Cardiovascular Diabetology

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Longitudinal changes of Left and Right Ventricular architecture and function (A) and exercise capacity (B) of patients grouped with regard to insulin action impairment. Delta changes of selected variables of left ventricle (LV) and right ventricle (RV) architecture and function from baseline at 36 months (A). Whereas delta changes of LV parameters did not significantly differ between three groups, T2D patients displayed a more prominent progression of RV parameters. This phenomenon is paralleled by a more important impairment in cardiovascular performance, as testified by the delta change of peak VO 2 from baseline (B)
Article
Background Findings from the T.O.S.CA. Registry recently reported that patients with concomitant chronic heart failure (CHF) and impairment of insulin axis (either insulin resistance—IR or diabetes mellitus—T2D) display increased morbidity and mortality. However, little information is available on the relative impact of IR and T2D on cardiac structure and function, cardiopulmonary performance, and their longitudinal changes in CHF. Methods Patients enrolled in the T.O.S.CA. Registry performed echocardiography and cardiopulmonary exercise test at baseline and at a patient-average follow-up of 36 months. Patients were divided into three groups based on the degree of insulin impairment: euglycemic without IR (EU), euglycemic with IR (IR), and T2D. Results Compared with EU and IR, T2D was associated with increased filling pressures (E/e′ratio: 15.9 ± 8.9, 12.0 ± 6.5, and 14.5 ± 8.1 respectively, p < 0.01) and worse right ventricular(RV)-arterial uncoupling (RVAUC) (TAPSE/PASP ratio 0.52 ± 0.2, 0.6 ± 0.3, and 0.6 ± 0.3 in T2D, EU and IR, respectively, p < 0.05). Likewise, impairment in peak oxygen consumption (peak VO 2 ) in TD2 vs EU and IR patients was recorded (respectively, 15.8 ± 3.8 ml/Kg/min, 18.4 ± 4.3 ml/Kg/min and 16.5 ± 4.3 ml/Kg/min, p < 0.003). Longitudinal data demonstrated higher deterioration of RVAUC, RV dimension, and peak VO 2 in the T2D group (+ 13% increase in RV dimension, − 21% decline in TAPSE/PAPS ratio and − 20% decrease in peak VO 2 ). Conclusion The higher risk of death and CV hospitalizations exhibited by HF-T2D patients in the T.O.S.CA. Registry is associated with progressive RV ventricular dysfunction and exercise impairment when compared to euglycemic CHF patients, supporting the pivotal importance of hyperglycaemia and right chambers in HF prognosis. Trial registration ClinicalTrials.gov identifier: NCT023358017
 
Article
The 7th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Renal, and Glycemic Outcomes, was held virtually on November 18–19, 2021. Pursuing the tradition of the previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed CVOTs. This year’s focus was placed on the outcomes of EMPEROR-Preserved, FIGARO-DKD, AMPLITUDE-O, SURPASS 1–5, and STEP 1–5. Trial implications for diabetes and obesity management and the impact on new treatment algorithms were highlighted for endocrinologists, diabetologists, cardiologists, nephrologists, and general practitioners. Discussions evolved from outcome trials using SGLT2 inhibitors as therapy for heart failure, to CVOTs with nonsteroidal mineralocorticoid receptor antagonists and GLP-1 receptor agonists. Furthermore, trials for glycemic and overweight/obesity management, challenges in diabetes management in COVID-19, and novel guidelines and treatment strategies were discussed. Trial registration The 8th Cardiovascular Outcome Trial Summit will be held virtually on November 10–11, 2022 ( http://www.cvot.org )
 
Study flow chart. DM, diabetes mellitus; DPP4, dipeptidyl peptidase-4; HF, heart failure: SGLT2, sodium-glucose cotransporter-2
Kaplan–Meier analysis of all-cause mortality (a) and HF readmission (b) for SGLT2 and DPP4 inhibitor use at discharge in overall patients and in patients aged ≥ 75 years. DPP4-I, dipeptidyl peptidase-4 inhibitor; HF, heart failure: SGLT2-I, sodium-glucose cotransporter-2 inhibitor
Stratified analysis for all-cause mortality (a) and HF readmission (b) in the propensity-matched cohort. AF, atrial fibrillation or atrial flutter; CAD, coronary artery disease; CI, confidence interval; DPP4, dipeptidyl peptidase-4; HF, heart failure; SGLT2, sodium-glucose cotransporter-2
Article
Background There is a lack of recent data reflecting the actual use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for heart failure (HF) and type 2 diabetes (DM) in the superaged society. The present study investigated the association between the use of SGLT2 inhibitors and one-year prognosis in patients hospitalized across a broad spectrum of HF patients with DM in the superaged society using the Nationwide Electric Health Database in Japan. Methods The patients hospitalized with the first episode of acute HF were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan between April 2014 and March 2019. A cohort of 2,277 users of SGLT2 inhibitors and 41,410 users of the active comparator, dipeptidyl peptidase-4 (DPP4) inhibitors were compared. A propensity score-matched cohort study of 2,101 users of each inhibitor was also conducted. A multivariable multilevel mixed-effects survival model was conducted with adjustments, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Results Among 300,398 patients discharged with HF in 4,176 hospitals, 216,016 (71.9%) were 75 years or older, and 60,999 (20.3%) took antidiabetic medications. Among them, the patients treated with SGLT2 inhibitors were younger and had a more severe status than those treated with DPP4 inhibitors. Kaplan–Meier analysis showed that patients treated with SGLT2 inhibitors had a lower mortality risk and HF readmission. In propensity-matched cohorts, SGLT2 inhibitor use was associated with a lower risk of mortality and HF readmission than DPP-4 inhibitor use (HR [95% CI]; 0.70 [0.56, 0.89] and 0.52 [0.45, 0.61], respectively). Very elderly (≥ 75 years) patients showed similar results. Favorable effects were also observed across all age groups, including ≥ 75 years, in patients with coronary artery disease or atrial fibrillation and with concomitant β-blocker, diuretics, or insulin. Conclusion The use of SGLT2 inhibitors at discharge was associated with a lower risk of one-year mortality and HF readmission in patients across a broad spectrum of HF with DM in the superaged society. The findings further support the benefits of using SGLT2 inhibitors in very elderly HF care and complement the current evidence.
 
Study flowchart. *A total of 708 patients with missing neutrophil or lymphocyte count and 845 patients with missing FBG or HbA1c levels were excluded. PCI, percutaneous coronary intervention; DES, drug-eluting stent; other abbreviations as in Table 1
Kaplan–Meier curves for cumulative incidence of MACCEs according to different NLR levels in the T2DM (A) and non-T2DM (B) groups. Abbreviations as in Table 1
Kaplan–Meier curves for cumulative incidence of MACCE according to different NLR levels (A), glycemic metabolism status (B), and status of both NLR levels and glycemic metabolism (C). Abbreviations as in Table 1
Forest Plot of MACCE According to Various Subgroups. Adjusted for age, male sex, hypertension, dyslipidemia, smoking history, previous MI, previous PCI, previous stroke, Previous PAD, ACS, HbA1c, TG, LDL-C, hsCRP, eGFR, LVEF, DAPT, β blocker, LM/three-vessel disease, CTO, moderate to severe calcification, number of treated vessels, number of stents, IABP use and SYNTAX score. Abbreviations as in Table 1
Article
Background Inflammation plays a crucial role in the pathogenesis and progression of coronary artery disease (CAD). The neutrophil to lymphocyte ratio (NLR) is a novel inflammatory biomarker and its association with clinical outcomes in CAD patients with different glycemic metabolism after percutaneous coronary intervention (PCI) remains undetermined. Therefore, this study aimed to investigate the effect of NLR on the prognosis of patients undergoing PCI with or without type 2 diabetes mellitus (T2DM). Methods We consecutively enrolled 8,835 patients with CAD hospitalized for PCI at Fuwai hospital. NLR was calculated using the following formula: neutrophil (*10 ⁹ /L)/lymphocyte (*10 ⁹ /L). According to optimal cut-off value, study patients were categorized as higher level of NLR (NLR-H) and lower level of NLR (NLR-L) and were further stratified as NLR-H with T2DM and non-T2DM, and NLR-L with T2DM and non-T2DM. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCEs), defined as all-cause mortality, myocardial infarction (MI), stroke and target vessel revascularization. Results A total of 674 (7.6%) MACCEs were recorded during a median follow-up of 2.4 years. The optimal cut-off value of NLR was 2.85 determined by the surv_cutpoint function. Compared to those in the NLR-H/T2DM groups, patients in the NLR-L/non-T2DM, NLR-H/non-T2DM and NLR-L/T2DM groups were at significantly lower risk of 2-year MACCEs [adjusted hazard ratio (HR): 0.67, 95% confidence interval (CI): 0.52 to 0.87, P = 0.003; adjusted HR: 0.62, 95%CI: 0.45 to 0.85, P = 0.003; adjusted HR: 0.77, 95%CI: 0.61 to 0.97, P = 0.025; respectively]. Remarkably, patients in the NLR-L/non-T2DM group also had significantly lower risk of a composite of all-cause mortality and MI than those in the NLR-H/T2DM group (adjusted HR: 0.57, 95%CI: 0.35 to 0.93, P = 0.024). Multivariable Cox proportional hazards model also indicated the highest risk of MACCEs in diabetic patients with higher level of NLR than others (P for trend = 0.009). Additionally, subgroup analysis indicated consistent impact of NLR on MACCEs across different subgroups. Conclusions Presence of T2DM with elevated NLR is associated with worse clinical outcomes in CAD patients undergoing PCI. Categorization of patients with elevated NLR and T2DM could provide valuable information for risk stratification of CAD patients.
 
Changes in cholesterol efflux capacity after intervention
Changes in carbamylated HDL levels after intervention
Correlation between changes in cholesterol efflux capacity and in carbamylated HDL levels after intervention
Effect of in vitro HDL carbamylation on cholesterol efflux capacity. Data are presented as means ± SD. Data are obtained from 9 replicates obtained in three independent experiments. KCN: potassium cyanate
Article
Background Reduced cholesterol efflux capacity (CEC) of HDLs is likely to increase cardiovascular risk in type 1 diabetes (T1D). We aimed to assess whether improvement of glycemic control in T1D patients is associated with changes in CEC in relation with changes in carbamylation of HDLs. Methods In this open-label trial, 27 uncontrolled T1D patients were given a three-month standard medical intervention to improve glycemic control. HDL fraction was isolated from plasma, and CEC was measured on THP-1 macrophages. Carbamylation of HDLs was evaluated by an immunoassay. Control HDLs from healthy subjects were carbamylated in vitro with potassium cyanate. Results HbA 1c decreased from 11.4% [10.2–12.9] (median [1st–3rd quartiles]) at baseline to 8.1% [6.6–9.0] after the three-month intervention (P < 0.00001). The CEC of HDLs increased after intervention in 19 (70%) patients (P = 0.038). At the same time, the carbamylation of HDLs decreased in 22 (82%) patients after intervention (P = 0.014). The increase in CEC significantly correlated with the decrease in carbamylated HDLs (r = −0.411, P = 0.034), even after adjustment for the change in HbA 1c (β = −0.527, P = 0.003). In vitro carbamylation of control HDLs decreased CEC by 13% (P = 0.041) and 23% (P = 0.021) using 1 and 10 mmol/L of potassium cyanate, respectively. Conclusions The improvement of CEC in relation to a decrease in the carbamylation of HDLs may likely contribute to the beneficial cardiovascular effect of glycemic control in T1D patients. Trial registration : NCT02816099 ClinicalTrials.gov.
 
Cumulative incidence of cardiovascular disease (A) and all-cause mortality (B) by quartiles of baseline TyG index
Adjusted hazard ratios of incident CVD events (A) and all-cause mortality (B) by baseline TyG index. Each hazard ratio was computed with a median baseline TyG index level of 7.8 (A and B). Both p for linearity < 0.01
Subgroup analysis of the association between baseline TyG index and incident CVD events. Subgroup analysis included sex (male or female), race (black or white), age (≤ 24 or ≥ 25 years), education (≤ high school or > high school), and BMI (≤ 28 or > 28 kg/m²)
Trajectories by TyG index in the Coronary Artery Risk Development in Young Adults study
Abbreviations CARDIA: Coronary artery risk development in young adults; TyG: Triglycerideglucose; CVD: Cardiovascular disease; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; BMI: Body mass index; WC: Waist circumference; TC: Total cholesterol; TG: Triglyceride; LDL-c: Low-density lipoprotein cholesterol; HDL-c: High-density lipoprotein cholesterol; FBG: Fasting blood glucose; PCEs: Pooled cohort equations.
Article
Background: This study aimed to investigate the associations between the triglyceride-glucose (TyG) index in young adulthood with incident cardiovascular disease (CVD) and mortality. Methods: We included 4,754 participants from the Coronary Artery Risk Development in Young Adults study at baseline. The TyG index was calculated as ln (fasting TG [mg/dl] × fasting glucose [mg/dl]/2), and the TyG index trajectories were identified by using the latent class growth mixture model. We evaluated the association between the baseline and trajectories of the TyG index with incident CVD events and all-cause mortality using Cox proportional hazards regression analysis. The added value of the TyG index included in pooled cohort equations for CVD prediction was also analyzed. Results: Among 4754 participants (mean age 24.72 years, 45.8% male, 51.2% black), there were 158 incident CVD events and 246 all-cause mortality during a median 25 years follow-up. After adjusting for multiple confounding variables, each one-unit increase in the TyG index was associated with a 96% higher CVD risk (hazard ratio [HR] 1.96, 95% confidence interval [CI] 1.44-2.66) and a 85% higher all-cause mortality risk (HR 1.85, 95% CI 1.45-2.36). Three distinct trajectories of the TyG index along the follow-up duration were identified: low (44.0%), moderate (45.5%), and high (10.5%). Compared with those participants in the low TyG index trajectory group, those in the high TyG index trajectory group had a greater risk of CVD events (HR 2.35, 95% CI 1.34-4.12) and all-cause mortality (HR 3.04, 95% CI 1.83-5.07). The addition of baseline TyG index to pooled cohort equations for CVD improved the C-statistics (P < 0.001), integrated discrimination improvement value (P < 0.001), and category-free net reclassification improvement value (P = 0.003). Conclusions: Higher baseline TyG index levels and higher long-term trajectory of TyG index during young adulthood were significantly associated with an increased risk of incident CVD events and all-cause mortality in later life.
 
