mL/min/1.73 m2 (4.0%), retinopathy (13.8%), atherosclerotic cardiovascular disease (5.2%), cancer (3.1%), emotional distress (26%-38%) and suboptimal adherence (54%) with 5-item EuroQol for Quality of Life index of 0.88 (0.87-0.96). Overall, 13.7% attained ≥3 metabolic targets defined in secondary outcomes. In the JADE-PRISM group, 4.5% had pathogenic/likely pathogenic variants of monogenic diabetes genes; 5% had autoantibodies and 8.4% had fasting C-peptide <0.2 nmol/L. Other significant events included low/large birth weight (33.4%), childhood obesity (50.7%), mental illness (10.3%) and previous suicide attempts (3.6%). Among the women, 17.3% had polycystic ovary syndrome, 44.8% required insulin treatment during pregnancy and 17.3% experienced adverse pregnancy outcomes. CONCLUSIONS: Young-onset diabetes is characterized by complex etiologies with comorbidities including mental illness and lifecourse events. TRIAL REGISTRATION NUMBER: NCT04049149.
Subject(s)
Diabetes Mellitus, Type 2 , Insulin Secretion , Precision Medicine , Humans , Female , Male , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/therapy , Adult , Precision Medicine/methods , Middle Aged , China/epidemiology , Age of Onset , Young Adult , Insulin/therapeutic use , Hypoglycemic Agents/therapeutic use , Follow-Up Studies , Blood Glucose/analysis , Glycated Hemoglobin/analysis , Asian People , Biomarkers/analysis , Prognosis , East Asian PeopleABSTRACT
AIM: Therapeutic inertia, hypoglycaemia and poor treatment persistence can lead to glycaemic fluctuation and poor outcomes in type 2 diabetes (T2D). We compared glycated haemoglobin (HbA1c) variability, insulin initiation, severe hypoglycaemia and clinical events in patients with T2D initiated dipeptidyl peptidase-4 inhibitors (DPP4is) at low versus high HbA1c thresholds. METHODS: Using territory-wide electronic medical records in Hong Kong, we curated a propensity score-matched cohort of patients initiated DPP4i at HbA1c <7.5% versus ≥7.5% in 2007-2019. We expressed the HbA1c variability score (HVS) as a proportion of HbA1c varied by ≥0.5% compared with preceding values. We used the Cox model to compare the risks of insulin initiation and clinical outcomes, adjusted for time-varying variables between the two groups. Mediation analysis estimated the effects of HbA1c variability on outcomes. RESULTS: Among 6874 insulin-naïve patients who initiated DPP4i, 88.7% were treated with metformin and 79.6% with sulphonylureas at baseline (54.9% men; mean age 65.2 ± 11.4 years). After a median follow-up of 4.6 years, compared with the high-threshold plus high-HVS group (≥50%), the low-threshold plus low-HVS (<50%) group had reduced hazard ratios (95% confidence interval) of insulin initiation (0.35, 0.31-0.40), severe hypoglycaemia (0.38, 0.34-0.44), major adverse cardiovascular endpoints (0.76, 0.66-0.88), heart failure (0.42, 0.36-0.49), end-stage kidney disease (0.65, 0.36-0.49) and mortality (0.45, 0.35-0.57). Reduced HbA1c variability explained 31.1%-81.2% of the effect size of DPP4i initiation at HbA1c <7.5% versus ≥7.5% on outcomes. CONCLUSIONS: In Chinese patients with T2D, avoiding therapeutic inertia with intensified glycaemic control at HbA1c <7.5% using drugs with low risk of hypoglycaemia and good tolerability, such as DPP4i, delayed insulin treatment, reduced HbA1c variability and improved clinical events.
Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Glycated Hemoglobin , Hypoglycemia , Hypoglycemic Agents , Humans , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Male , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/blood , Female , Glycated Hemoglobin/analysis , Glycated Hemoglobin/metabolism , Aged , Middle Aged , Hypoglycemia/chemically induced , Hypoglycemia/epidemiology , Hypoglycemic Agents/therapeutic use , Hong Kong/epidemiology , Insulin/therapeutic use , Sulfonylurea Compounds/therapeutic use , Cohort Studies , Blood Glucose/drug effects , Blood Glucose/metabolism , Blood Glucose/analysis , Propensity ScoreABSTRACT
AIMS: Asians have a high prevalence of young-onset diabetes, but the pattern of monogenic diabetes is unknown. We aimed to determine the prevalence of monogenic diabetes in Chinese patients with young-onset diabetes and compare the clinical characteristics and outcome between patients with and without monogenic diabetes. MATERIALS AND METHODS: We sequenced a targeted panel of 33 genes related to monogenic diabetes in 1021 Chinese patients with non-type 1 diabetes diagnosed at age ≤40 years. Incident complications including cardiovascular disease (CVD), end-stage kidney disease (ESKD) and all-cause death were captured since enrolment (1995-2012) until 2019. RESULTS: In this cohort (mean ± SD age at diagnosis: 33.0 ± 6.0 years, median[IQR] diabetes duration 7.0[1.0-15.0] years at baseline, 44.9% men), 22(2.2%, 95% confidence interval[CI] 1.4%-3.2%) had monogenic diabetes. Pathogenic (P) or likely pathogenic (LP) variants were detected in GCK (n = 6), HNF1A (n = 9), HNF4A (n = 1), PLIN1 (n = 1) and PPARG (n = 2), together with copy number variations in HNF1B (n = 3). Over a median follow-up of 17.1 years, 5(22.7%) patients with monogenic diabetes (incidence rate 12.3[95% CI 5.1-29.4] per 1000 person-years) versus 254(25.4%) without monogenic diabetes (incidence rate 16.7[95% CI 14.8-18.9] per 1000 person-years) developed the composite outcome of CVD, ESKD and/or death (p = 0.490). The multivariable Cox model did not show any difference in hazards for composite events between groups. CONCLUSIONS: In Chinese with young-onset non-type 1 diabetes, at least 2% of cases were contributed by monogenic diabetes, over 80% of which were accounted for by P/LP variants in common MODY genes. The incidence of diabetes complications was similar between patients with and without monogenic diabetes.
Subject(s)
Age of Onset , Humans , Male , Female , Follow-Up Studies , Hong Kong/epidemiology , Adult , Prospective Studies , Prognosis , Asian People/genetics , Young Adult , Diabetes Mellitus/genetics , Diabetes Mellitus/epidemiology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/epidemiology , Prevalence , Adolescent , Incidence , East Asian PeopleABSTRACT
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.
Subject(s)
Blood Glucose , Diabetes Mellitus, Type 2 , Glucose Tolerance Test , Humans , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/diagnosis , Hong Kong/epidemiology , Male , Adult , Female , Middle Aged , Blood Glucose/analysis , Blood Glucose/metabolism , Glucose Intolerance/blood , Glucose Intolerance/epidemiology , Glucose Intolerance/diagnosis , Young Adult , Adolescent , Fasting/blood , Asian People/statistics & numerical data , Disease Progression , East Asian PeopleABSTRACT
BACKGROUND: The community-based participatory approach (CBPA) has gained increasing recognition worldwide for enhancing the effectiveness of intervention. It is relatively new in Chinese societies and participants' perceptions are underexplored. This study aims to explore abused Chinese women's perceptions on the CBPA programme in addressing their needs. METHODS: A total of 11 abused Chinese women were recruited for a focus group and individual interviews. A semi-structured interview guide was used. All interviews were audio-recorded and data were transcribed verbatim. Conventional content analysis was used for analysis. RESULTS: Four themes were identified regarding the women's perceptions and experiences of the community-based participatory approach programme: (1) Women's perceived acceptability of the CBPA programme; (2) Women's perceived usefulness of the CBPA programme; (3) Women's perceived feasibility of the CBPA programme; and (4) Empowering the women through participating in CBPA. CONCLUSIONS: Abused Chinese women had high perceived acceptance and positive experiences towards the community-based participatory approach. Women benefited from their robust participation throughout the process. The findings confirm the potential of using the community-based participatory approach in designing interventions for future programme planning and intervention to address the needs of abused Chinese women.
