Effect of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes treated with an implantable cardioverter-defibrillator: the EMPA-ICD trial.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death with type 2 diabetes; however, their effect on arrhythmias is unclear. The purpose of this study was to investigate the effects of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes. METHODS: A total of 150 patients with type 2 diabetes who were treated with an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator (ICD/CRT-D) were randomized to once-daily empagliflozin or placebo for 24 weeks. The primary endpoint was the change in the number of ventricular arrhythmias from the 24 weeks before to the 24 weeks during treatment. Secondary endpoints included the change in the number of appropriate device discharges and other values. RESULTS: In the empagliflozin group, the number of ventricular arrhythmias recorded by ICD/CRT-D decreased by 1.69 during treatment compared to before treatment, while in the placebo group, the number increased by 1.79. The coefficient for the between-group difference was - 1.07 (95% confidence interval [CI] - 1.29 to - 0.86; P < 0.001). The change in the number of appropriate device discharges during and before treatment was 0.06 in the empagliflozin group and 0.27 in the placebo group, with no significant difference between the groups (P = 0.204). Empagliflozin was associated with an increase in blood ketones and hematocrit and a decrease in blood brain natriuretic peptide and body weight. CONCLUSIONS: In patients with type 2 diabetes treated with ICD/CRT-D, empagliflozin reduces the number of ventricular arrhythmias compared with placebo. Trial registration jRCTs031180120.

Familial hypercholesterolemia is related to cardiovascular disease, heart failure and atrial fibrillation. Results from a population-based study.

BACKGROUND: Familial hypercholesterolemia (FH) is associated with atherosclerotic cardiovascular disease (ASCVD). However, the prevalence of FH among a general population remains unknown, and it is unclear if FH is associated with other cardiovascular complications, including heart failure (HF) and atrial fibrillation (AF). METHODS: Analyses were conducted on individuals without a prior history of cardiovascular disease using a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2022 (n = 4,126,642; median age, 44 years; 57.5% men). We defined FH as either LDL cholesterol ≥250 mg/dL or LDL cholesterol ≥175 mg/dL under the lipid-lowering medications under the assumption that lipid-lowering medications reduced LDL cholesterol by 30%. We assessed the associations between FH and composite outcomes, including, ASCVD (myocardial infarction, angina pectoris, and stroke), HF, and AF using Cox proportional hazard model. RESULTS: We identified 11,983 (.29%) FH patients. In total, 181,150 events were recorded during the mean follow-up period of 3.5 years. The status FH was significantly associated with composite outcomes after adjustments (hazard ratio [HR]; 1.38, 95% confidence interval [CI]: 1.30-1.47, p < .001). Interestingly, the status FH was significantly associated with HF (HR: 1.48, 95% CI: 1.36-1.61, p < .001) and AF (HR: 1.33, 95% CI: 1.08-1.64, p < .001) in addition to angina pectoris (HR: 1.45, 95% CI: 1.33-1.58, p < .001) and stroke (HR: 1.19, 95% CI: 1.04-1.36, p < .001). CONCLUSION: We found that the prevalence of FH was .29% in a general population. FH was significantly associated with a higher risk of developing cardiovascular disease, HF and AF. LAY SUMMARY: We sought to identify the prevalence of FH among a general population, and to clarify whether FH increases the risk of not only ASCVD but also HF and AF.

Association of Cancer and Its Interaction with Conventional Risk Factors on Cardiovascular Disease Risk.