The age-specific associations between glycemic measurements and OR (95% CI) for elevated baPWV. a FPG; b 2 h-PPG; c HbA1c. OR, odds ratio; CI, confidence interval; baPWV, branchial-ankle pulse wave velocity; FPG, fasting plasma glucose; 2 h-PPG, 2 h-postload plasma glucose; HbA1c, glycated hemoglobin
Article
Abstract Background Prediabetes is an important risk factor of cardiovascular disease (CVD) and is associated with subclinical atherosclerosis. However, the evidence of prediabetes as a cardiovascular risk factor is mainly derived from middle-aged adults. Recently, multiple studies supported that prediabetes in older adults would not lead to higher risk of CVD or mortality. We aimed to investigate the age-specific difference in the association between prediabetes and subclinical atherosclerosis in a Chinese prospective cohort study. Methods We included 4739 individuals aged ≥ 40 years and without diagnosed diabetes or CVD history, and divided them into middle-aged adults (age
 
Flow diagram of the study. CTO chronic total occlusion, eGFR estimated glomerular filtration rate, MACCEs major adverse cardiac and cerebrovascular events, PCI percutaneous coronary intervention
Kaplan–Meier curve of cumulative risk of cardiovascular events according to different TyG index levels. TyG index triglyceride-glucose index
The restricted cubic spline of MACCEs and the TyG index. HR hazard ratio, CI confidence interval, MACCEs major adverse cardiovascular and cerebral events, TyG index triglyceride-glucose index
Article
Background Chronic total occlusion (CTO) of the coronary artery is a difficult problem in clinical practice. The triglyceride – glucose (TyG) index is an effective risk predictor of cardiovascular risk. However, the relationship between the TyG index and the prognosis of CTO patients remains unstudied. Thus, the present study aimed to investigate the relationship between the TyG index and cardiovascular risk in CTO patients. Methods This was a single-centre, retrospective cohort study. We retrospectively enrolled 652 patients with CTO lesions diagnosed by angiography and who underwent revascularization through PCI. Patients were routinely followed up for 24 months unless meeting the endpoint. The primary endpoint was the composite of all-cause death, nonfatal myocardial infarction, unplanned revascularization, and nonfatal ischaemic stroke. To test the association of the TyG index with cardiovascular risk, the categorized TyG index and Cox proportional hazards regression models were utilized. Results A total of 652 patients were enrolled in the final analysis (male: 83.7%, age: 58.2 ± 10.49 years). The average TyG index was 8.8 ± 0.57. CTO PCIs were procedurally successfully completed in 503 (77.15%) patients. During the follow-up period of 22.8 ± 3.84 months, 73 (11.19%) major adverse cardiovascular and cerebral events (MACCEs) occurred. When fully adjusted, there was a 2.09-fold risk for MACCEs among patients with the highest TyG index compared with those with the lowest TyG index [T2 vs. T1: hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.65–2.38, P = 0.057; T3 vs. T1: HR 2.09, 95% CI 1.14–3.86, P = 0.018; P for trend = 0.036]. The restricted cubic spline (RCS) analysis showed that the HR for MACCEs increased as the TyG index increased over 8.71 [HR per standard deviation (SD) 1.740, 95% CI 1.23–2.46, P = 0.002]. The risk of MACCEs increased with increasing tertiles of TyG index in successful CTO PCI patients and nondiabetes mellitus (DM) patients ( P < 0.05) but not in patients with failed CTO PCI and DM patients. Conclusion The study revealed that the TyG index had significant relevance to cardiovascular risk in CTO patients and suggests that the TyG index is feasible for predicting cardiovascular risk in CTO patients.
 
Article
Coronary artery calcium score (CACs) is a measurement of calcification in coronary arteries using a computed tomography scan. It has a predictive role for future myocardial infarction thus it aids in cardiovascular risk assessment and physician decision making. Multiple risk factors have been attributed to coronary artery calcification including age, male gender and ethnicity. Herein, we report our concerns regarding neglecting ethnicity within participants demographics and data analysis, which may affect the findings of the study.
 
Upper panel: Time course of plasma glucose levels during the oral glucose tolerance tests (OGTT) in the 88 patients tested at baseline (0 h) and at 1, 1.5 and 2 h. Lower panel: Time course of median plasma glucose (PG) levels during the oral glucose tolerance tests (OGTT) of the four groups tested at baseline (0 h) and at 1, 1.5 and 2 h
Box plot of admission (upper panel) and peak (lower panel) high-sensitivity troponin T (hs-TnT) distributions on the base of previously defined OGTT groups. Box plots display the 25th, the 50th (median) and the 75th percentiles in the box, and whiskers display the minimum and the maximum of the data set. Horizontal brackets join groups for which statistically significant differences (P < 0.05) were found at multiple comparisons
Box plot of admission N-terminal prohormone of the brain natriuretic peptide (NT-proBNP, upper panel) and admission % left ventricular ejection fraction (LVEF) distributions on the base of previously defined OGTT groups. Box plots display the 25th, the 50th (median) and the 75th percentiles in the box, and whiskers display the minimum and the maximum of the data set. Horizontal brackets join groups for which statistically significant differences (P < 0.05) were found at multiple comparisons
Article
Objective Impaired glucose tolerance (IGT) has been related to adverse cardiovascular outcomes. We investigated the added value of 1-h plasma glucose (PG) at the oral glucose tolerance test (OGTT) in predicting admission and peak cardiac high-sensitivity troponin T (hs-TnT) and NT-proBNP values in IGT patients admitted for an acute coronary syndrome (ACS). Research design and methods Among 192 consecutive ACS patients, 109 had Hb1Ac and fasting plasma glucose negative for newly diagnosed diabetes. Upon OGTT performed > 96 h after admission, 88, conventionally diagnosed as IGT, were divided into: “full glucose tolerance” (1-h PG-OGTT < 155 mg/dL and 2-h PG-OGTT < 140 mg/dL, N = 12);”early IGT” (1 h-PG-OGTT ≥ 155 mg/dL and 2-h PG-OGTT < 140 mg/dL, N = 33); ” late IGT” (1-h PG-OGTT < 155 mg/dL and 2-h PG-OGTT ≥ 140 mg/dL, N = 8); and “full IGT” (1-h PG-OGTT ≥ 155 mg/dL and 2-h PG-OGTT ≥ 140 mg/dL, N = 35). The 4 groups were compared for cardiac markers. Results The first three groups had similar cardiac marker values, but only full IGT patients had significantly higher admission hs-TnT compared with the 3 other groups [median (interquartile range): 911 (245-2976) vs 292 (46-1131), P < 0.001]. Full IGT patients also had higher hs-TnT peak compared with fully glucose tolerant and early IGT patients. Only full IGT patients had longer hospitalization and higher NT-proBNP vs fully glucose tolerant patients (P = 0.005). Conclusions Among non-diabetic ACS patients, only those with both 1-h PG ≥ 155 mg/dL and 2-h PG ≥ 140 mg/dL had more severe myocardial injury and longer hospitalization. One-h PG-OGTT importantly contributes to assessing post-ACS cardiac risk.
 
Flow chart of study participants
Changes from baseline to week 24 in serum insulin concentrations and HOMA-IR. A Serum insulin concentrations. B HOMA-IR. The data are expressed as the absolute change (mean and 95% confidence interval) from baseline to week 24. HOMA-IR homeostasis model assessment of insulin resistance
Associations between changes in insulin indices and NYHA class. The data are expressed as the median (interquartile range) change from baseline to week 24 in serum insulin concentrations A and HOMA-IR B in subgroups stratified by the categorical changes in NYHA class at week 24. HOMA-IR homeostasis model assessment of insulin resistance, NYHA New York Heart Association
Changes from baseline in NYHA class at week 24 in subgroups stratified by baseline median serum insulin concentrations (left) and HOMA-IR (right). The numbers next to the bars indicate the frequency of cases in which NYHA improved or worsened at week 24. Between-subgroup differences in the treatment effect on NYHA class are analyzed as Pfor interaction. HOMA-IR, homeostasis model assessment of insulin resistance; NYHA, New York Heart Association
Article
Abstract Background Insulin resistance and hyperinsulinemia in patients with type 2 diabetes (T2D) are adversely associated with the development and worsening of heart failure (HF). Herein, we sought to investigate the effect of canagliflozin on insulin concentrations and the associations of changes in insulin concentrations with HF-related clinical parameters in patients with T2D and HF. Methods This was a post-hoc analysis of the investigator-initiated, multicenter, open-label, randomized, controlled CANDLE trial for patients with T2D and chronic HF (UMIN000017669). The endpoints were the effects of 24 weeks of canagliflozin treatment, relative to glimepiride treatment, on insulin concentrations and the relationship between changes in insulin concentrations and clinical parameters of interest, including New York Heart Association (NYHA) classification. The effects of canagliflozin on those parameters were also analyzed by baseline insulin level. Results Among the participants in the CANDLE trial, a total of 129 patients (canagliflozin, n = 64; glimepiride, n = 65) who were non-insulin users with available serum insulin data both at baseline and week 24 were included in this analysis. Overall, the mean age was 69.0 ± 9.4 years; 75% were male; the mean HbA1c was 6.8 ± 0.7%; and the mean left ventricular ejection fraction was 59.0 ± 14.1%, with parameters roughly balanced between treatment groups. Canagliflozin treatment significantly reduced insulin concentrations at week 24 (p
 
Time course of FMD in patients administered evolocumab plus empagliflozin (circle) or empagliflozin (square). Graph A plots resting FMD curves in both study arms during the pre-randomization phase. Graphs B and C show resting FMD curves for the empagliflozin and evolocumab plus empagliflozin arms, respectively, at baseline, 8 weeks, and after 16 weeks of treatment
Individual time response curves for the AUC of the 5-min course of the FMD between randomization, 8 weeks, and 16 weeks
Article
Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve endothelial dysfunction and reduce cardiovascular events in individuals with type 2 diabetes (T2D). Proprotein convertase subtilisin/kexin 9 (PCSK9i) inhibitors reduce cardiovascular events in high-risk patients. Whether the addition of PCSK9i to SGLT2i treatment adds benefits is not known. Objectives To assess the PCSK9-i effect on the endothelial function of T2D individuals under treatment with SGLT2-i. Methods Individuals with T2D were randomized in a 1:1 ratio to a 16-week treatment with either empagliflozin (E) or empagliflozin plus evolocumab (EE). The primary endpoint was post-treatment change from baseline in flow-mediated dilation (FMD) at 1-min. Secondary outcomes included changes in plasma levels of nitric oxide metabolites and isoprostane. Results A total of 110 patients were enrolled, the mean age was 58 years, and 71% were men. The median post-treatment change in FMD at 1-min was 2.7% (interquartile range [IQR]: 0.9%) and 0.4% (IQR: 0.9%) in the EE and E groups, respectively (p < 0.001). There was a greater increase in plasma levels of nitrate [5.9 (16.5) vs. 2.6 (11.8); p = 0.001] and nitrite [0.14 (0.72) vs. 0.02 (0.74); p = 0.025] in the EE group than in the E group, respectively. Isoprostane reduction was more pronounced in the EE group when compared to the E group [−1.7 (5.9) vs. −1.1 (5.3); p < 0.001). Conclusions In individuals with T2D, the addition of evolocumab on top of empagliflozin improves endothelial function.
 
Article
Background Fibrin(ogen) amyloid microclots and platelet hyperactivation previously reported as a novel finding in South African patients with the coronavirus 2019 disease (COVID-19) and Long COVID/Post-Acute Sequelae of COVID-19 (PASC), might form a suitable set of foci for the clinical treatment of the symptoms of Long COVID/PASC. A Long COVID/PASC Registry was subsequently established as an online platform where patients can report Long COVID/PASC symptoms and previous comorbidities. Methods In this study, we report on the comorbidities and persistent symptoms, using data obtained from 845 South African Long COVID/PASC patients. By using a previously published scoring system for fibrin amyloid microclots and platelet pathology, we also analysed blood samples from 80 patients, and report the presence of significant fibrin amyloid microclots and platelet pathology in all cases. Results Hypertension, high cholesterol levels (dyslipidaemia), cardiovascular disease and type 2 diabetes mellitus (T2DM) were found to be the most important comorbidities. The gender balance (70% female) and the most commonly reported Long COVID/PASC symptoms (fatigue, brain fog, loss of concentration and forgetfulness, shortness of breath, as well as joint and muscle pains) were comparable to those reported elsewhere. These findings confirmed that our sample was not atypical. Microclot and platelet pathologies were associated with Long COVID/PASC symptoms that persisted after the recovery from acute COVID-19. Conclusions Fibrin amyloid microclots that block capillaries and inhibit the transport of O 2 to tissues, accompanied by platelet hyperactivation, provide a ready explanation for the symptoms of Long COVID/PASC. Removal and reversal of these underlying endotheliopathies provide an important treatment option that urgently warrants controlled clinical studies to determine efficacy in patients with a diversity of comorbidities impacting on SARS-CoV-2 infection and COVID-19 severity. We suggest that our platelet and clotting grading system provides a simple and cost-effective diagnostic method for early detection of Long COVID/PASC as a major determinant of effective treatment, including those focusing on reducing clot burden and platelet hyperactivation.
 
Article
Background High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control. Objectives We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1–9, Ang 1–7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts. Methods We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1–9, Ang 1–7, MasR, NAFT, and fibrosis. Results GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1–9, Ang 1–7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression. Conclusion Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition. Trial registration: https://clinicaltrials.gov/ NCT03546062.
 
Cumulative incidence of the incidence of primary endpoint and each clinical event according to the TyG index tertiles .Kaplan-Meier curves for the incidence of MACEs (A), all-cause death (B), cardiac death (C), unplanned repeat revascularization (D), nonfatal myocardial infarction (E), and nonfatal stroke (F) among the 3 study groups based on the TyG index tertiles. TyG indicates triglyceride-glucose
ROC curve analysis evaluating the diagnostic performance for MACEs in ACS patients undergoing PCI. A The area under the curve (AUC) of the TyG index for predicting MACEs was 0.607 (95% CI: 0.576–0.638, P = 0.001). B The AUC of the FBG for predicting MACEs was 0.586 (95% CI: 0.554–0.617, P = 0.005). The AUC of the TG (C) for predicting MACEs was 0.563 (95% CI: 0.532–0.594, P = 0.0039). The AUC of the GRACE score (D) for predicting MACEs was 0.723 (95% CI: 0.694–0.750, P < 0.001). ROC, receiver operating characteristic; ACS, acute coronary syndrome; MACEs, major adverse cardiac events; PCI, percutaneous coronary intervention; TyG, triglyceride-glucose; FBG, fasting blood glucose; TG, triglyceride
Subgroups analyses of the TyG index for MACEs. HR was evaluated by 1-point increase of the TyG index. HR, hazard ratio; TyG, triglyceride-glucose; CI, confidence interval; ACS, acute coronary syndrome; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction; CR, complete revascularization, defined as residual SYNTAX score = 0
ROC curve analysis of the model performance after adding the TyG index to the baseline GRACE score. The areas under the ROC curves were used to compare the predictive ability between the baseline GRACE score and the TyG index plus the GRACE score for MACEs (A), all-cause death (B), cardiac death (C), and all-cause death, MI, or unplanned revascularization (D). ROC, receiver operating characteristic; TyG, triglyceride-glucose; MACEs, major adverse cardiac events; MI, myocardial infarction
The calibration plots for adverse cardiovascular events. Calibration curves for MACEs (A), all-cause death (B), cardiac death (C), and all-cause death, MI or unplanned revascularization (D). The x-axis represents the predicted adverse cardiovascular events risk. The y-axis represents the actual adverse cardiovascular events rate. The grey line indicates a perfect prediction by an ideal model. The red solid line indicates the performance of the predicting model, of which a closer fit to the grey line suggests better prediction. MACEs, major adverse cardiac events; MI, myocardial infarction
Article
Background The Global Registry of Acute Coronary Events (GRACE) score derived from clinical parameters at the time of hospital discharge is a powerful predictor of long-term mortality and reinfarction after acute coronary syndrome (ACS). The triglyceride glucose (TyG) index, which is a simple and reliable surrogate marker of insulin resistance, has been demonstrated to be an independent predictor of long-term adverse major adverse cardiac events, irrespective of diabetes mellitus. We investigate whether the addition of the TyG index improves the predictive ability of the GRACE score after percutaneous coronary intervention (PCI) in ACS patients regardless of diabetes mellitus. Method A retrospective cohort of 986 ACS patients undergoing PCI was enrolled in the present analyses. The GRACE score for discharge to 6 months and the TyG index were calculated. The primary endpoint was the composite of MACEs, including all-cause death and nonfatal myocardial infarction. Patients were stratified according to the primary endpoint and the tertiles of the TyG index. Cumulative curves were calculated using the Kaplan–Meier method. Multivariate Cox regression was adopted to identify predictors of MACEs. The predictive value of the GRACE score alone and combined with the TyG index or fasting blood glucose (FBG) was estimated by the area under the receiver‑operating characteristic curve, likelihood ratio test, Akaike’s information criteria, continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Internal validation was assessed using the means of bootstrap method with 1000 bootstrapped samples. Results During a median follow-up of 30.72 months ((interquartile range, 26.13 to 35.07 months), 90 patients developed MACEs, more frequently in the patients with a higher TyG index. Multivariate Cox hazards regression analysis found that the TyG index, but not FBG was an independent predictor of MACEs (hazard ratio 1.6542; 95% CI 1.1555–2.3681; P = 0.006) in all types of ACS regardless of diabetes mellitus when included in the same model as GRACE score. Furthermore, Kaplan–Meier analysis revealed that the incidence of the primary endpoint rose with increasing TyG index tertiles (log-rank, P < 0.01). Adjustment the GRACE score by the TyG index improved the predictive ability for MACEs (increase in C-statistic value from 0.735 to 0.744; NRI, 0.282, 95% CI 0.028–0.426, P = 0.02; IDI, 0.019, 95% CI 0.004–0.046, P = 0.01). Likelihood ratio test showed that the TyG index significantly improved the prognostic ability of the GRACE score (χ² = 12.37, 1 df; P < 0.001). The results remained consistent when the models were confirmed by internal bootstrap validation method. Conclusion The TyG index, but not FBG is an independent predictor of long-term MACEs after PCI in all types of ACS patients regardless of diabetes mellitus after adjusting for the GRACE score, and improves the ability of the GRACE score to stratify risk and predict prognosis of ACS patients undergoing PCI.
 