Subject(s)
Community-Based Participatory Research , Gender-Based Violence , Female , Humans , China , Focus Groups , Qualitative Research , East Asian People , Battered Women , Health Services Needs and DemandABSTRACT
Background: Psychosocial status and patient reported outcomes (PRO) [depression and health-related quality-of-life (HRQoL)] are major health determinants. We investigated the association between depression and clinical outcomes in Chinese patients with type 2 diabetes (T2D), adjusted for PRO. Methods: Using prospective data from Hong Kong Diabetes Register (2013-2019), we estimated the hazard-ratio (HR, 95%CI) of depression (validated Patient Health Questionnaire 9 (PHQ-9) score≥7) with incident cardiovascular disease (CVD), ischemic heart disease (IHD), chronic kidney disease (CKD: eGFR<60 ml/min/1.73m2) and all-cause mortality in 4525 Chinese patients with T2D adjusted for patient characteristics, renal function, medications, self-care and HRQoL domains (mobility, self-care, usual activities, pain/discomfort, anxiety/depression measured by EQ-5D-3L) in linear-regression models. Results: In this cohort without prior events [mean ± SD age:55.7 ± 10.6, 43.7% women, median (IQR) disease duration of 7.0 (2.0-13.0) years, HbA1c, 7.2% (6.6%-8.20%), 26.4% insulin-treated], 537(11.9%) patients had depressive symptoms and 1923 (42.5%) patients had some problems with HRQoL at baseline. After 5.6(IQR: 4.4-6.2) years, 141 patients (3.1%) died, 533(11.8%) developed CKD and 164(3.6%) developed CVD. In a fully-adjusted model (model 4) including self-care and HRQoL, the aHR of depression was 1.99 (95% confidence interval CI):1.25-3.18) for CVD, 2.29 (1.25-4.21) for IHD. Depression was associated with all-cause mortality in models 1-3 adjusted for demographics, clinical characteristics and self-care, but was attenuated after adjusting for HRQoL (model 4- 1.54; 95%CI: 0.91-2.60), though HR still indicated same direction with important magnitude. Patients who reported having regular exercise (3-4 times per week) had reduced aHR of CKD [0.61 (0.41-0.89)]. Item 4 of PHQ-9 (feeling tired, little energy) was independently associated with all-cause mortality with aHR of 1.66 (1.30-2.12). Conclusion: Depression exhibits significant association with CVD, IHD, and all-cause mortality in patients with diabetes, adjusting for their HRQoL and health behaviors. Despite the association between depression and all-cause mortality attenuated after adjusting for HRQoL, the effect size remains substantial. The feeling of tiredness or having little energy, as assessed by item Q4 of the PHQ-9 questionnaire, was found to be significantly associated with an increased risk of all-cause mortality after covariate adjustments. Our findings emphasize the importance of incorporating psychiatric evaluations into holistic diabetes management.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Renal Insufficiency, Chronic , Humans , Female , Male , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Hong Kong/epidemiology , Depression/complications , Depression/epidemiology , Kidney , Renal Insufficiency, Chronic/complications , Cardiovascular Diseases/complications , Cardiovascular Diseases/epidemiology , Patient Reported Outcome MeasuresABSTRACT
Background: Current labelling advises discontinuation of metformin when estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 due to increased risk of lactic acidosis. However, in real-world practice, the risk-benefit ratios remain uncertain. We examined the risk associations of discontinued-metformin use with cardiorenal and clinical outcomes in patients with type 2 diabetes (T2D) and advanced chronic kidney disease. Methods: In this territory-wide, retrospective cohort and target trial emulation study, we included Chinese patients attending the Hong Kong Hospital Authority (HA) and enrolled in the Risk-Assessment-and-Management-Programme-for-Diabetes-Mellitus (RAMP-DM) from 2002 to 2019. Patients were stratified by discontinuation of metformin within six months after reaching eGFR < 30 ml/min/1.73 m2 from January 1, 2002 to December 31, 2018, and followed up until December 31 2019. We excluded patients who had observational time <6 months from eGFR < 30 ml/min/1.73 m2, and had their eGFR measured during a hospitalisation episode due to acute kidney injury, or missing diagnosis date of diabetes. We compared the risk associations of metformin discontinuation with clinical outcomes. The primary outcomes were major adverse cardiovascular events (MACE), end-stage