Risk stratification of cardiac arrhythmias and sudden cardiac death in type 2 diabetes mellitus patients receiving insulin therapy: A population-based cohort study

Introduction Metabolic abnormalities may exacerbate the risk of adverse outcomes in patients with type 2 diabetes mellitus. The present study aims to assess the predictive value of HbA1c and lipid variability on the risks of sudden cardiac death (SCD) and incident atrial fibrillation (AF). Methods The retrospective observational study consists of type 2 diabetic patients prescribed with insulin, who went to publicly funded clinics and hospitals in Hong Kong between January 1, 2009 and December 31, 2009. Variability in total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglyceride, and HbA1c were assessed through their SD and coefficient of variation. The primary outcomes were incident (1) ventricular tachycardia/ventricular fibrillation, actual or aborted SCD and (2) AF. Results A total of 23 329 patients (mean ± SD age: 64 ± 14 years old; 51% male; mean HbA1c 8.6 ± 1.3%) were included. On multivariable analysis, HbA1c, total cholesterol, LDL-C and triglyceride variability were found to be predictors of SCD (p < .05). Conclusion HbA1c and lipid variability were predictive of SCD. Therefore, poor glucose control and variability in lipid parameters in diabetic patients are associated with aborted or actual SCD. These observations suggest the need to re-evaluate the extent of glycemic control required for outcome optimization

Group B Streptococcus suppression of phagocyte functions by protein-mediated engagement of human Siglec-5

Group B Streptococcus (GBS) is a leading cause of invasive bacterial infections in human newborns. A key GBS virulence factor is its capsular polysaccharide (CPS), displaying terminal sialic acid (Sia) residues which block deposition and activation of complement on the bacterial surface. We recently demonstrated that GBS Sia can bind human CD33-related Sia-recognizing immunoglobulin (Ig) superfamily lectins (hCD33rSiglecs), a family of inhibitory receptors expressed on the surface of leukocytes. We report the unexpected discovery that certain GBS strains may bind one such receptor, hSiglec-5, in a Sia-independent manner, via the cell wall–anchored β protein, resulting in recruitment of SHP protein tyrosine phosphatases. Using a panel of WT and mutant GBS strains together with Siglec-expressing cells and soluble Siglec-Fc chimeras, we show that GBS β protein binding to Siglec-5 functions to impair human leukocyte phagocytosis, oxidative burst, and extracellular trap production, promoting bacterial survival. We conclude that protein-mediated functional engagement of an inhibitory host lectin receptor promotes bacterial innate immune evasion

The impact of cardiac comorbidity sequence at baseline and mortality risk in type 2 Diabetes Mellitus: a retrospective population-based cohort study

Introduction: The presence of multiple comorbidities increases the risk of all-cause mortality, but the effects of the comorbidity sequence before the baseline date on mortality remain unexplored. This study investigated the relationship between coronary heart disease (CHD), atrial fibrillation (AF) and heart failure (HF) through their sequence of development and the effect on all-cause mortality risk in type 2 diabetes mellitus. Methods: This study included patients with type 2 diabetes mellitus prescribed antidiabetic/cardiovascular medications in public hospitals of Hong Kong between 1 January 2009 and 31 December 2009, with follow-up until death or 31 December 2019. The Cox regression was used to identify comorbidity sequences predicting all-cause mortality in patients with different medication subgroups. Results: A total of 249,291 patients (age: 66.0 ± 12.4 years, 47.4% male) were included. At baseline, 7564, 10,900 and 25,589 patients had AF, HF and CHD, respectively. Over follow-up (3524 ± 1218 days), 85,870 patients died (mortality rate: 35.7 per 1000 person-years). Sulphonylurea users with CHD developing later and insulin users with CHD developing earlier in the disease course had lower mortality risks. Amongst insulin users with two of the three comorbidities, those with CHD with preceding AF (hazard ratio (HR): 3.06, 95% CI: [2.60–3.61], p < 0.001) or HF (HR: 3.84 [3.47–4.24], p < 0.001) had a higher mortality. In users of lipid-lowering agents with all three comorbidities, those with preceding AF had a higher risk of mortality (AF-CHD-HF: HR: 3.22, [2.24–4.61], p < 0.001; AF-HF-CHD: HR: 3.71, [2.66–5.16], p < 0.001). Conclusions: The sequence of comorbidity development affects the risk of all-cause mortality to varying degrees in diabetic patients on different antidiabetic/cardiovascular medications

Gender-specific clinical risk scores incorporating blood pressure variability for predicting incident dementia