Article
Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in patients with type 2 diabetes (T2D). Historical concerns about cardiovascular (CV) risks associated with certain glucose-lowering medications gave rise to the introduction of cardiovascular outcomes trials (CVOTs). Initially implemented to help monitor the CV safety of glucose-lowering drugs in patients with T2D, who either had established CVD or were at high risk of CVD, data that emerged from some of these trials started to show benefits. Alongside the anticipated CV safety of many of these agents, evidence for certain sodium–glucose transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revealed potential cardioprotective effects in patients with T2D who are at high risk of CVD events. Reductions in 3-point major adverse CV events (3P-MACE) and CV death have been noted in some of these CVOTs, with additional benefits including reduced risks of hospitalisation for heart failure, progression of renal disease, and all-cause mortality. These new data are leading to a paradigm shift in the current management of T2D, with international guidelines now prioritising SGLT2 inhibitors and/or GLP-1 RAs in certain patient populations. However, clinicians are faced with a large volume of CVOT data when seeking to use this evidence base to bring opportunities to improve CV, heart failure and renal outcomes, and even reduce mortality, in their patients with T2D. The aim of this review is to provide an in-depth summary of CVOT data—crystallising the key findings, from safety to efficacy—and to offer a practical perspective for physicians. Finally, we discuss the next steps for the post-CVOT era, with ongoing studies that may further transform clinical practice and improve outcomes for people with T2D, heart failure or renal disease.
 
Flow diagram of patient selection. ┼ Including severe valvular heart disease, decompensated heart failure, non-ischemic dilated cardiomyopathy, severe renal or hepatic disease, acute infection and/or inflammation, malignancy, hematologic disease or autoimmune disease
Kaplan–Meier survival curve for MACE across the TyG index tertiles
Subgroup and interaction analysis between the TyG index (Per SD) and MACE across various subgroups
Time-dependent ROC curves of the TyG index for the prediction of MACE
Article
Background: Premature coronary artery disease (PCAD) has become more common in recent years and is often associated with poor outcomes. Triglyceride-glucose (TyG) index is a simple and reliable surrogate for insulin resistance (IR) and is an independent predictor of cardiovascular prognosis. However, the prognostic value of the TyG index in patients with PCAD remains uncertain. Thus, this study aimed to investigate the prognostic value and predictive performance of the TyG index in patients with PCAD. Methods: A total of 526 young subjects (male < 45 years, female < 55 years) with angiographically proven CAD from January 2013 to December 2018 were included consecutively in this study. Their clinical and laboratory parameters were collected, and the TyG index was calculated as [Formula: see text]. The follow-up time after discharge was 40-112 months (median, 68 months; interquartile range, 49‒83 months). The primary endpoint was the occurrence of the major adverse cardiovascular events (MACE), defined as the composite of all-cause death, non-fatal myocardial infarction (MI), coronary artery revascularization, and non-fatal stroke. Results: The TyG index was significantly associated with traditional cardiovascular risk factors and the Gensini score (GS). Kaplan-Meier survival (MACE-free) curves by tertiles of the TyG index showed statistically significant differences (log-rank test, p = 0.001). In the fully adjusted Cox regression model, the Hazard ratio (95% CI) of MACE was 2.17 (1.15-4.06) in tertile 3 and 1.45 (1.11-1.91) for per SD increase in the TyG index. Time-dependent ROC analyses of the TyG for prediction of MACE showed the area under the curves (AUC) reached 0.631 at 3 years, 0.643 at 6 years, and 0.710 at 9 years. Furthermore, adding TyG index to existing risk prediction model could improve outcome prediction [C-statistic increased from 0.715 to 0.719, p = 0.007; continuous net reclassification improvement (NRI) = 0.101, p = 0.362; integrated discrimination improvement (IDI) = 0.011, p = 0.017]. Conclusion: The TyG index is an independent predictor of MACE in patients with PCAD, suggesting that the TyG index has important clinical implications for risk stratification and early intervention of PCAD.
 
Flow diagram of the study selection process
The influence of diabetes on all-cause mortality (A) and cardiac mortality (B) in ICD recipients compared with non-diabetes. ICD implantable cardioverter-defibrillator
Subgroup analysis of the increased all-cause mortality caused by diabetes in ICD recipients, stratified according to primary prevention, secondary prevention and primary or secondary prevention
The influence of diabetes on appropriate therapy (A), inappropriate therapy (B), appropriate shock (C), inappropriate shock (D), appropriate ATP (E) and inappropriate ATP (F) in ICD recipients compared with non-diabetes. ICD implantable cardioverter-defibrillator ATP anti-tachycardia pacing
Article
Background The influence of diabetes on the mortality and risk of implantable cardioverter defibrillator (ICD) therapies is still controversial, and a comprehensive assessment is lacking. We performed this systematic review and meta-analysis to address this controversy. Methods We systematically searched the PubMed, Embase, Web of Science and Cochrane Library databases to collect relevant literature. Fixed and random effects models were used to estimate the hazard ratio (HR) with 95% CIs. Results Thirty-six articles reporting on 162,780 ICD recipients were included in this analysis. Compared with nondiabetic ICD recipients, diabetic ICD recipients had higher all-cause mortality (HR = 1.45, 95% CI 1.36–1.55). The subgroup analysis showed that secondary prevention patients with diabetes may suffer a higher risk of all-cause mortality (HR = 1.89, 95% CI 1.56–2.28) (for subgroup analysis, P = 0.03). Cardiac mortality was also higher in ICD recipients with diabetes (HR = 1.68, 95% CI 1.35–2.08). However, diabetes had no significant effect on the risks of ICD therapies, including appropriate or inappropriate therapy, appropriate or inappropriate shock and appropriate anti-tachycardia pacing (ATP). Diabetes was associated with a decreased risk of inappropriate ATP (HR = 0.56, 95% CI 0.39–0.79). Conclusion Diabetes is associated with an increased risk of mortality in ICD recipients, especially in the secondary prevention patients, but does not significantly influence the risks of ICD therapies, indicating that the increased mortality of ICD recipients with diabetes may not be caused by arrhythmias. The survival benefits of ICD treatment in diabetes patients are limited.
 
Triglyceride-glucose index trajectory in hypertensive patients during 2006–2010
Kaplan–Meier curves of incidence of outcomes according to TyG index trajectory. a Stroke; b Ischemic stroke; c Hemorrhage stroke
Article
Background It has been suggested that the baseline triglyceride-glucose (TyG) index, a simple surrogate measure for insulin resistance, is significantly associated with the occurrence of stroke. Nevertheless, the impact of longitudinal patterns of TyG on the stroke risk in hypertensive patients is still unknown. Hence, this study aimed to investigate the association between TyG index trajectory and stroke risk among hypertensive patients. Methods This prospective study included 19,924 hypertensive patients from the Kailuan Study who underwent three waves survey and were free of myocardial infarction, cancer and stroke before or during 2010. The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting plasma glucose (mg/dL)/2], and latent mixed modelling was used to identify the trajectory of TyG during the exposure period (2006–2010). Furthermore, the Cox proportional hazard models were applied to estimate the hazard ratio (HR) and 95% confidence interval (CI) for incident stroke of different trajectory groups. Results Five distinct TyG trajectory were identified during 2006–2010: low-stable (n = 2483; range, 8.03–8.06), moderate low-stable (n = 9666; range, 8.58–8.57), moderate high-stable (n = 5759; range, 9.16–9.09), elevated-stable (n = 1741; range, 9.79–9.75), and elevated-increasing (n = 275; range, 10.38–10.81). During the median follow-up of 9.97 years, 1,519 cases of incident stroke were identified, including 1,351 with ischemic stroke and 215 with hemorrhage stroke. After adjusting for confounding variables, the HR and 95% CI of stroke were 2.21 (1.49,3.28) for the elevated-increasing group, 1.43 (1.13,1.83) for the elevated-stable group, 1.35 (1.10,1.64) for the moderate high-stable group, 1.26 (1.06,1.52) for the moderate low-stable group, respectively, when compare with the low-stable group. Similar results were observed in ischemic stroke, but a significant association was not found between TyG trajectory and risk of hemorrhage stroke. Conclusion A long-term elevated TyG index in hypertensive patients is associated with an increased risk of stroke, especially ischemic stroke. This finding implies that regular monitoring of TyG index may assist in identifying individuals at a higher risk of stroke among patients with hypertension.
 
Kaplan Meier survival curve for the occurrence of any major adverse cardiovascular event according to the presence of stress induced hyperglycemia with or without diabetes
Article
Background Stress induced hyperglycemia (SIH) is common among patients with ST-elevation myocardial infarction (STEMI), even in patients without diabetes mellitus. However, evidence regarding its role on the angiographic outcomes and the prognosis of patients presenting with STEMI is scarce. Methods This study included 309 consecutively enrolled STEMI patients undergoing primary percutaneous coronary intervention (pPCI). Patients were diagnosed with SIH if blood glucose on admission was > 140 mg/dl. Also, patients had to fast for at least 8 hours before blood sampling. The objective was to assess whether SIH was associated with major adverse cardiovascular and cerebrovascular (MACCE) events and explore its relationship with angiographic predictors of worse prognosis such as poor initial TIMI flow, intracoronary thrombus burden, distal embolization, and presence of residual thrombus after pPCI. Results SIH in diabetic and non-diabetic patients was associated with a higher incidence of LTB (aOR = 2.171, 95% CI 1.27–3.71), distal embolization (aOR = 2.71, 95% CI 1.51–4.86), and pre-procedural TIMI flow grade = 0 (aOR = 2.69, 95% CI 1.43–5.04) after adjusting for relevant clinical variables. Importantly, during a median follow-up of 1.7 years STEMI patients with SIH with or without diabetes experienced increased occurrence of MACCE both in univariate (HR = 1.92, 95% CI 1.19–3.01) and multivariate analysis (aHR = 1.802, 95% CI 1.01–3.21). Conclusions SIH in STEMI patients with or without diabetes was independently associated with increased MACCE. This could be attributed to the fact that SIH was strongly correlated with poor pre-procedural TIMI flow, LTB, and distal embolization. Large clinical trials need to validate SIH as an independent predictor of adverse angiographic and clinical outcomes to provide optimal individualized care for patients with STEMI.
 
Flow diagram showing the study selection process
Effects of different types of sodium-glucose cotransporter-2 inhibitors on systolic blood pressure. CI confidence interval, CANA canagliflozin, DAPA dapagliflozin, EMPA empagliflozin, IV inverse variance, Luse luseogliflozin, SD standard deviation, SGLT2i sodium-glucose cotransporter-2 inhibitors
Effect of sodium-glucose cotransporter-2 inhibitors on systolic blood pressure according to left ventricular ejection fraction status. HFrEF heart failure with reduced ejection fraction, HFpEF heart failure with preserved ejection fraction, LVEF left ventricular ejection fraction
Effect of sodium-glucose cotransporter-2 inhibitors on diastolic blood pressure. CI confidence interval, CANA canagliflozin, DAPA dapagliflozin, EMPA empagliflozin, IV inverse variance, Luse luseogliflozin, SD standard deviation, SGLT2i sodium-glucose cotransporter-2 inhibitors
Effects of sodium-glucose cotransporter-2 inhibitors on secondary outcomes. A: Body weight. B: Hematocrit; C: Heart rate. D: Glycated hemoglobin. CI confidence interval, SD standard deviation, SGLT2i sodium-glucose cotransporter-2 inhibitors
Article
Background Recent studies have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) can achieve significant improvement in blood pressure in people with diabetes. Furthermore, randomized controlled trials (RCTs) have established that SGLT2i have a cardioprotective effect in adults with heart failure (HF). Therefore, we performed this systematic review an meta-analysis to determine the effect of SGLT2i on blood pressure in patients with HF. Methods We used the Medline, Cochrane Library, Embase, and PubMed databases to identify RCTs (published through to April 29, 2022) that evaluated the effect of SGLT2i on HF. The primary endpoint was defined as change in blood pressure. Secondary composite outcomes were heart rate, hematocrit, body weight, and glycated hemoglobin. The N-terminal pro-brain natriuretic peptide level, Kansas City Cardiomyopathy Questionnaire scores, and estimated glomerular filtration rate were also evaluated. Results After a literature search and detailed evaluation, 16 RCTs were included in the quantitative analysis. Pooled analyses showed that SGLT2i were associated with a statistically significant reduction in systolic blood pressure of 1.68 mmHg (95% confidence interval [CI] − 2.7, − 0.66; P = 0.001; I² = 45%) but not diastolic blood pressure (mean difference [MD] −1.06 mmHg; 95% CI −3.20, 1.08; P = 0.33; I² = 43%) in comparison with controls. Furthermore, SGLT2i decreased body weight (MD − 1.36 kg, 95% CI − 1.68, − 1.03; P < 0.001; I² = 61%) and the glycated hemoglobin level (MD − 0.16%, 95% CI − 0.28, −0.04, P = 0.007; I² = 91%) but increased hematocrit (MD 1.63%, 95% CI 0.63, 2.62, P = 0.001; I² = 100%). There was no significant between-group difference in heart rate (MD − 0.35; 95% CI − 2.05, 1.35, P = 0.69; I² = 0). Conclusions SGLT2i decreased systolic blood pressure in patients with HF but had no effect on diastolic blood pressure. These inhibitors may have numerous potentially beneficial clinical effects in patients with HF.
 