Introduction We sought to examine the association of cancer history with the incidence of individual cardiovascular disease events and to clarify whether the history of cancer modifies the relationship between conventional cardiovascular risk factors and incident cardiovascular disease. Methods This retrospective cohort study used the JMDC Claims Database, including 3,531,683 individuals. The primary endpoint was the composite cardiovascular disease outcome, which included myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation. Results During a follow-up, 144,162 composite endpoints were recorded. Individuals with a history of cancer had a higher risk of developing composite cardiovascular disease events (HR 1.26, 95% CI 1.22-1.29). The HRs for myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation were 1.11 (95% CI 0.98-1.27), 1.15 (95% CI 1.10-1.20), 1.11 (95% CI 1.05-1.18), 1.39 (95% CI 1.34-1.44), and 1.22 (95% CI 1.13-1.32), respectively. Individuals who required chemotherapy for cancer had a higher risk of developing cardiovascular disease. Although conventional risk factors (e.g., overweight/obesity, hypertension, and diabetes) were associated with incident composite cardiovascular disease even in individuals with a history of cancer, the total population-attributable fractions of conventional risk factors were less in individuals with a history of cancer. Conclusion Individuals with a history of cancer (particularly those requiring chemotherapy) have a higher risk of cardiovascular disease. Traditional risk factors are important in the development of cardiovascular disease in individuals with and without a history of cancer. In individuals with a history of cancer, however, the total population-attributable fractions of conventional risk factors decreased.

Significance of eGFR and proteinuria for cardiovascular disease in individuals beyond 85 years.

BACKGROUND: There are limited data on how advancing age influences prediction of CVD risk based on the estimated glomerular filtration rate (eGFR) and proteinuria, especially in older adults, including those aged ≥ 85 years. This study aimed to clarify the association of eGFR and proteinuria with CVD outcomes and the impact of age on this association. METHODS: The distribution of eGFR and urine protein in Japan was assessed retrospectively using real-world administrative claims and health checkup data collected between April 2014 and November 2022. We investigated the associations of these two parameters with the incidence of CVD, with an emphasis on the impact of aging. RESULTS: We assessed 1 829 020 individuals for distribution of eGFR and proteinuria; after excluding those with known CVD, their association with CVD risk was examined in 1 040 101 individuals aged ≥ 40 years. The prevalence of impaired kidney function (eGFR <60 mL/min/1.73 m2) increased with age, being 0.7%, 9.2%, 21.9%, 40.2%, and 60.2% at the ages of 18-39, 40-64, 65-74, 75-84, and ≥ 85 years (P for trend < 0.001); similarly, the proportion with positive proteinuria increased with age, being 2.7%, 4.3%, 5.6%, 9.2%, and 15.8%, respectively (P for trend < 0.001). Both eGFR and urine protein were identified to be independent risk factors for CVD. Hazard ratios for CVD increased significantly when eGFR was <45 mL/min/1.73 m2 at the ages of 40-64, 65-74, and 75-84 and <30 mL/min/1.73 m2 at ≥ 85 years, while proteinuria remained significantly associated with a high CVD risk regardless of age. These findings were consistent even when analyzed separately by sex. CONCLUSIONS: This study identified eGFR and urine dipstick proteinuria to be independent risk factors for CVD, even among individuals aged ≥ 85 years. However, the contribution of eGFR to the CVD risk was attenuated by aging, whereas proteinuria remained less affected by advancing age.

Erythropoiesis and estimated fluid volume regulation following initiation of ipragliflozin treatment in patients with type 2 diabetes mellitus and chronic kidney disease: A post-hoc analysis of the PROCEED trial.

AIMS: To analyse the changes in erythropoietic and estimated fluid volume parameters after the initiation of ipragliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). METHODS: This was a post-hoc analysis of the PROCEED trial, which evaluated the effect of 24-week ipragliflozin treatment on endothelial dysfunction in patients with T2DM and CKD. We evaluated the changes in erythropoietic and estimated fluid volume parameters from baseline to 24 weeks post-treatment in 53 patients who received ipragliflozin (ipragliflozin group) and 55 patients with T2DM and CKD without sodium-glucose co-transporter 2 inhibitors (control group), a full analysis set of the PROCEED trial. RESULTS: The increases in haemoglobin [estimated group difference, 0.5 g/dl; 95% confidence interval (CI), 0.3-0.8; p < .001], haematocrit (estimated group difference, 2.2%; 95% CI, 1.3-3.1; p < .001) and erythropoietin (estimated log-transformed group difference, 0.1; 95% CI, 0.01-0.3; p = .036) were significantly greater in the ipragliflozin group than those in the control group. Ipragliflozin treatment was significantly associated with an increase in erythropoietin, independent of the corresponding change in haemoglobin (ß = 0.253, p < .001) or haematocrit (ß = 0.278, p < .001). Reductions in estimated plasma volume (estimated group difference, -7.94%; 95% CI, -11.6 to -4.26%; p < .001) and estimated extracellular volume (estimated group difference, -181.6 ml; 95% CI, -275.7 to -87.48 ml; p < .001) were significantly greater in the ipragliflozin group than those in the control group. CONCLUSIONS: Erythropoiesis was enhanced and estimated fluid volumes were reduced by ipragliflozin in patients with T2DM and CKD. CLINICAL TRIAL: PROCEED trial (registration number: jRCTs071190054).