kidney disease (ESKD), cancer, and all-cause mortality. A Cox-model with time-dependent exposure and covariates was used to estimate the hazard ratio (HR) of outcomes in a propensity-score overlap-weighted cohort. The risk of occurrence of lactic acidosis (serum lactate > 5.0 mmol/L with a concomitant blood pH < 7.35 or ICD-9 codes of 276.2) in discontinued-metformin versus continued-metformin users was assessed in a separate register-based cohort. Findings: A total of 33,586 metformin users with new-onset eGFR < 30 ml/min/1.73 m2 were included in the study, 7500 (22.3%) of whom discontinued metformin within 6 months whereas 26,086 (77.7%) continued use of metformin. During a median follow-up of 3.8 (IQR: 2.2-6.1) years, 16.4% (5505/33,586), 30.1% (10,113/33,586), and 7.1% (2171/30,682) had incident MACE, ESKD, and cancer respectively, and 44.4% (14,917/33,586) died. Compared to continued-metformin use, discontinuation was associated with higher risk of MACE (weighted and adjusted HR = 1.40, 95% CI: 1.29-1.52), ESKD (HR = 1.52, 1.42-1.62), and death (HR = 1.22, 1.18-1.27). No association was observed for cancer (HR = 0.93, 0.85-1.01). Discontinued-metformin users had higher change in HbA1c change at 6-month of follow-up versus continued-metformin users (weighted mean HbA1c level change: 0.5% [0.4-0.6%] versus 0.2% [0.1-0.2]). In the separate register-based cohort (n = 3235), null association was observed between metformin use and risk of lactic acidosis (weighted HR = 0.94 [0.53-1.64]). Interpretation: Our results suggest that discontinuation of metformin in patients with T2D and chronic kidney disease may be associated with increased risk of cardiovascular-renal events. Use of metformin below eGFR of 30 ml/min/1.73 m2 may be associated with cardiovascular, renal, and mortality benefits that need to be weighed against the risk of lactic acidosis, but further research is needed to validate these findings. Funding: CUHK Impact Research Fellowship Scheme.
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BACKGROUND: Older adults with diabetes are at high risk of severe hypoglycemia (SH). Many machine-learning (ML) models predict short-term hypoglycemia are not specific for older adults and show poor precision-recall. We aimed to develop a multidimensional, electronic health record (EHR)-based ML model to predict one-year risk of SH requiring hospitalization in older adults with diabetes. METHODS AND FINDINGS: We adopted a case-control design for a retrospective territory-wide cohort of 1,456,618 records from 364,863 unique older adults (age ≥65 years) with diabetes and at least 1 Hong Kong Hospital Authority attendance from 2013 to 2018. We used 258 predictors including demographics, admissions, diagnoses, medications, and routine laboratory tests in a one-year period to predict SH events requiring hospitalization in the following 12 months. The cohort was randomly split into training, testing, and internal validation sets in a 7:2:1 ratio. Six ML algorithms were evaluated including logistic-regression, random forest, gradient boost machine, deep neural network (DNN), XGBoost, and Rulefit. We tested our model in a temporal validation cohort in the Hong Kong Diabetes Register with predictors defined in 2018 and outcome events defined in 2019. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC) statistics, and positive predictive value (PPV). We identified 11,128 SH events requiring hospitalization during the observation periods. The XGBoost model yielded the best performance (AUROC = 0.978 [95% CI 0.972 to 0.984]; AUPRC = 0.670 [95% CI 0.652 to 0.688]; PPV = 0.721 [95% CI 0.703 to 0.739]). This was superior to an 11-variable conventional logistic-regression model comprised of age, sex, history of SH, hypertension, blood glucose, kidney function measurements, and use of oral glucose-lowering drugs (GLDs) (AUROC = 0.906; AUPRC = 0.085; PPV = 0.468). Top impactful predictors included non-use of lipid-regulating drugs, in-patient admission, urgent emergency triage, insulin use, and history of SH. External validation in the HKDR cohort yielded AUROC of 0.856 [95% CI 0.838 to 0.873]. Main limitations of this study included limited transportability of the model and lack of geographically independent validation. CONCLUSIONS: Our novel-ML model demonstrated good discrimination and high precision in predicting one-year risk of SH requiring hospitalization. This may be integrated into EHR decision support systems for preemptive intervention in older adults at highest risk.