Consolidated Standards of Reporting Trials (CONSORT) diagram illustrating the flow of participants in the CETUS trial
Effect of the KEβHB versus placebo drinks on A total cholesterol, B HDL cholesterol, C LDL cholesterol, D remnant cholesterol, E triglycerides, and F the triglycerides to HDL cholesterol ratio. Area under the curve (AUC0-150) data are presented as mean ± standard deviation. *p < 0.05 for the difference between the KEβHB and placebo drinks. AUC area under the curve; HDL high-density lipoprotein, KEβHB ketone monoester (β-hydroxybutyrate), LDL low-density lipoprotein
Effect of the KEβHB versus placebo drinks on lipid profile according to intake of saturated fat. Participants were stratified based on the median value of habitual dietary saturated fat intake. Area under the curve (AUC0-150) data are presented as mean ± standard deviation. *p < 0.05 for the difference between the KEβHB and placebo drinks. HDL high-density lipoprotein, KEβHB ketone monoester (β-hydroxybutyrate), LDL low-density lipoprotein, SF saturated fat
Article
Background: Ketone monoester β-hydroxybutyrate (KEβHB) ingestion has emerged as an effective method of inducing acute ketosis. Although evidence suggests that KEβHB can offer several therapeutic benefits, whether KEβHB affects lipid profile is still unknown. Aims: The primary aim was to study the effect of KEβHB on plasma lipid profile in individuals with prediabetes. The secondary aim was to investigate the role of saturated fat intake in that effect. Methods: This study was a randomized controlled trial with cross-over design. Following an overnight fast, 18 adults (six women and 12 men) with prediabetes (diagnosed based on the American Diabetes Association criteria) ingested a single dose of KEβHB drink or placebo drink. Blood samples were collected every 30 min, from baseline to 150 min. Outcome variables included changes in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, remnant cholesterol, triglycerides, and the triglycerides to HDL cholesterol ratio. The area under the curve (AUC) over 150 min was calculated for each outcome following ingestion of the drinks. Habitual saturated fat intake was ascertained using the EPIC-Norfolk food frequency questionnaire. Results: Significant elevation of blood β-hydroxybutyrate from 0.2 mmol/L to 3.5 mmol/L (p < 0.001) was achieved within 30 min. Acute ketosis resulted in significantly lower AUCs for remnant cholesterol (p = 0.022) and triglycerides (p = 0.022). No statistically significant differences in the AUCs for total cholesterol, HDL cholesterol, LDL cholesterol, and the triglycerides to HDL cholesterol ratio were found. The changes in remnant cholesterol and triglycerides were statistically significant in individuals with high, but not low, habitual saturated fat intake. Conclusion: Acute ketosis had no untoward effect on plasma lipid profile. Moreover, it led to significantly reduced circulating levels of remnant cholesterol and triglycerides. This paves the way for investigating whether exogenous ketone supplementation reduces cardiovascular disease risk (via its actions on triglyceride-rich lipoproteins) in at-risk populations. Trial registration: ClinicalTrials.gov, NCT03889210.
 
Subgroup analyses for the association of the quartiles of TyG index with CA, CMT, plaques and stenosis. Adjusted for sex, age, education, smoke, drink, physical activity, BMI, SBP, DBP, TC, LDL-C, HDL-C, history of diseases including cerebrovascular disease, heart diseases, hypertension, dyslipidemia and diabetes
Article
Background Several previous studies have indicated that the triglyceride-glucose index (TyG) index is associated with carotid atherosclerosis (CA); however, the evidence of the association is limited and inconsistent, which may result from small sample sizes or differences in study populations. Therefore, we examined the relation between the TyG index and CA in a large general population of Chinese middle-aged and elderly population. Methods A total of 59,123 middle-aged and elderly participants were enrolled. The TyG index was calculated as ln[fasting triglycerides (mg/dL)×fasting glucose (mg/dL)/2]. Logistic regression models were used to analyze the relationship between the TyG index as continuous variables and quartiles and CA. The relationships between the TyG index and CA according to sex, age groups, blood pressure groups and body mass index groups were also assessed. Results The multivariate logistic regression analysis showed that the TyG index was significantly associated with the prevalence of CA (OR: 1.48; 95% CI 1.39–1.56), carotid intima-media thickness (CMT) (1.55; 1.45–1.67), plaques (1.38; 1.30–1.47) and stenosis severity (> 50%) (1.33; 1.14–1.56). Compared with the quartile 1, quartile 4 was significantly associated with a higher prevalence of CA (1.59; 1.45–1.75), CMT (1.93; 1.82–2.18), plaques (1.36; 1.22–1.51) and stenosis severity (> 50%) (1.56; 1.20–2.04). Subgroup analyses showed significant associations between the continuous TyG index and the prevalence of CA, CMT, plaques and stenosis severity (> 50%) according to sex, with a higher prevalence of CA, CMT, and plaques among males, while a higher prevalence of stenosis severity in females (> 50%). For participants aged < 60 years old and with hypertension, the relationship between the TyG index and stenosis severity (> 50%) was not observed (1.47; 0.97–2.22 and 1.13; 0.91–1.41). For body mass index (BMI), the association was just observed among overweight participants (1.48; 1.17–1.86). In addition, similar results were also observed when the TyG index was used as a categorical variable. Conclusions There is a positive association between the TyG index and CA. The association is higher in males and middle-aged individuals than those in females and elderly individuals. Besides, the relationship is stronger among individuals with normal blood pressure and underweight subjects.
 
Characteristics of in-sample and out-of-sample patients. Blood samples were collected from 537 patients hospitalized with COVID-19 during an early surge in the outbreak, between March 10th and June 1st of 2020. Data from patients who were hospitalized early in the surge (before April 22, 2020) was used to analyze the cardiometabolic protein biomarkers and develop logistic regression and random forest models for severe outcomes. These patients comprised the in-sample group (shown in grey). These models were then used to predict the outcomes of the out-of-sample patients (shown in gold) who were hospitalized later in the surge (starting April 22, 2020). The in-sample and out-of-sample patients were compared across various demographic and clinical variables using a two-sided t-test for continuous variables and chi-square test for categorical variables. All race/ethnicity categories were self-reported. BMI categorization: < 18.5 kg/m² for underweight, 18.5–24.9 kg/m² for normal weight, 25.0–29.9 kg/m² for overweight, and ≥ 30.0 kg/m² for obese. SD Standard deviation, AA African American, BMI body mass index, CAD coronary artery disease, COPD chronic obstructive pulmonary disease, CRP C-reactive protein, LDH lactate dehydrogenase
Volcano plot of the 92 cardiometabolic biomarkers and 24 hospital laboratory tests. The plot includes, for each protein biomarker and hospital lab, the odds ratio on the x-axis and P value (-log10) on the y-axis resulting from a logistic regression model with ICU/death as the outcome, adjusted for the covariates: age, gender, BMI, and self-reported race/ethnicity. To account for non-normality, the P values were calculated after applying rank-based inverse normal transformation. To preserve interpretability, the odds ratios were calculated from the data standardized to have a mean of 0 a standard deviation of 1. The threshold P < 0.05/116 hospital laboratory tests and protein biomarkers = 4 × 10–4 was used to identify significant results (shown in red). Nominally significant results (P < 0.05) are shown in green. SD Standard deviation, CRP C-reactive protein, LDH lactate dehydrogenase
Hierarchical clustering and correlation matrix with significant cardiometabolic biomarkers. A heatmap (top left) and correlation matrix (top right and bottom) for the 31 protein biomarkers significantly associated with ICU/death (P < 0.05/116 hospital laboratory tests and biomarkers = 4 × 10–4). The correlation matrix shows how the protein biomarkers, ordered based on hierarchical clustering, correlate with one another (top right) and how they correlate with the demographic factors, clinical variables, and hospital laboratory tests (bottom). The color reflects the magnitude and direction of the Pearson correlation coefficient. The cells corresponding to correlations with P > 0.05 were left blank. The P values and odds ratios (OR) reported for the association of each variable with ICU/death are the same as those shown in Fig. 2. Box A shows the association of the largest cluster, comprised of 16 biomarkers, with type 2 diabetes, chronic kidney disease (CKD), and cardiac disease. Boxes B and C show how this cluster correlates with the hospital labs. Finally, Box D shows correlations between the hospital laboratory tests and a smaller cluster, comprising the five biomarkers that were negatively associated with ICU/death. SD Standard deviation, CI confidence interval, AA African American, COPD chronic obstructive pulmonary disease, CAD coronary artery disease, HFpEF heart failure with preserved ejection fraction, HFrEF heart failure with reduced ejection fraction, BUN blood urea nitrogen, ERS erythrocyte sedimentation rate, LDH lactate dehydrogenase, AST aspartate aminotransferase, WBC white blood cells, CRP C-reactive protein, ALC absolute lymphocyte count, eGFR estimated glomerular filtration rate
Prediction of ICU/death outcome in out-of-sample patients. A Violin plots for the set of seven cardiometabolic protein biomarkers that were included in the best model with biomarkers for both logistic regression and random forest. The figure depicts the distribution and box plot of these seven biomarkers, stratified by the ICU/death outcome, in the in-sample patient population. The P values shown for each biomarker are based on the rank-inverse normalized data, while the odds ratios (OR) are based on the data standardized to have a mean of 0 and standard deviation of 1. B The predictive performance of the best models with and without biomarkers in the out-of-sample patients. The figure shows the receiver operating characteristic curve and corresponding area under the curve (AUC) for the best logistic regression (left) and random forest (right) models with biomarkers (gold) and without biomarkers (bronze) in the out-of-sample patients. The best model with biomarkers, for both the logistic regression and random forest, included the same set of seven biomarker, shown in (A), along with two hospital labs: procalcitonin and LDH. All models were developed and trained using only the in-sample data. Thrombotic thrombocytopenic purpura, TTP; acute respiratory distress syndrome, ARDS
Article
Background The high heterogeneity in the symptoms and severity of COVID-19 makes it challenging to identify high-risk patients early in the disease. Cardiometabolic comorbidities have shown strong associations with COVID-19 severity in epidemiologic studies. Cardiometabolic protein biomarkers, therefore, may provide predictive insight regarding which patients are most susceptible to severe illness from COVID-19. Methods In plasma samples collected from 343 patients hospitalized with COVID-19 during the first wave of the pandemic, we measured 92 circulating protein biomarkers previously implicated in cardiometabolic disease. We performed proteomic analysis and developed predictive models for severe outcomes. We then used these models to predict the outcomes of out-of-sample patients hospitalized with COVID-19 later in the surge (N = 194). Results We identified a set of seven protein biomarkers predictive of admission to the intensive care unit and/or death (ICU/death) within 28 days of presentation to care. Two of the biomarkers, ADAMTS13 and VEGFD, were associated with a lower risk of ICU/death. The remaining biomarkers, ACE2, IL-1RA, IL6, KIM1, and CTSL1, were associated with higher risk. When used to predict the outcomes of the future, out-of-sample patients, the predictive models built with these protein biomarkers outperformed all models built from standard clinical data, including known COVID-19 risk factors. Conclusions These findings suggest that proteomic profiling can inform the early clinical impression of a patient’s likelihood of developing severe COVID-19 outcomes and, ultimately, accelerate the recognition and treatment of high-risk patients.
 
Association between metabolite level at baseline and cardiovascular events during the follow-up. Shown are the hazard ratio (x-axis) per 1 SD of the metabolite level) of metabolites (rows) associated with any cardiovascular event (upper panel) and cardiovascular mortality (lower panel). Association and 95% confidence intervals are shown from the crude model (left panel) and from the model adjusted for clinical covariates; sex, baseline age, Hemoglobin A1c, mean arterial pressure, smoking, BMI, LDL cholesterol, estimated glomerular filtration rate, urinary albumin excretion rate and previous cardiovascular disease (right panel). Metabolites with a crude association at FDR < 5% are included in the figure, and associations with p < 0.05 are shown in red
Baseline blood levels (y-axis) of CVD-associated molecules, stratified by participants experiencing any cardiovascular event (n = 95) or not. Plasma metabolite or molecular lipid species level in an individual is shown with a dot, and the population distribution is shown with a violin plot, where horizontal lines indicate the quartiles. Metabolites are shown in the first column and molecular lipid species in the two other columns
Association between lipid level at baseline and cardiovascular events during follow-up. Shown are hazard ratio (x-axis) per 1 SD of the lipid level) of molecular lipid species (rows) associated with any cardiovascular event (upper panel) and cardiovascular mortality (lower panel). Association and 95% confidence intervals are shown from the crude model (left panel) and from the model adjusted for clinical covariates: sex, baseline age, Hemoglobin A1c, mean arterial pressure, smoking, BMI, LDL cholesterol, total plasma triglycerides, estimated glomerular filtration rate, urinary albumin excretion rate, previous cardiovascular disease, and statin use (right panel). Molecular lipid species with a crude association at FDR < 5% are included in the figure, and associations with p < 0.05 are shown in red
Article
Abstract Background Cardiovascular disease remains the leading cause of mortality in individuals with diabetes and improved understanding of its pathophysiology is needed. We investigated the association of a large panel of metabolites and molecular lipid species with future cardiovascular events in type 1 diabetes. Methods The study included 669 individuals with type 1 diabetes. Non-targeted serum metabolomics and lipidomics analyses were performed using mass spectrometry. Data on cardiovascular events (cardiovascular mortality, coronary artery disease, stroke, and peripheral arterial interventions) were obtained from Danish Health registries and analyzed by Cox hazards models. Metabolites and molecular lipid species were analyzed in univariate models adjusted for false discovery rate (FDR). Metabolites and molecular lipid species fulfilling a pFDR
 
Article
Abstract Background We examined multi-dimensional clinical and laboratory data in participants with normoglycemia, prediabetes, and diabetes to identify characteristics of prediabetes and predictors of progression from prediabetes to diabetes or reversion to no diabetes. Methods The Project Baseline Health Study (PBHS) is a multi-site prospective cohort study of 2502 adults that conducted deep clinical phenotyping through imaging, laboratory tests, clinical assessments, medical history, personal devices, and surveys. Participants were classified by diabetes status (diabetes [DM], prediabetes [preDM], or no diabetes [noDM]) at each visit based on glucose, HbA1c, medications, and self-report. Principal component analysis (PCA) was performed to create factors that were compared across groups cross-sectionally using linear models. Logistic regression was used to identify factors associated with progression from preDM to DM and for reversion from preDM to noDM. Results At enrollment, 1605 participants had noDM; 544 had preDM; and 352 had DM. Over 4 years of follow-up, 52 participants with preDM developed DM and 153 participants reverted to noDM. PCA identified 33 factors composed of clusters of clinical variables; these were tested along with eight individual variables identified a priori as being of interest. Six PCA factors and six a priori variables significantly differed between noDM and both preDM and DM after false discovery rate adjustment for multiple comparisons (q
 
Density distribution for the HbA1c levels among all the included patients
Hazard ratios for risk of CVD events in relation to different HbAlc levels (shadows indicating 95% confidence intervals for hazard ratios)
Article
Background Evidence for the relationship between glycated hemoglobin (HbA1c) levels and risk of cardiovascular diseases (CVD) in patients with gout remained sparse and limited. This study aims to explore the associations between HbA1c levels and risks of incident CVD in patients with gout. Methods We included patients with gout who had an HbA1c measurement at baseline from the UK Biobank. CVD events were identified from through medical and death records. We used multivariable Cox proportional hazards model with a restricted cubic spline to assess the potential non-linear effect of HbA1c on CVD risk. Results We included a total of 6,685 patients (mean age 59.7; 8.1% females) with gout for analyses. During a mean follow-up of 7.3 years, there were 1,095 CVD events documented with an incidence of 2.26 events per 100 person-years (95% confidence interval [CI]: 2.13–2.40). A quasi J-shaped association between HbA1c and risk of CVD was observed, with the potentially lowest risk found at the HbA1c of approximately 5.0% (hazard ratio [HR] = 0.65, 95% CI: 0.53–0.81). When compared with the HbAlc level of 7%, a significantly decreased risk of CVD was found from 5.0 to 6.5%, while an increased risk was observed at 7.5% (HR = 1.05) and 8.0% (HR = 1.09). Subgroup analyses yielded similar results to the main findings in general. Conclusions Based on data from a nationwide, prospective, population-based cohort, we found a quasi J-shaped relationship between HbA1c and risk of CVD in patients with gout. More high-quality evidence is needed to further clarify the relationship between HbA1c and CVD risk in patients with gout.
 