Introduction: The present study examined the gender-specific prognostic value of blood pressure (BP) and its variability in the prediction of dementia risk and developed a score system for risk stratification. Materials and Methods This was a retrospective, observational population-based cohort study of patients admitted to government-funded family medicine clinics in Hong Kong between January 1, 2000 and March 31, 2002 with at least 3 blood pressure measurements. Gender-specific risk scores for dementia were developed and tested. Results The study consisted of 74 855 patients, of whom 3550 patients (incidence rate: 4.74%) developed dementia over a median follow-up of 112 months (IQR= [59.8–168]). Nonlinear associations between diastolic/systolic BP measurements and the time to dementia presentation were identified. Gender-specific dichotomized clinical scores were developed for males (age, hypertension, diastolic and systolic BP and their measures of variability) and females (age, prior cardiovascular, respiratory, gastrointestinal diseases, diabetes mellitus, hypertension, stroke, mean corpuscular volume, monocyte, neutrophil, urea, creatinine, diastolic and systolic BP and their measures of variability). They showed high predictive strengths for both male (hazard ratio [HR]: 12.83, 95% confidence interval [CI]: 11.15–14.33, P value &amp;lt; .0001) and female patients (HR: 26.56, 95% CI: 14.44–32.86, P value &amp;lt; .0001). The constructed gender-specific scores outperformed the simplified systems without considering BP variability (C-statistic: 0.91 vs 0.82), demonstrating the importance of BP variability in dementia development. Conclusion Gender-specific clinical risk scores incorporating BP variability can accurately predict incident dementia and can be applied clinically for early disease detection and optimized patient management

Comparison of sodium-glucose cotransporter-2 inhibitor and dipeptidyl peptidase-4 inhibitor on the risks of new-onset atrial fibrillation, stroke and mortality in diabetic patients: A propensitysScore-matched study in Hong Kong

Objective To compare the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2Is) and dipeptidyl peptidase-4 inhibitors (DPP4Is) on adverse outcomes in diabetic patients in Hong Kong. Methods This was a retrospective population-based cohort study of type 2 diabetes mellitus patients (n = 72,746) treated with SGLT2I or DPP4I between January 1, 2015, and December 31, 2020, in Hong Kong. Patients with exposure to both DPP4I and SGLT2I therapy, without complete demographics or mortality data, or who had prior atrial fibrillation (AF) were excluded. The study outcomes were new-onset AF, stroke/transient ischemic attack, cardiovascular mortality and all-cause mortality. Propensity score matching (1:1 ratio) between SGLT2I and DPP4I users was performed. Results The unmatched study cohort included 21,713 SGLT2I users and 39,510 DPP4I users (total: n = 61,233 patients; 55.37% males, median age: 62.7 years [interquartile range (IQR): 54.6–71.9 years]). Over a median follow-up of 2030 (IQR: 1912–2117) days, 2496 patients (incidence rate [IR]: 4.07%) developed new-onset AF, 2179 patients (IR: 3.55%) developed stroke/transient ischemic attack, 1963 (IR: 3.20%) died from cardiovascular causes and 6607 patients (IR: 10.79%) suffered from all-cause mortality. After propensity score matching (SGLT2I: n = 21,713; DPP4I: n = 21,713), SGLT2I users showed lower incidence of new-onset AF (1.96% vs. 2.78%, standardized mean difference [SMD] = 0.05), stroke (1.80% vs. 3.52%, SMD = 0.11), cardiovascular mortality (0.47% vs. 1.56%, SMD = 0.11) and all-cause mortality (2.59% vs. 7.47%, SMD = 0.22) compared to DPP4I users. Cox regression found that SGLT2I users showed lower risk of new-onset AF (hazard ratio [HR]: 0.68, 95% confidence interval [CI]: [0.56, 0.83], P = 0.0001), stroke (HR: 0.64, 95% CI: [0.53, 0.79], P < 0.0001), cardiovascular mortality (HR: 0.39, 95% CI: [0.27, 0.56], P < 0.0001) and all-cause mortality (HR: 0.44, 95% CI: [0.37, 0.51], P < 0.0001) after adjusting for significant demographics, past comorbidities, medications and laboratory tests. Conclusions Based on real-world data of type 2 diabetic patients in Hong Kong, SGLT2I use was associated with lower risk of incident AF, stroke/transient ischemic attack, and cardiovascular and all-cause mortality outcomes compared to DPP4I use

Risk stratification of cardiac arrhythmias and sudden cardiac death in type 2 diabetes mellitus patients receiving insulin therapy: A population-based cohort study

Introduction: Metabolic abnormalities may exacerbate the risk of adverse outcomes in patients with type 2 diabetes mellitus. The present study aims to assess the predictive value of HbA1c and lipid variability on the risks of sudden cardiac death (SCD) and incident atrial fibrillation (AF). // Methods: The retrospective observational study consists of type 2 diabetic patients prescribed with insulin, who went to publicly funded clinics and hospitals in Hong Kong between January 1, 2009 and December 31, 2009. Variability in total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglyceride, and HbA1c were assessed through their SD and coefficient of variation. The primary outcomes were incident (1) ventricular tachycardia/ventricular fibrillation, actual or aborted SCD and (2) AF. // Results: A total of 23 329 patients (mean ± SD age: 64 ± 14 years old; 51% male; mean HbA1c 8.6 ± 1.3%) were included. On multivariable analysis, HbA1c, total cholesterol, LDL-C and triglyceride variability were found to be predictors of SCD (p < .05). // Conclusion: HbA1c and lipid variability were predictive of SCD. Therefore, poor glucose control and variability in lipid parameters in diabetic patients are associated with aborted or actual SCD. These observations suggest the need to re-evaluate the extent of glycemic control required for outcome optimization

Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors vs. Dipeptidyl Peptidase-4 (DPP4) inhibitors for new-onset dementia: A propensity score-matched population-based study with competing risk analysis

The effects of sodium-glucose cotransporter 2 inhibitors (SGLT2I) and dipeptidyl peptidase-4 inhibitors (DPP4I) on new-onset cognitive dysfunction in type 2 diabetes mellitus remain unknown. This study aimed to evaluate the effects of the two novel antidiabetic agents on cognitive dysfunction by comparing the rates of dementia between SGLT2I and DPP4I users. This was a population-based cohort study of type 2 diabetes mellitus patients treated with SGLT2I and DPP4I between January 1, 2015 and December 31, 2019 in Hong Kong. Exclusion criteria were <1-month exposure or exposure to both medication classes, or prior diagnosis of dementia or major neurological/psychiatric diseases. Primary outcomes were new-onset dementia, Alzheimer's, and Parkinson's. Secondary outcomes were all-cause, cardiovascular, and cerebrovascular mortality. A total of 13,276 SGLT2I and 36,544 DPP4I users (total = 51,460; median age: 66.3 years old [interquartile range (IQR): 58-76], 55.65% men) were studied (follow-up: 472 [120-792] days). After 1:2 matching (SGLT2I: = 13,283; DPP4I: = 26,545), SGLT2I users had lower incidences of dementia (0.19 vs. 0.78%, < 0.0001), Alzheimer's (0.01 vs. 0.1%, = 0.0047), Parkinson's disease (0.02 vs. 0.14%, = 0.0006), all-cause (5.48 vs. 12.69%, < 0.0001), cerebrovascular (0.88 vs. 3.88%, < 0.0001), and cardiovascular mortality (0.49 vs. 3.75%, < 0.0001). Cox regression showed that SGLT2I use was associated with lower risks of dementia (hazard ratio [HR]: 0.41, 95% confidence interval [CI]: [0.27-0.61], < 0.0001), Parkinson's (HR:0.28, 95% CI: [0.09-0.91], = 0.0349), all-cause (HR:0.84, 95% CI: [0.77-0.91], < 0.0001), cardiovascular (HR:0.64, 95% CI: [0.49-0.85], = 0.0017), and cerebrovascular (HR:0.36, 95% CI: [0.3-0.43], < 0.0001) mortality. The use of SGLT2I is associated with lower risks of dementia, Parkinson's disease, and cerebrovascular mortality compared with DPP4I use after 1:2 ratio propensity score matching. [Abstract copyright: Copyright © 2021 Mui, Zhou, Lee, Leung, Lee, Chou, Tsang, Wai, Liu, Wong, Chang, Tse and Zhang.

Role of macrophage sialoadhesin in host defense against the sialylated pathogen group B <em>Streptococcus</em>

ABSTRACT: Several bacterial pathogens decorate their surfaces with sialic acid (Sia) residues within cell wall components or capsular exopolysaccharides. Sialic acid expression can promote bacterial virulence by blocking complement activation or by engagement of inhibitory sialic acid-binding immunoglobulin-like lectins (Siglecs) on host leukocytes. Expressed at high levels on splenic and lymph node macrophages, sialoadhesin (Sn) is a unique Siglec with an elongated structure that lacks intracellular signaling motifs. Sialoadhesin allows macrophage to engage certain sialylated pathogens and stimulate inflammatory responses, but the in vivo significance of sialoadhesin in infection has not been shown. We demonstrate that macrophages phagocytose the sialylated pathogen group B Streptococcus (GBS) and increase bactericidal activity via sialoadhesin-sialic-acid-mediated recognition. Sialoadhesin expression on marginal zone metallophillic macrophages in the spleen trapped circulating GBS and restricted the spread of the GBS to distant organs, reducing mortality. Specific IgM antibody responses to GBS challenge were also impaired in sialoadhesin-deficient mice. Thus, sialoadhesin represents a key bridge to orchestrate innate and adaptive immune defenses against invasive sialylated bacterial pathogens. KEY MESSAGE: Sialoadhesin is critical for macrophages to phagocytose and clear GBS. Increased GBS organ dissemination in the sialoadhesin-deficient mice. Reduced anti-GBS IgM production in the sialoadhesin-deficient mice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00109-014-1157-y) contains supplementary material, which is available to authorized users