Subject(s)
Diabetes Mellitus , Hypoglycemia , Humans , Aged , Electronic Health Records , Retrospective Studies , Hypoglycemia/diagnosis , Hypoglycemia/epidemiology , Diabetes Mellitus/diagnosis , Diabetes Mellitus/epidemiology , Hospitalization , Machine LearningABSTRACT
AIMS: To examine the patterns of use of potentially interacting supplement-drug pairs in adults with type 2 diabetes (T2D) in real-world settings, and to explore the impact of potentially interacting supplement-drug pairs on downstream outcomes. METHODS: Potentially interacting supplement-drug pairs were identified from four tertiary databases. We categorized the potential pharmacodynamic interactions into different clinical types according to their related outcomes and explored their associations with incident outcomes using Cox models. RESULTS: 26,394 participants with T2D in the UK Biobank were included. Half (48.5 %) were supplement users, of whom 85.0 % were taking potentially interacting supplement-drug pairs. The potential pharmacodynamic interactions were related to various clinical outcomes, including reducing the effects of glucose-lowering drugs (50.7 %), hypotension (49.8 %), bleeding (50.4 %) and hepatotoxicity (34.8 %). Exploratory analyses found that the use of potentially interacting supplement-drug pairs was associated with incident hepatic diseases (hazard ratio = 1.26, 95 % confidence interval 1.10-1.44, P < 0.001). CONCLUSIONS: Real-world data suggests that most adults with T2D who concurrently used supplements and drugs were on potentially interacting supplement-drug combinations, with the potential of causing adverse outcomes such as incident hepatic diseases. Clinicians should communicate with patients and assess the potential risk of supplement-drug interactions in clinical settings.
Subject(s)
Biological Specimen Banks , Diabetes Mellitus, Type 2 , Dietary Supplements , Hypoglycemic Agents , Humans , Diabetes Mellitus, Type 2/drug therapy , Male , Female , Middle Aged , United Kingdom/epidemiology , Hypoglycemic Agents/therapeutic use , Aged , Cohort Studies , Drug Interactions , Adult , UK BiobankABSTRACT
Normal-weight individuals with usual-onset type 2 diabetes have reduced ß-cell function and greater insulin sensitivity compared with their obese counterparts. The relative contribution of ß-cell dysfunction and insulin resistance to young-onset type 2 diabetes (YOD) among normal-weight individuals is not well established. In 44 individuals with YOD (24 with normal weight and 20 with obesity) and 24 healthy control individuals with normoglycemia (12 with normal weight and 12 with obesity), we conducted 2-h 12 mmol/L hyperglycemic clamps to measure acute (0-10 min) and steady-state (100-120 min) insulin and C-peptide responses, as well as insulin sensitivity index. Normal-weight individuals with YOD had lower acute insulin response, steady-state insulin and C-peptide responses, and a higher insulin sensitivity index compared with their obese counterparts with YOD. Compared with BMI-matched healthy control individuals, normal-weight individuals with YOD had lower acute and steady-state insulin and C-peptide responses but a similar insulin sensitivity index. The impairment of steady-state ß-cell response relative to healthy control individuals was more pronounced in normal-weight versus obese individuals with YOD. In conclusion, normal-weight Chinese with YOD exhibited worse ß-cell function but preserved insulin sensitivity relative to obese individuals with YOD and BMI-matched healthy individuals with normoglycemia. The selection of glucose-lowering therapy should account for pathophysiological differences underlying YOD between normal-weight and obese individuals.
Subject(s)
C-Peptide , Diabetes Mellitus, Type 2 , Insulin Resistance , Insulin-Secreting Cells , Insulin , Obesity , Humans , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/physiology , Insulin Resistance/physiology , Obesity/metabolism , Obesity/physiopathology , Male , Female , Adult , C-Peptide/blood , C-Peptide/metabolism , Insulin/metabolism , Insulin/blood , Glucose Clamp Technique , Blood Glucose/metabolism , Body Mass Index , China/epidemiology , Age of Onset , Asian People , Young Adult , Case-Control Studies , East Asian PeopleABSTRACT