A CVD incidence rates according to the risk groups of T2D PRS. B Hazard plot for CVD risk according to the risk group of T2D PRS. T2D PRS risk groups: low (0–19th percentile), intermediate (20–79th percentile), high (80–98th percentile), and very high (99th percentile). Error bars represent 95% CI of estimated cumulative incidence. CVD: cardiovascular disease; T2D: type 2 diabetes; PRS: polygenic risk score; HR: hazard ratio; CI: confidence interval
Hazard ratio for overall and subtypes of cardiovascular outcome according to T2D PRS risk group. CVD: cardiovascular disease; T2D: type 2 diabetes; PRS: polygenic risk score; HR: hazard ratio; CI: confidence interval; SD: standard deviation
Forest plot for cardiovascular disease risk reduced by metabolic health status and lifestyle behavior in high and low genetic risk group for type 2 diabetes. Participants were categorized according to type 2 diabetes genetic risk into the following two subgroups: low (0–80th percentile), high (80–99th percentile). MetS, metabolic syndrome; HR, hazard ratio; CI, confidence interval
Article
Background Few studies have examined associations between genetic risk for type 2 diabetes (T2D), lifestyle, clinical risk factors, and cardiovascular disease (CVD). We aimed to investigate the association of and potential interactions among genetic risk for T2D, lifestyle behavior, and metabolic risk factors with CVD. Methods A total of 345,217 unrelated participants of white British descent were included in analyses. Genetic risk for T2D was estimated as a genome-wide polygenic risk score constructed from > 6 million genetic variants. A favorable lifestyle was defined in terms of four modifiable lifestyle components, and metabolic health status was determined according to the presence of metabolic syndrome components. Results During a median follow-up of 8.9 years, 21,865 CVD cases (6.3%) were identified. Compared with the low genetic risk group, participants at high genetic risk for T2D had higher rates of overall CVD events, CVD subtypes (coronary artery disease, peripheral artery disease, heart failure, and atrial fibrillation/flutter), and CVD mortality. Individuals at very high genetic risk for T2D had a 35% higher risk of CVD than those with low genetic risk (HR 1.35 [95% CI 1.19 to 1.53]). A significant gradient of increased CVD risk was observed across genetic risk, lifestyle, and metabolic health status ( P for trend > 0.001). Those with favorable lifestyle and metabolically healthy status had significantly reduced risk of CVD events regardless of T2D genetic risk. This risk reduction was more apparent in young participants (≤ 50 years). Conclusions Genetic risk for T2D was associated with increased risks of overall CVD, various CVD subtypes, and fatal CVD. Engaging in a healthy lifestyle and maintaining metabolic health may reduce subsequent risk of CVD regardless of genetic risk for T2D.
 
Flowchart illustrating the steps of selection of individuals and FG measurements for analysis
Distribution of FG (mg/dl) across different age groups for three subgroups of FG measures, filtered for all drugs
FG by duration of statin exposure for all statin users and two sub-groups; adjusted for age, sex, BMI, race/ethnicity and average FG during the 5 years prior to start of statin
Summary of FG measures in different groups
Association of statin exposure (cumulative supply) with normalized FG from all statin users and those with normal FG (< 100) within 2 years prior to statin initiation, by statin type b , filtered for all drugs
Article
Background Prior studies of the glycemic effect of statins have been inconsistent. Also, most studies have only considered a short duration of statin use; the effect of long-term statin use on fasting glucose (FG) has not been well examined. The aim of this work is to investigate the effect of long-term statin exposure on FG levels. Methods Using electronic health record (EHR) data from a large and diverse longitudinal cohort, we defined long-term statin exposure in two ways: the cumulative years of statin use (cumulative supply) and the years’ supply-weighted sum of doses (cumulative dose). Simvastatin, lovastatin, atorvastatin and pravastatin were included in the analysis. The relationship between statin exposure and FG was examined using linear regression with mixed effects modeling, comparing statin users before and after initiating statins and statin never-users. Results We examined 593,130 FG measurements from 87,151 individuals over a median follow up of 20 years. Of these, 42,678 were never-users and 44,473 were statin users with a total of 730,031 statin prescriptions. FG was positively associated with cumulative supply of statin but not comulative dose when both measures were in the same model. While statistically significant, the annual increase in FG attributable to statin exposure was modest at only 0.14 mg/dl, with only slight and non-significant differences among statin types. Conclusions Elevation in FG level is associated with statin exposure, but the effect is modest. The results suggest that the risk of a clinically significant increase in FG attributable to long-term statin use is small for most individuals.
 
Article
Background Liver pathology (LP) characteristic of non-alcoholic fatty acid disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is a prevalent co-morbidity of type 2 diabetes (T2D). Accumulating evidence indicates that neutrophils driving insulin resistance (IR), including hepatic IR, precipitate T2D-associated NAFLD/NASH. We hypothesized that targeting neutrophil accumulation into insulin-sensitive tissues in mice using a CXCR2 antagonist under T2D-precipitating high fat diet (HFD) could improve insulin sensitivity and prevent the progression towards liver pathology reminiscent of NAFLD/NASH. Methods Mice were age-matched and on standard rodent chow prior to 1:1 randomization into control and HFD formulated with the CXCR2 antagonist AZD5069 or with biologically inactive substitute. They were monitored for metabolic changes including insulin sensitivity using the hyperinsulinemic-euglycemic clamp and hepatic histopathologic evaluation in H&E-stained sections as well as via immunofluorescence microscopy of liver sections for leukocyte markers, collagen 1A1 formation, α-smooth muscle actin (SMA), and galectin-3 expression, for 16 weeks. Statistical tests used to determine significant differences among study groups and outcomes include Student’s t-test, one-way ANOVA, repeated measures two-way ANOVA, and Fisher’s exact test, depending on the analytical question. Results Compared to mice on HFD, mice in the AZD5069-formulated HFD exhibited improved insulin sensitivity, a modest reduction in weight gain, and a significant improvement in LP and markers related to NAFLD/NASH. Mice in the AZD5069-formulated HFD also exhibited reduced neutrophil accumulation into the liver at the end of the 16 week study period. Conclusions These results show, for the first time, the effectiveness of a selective CXCR2 antagonist to improve insulin sensitivity, concomitantly preventing the progression towards LP characteristic of NAFLD/NASH. This represents a novel approach to target IR and developing LP under T2D-susceptible conditions using a single agent. Furthermore, our data extend the growing evidence in support of neutrophils as a leukocyte population that imprints and maintains a chronic inflammatory state in the progression of dysregulated metabolism in liver-specific co-morbid conditions.
 
Distribution of serum mannose binding lectin levels (μg/L) in patients at discharge and at three months and in controls at baseline. The bottom of each box represents the 25th percentile, the top the 75th percentile and the line in the middle the median, with the corresponding value; whiskers are minimum and maximum values. P-values are displayed for differences between groups. MBL mannose binding lectin
Distribution of serum mannose binding lectin levels (μg/L) in patients at discharge and at 3 months and in controls at baseline, divided by glycaemic status. The bottom of each box represents the 25th percentile, the top the 75th percentile and the line in the middle the median, with the corresponding value; whiskers are minimum and maximum values. P-values represent significance between MBL levels in patients and controls with and without dysglycemia respectively. MBL mannose binding lectin, NGT normal glucose tolerance, DYS dysglycaemia
Kaplan–Meier curves in patients (A) and controls (B) according to serum mannose binding lectin levels below (in blue) or above the median (in red). MBL mannose binding lectin
Article
Background: Mannose binding lectin (MBL) has been suggested to be associated with an impaired cardiovascular prognosis in dysglycaemic conditions, but results are still contrasting. Our aims are (i) to examine whether MBL levels differ between patients with an acute myocardial infarction (MI) and healthy controls and between subgroups with different glucose tolerance status, and (ii) to investigate the relation between MBL and future cardiovascular events. Methods: MBL levels were assessed at discharge and after 3 months in 161 AMI patients without any previously known glucose perturbations and in 183 age- and gender-matched controls from the Glucose metabolism in patients with Acute Myocardial Infarction (GAMI) study. Participants were classified as having dysglycaemia, i.e. type 2 diabetes or impaired glucose tolerance, or not by an oral glucose tolerance test. The primary outcome was a composite of cardiovascular events comprising cardiovascular death, AMI, stroke or severe heart failure during 11 years of follow-up. Total and cardiovascular mortality served as secondary outcomes. Results: At hospital discharge patients had higher MBL levels (median 1246 μg/L) than three months later (median 575 μg/L; p < 0.01), the latter did not significantly differ from those in the controls (801 μg/L; p = 0.47). MBL levels were not affected by dysglycaemia either in patients or controls. Independent of glycaemic state, increasing MBL levels did not predict any of the studied outcomes in patients. In unadjusted analyses increasing MBL levels predicted cardiovascular events (hazard ratio HR: 1.67, 95% confidence interval CI 1.06-2.64) and total mortality (HR 1.53, 95% CI 1.12-2.10) in the control group. However, this did not remain in adjusted analyses. Conclusions: Patients had higher MBL levels than controls during the hospital phase of AMI, supporting the assumption that elevated MBL reflects acute stress. MBL was not found to be independently associated with cardiovascular prognosis in patients with AMI regardless of glucose state.
 
Flow chart of patients selection for analytic
Kaplan–Meier survival analysis curves for all-cause mortality. TyG index: Q1 (6.23–8.65), Q2 (8.65–9.08), Q3 (9.08–9.59), Q4 (9.59–12.43). Kaplan–Meier curves showing cumulative probability of all-cause mortality according to groups at 10 years (A), landmark analysis from 6 months to 10 years (B), landmark analysis at 6 months (C), and Kaplan–Meier survival analysis curves for all-cause mortality according to groups at 1 month (D)
Restricted cubic spline regression analysis of TyG index with in hospital all-cause mortality. Heavy central lines represent the estimated adjusted hazard ratios, with shaded ribbons denoting 95% confidence intervals. TyG index 9.2 was selected as the reference level represented by the vertical dotted lines. The horizontal dotted lines represent the hazard ratio of 1.0. A Restricted cubic spline for hospital death. B Restricted cubic spline for ICU death. HR hazard ratio, CI confidence interval, TyG triglyceride-glucose
Forest plots of hazard ratios for the primary outcome in different subgroups. HR hazard ratio, CI confidence interval, TyG triglyceride-glucose, ICU intensive care unit, BMI body mass index, DM diabetes mellitus
Article
Background Triglyceride-glucose (TyG) index as a reliable surrogate of insulin resistance (IR) has been shown to be related to adverse clinical outcomes in patients with acute coronary syndrome, heart failure, ischemic stroke and so on. However, the relationship between TyG index and all-cause mortality in intensive care unit (ICU) patients remains unknown. The purpose of this study was to investigate the correlation between TyG index and all-cause mortality to evaluate the impact of IR on the prognosis of this population. Methods This was a retrospective observational study that included 3026 patients who had an initial triglyceride and glucose data on the first day of ICU admission, and all data were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. These patients were grouped into quartiles (Q1–Q4) according to TyG index. The Kaplan–Meier analysis was used to compare all-cause mortality among the above four groups. Cox proportional hazards analyses were performed to examine the association between TyG index and all-cause mortality. Results During 10.46 years of follow-up, 1148 (37.9%) patients died, of which 350 (11.6%) occurred during the hospital stay and 258 (8.5%) occurred during the ICU stay. Kaplan–Meier analysis showed that the risk of all-cause mortality was significantly higher in patients with higher TyG index (log-rank P = 0.021). Multivariable Cox proportional hazards analyses showed that the TyG index was an independent risk predictor of ICU death (HR: 1.72, 95% CI 1.18–2.52, P = 0.005) and hospital death (HR: 2.19, 95% CI 1.59–3.03, P < 0.001), and each 1-unit increased in the TyG index, a 1.19-fold increase in the risk of death during the hospital stay. Conclusions TyG index is strongly related to the all-cause mortality increasing in critically ill patients. This finding indicates that the TyG index might be useful in identifying people at high risk of ICU death and hospital death.
 
a Kaplan–Meier plot of time to first hospitalized heart failure by baseline serum gGT value (top quartile vs rest of the distribution); b Kaplan–Meier plot of time to first hospitalized heart failure by baseline serum ALT value (top quartile vs rest of the distribution)
Multivariate Cox proportional hazards model of the association of updated LFTs, risk markers and canagliflozin treatment with incident hospitalized HF (left) and renal outcome (right). M male sex; SD standard deviation; BMI body mass index; T2D type 2 diabetes; eGFR estimated glomerular filtration rate; SBP systolic blood pressure; HDL high-density lipoprotein cholesterol; LDL low density lipoprotein cholesterol; CV cardiovascular; HF heart failure; RAASi renin angiotensin aldosterone system inhibitors; ALT alanine aminotransferase; AST aspartic aminotransferase; ALP alkaline phosphatase; gGT gamma-glutamyl transferase
Article
Background Raised liver function tests (LFTs) have been correlated with multiple metabolic abnormalities and variably associated with cardiorenal outcomes. We sought to systematically test the relationship between LFT levels within the accepted range and major cardiorenal outcomes in a large clinical trial in type 2 diabetes, and the possible impact of placebo-controlled canagliflozin treatment. Methods We measured serum alanine aminotransferase (ALT), aspartic aminotransferase (AST), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), and bilirubin concentrations in 10,142 patients, at baseline and repeatedly over follow-up. The relation of LFTs to first hospitalized heart failure (HHF), cardiovascular (CV) and all-cause mortality, and progression of renal impairment was investigated using multivariate proportional-hazards models. Results In univariate association, ALT was reciprocally predictive, and ALP was positively predictive, of all adjudicated outcomes; γGT also was directly associated with CV—but not renal—outcomes. In multivariate models including all 5 LFTs and 19 potential clinical confounders, ALT was independently associated with lower, and γGT with higher, CV outcomes risk. Canagliflozin treatment significantly reduced ALT, AST, and γGT over time. In a fully adjusted model including updated LFT levels and treatment, γGT was independently associated with CV and all-cause mortality, ALP with renal dysfunction progression, and canagliflozin treatment with significant reduction in HHF and renal risk. Conclusions Higher γGT levels are top LFT markers of risk of HHF and death in patients with diabetes and high CV risk, while ALT are protective. Canagliflozin lowers the risk of HHF and renal damage independently of LFTs and potential confounders.
 
Article
Background Outcome prediction tools for patients with type 2 diabetes mellitus (T2DM) undergoing percutaneous coronary intervention (PCI) are lacking. Here, we developed a machine learning-based metabolite classifier for predicting 1-year major adverse cardiovascular events (MACEs) after PCI among patients with T2DM. Methods Serum metabolomic profiling was performed in a nested case–control study of 108 matched pairs of patients with T2DM occurring and not occurring MACEs at 1 year after PCI, then the matched pairs were 1:1 assigned into the discovery and internal validation sets. External validation was conducted using targeted metabolite analyses in an independent prospective cohort of 301 patients with T2DM receiving PCI. The function of candidate metabolites was explored in high glucose-cultured human aortic smooth muscle cells (HASMCs). Results Overall, serum metabolome profiles differed between diabetic patients with and without 1-year MACEs after PCI. Through VSURF, a machine learning approach for feature selection, we identified the 6 most important metabolic predictors, which mainly targeted the nicotinamide adenine dinucleotide (NAD ⁺ ) metabolism. The 6-metabolite model based on random forest and XGBoost algorithms yielded an area under the curve (AUC) of ≥ 0.90 for predicting MACEs in both discovery and internal validation sets. External validation of the 6-metabolite classifier also showed good accuracy in predicting MACEs (AUC 0.94, 95% CI 0.91–0.97) and target lesion failure (AUC 0.89, 95% CI 0.83–0.95). In vitro, there were significant impacts of altering NAD ⁺ biosynthesis on bioenergetic profiles, inflammation and proliferation of HASMCs. Conclusion The 6-metabolite model may help for noninvasive prediction of 1-year MACEs following PCI among patients with T2DM.
 
Flow-chart of the MPP-RES cohort stratified for individuals with and without obesity, as well as history of hospitalization for somatic disorders in subjects with obesity, respectively
Article
Background Obesity is strongly associated with the development of cardiovascular disease (CVD). However, the heterogenous nature of obesity in CVD-risk is still poorly understood. We aimed to explore novel CVD biomarkers and their possible association with presumed unhealthy obesity, defined as hospitalized subjects with obesity (HO). Methods Ninety-two proteins associated with CVD were analyzed in 517 (mean age 67 ± 6 years; 33.7% women) individuals with obesity (BMI ≥30 kg/m ² ) from the Malmö Preventive Project cohort, using a proximity extension array technique from the Olink CVD III panel. Individuals with at least one recorded hospitalization for somatic disease prior to study baseline were defined as HO phenotypes. Associations between proteins and HO (n = 407) versus non-hospitalized subjects with obesity (NHO, n = 110), were analyzed using multivariable binary logistic regression, adjusted for traditional risk factors. Results Of 92 analyzed unadjusted associations between biomarkers and HO, increased levels of two proteins were significant at a false discovery rate < 0.05: Galectin-4 (Gal-4) and insulin-like growth factor-binding protein 1 (IGFBP-1). When these two proteins were included in logistic regression analyses adjusted for age and sex, Gal-4 remained significant. Gal-4 was independently associated with the HO phenotype in multivariable logistic regression analysis (OR 1.72; CI95% 1.16–2.54). Post-hoc analysis revealed that this association was only present in the subpopulation with diabetes (OR 2.26; CI95% 1.25–4.07). However, an interaction analysis was performed, showing no significant interaction between Gal-4 and prevalent diabetes (p = 0.16). Conclusions In middle-aged and older individuals with obesity, increased Gal-4 levels were associated with a higher probability of HO. This association was only significant in subjects with diabetes only, further implying a role for Gal-4 in diabetes and its complications.
 
Exosome biogenesis. The invagination of the cell membrane results in the formation of the early endosome (A). Various budding into the endosomal lumen, initiates the process of forming exosomes/intraluminal vesicles in the late sorting endosome (B). Cargo is shuttled between the trans-golgi network (C), endoplasmic reticulum (D)and the late sorting endosome (B). Cumulatively, this leads to the formation of a multivesicular body (E) with fully formed intraluminal vesicles/exosomes in it. The multivesicular body can be further processed within the cell by the lysosome (F) or autophagosome (G) to breakdown the components of the multivesicular body into the cell. Otherwise, the multivesicular body can be docked (H) and fused to the cell membrane to release the exosomes (I) into the extracellular space. Exosomes can be characterized using different surface markers (J) that are consistently expressed by them. Exosomal functionality (K) is based on the varying cargo within the exosomes. Image Created with Biorender.com with valid license
Function of exosomes under DHD conditions. Studies have been conducted on exosomes isolated from DHD biological fluids as well as from culture media under DHD conditions. Exosomes released from patients with DHD has been demonstrated to increase calcification, plaque rupture, adverse remodeling and blood pressure in the vasculature. This was mimicked in the in vitro experiments where diabetic exosomes increased endothelial cell apoptosis, while decreasing proliferation, angiogenesis and migration. Similarly, DHD exosomes in vivo resulted in increased apoptosis, fibrosis and adverse remodeling of the heart as well as reduced cell survival. Just as in in vitro experiments, DHD exosomes promoted cardiomyocyte apoptosis while reducing cardiomyocyte survival
Article
Diabetes is a metabolic disorder that affects millions of people worldwide. Diabetic heart disease (DHD) comprises coronary artery disease, heart failure, cardiac autonomic neuropathy, peripheral arterial disease, and diabetic cardiomyopathy. The onset and progression of DHD have been attributed to molecular alterations in response to hyperglycemia in diabetes. In this context, microRNAs (miRNAs) have been demonstrated to have a significant role in the development and progression of DHD. In addition to their effects on the host cells, miRNAs can be released into circulation after encapsulation within the exosomes. Exosomes are extracellular nanovesicles ranging from 30 to 180 nm in diameter secreted by all cell types. They carry diverse cargos that are altered in response to various conditions in their parent cells. Exosomal miRNAs have been extensively studied in recent years due to their role and therapeutic potential in DHD. This review will first provide an overview of exosomes, their biogenesis and function, followed by the role of exosomes in cardiovascular disease and then focuses on the known role of exosomes and associated miRNAs in DHD.
 
Flowchart of the study selection for the meta-analysis for the association between TyG index and cardiovascular diseases and mortality in general population.\ Abbreviation: TyG: Triglyceride-glucose
Forest plot and non-linear dose–response curve (C) for the association between TyG index and CAD in general population, analyzed as category variables (highest vs. lowest) (A) or continuous variables (per 1-unit increasement) (B). In the forest plot, the diamond indicates the pooled estimate. Red boxes are relative to study size and the black vertical lines indicate 95% CIs around the effect size estimate. The dose–response association were fitted by using restricted cubic spline regression model. The bold lines indicate the pooled restricted cubic spline model and the black dashed line indicates the 95% CIs of the pooled curve. TyG: Triglyceride-glucose; CAD: coronary artery disease
Forest plot for the association between TyG index and MI in general population, analyzed as category variables (highest vs. lowest). TyG: Triglyceride-glucose; MI: myocardial infarction
Forest plot and non-linear dose–response curve (C) for association between TyG and CVD in general population, analyzed as category variables (highest vs. lowest) (A) or continuous variables (per 1-unit increasement) (B). In the forest plot, the diamond indicates the pooled estimate. Red boxes are relative to study size and the black vertical lines indicate 95% CIs around the effect size estimate. The dose–response association were fitted by using restricted cubic spline regression model. The bold lines indicate the pooled restricted cubic spline model and the black dashed line indicates the 95% CIs of the pooled curve. TyG: Triglyceride-glucose; CVD: cardiovascular disease
Forest plot for the association between TyG index and CV mortality (A) and all-cause mortality (B) in general population. TyG: Triglyceride-glucose; CV mortality: cardiovascular mortality
Article
Background The triglyceride-glucose (TyG) index is a new alternative measure for insulin resistance. This meta-analysis was conducted to assess the associations of the TyG index with the risks of cardiovascular diseases and mortality in the general population. Methods The PubMed, Cochrane Library and Embase databases were searched for randomized controlled trials or observational cohort studies reporting associations of the TyG index with cardiovascular diseases and mortality from inception to April 16, 2022. Effect sizes were pooled using random-effects models. Robust error meta-regression methods were applied to fit nonlinear dose–response associations. Evidence quality levels and recommendations were assessed using the Grading of Recommendations Assessment, Development and Evaluation system (GRADE). Results Twelve cohort studies (6 prospective and 6 retrospective cohorts) involving 6,354,990 participants were included in this meta-analysis. Compared with the lowest TyG index category, the highest TyG index was related to a higher incidence of coronary artery disease (CAD) (3 studies; hazard ratio [HR] = 2.01; 95% confidence interval [CI] 1.68–2.40; I ² = 0%), myocardial infarction (MI) (2 studies; HR = 1.36; 95% CI 1.18–1.56; I ² = 35%), and composite cardiovascular disease (CVD) (5 studies; HR = 1.46; 95% CI 1.23–1.74; I ² = 82%). However, there was no association between the TyG index and mortality (cardiovascular mortality [3 studies; HR = 1.10; 95% CI 0.82–1.47; I ² = 76%] or all-cause mortality [4 studies; HR = 1.08; 95% CI 0.92–1.27; I ² = 87%]). In the dose–response analysis, there was a linear association of the TyG index with the risk of CAD (P nonlinear = 0.3807) or CVD (P nonlinear = 0.0612). GRADE assessment indicated very low certainty for CVD, MI, cardiovascular mortality and all-cause mortality, and moderate certainty for CAD. Conclusions Based on our current evidence, a higher TyG index may be associated with an increased incidence of CAD (moderate certainty), MI (very low certainty) and CVD (very low certainty) in the general population. There is a potential linear association of the TyG index with CAD and the composite CVD incidence. Further prospective studies (especially in non-Asians) are needed to confirm our findings.
 
Forest plots of independent factors associated with CHD in NAFLD
ROC analyses of different levels of TyG index. The rule-in threshold of three ROC was respectively minimum value of TyG (7.91) and the tri-sectional quantiles of TyG (8.78,9.22)
The relationship of Gensini score and TyG in NAFLD-CHD patients. The red bar chart illustrates Gensini score in tri-sectional TyG groups among NAFLD-CHD patients (each group = 85), and the blue bar chart illustrates TyG index in tri-sectional Gensini score groups among NAFLD-CHD patients(each group = 85)
Gaussian graph of the relationship between Gensini score and TyG index
ROC curve analyses of different levels of TyG index
Article
Background: Insulin resistance (IR), endothelial dysfunction, inflammation, glucose and lipid metabolism disorders, and thrombosis are believed involved in coronary heart disease (CHD) and non-alcoholic fatty liver disease (NAFLD). Triglyceride-glucose (TyG) index, a new IR indicator, is correlated with NAFLD occurrence and severity, but its relationship with CHD risk remains unclear. This study investigated the correlation between TyG index and CHD risk among NAFLD patients. Methods: This cross-sectional study included 424 patients with NAFLD and chest pain in the Department of Cardiology, The Second Hospital of Shanxi Medical University, from January 2021 to December 2021. The TyG index was calculated and coronary angiography performed. All individuals were divided into NAFLD + CHD and NAFLD groups and then by TyG index level. The t-test, Mann-Whitney U-test, or one-way analysis of variance compared differences in continuous variables, while the chi-square test or Fisher's exact test compared differences in categorical variables. Logistic regression analysis determined the independent protective or hazardous factors of NAFLD with CHD. The receiver operating characteristic curve evaluated the ability of different TyG index rule-in thresholds to predict CHD. The relationship between Gensini score and TyG index was evaluated using linear correlation and multiple linear regression. Results: CHD was detected in 255 of 424 patients. Compared to NAFLD group, multivariate logistic regression showed that TyG index was a risk factor for CHD among NAFLD patients after adjustment for age, sex, hypertension, and diabetes mellitus with the highest odds ratio (OR, 2.519; 95% CI, 1.559-4.069; P < 0.001). TG, low-density lipoprotein cholesterol, FBG and TYG-body mass index were also risk factors for CHD among NAFLD patients. High-density lipoprotein cholesterol level was a protective factor for CHD events in patients with NAFLD. In an in-depth analysis, multivariate logistic regression analysis showed that each 1-unit increase in TyG index was associated with a 2.06-fold increased risk of CHD (OR, 2.06; 95% CI, 1.16-3.65; P = 0.013). The multifactor linear regression analysis showed each 0.1-unit increase in TyG in the NAFLD-CHD group was associated with a 2.44 increase in Gensini score (β = 2.44; 95% CI, 0.97-3.91; P = 0.002). Conclusions: The TyG index was positively correlated with CHD risk in NAFLD patients and reflected coronary atherosclerosis severity.
 
Flow chart of the study. LDL-C: low-density lipoprotein cholesterol; CCTA: Coronary computed tomographic angiography
Schematic diagram of quantitative coronary plaque analysis. After a landmark in the ascending aorta is placed, coronary centerlines generation automatically (a red and light purple lines). A surface reconstruction image of the target vessel is automatically generated (b), and the stenosis marker and lesion range are defined on the surface reconstruction images. After the plaque quantitative analysis is completed, different plaque components are marked with colors (c, yellow for calcified plaque, orange for non-calcified plaque, and red for low-density non-calcified plaque)
Representative imaging. A 48-year-old female diabetic patient whose ASCVD risk category is very high risk. There was a non-calcific plaque on the proximal left anterior descending coronary artery at the baseline CCTA (a1, a2). The non-calcified plaque volume was 107.21 mm³, and the stenosis degree was 30.26%. After an 18-month follow-up, the LDL-C at follow-up was 3.6 mmol/L. Follow-up CCTA showed an increase in the extent of the original lesion, along with new formation of calcified components. The calcified volume in the plaque was 97.4 mm³ and the non-calcified volume was 144.24 mm³, with a stenosis of 65.5% (b1, b2) .
Article
Background: In statins-treated diabetic mellitus (DM) patients, longitudinal coronary CTA (CCTA) evidence is scarce regarding the relationship between coronary Agatston artery calcification scores (CACs) and coronary plaque progression. This study was designed to investigate whether the association between CACs progression and compositional plaque volumes (PVs) progression differed between follow-up low-density lipoprotein cholesterol (LDL-C) controlled and uncontrolled groups in statins-treated DM patients. Methods: From January 2015 to June 2021, 208 patients who submitted serial clinically indicated CCTAs in our hospital were included in this study. Participants were further subdivided into LDL-C controlled (n = 75) and LDL-C uncontrolled (n = 133) groups according to whether the LDL-C reached the treatment goals at follow-up. Baseline and follow-up CCTA image datasets were quantified analysis at per-patient and per-plaque levels. The annual change of total PV (TPV), calcific PV(CPV), non-calcific PV (NCPV), low-density non-calcific PV (LD-NCPV), and CACs were assessed and further compared according to follow-up LDL-C status. The effect of CACs progression on the annual change of componential PVs was evaluated according to follow-up LDL-C status at both per-patient and per-plaque levels. Results: The annual change of CACs was positively associated with the annual change of TPV (β = 0.43 and 0.61, both p < 0.001), CPV (β = 0.23 and β = 0.19, p < 0.001 and p = 0.004, respectively), NCPV (β = 0.20 and β = 0.42, p < 0.001 and p = 0.006, respectively), and LD-NCPV (β = 0.08 and 0.13, p < 0.001 and p = 0.001, respectively) both on per-patients and per-plaque levels. LDL-C status had no effect on the annual change of TPV, CPV, NCPV, and LD-NCPV (all p > 0.05). After adjusting for confounding factors, on the per-patient level, the increase in CACs was independently associated with annual change of TPV (β = 0.650 and 0.378, respectively, both p < 0.001), CPV (β = 0.169 and 0.232, respectively, p = 0.007 and p < 0.001), NCPV (β = 0.469 and 0.144, respectively, both p = 0.001), and LD-NCPV (β = 0.082 and 0.086, respectively, p = 0.004 and p = 0.006) in LDL-C controlled and LDL-C uncontrolled group. On the per-plaque level, the increase in CACs was independently associated with the annual change of NCPV and LD-NCPV in LDL-C uncontrolled patient (β = 0.188 and 0.106, p < 0.001), but not in LDL-C controlled group (β = 0.268 and 0.056, p = 0.085 and 0.08). Conclusions: The increase of CACs in statins-treated DM patients indicates the progression of compositional PVs. From a per-plaque perspective, there might be increased instability of individual plaques concomitant with CACs increase in LDL-C uncontrolled patients.
 