AIMS: Direct comparisons of population-level trends in all-cause and cause-specific mortalities among older adults with and without diabetes are lacking. METHODS: We performed a territory-wide analysis of 1,142,000 unique older adults aged ≥ 65 years (31.7 % with diabetes) with at least one attendance in the Hong Kong Hospital Authority in 2014-2018. We used Joinpoint regression to describe trends of age- and sex-standardised all-cause and cause-specific mortalities (cardiovascular disease [CVD], cancer, and non-CVD and non-cancer) in older adults with and without diabetes. RESULTS: All-cause mortality decreased in older adults with (average annual percent change [AAPC] = -1.6, 95 % confidence interval [-2.7, -0.4]) and without (AAPC = -3.1 [-4.2, -2.1]) diabetes. Largest declines were seen for CVD-cause mortalities for people with and without diabetes (AAPC = -5.5 [-6.8, -4.1] vs AAPC = -5.8 [-8.6, -2.9], respectively). Cancer-cause mortalities were similar in both groups with no change. Men with diabetes showed less favourable improvements. An increasing mortality trend was seen only in the 65-69 age-group regardless of diabetes status. CONCLUSIONS: Mortality continued to decline in older adults with and without diabetes, mainly driven by a decline in CVD deaths, with no narrowing of the mortality gap. Our findings call for continued actions to address excess mortalities especially in older men with diabetes and younger older adults.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus , Neoplasms , Male , Humans , Aged , Hong Kong/epidemiology , Cause of Death , MortalityABSTRACT
AIMS/INTRODUCTION: To determine the population health burden attributable to the development of diabetes among women with a history of gestational diabetes mellitus (GDM). MATERIALS AND METHODS: We conducted a retrospective analysis of women with a history of GDM attending the Hong Kong Hospital Authority between 2000 and 2019. The time-varying population attributable fraction was calculated. RESULTS: A total of 76,181 women with a history of gestational diabetes mellitus were included, 6,606 of them developed diabetes during a median follow-up of 8.6 years. The respective hazard ratios (95% confidence interval) among women with GDM who developed diabetes vs those with GDM only were 2.8 (2.2, 3.7) for cardiovascular disease (CVD), 4.8 (3.0, 7.7) for end-stage kidney disease (ESKD), 2.2 (1.9, 2.6) for infection-related hospitalization, and 1.8 (1.3, 2.4) for all-cause mortality. The development of diabetes was associated with 1.3 (0.8, 1.7), 0.6 (0.3, 0.8), 3.2 (2.4, 4.0), and 0.5 (0.2, 0.9) additional incident cases per 1,000 person-years, accounting for 24.0% (13.2%, 35.9%), 42.0% (22.5%, 58.8%), 10.8% (7.1%, 14.9%), and 6.0% (-3.1%, 16.1%) of absolute number of CVD, ESKD, infection-related hospitalization, and all-cause mortality over 20 years after GDM, respectively. CONCLUSIONS: Diabetes is a significant contributor to the population health burden of some clinical outcomes in women with a history of gestational diabetes mellitus, but other risk factors need to be considered.
Subject(s)
Diabetes, Gestational , Humans , Female , Diabetes, Gestational/epidemiology , Pregnancy , Hong Kong/epidemiology , Retrospective Studies , Adult , Risk Factors , Follow-Up Studies , Middle Aged , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Incidence , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/complicationsABSTRACT
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.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Renal Insufficiency, Chronic , Humans , Diabetic Nephropathies/metabolism , Cardiovascular Diseases/complications , Prospective Studies , Hong Kong/epidemiology , Albuminuria , Biological Specimen Banks , Glomerular Filtration Rate , Biomarkers , AlbuminsABSTRACT
INTRODUCTION: Type 2 diabetes is preventable in subjects with impaired glucose tolerance based on 2-hour plasma glucose (2hPG) during 75 g oral glucose tolerance test (OGTT). We incorporated routine biochemistry to improve the performance of a non-invasive diabetes risk score to identify individuals with abnormal glucose tolerance (AGT) defined by 2hPG≥7.8 mmol/L during OGTT. RESEARCH DESIGN AND METHODS: We used baseline data of 1938 individuals from the community-based "Better Health for Better Hong Kong - Hong Kong Family Diabetes Study (BHBHK-HKFDS) Cohort" recruited in 1998-2003. We incorporated routine biochemistry in a validated non-invasive diabetes risk score, and evaluated its performance using area under receiver operating characteristics (AUROC) with internal and external validation. RESULTS: The AUROC of the original non-invasive risk score to predict AGT was 0.698 (95% CI, 0.662 to 0.733). Following additional inclusion of fasting plasma glucose, serum potassium, creatinine, and urea, the AUROC increased to 0.778 (95% CI, 0.744 to 0.809, p<0.001). Net reclassification improved by 31.9% (p<0.001) overall, by 30.8% among people with AGT and 1.1% among people without AGT. The extended model showed good calibration (χ2=11.315, p=0.1845) and performance on external validation using an independent data set (AUROC=0.722, 95% CI, 0.680 to 0.764). CONCLUSIONS: The extended risk score incorporating clinical and routine biochemistry can be integrated into an electronic health records system to select high-risk subjects for evaluation of AGT using OGTT for prevention of diabetes.