5 years Survival rate by DM groups
Article
Background Type 2 diabetes mellitus (DM) is a frequent co-morbidity among patients suffering from infective endocarditis (IE). The aim of the study was to evaluate the impact of type 2 DM on the early-, intermediate- and long-term mortality of patients who underwent surgical treatment of endocarditis. Methods We performed an observational cohort study in the large tertiary center in Israel during 14 years. All data of patients who underwent surgical treatment of endocarditis, performed between 2006 and 2020 were extracted from the departmental database. Patients were divided into two groups: Group I (non-diabetic patients), and Group II (diabetic patients). Results The study population includes 420 patients. Group I (non-diabetic patients), comprise 326 patients, and Group II (diabetic patients), comprise 94 patients. Mean follow-up duration was 39.3 ± 28.1 months. Short-term, 30-day and in-hospital mortality, also intermediate-term mortality (1- and 3-year) was higher in the DM group compared with the non-DM group, but did not reach statistical significance: 11.7% vs. 7.7%. (p = 0.215); 12.8% vs. 8.3% (p = 0.285); 20.2% vs. 13.2% (p = 0.1) and 23.4% vs. 15.6% (p = 0.09) respectively. Long-term, 5-year mortality was significantly higher in the DM group, compared to the non-DM group: 30.9% vs. 16.6% (p = 0.003). Furthermore, predictors for long-term mortality included diabetes (CI 1.056–2.785, p = 0.029), as demonstrated by regression analysis. Conclusions Diabetic patients have trend to increasing mortality at the short- and intermediate period post-surgery for IE, but this is not statistically significant. Survival of diabetic patients deteriorates after more than three years follow surgery. Diabetes is an independent predictor for long-term, 5-year mortality after surgical treatment of endocarditis, regardless of the patients age and comorbidities. Trial registration Ethical Committee of Sheba Medical Centre, Israel on 02.12. 2014, Protocol 4257
 
Schematic representation of possible mechanisms by which SGLT2 inhibitors reduce incident atrial fibrillation. Abbreviations: epicardial adipose tissue (EAT); sodium-hydrogen exchanger (NHE); left ventricular (LV); left atrial (LA); pulmonary vein (PV); cardiomyocytes (CM)
Article
Atrial fibrillation, the most common cardiac arrhythmia, results in substantial morbidity and mortality related to its increased risks of stroke, heart failure, and impaired cognitive function. The incidence and prevalence of atrial fibrillation in the general population is rising, making atrial fibrillation treatment and management of its risk factors highly relevant clinical targets. One well-studied risk factor for the development of atrial fibrillation is diabetes mellitus. Inhibitors of sodium-glucose cotransporter 2 (SGLT2), common medications used to treat diabetes mellitus, have been observed to decrease the incidence of atrial fibrillation. This review discusses the SGLT2 and its role in glucose homeostasis, molecules inhibiting the transporter, possible physiological mechanisms responsible for the decreased incident atrial fibrillation in patients treated with SGLT2 inhibitors and proposes mechanistic studies to further our understanding of the biological processes involved.
 
Enrollment of patients with type 2 diabetes (T2D) treated with sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonist (GLP-1RA), and dipeptidyl peptidase-4 inhibitors (DPP4i). A total of 344,893, 44,370, and 393,100 patients with T2D without pre-existing atrial fibrillation (AF) treated with SGLT2i, GLP-1RA, and DPP4i from May 1, 2016 to December 31, 2019, respectively, were enrolled in the present study. There were 245,442, 43,682, and 39,190 paired cohorts of SGLT2i versus DPP4i, SGLT2i versus GLP-1RA, and GLP-1RA versus DPP4i, respectively, after propensity score matching (PSM)
Cumulative risk of incident AF for the paired study cohorts treated with SGTL2i versus DPP4i (A), SGLT2i versus GLP-1RA (B), and GLP-1RA versus DPP4i (C) after PSM. There was a clear separation of event curves for new-onset AF between the paired SGLT2i and DPP4i group and the paired SGLT2i and GLP-1RA group after PSM adjustment. SGLT2i treatment was associated with a lower risk of new-onset AF in participants with type 2 diabetes compared with DPP4i or GLP-1RA treatment after PSM. Conversely, there was no difference in the risk of incident AF between the GLP-1RA and DPP4i treatment
Sensitivity analyses of the hazard ratio for incident AF for the paired study cohorts treated with SGTL2i versus DPP4i, SGLT2i versus GLP-1RA, and GLP-1RA versus DPP4i after PSM. The sensitivity analyses showed the results were robust, and consistent with the main analysis. The use of SGLT2i was still associated with a lower risk of new-onset AF compared with either DPP4i or GLP-1RA after PSM, using death as a competing risk factor consistent with the main analysis. Specifically, we identified incident AF using either hospitalized diagnosed AF; AF with treatment using anti-arrhythmic drugs, cardioversion, or catheter ablation; or only patients without previous drug exposure, underlying ESKD, or concomitant use of insulin, the results remained consistent with the main analyses. There were no differences in the risk of incident AF with consequent use of oral anticoagulant treatment for three paired study groups
Article
Background: Although a few meta-analyses were conducted to compare the risk of incident atrial fibrillation (AF) between sodium-glucose cotransporter-2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and other anti-hyperglycemic agents using indirect or direct comparison, the above analyses showed conflicting results with each other. We aimed to evaluate the risk of new-onset AF associated with the use of SGLT2i, GLP-1RA, and dipeptidyl peptidase-4 inhibitor (DPP4i) among a large longitudinal cohort of diabetic patients. Methods: In this nationwide retrospective cohort study based on the Taiwan National Health Insurance Research Database, a total of 344,893, 44,370, and 393,100 consecutive patients with type 2 diabetes without preexisting AF receiving GLP-1RA, SGLT2i, and DPP4i, respectively, were enrolled from May 1, 2016, to December 31, 2019. We used 1:1 propensity score matching (PSM) to balance covariates across paired study groups. Patients were followed from the drug index date until the occurrence of AF, death, discontinuation of the index drug, or the end of the study period (December 31, 2020), whichever occurred first. Results: After PSM, there were 245,442, 43,682, and 39,190 paired cohorts of SGLT2i-DPP4i, SGLT2i-GLP-1RA, and GLP-1RA-DPP4i, respectively. SGLT2i treatment was associated with lower risk of new-onset AF in participants with type 2 diabetes compared with either DPP4i [hazard ratio (HR):0.90; 95% confidential interval (CI) 0.84-0.96; P = 0.0028] or GLP-1RA [HR 0.74; 95% CI 0.63-0.88; P = 0.0007] treatment after PSM. There was no difference in the risk of incident AF between GLP-1RA and DPP4i users [HR 1.01; 95% CI 0.86-1.19; P = 0.8980]. The above findings persisted among several important subgroups. Dapagliflozin was specifically associated with a lower risk of new-onset AF compared with DPP4i (P interaction = 0.02). Conclusions: Compared with DPP4i, SGLT2i but not GLP-1RA was associated with a lower risk of incident AF in patients with type 2 diabetes.
 
Article
Background To determine whether there were racial differences in short-term cardiometabolic responses to once-weekly exenatide (EQW) in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). Methods EXSCEL enrolled 14,752 patients with type 2 diabetes (hemoglobin A1c (HbA1c) 6.5–10.0% [48–86 mmol/mol]) with or without cardiovascular disease who were randomized double-blind to EQW or placebo. Background glucose-lowering/other cardiovascular therapies were unaltered for 6 months post-randomization unless clinically essential, facilitating comparison of EQW-associated effects in 14,665 evaluable participants self-identifying as White (n = 11,113), Asian (n = 1444), Black (n = 870), or Other Race (n = 1,238. Placebo-adjusted 6 month absolute changes in cardiometabolic variables were assessed using generalized linear models. Results Mean 6-month placebo-adjusted HbA1c reductions were similar in the four groups (range 0.54–0.67% [5.9 to 7.3 mmol/mol], P = 0.11 for race×treatment interaction), with no significant difference in Asians (reference) versus other groups after covariate adjustment (all P ≥ 0.10). Six-month placebo-adjusted mean changes in systolic (−1.8 to 0.0 mmHg) and diastolic (0.2 to 1.2 mmHg) blood pressure, serum LDL (− 0.06 to 0.02 mmol/L) and HDL (0.00 to 0.01 mmol/L) cholesterol, and serum triglycerides (−0.1 to 0.0 mmol/L) were similar in the racial groups (P ≥ 0.19 for race×treatment interaction and all P ≥ 0.13 for comparisons of Asians with other races). Resting pulse rate increased more in Asians (4 beats/min) than in other groups (≤ 3 beats/min, P = 0.016 for race×treatment interaction and all P ≤ 0.050 for comparisons of Asians with other races). Conclusions Short-term cardiometabolic responses to EQW were similar in the main racial groups in EXSCEL, apart from a greater pulse rate increase in Asians. Trial registration: https://clinicaltrials.gov NCT01144338.
 
The distribution of LDL-C and RC by the discordant/concordant groups. a The box plot of the different LDL-C and RC levels. b the relative proportions of the discordant/concordant groups. Groups 1–4 represent the low LDL-C/low RC group, low LDL-C/high RC group, high LDL-C/low RC group and the high LDL-C/high RC group, respectively. LDL-C low-density lipoprotein cholesterol, RC remnant cholesterol
Association of the discordance/concordance of LDL-C (2.60 mmol/L cutoffs) and RC (0.62 mmol/L cutoffs) with DM. a The proportion of the discordant/concordant groups in DM and non-DM population. b The odds ratios (95% CIs) of DM according to the discordance/concordance of LDL-C and RC. Model adjusted for age, sex, BMI, educational level, smoking, alcohol consumption, and chronic kidney disease. DM diabetes mellitus, LDL-C low-density lipoprotein cholesterol, RC remnant cholesterol, OR odds ratio, CI confidence interval
Mediation analysis of the association between RC and DM. RC remnant cholesterol, DM diabetes mellitus, HOMA-IR homeostasis model assessment of insulin resistance, Hs-CRP high-sensitivity C-reactive protein, WBC white blood cell
Article
Background Previous research has linked elevated low-density lipoprotein cholesterol (LDL-C) and remnant cholesterol (RC) with diabetes mellitus (DM). The present study aims to estimate the RC-related DM risk beyond LDL-C, and to investigate the extent to which the association of RC and DM is mediated via insulin resistance and inflammation. Methods We enrolled 7308 individuals without previous history of DM into the present study from the China Health and Nutrition Survey. Fasting RC was calculated as total cholesterol minus LDL-C and high-density lipoprotein cholesterol. Subjects were divided into four groups according to their LDL-C (100 mg/dL) and RC (24 mg/dL) levels to evaluate the role of LDL-C vs. RC on DM. A logistic regression analysis was then employed to evaluate the relationships between the discordant/concordant LDL-C and RC and DM. A mediation analysis was undertaken to identify potential mediators. Results Of all the participants, a total of 625 (8.55%) patients were newly diagnosed with DM. Compared to the high LDL-C/low RC group, the low LDL-C/high RC group was more common in DM patients. After a multivariate adjustment, elevated LDL-C and RC were associated with DM. Moreover, the low LDL-C/high RC group and the high LDL-C/low RC group manifested a 4.04-fold (95% CI 2.93–5.56) and 1.61-fold (95% CI 1.21–2.15) higher risk of DM, relative to those with low LDL-C/low RC. The subgroup analysis indicated that low LDL-C/high RC was more likely to be related to DM in females. Similar results were also shown when the sensitivity analyses were performed with different clinical cut-points of LDL-C. Insulin resistance and inflammation partially mediated the association between RC and DM. Conclusions Our findings provided evidence for RC beyond the LDL-C associations with DM that may be mediated via insulin resistance and the pro-inflammatory state. In addition, women are more susceptible to RC exposure-related DM.
 
ROC curve analysis of the TyG index for MACEs. The receiver operating characteristic (ROC) curve of the triglyceride-glucose (TyG) index as a marker to predict MACEs in T2DM patients after PCI. The area under the ROC curve (AUC) of the TyG index for predicting the occurrence of MACEs in T2DM patients within 18 months after PCI was 0.612 (95% CI 0.573 to 0.650; P < 0.001). T2DM type 2 diabetes mellitus, MACE major adverse cardiac events, PCI percutaneous coronary intervention
Cumulative incidence of endpoint events according to the optimal cutoff value of the TyG index. Kaplan–Meier curves for the incidence of the primary endpoint (A), all-cause death (B), cardiovascular death (C), nonfatal myocardial infarction (D), unplanned repeat revascularization (E), and nonfatal stroke (F) between the 2 study groups based on the TyG index. The groups were stratified by the optimal cutoff value of the TyG index determined by receiver‑operating characteristic curve analysis. TyG indicates triglyceride-glucose
ROC curve analysis of the rSS for MACEs. The receiver operating characteristic (ROC) curve of the residual SYNTAX score (rSS) as a marker to predict MACEs in T2DM patients after PCI. The area under the ROC curve (AUC) of the rSS for predicting the occurrence of MACEs in T2DM patients within 18 months after PCI was 0.673 (95% CI 0.635 to 0.710, P < 0.001). T2DM, type 2 diabetes mellitus; MACE, major adverse cardiac events; PCI, percutaneous coronary intervention
Cumulative incidence of endpoint events according to the optimal cutoff value of the rSS. Kaplan–Meier curves for the incidence of the primary endpoint (A), all-cause death (B), cardiovascular death (C), nonfatal myocardial infarction (D), unplanned repeat revascularization (E), and nonfatal stroke (F) between the 2 study groups based on the rSS. The groups were stratified by the optimal cutoff value of the rSS determined by receiver‑operating characteristic curve analysis. The rSS indicates the residual SYNTAX score
ROC curve analysis of the 4 models to predict MACEs after PCI in T2DM patients. The areas under the ROC curves of Model 1, Model 2, Model 3, and Model 4 for predicting the occurrence of MACEs in T2DM patients within 18 months after PCI were 0.660 (95% CI 0.622 to 0.697; P < 0.01), 0.710 (0.673 to 0.746; P < 0.01), 0.691 (0.653 to 0.726; P < 0.01), and 0.732 (0.696 to 0.766; P < 0.01), respectively. ROC, receiver operating characteristic; MACE, major adverse cardiac events; PCI, percutaneous coronary intervention; T2DM, type 2 diabetes mellitus
Article
Background: The residual SYNTAX score (rSS), a quantitative measure of angiographic completeness of revascularization after percutaneous coronary intervention (PCI), and the triglyceride-glucose index (TyG index), a reliable surrogate marker of insulin resistance, have been regarded as independent predictors of major adverse cardiac events (MACEs) after PCI. Whether a combination of the rSS and the TyG index improves the predictive ability for MACEs in patients with type 2 diabetes mellitus (T2DM) undergoing PCI remains unknown. Methods: A total of 633 consecutive patients with T2DM who underwent PCI were included in the present analyses. Patients were stratified according to the optimal cutoff point value of the TyG index, or the rSS determined by receiver‑operating characteristic (ROC) curve analysis. The primary endpoint was the composite of MACEs, including all-cause death, nonfatal myocardial infarction, and unplanned repeat revascularization. Cumulative curves were calculated using the Kaplan-Meier method. Multivariate Cox regression was used to identify predictors of MACEs. The predictive value of the TyG index combined with the rSS was estimated by the area under the ROC curve, continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results: During a median follow-up of 18.83 months, 99 patients developed MACEs, more frequently in the patients with a higher TyG index or rSS. Multivariate Cox hazards regression analysis revealed that both the TyG index and rSS were independent predictors of MACEs (hazard ratio 1.8004; 95% CI 1.2603-2.5718; P = 0.0012; 1.0423; 95% CI 1.0088-1.0769; P = 0.0129, respectively). Furthermore, Kaplan-Meier analysis demonstrated that both the TyG index and the rSS were significantly associated with an increased risk of MACEs (log-rank, all P < 0.01). The addition of the rSS and the TyG index to the baseline risk model had an incremental effect on the predictive value for MACE (increase in C-statistic value from 0.660 to 0.732; IDI 0.018; NRI 0.274; all P < 0.01). Conclusions: The TyG index predicts intermediate-term MACE after PCI in patients with T2DM independent of known cardiovascular risk factors. Adjustment of the rSS by the TyG index further improves the predictive ability for MACEs in patients with T2DM undergoing PCI.
 
Hazard Ratios of All-Cause Mortality According to FBG levels in AMI patients. A non-diabetic patients and all-cause mortality. B diabetic patients and all-cause mortality. Solid red lines are hazard ratios and dashed lines show 95% confidence intervals based on restricted cubic spline regressions. Reference line for no association (hazard ratio: 1.0) is indicated by dashed grey line while areas of purple show fraction of population at different FBG concentrations. The red points for hazard ratio = 1
Short and long-term outcomes of AMI patients, according to FBG levels. A Stacked bar chart of short-term outcomes. B Kaplan–Meier survival curves of all-cause mortality. C Kaplan–Meier survival curves of major adverse cardiovascular event (MACE)
Risk for short and long-term mortality according to FBG levels. All models were inverse probability of treatment weighted (IPTW). IPTW included all the clinical variables listed in Table 1. Model 1 included FBG categories only. Model 2 included FBG categories, age, gender, ethnic, hypertension, diagnosis, Killip class, and EF. Model 3 included FBG categories, age, gender, Killip class, ethnic, drinking, hypertension, COPD, liver disease, lung disease, diagnosis, EF, PCI, CABG, ACE inhibitor/ARB, and beta-blocker. CI confidence interval; HR hazard ratio. Test for trend based on variable containing median value for each quintile
Article
Objective: Admission hyperglycemia is associated with poor prognosis in patients with acute myocardial infarction (AMI), but the effects of baseline diabetes status on this association remain elusive. We aim to investigate the impact of admission hyperglycemia on short and long-term outcomes in diabetic and non-diabetic AMI patients. Methods: In this retrospective cohort study, 3330 patients with regard to first-time AMI between July 2012 and July 2020 were identified. Participants were divided into two groups according to diabetes status (1060 diabetic patients and 2270 non-diabetic patients). Thereafter, they were divided into four groups according to diabetes status-specific cutoff values of fasting blood glucose (FBG) identified by restricted cubic spline. Short-term outcomes included in-hospital death and cardiac complications. Long-term outcomes were all-cause mortality and major adverse cardiovascular events (MACE). Inverse probability of treatment weighting (IPTW) was conducted to adjust for baseline differences among the groups, followed by a weighted Cox proportional hazards regression analysis to calculate hazard ratios and 95% confidence intervals for all-cause mortality associated with each FBG category. Subgroup analysis and sensitivity analysis were performed to test the robustness of our findings. Results: During a median follow-up of 3.2 years, 837 patients died. There was a significant interaction between diabetes status and FBG levels for all-cause mortality during long-term follow-up (p-interaction < 0.001). Moreover, restricted cubic spline curves for the association between FBG and all-cause mortality followed a J shape in patients with diabetes and a non-linear in patients without diabetes. Kaplan-Meier analysis demonstrated greater survival in non-hyperglycemia patients compared to hyperglycemia patients for both diabetic and non-diabetic patients groups. Survival of hyperglycemia patients without diabetes greater than in hyperglycemia patients with diabetes. In the weighted Multivariable cox analysis, admission hyperglycemia predicted higher short and long-term mortality. Subgroup analysis and sensitivity analysis showed the robustness of the results. Conclusions: The inflection points of FBG level for poor prognosis were 5.60 mmol/L for patients without diabetes and 10.60 mmol/L for patients with diabetes. Admission hyperglycemia was identified as an independent predictor of worse short and long-term outcomes in AMI patients, with or without diabetes. These findings should be explored further.
 
Prevalence and mortality of cardiovascular diseases in China and high-income countries from 1990 to 2019. A Number (left panel) and rate (right panel) of CVD prevalent cases in China and high-income countries; B Numebr of CVD deaths (left panel) and mortality rate (right panel) in China and high-income countries. Figures were developed according to data from http://ghdx.healthdata.org/gbd-results-tool
Trend in the prevalence and mean value of conventional cardiometabolic risk factors in China and the US. Temporal treads in the mean values or prevalence of cardiometabolic risk factor among male and female adults in China (left panel) and the United States (right panel). Adapted from https://www.ncdrisc.org/index.html
An interactive network of cardiometabolic risk factors. Cardiometabolic risk factors include health conditions, biomarkers, and environmental factors. The heath conditions, including overweight or obesity, abdominal obesity, impaired glucose metabolism, dyslipidemia, and hypertension, frequently cluster in individuals at risk for CVDs and may contribute to each other. Underlying this phenomenon is a close link between different organs and tissues. At the molecular level, these health conditions are usually accompanied by an increase in biomarkers such as cytokines, C-reactive protein, adipokines, uric acid, and homocysteine in the blood stream; the increase in these biomarkers represent a proinflammatory state and oxidative stress, which contribute to atherosclerosis and development of CVDs. CVD, cardiovascular disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein
Article
With rapid economic growth and changes at all levels (including environmental, social, individual), China is facing a cardiovascular disease (CVD) crisis. In China, more than 40% of deaths are attributable to CVDs, and the number of CVD deaths has almost doubled in the past decades, in contrast to a decline in high-income countries. The increasing prevalence of cardiometabolic risk factors underlies the rise of CVDs, and thus curbing the rising cardiometabolic pandemic is imperative. Few articles have addressed this topic and provided an updated review of the epidemiology of cardiometabolic risk factors in China. In this narrative review, we describe the temporal changes in the prevalence of cardiometabolic risk factors in the past decades and their management in China, including both the well-recognized risk factors (general obesity, central obesity, diabetes, prediabetes, dyslipidemia, hypertension) and the less recognized ones (hyperhomocysteinemia, hyperuricemia, and high C-reactive protein). We also summarize findings from landmark clinical trials regarding effective interventions and treatments for cardiometabolic risk factors. Finally, we propose strategies and approaches to tackle the rising pandemic of cardiometabolic risk factors in China. We hope that this review will raise awareness of cardiometabolic risk factors not only in Chinese population but also global visibility, which may help to prevent cardiovascular risk.
 
Flowchart of participants included in the analysis
Effect of Model 2 covariates on glucose and insulin measure estimates (each covariate is added one at a time)
Article
Objective We evaluated whether measures of glucose dysregulation are associated with subclinical cardiac dysfunction, as assessed by speckle-tracking echocardiography, in an older population. Methods Participants were men and women in the Cardiovascular Health Study, age 65+ years and without coronary heart disease, atrial fibrillation, or heart failure at baseline. We evaluated fasting insulin resistance (IR) with the homeostatic model of insulin resistance (HOMA-IR) and estimated the Matsuda insulin sensitivity index (ISI) and insulin secretion with an oral glucose tolerance test. Systolic and diastolic cardiac mechanics were measured with speckle-tracking analysis of echocardiograms. Multi-variable adjusted linear regression models were used to investigate associations of insulin measures and cardiac mechanics. Results Mean age for the 2433 included participants was 72.0 years, 33.6% were male, and 3.7% were black. After adjustment for age, sex, race, site, speckle-tracking analyst, echo image and quality score, higher HOMA-IR, lower Matsuda ISI, and higher insulin secretion were each associated with worse left ventricular (LV) longitudinal strain and LV early diastolic strain rate (p-value < 0.005); however, associations were significantly attenuated after adjustment for waist circumference, with the exception of Matsuda ISI and LV longitudinal strain (increase in strain per standard deviation increment in Matsuda ISI = 0.18; 95% confidence interval = 0.03–0.33). Conclusion In this cross-sectional study of older adults, associations of glucose dysregulation with subclinical cardiac dysfunction were largely attenuated after adjusting for central adiposity.
 
Kaplan-Meier analysis depicting type 2 diabetes according to tertiles of triglycerides (log rank test, p value < 0.001)
Relative risk of type 2 diabetes development according to triglyceride levels. Relative risk was obtained by Cox regression analysis using log2 transformed triglycerides, adjusted for age and sex. The reference value is the median of plasma triglycerides in this cohort (82.4 mg·dL)
Hazard ratios for incident type 2 diabetes per 10 mg/dL increase in normal plasma triglyceride values by several participant-level characteristics. HR (95% CI) for the association of baseline triglyceride concentrations with incident type 2 diabetes were obtained using Cox regression analysis. Age is given in years, BMI, body mass index (kg/m²); waist is given in cm; eGFR, estimated glomerular filtration rate (mL/min/1.73 m²). Hypertension was defined as a systolic blood pressure > 140 mmHg
Article
Background Type 2 diabetes is increasing worldwide. Traditionally, only hypertriglyceridemia is considered a risk factor. We investigated whether also normal triglycerides prospectively associate with incident type 2 diabetes in healthy subjects. Methods Incident type 2 diabetes was determined in healthy individuals with normal triglyceride levels from a prospective longitudinal cohort study (PREVEND, n = 2085, 11.4-year median follow-up). Results Type 2 diabetes incidence was 3.8%. In linear regression analysis baseline insulin, HOMA-IR, total cholesterol, HDL cholesterol, eGFR, systolic blood pressure (all p < 0.001), glucose, age and creatinine (all p < 0.01) independently associated with triglycerides within the normal range, comparable to what would be expected from associations with increased triglycerides. In Kaplan-Meier analysis sex-stratified tertiles of normal triglycerides prospectively associated with de novo type 2 diabetes (p < 0.001). Cox regression confirmed a significant prospective association independent of HOMA-IR [HR (95% CI), 1.39 (1.12, 1.74), p = 0.002] and several other recognized risk factors. Conclusions Even in healthy subjects without metabolic syndrome increasing triglyceride levels within the normal range confer a continuous increase in type 2 diabetes incidence. These data indicate that virtually everyone could potentially benefit from triglyceride lowering, further encouraging implementation of lifestyle changes in the general population.
 
Mean HbA1c values at randomization and at follow-up, in PARAGON-HF participants with diabetes, by treatment groups. Error bars represent 95% confidence intervals. P from mixed model for equality of HbA1c slopes
Cumulative incidence of different outcomes in PARAGON-HF participants with diabetes. A New use of insulin. B New use of non-insulin antihyperglycemic medications. C Hypoglycemia. HR hazard ratio, CI confidence interval
Treatment effects of sacubitril/valsartan compared with control treatment (valsartan in PARAGON-HF and enalapril in PARADIGM-HF) in patients with heart failure and diabetes, by left ventricular ejection fraction. A HbA1c reduction from randomization to 48 weeks (n = 5241). B New use of insulin (n = 4778). C New use of non-insulin antihyperglycemic medications (n = 2232). D Hypoglycemia (n = 6173)
Article
Background Compared with enalapril, sacubitril/valsartan lowered HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial. We sought to assess the glycemic effects of sacubitril/valsartan in heart failure with preserved ejection fraction (HFpEF) and diabetes, and across the spectrum of left ventricular ejection fraction (LVEF) in heart failure and diabetes. Methods We compared the effect of sacubitril/valsartan, relative to valsartan, on HbA1c, new insulin therapy and hypoglycemia in the randomized controlled trial PARAGON-HF, and performed pooled analyses of PARAGON-HF and PARADIGM-HF. Results Among 2395 patients with HFpEF and diabetes in PARAGON-HF, sacubitril/valsartan compared with valsartan reduced HbA1c (baseline-adjusted between-group difference in HbA1c change at 48 weeks: − 0.24%, 95% CI − 0.33 to − 0.16%, P < 0.001). Numerically, new insulin treatment was initiated less often in the sacubitril/valsartan group than in the valsartan group, but the difference was not statistically significant (12.8% vs. 16.1%; HR: 0.80, 95% CI 0.62–1.02, P = 0.07). Hypoglycemia adverse event reports were low, but more frequent in those receiving sacubitril/valsartan than in the valsartan group (4.2% vs. 2.6%; HR: 1.64, 95% CI 1.05–2.56, P = 0.030). In a pooled analysis of PARAGON-HF and PARADIGM-HF, the effect of sacubitril/valsartan on change in HbA1c was not significantly modified by LVEF (P interaction = 0.56). Across the spectrum of LVEF, sacubitril/valsartan reduced new insulin therapy (HR: 0.75, 95% CI 0.63–0.89, P = 0.001), compared with enalapril or valsartan. Conclusions Sacubitril/valsartan reduced HbA1c and new insulin therapy in patients with heart failure and diabetes across the spectrum of LVEF but may be associated with a slightly higher risk for hypoglycemia. Trial registration ClinicalTrials.gov NCT01920711
 
Top-cited authors
Enrique Zvi Fisman
  • Tel Aviv University
Melvin Hayden
  • University of Missouri
Sudhesh Kumar
  • The University of Warwick
Hans-Juergen Woerle
  • Nestle Health Science
Odd Erik Johansen
  • Nestlé S.A.