Comparison of estimated glomerular filtration rate change with sodium-glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists among people with diabetes: A propensity-score matching study.

AIM: To compare the risk of developing kidney outcomes with use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus use of sodium-glucose cotransporter-2 (SGLT2) inhibitors among individuals with diabetes. MATERIALS AND METHODS: In this retrospective observational study, we analysed 12 338 individuals with diabetes who newly initiated SGLT2 inhibitors or GLP-1RAs using data from the JMDC claims database. The primary outcome was change in the estimated glomerular filtration rate (eGFR), estimated using a linear mixed-effects model. A 1:4 propensity-score-matching algorithm was used to compare the changes in eGFR between GLP-1RA and SGLT2 inhibitor users. RESULTS: After propensity-score matching, 2549 individuals (median [range] age 52 [46-58] years, 80.6% men) were analysed (510 GLP-1RA new users and 2039 SGLT2 inhibitor new users). SGLT2 inhibitor use was associated with a slower eGFR decline when compared with GLP-1RA use (-1.41 [95% confidence interval -1.63 to -1.19] mL/min/1.73 m2 vs. -2.62 [95% confidence interval -3.15 to -2.10] mL/min/1.73 m2). CONCLUSIONS: Our analysis demonstrates the potential advantages of SGLT2 inhibitors over GLP-1RAs in terms of kidney outcomes in individuals with diabetes.

Pulmonary Vein Intervention for Severe Pulmonary Vein Stenosis After Atrial Fibrillation Ablation　- A Retrospective Cohort Study.

BACKGROUND: Pulmonary vein (PV) stenosis (PVS) is a serious complication of atrial fibrillation (AF) ablation. The objective of this study was to describe interventional treatments for PVS after AF ablation and long-term outcomes in Japanese patients.Methods and Results: This multicenter retrospective observational study enrolled 30 patients (26 [87%] male; median age 55 years) with 56 severe PVS lesions from 43 PV interventional procedures. Twenty-seven (90%) patients had symptomatic PVS and 19 (63%) had a history of a single AF ablation. Of the 56 lesions, 41 (73%) were de novo lesions and 15 (27%) were retreated. Thirty-three (59%) lesions were treated with bare metal stents, 14 (25%) were treated with plain balloons, and 9 (16%) were treated with drug-coated balloons. All lesions were successfully treated without any systemic embolic event. Over a median follow-up of 584 days (interquartile range 265-1,165 days), restenosis rates at 1 and 2 years were 35% and 47%, respectively. Multivariate Cox regression analysis revealed devices <7 mm in diameter (hazard ratio [HR] 2.52; 95% confidence interval [CI] 1.04-6.0; P=0.040) and totally occluded lesions (HR 3.33; 95% CI 1.21-9.15; P=0.020) were independent risk factors for restenosis. CONCLUSIONS: All PVS lesions were successfully enlarged by the PV intervention; however, restenosis developed in approximately half the lesions within 2 years.

Benign Prostatic Hyperplasia and Incident Cardiovascular Disease.

BACKGROUND: Data regarding the relationship between benign prostatic hyperplasia (BPH) and incident cardiovascular disease (CVD) are scarce. We aimed to clarify the association of BPH with the risk of developing CVD using a nationwide epidemiological database.Methods and Results: This retrospective observational cohort study analyzed data from the JMDC Claims Database between 2005 and 2022, including 2,370,986 men (median age 44 years). The primary endpoints were myocardial infarction (MI), angina pectoris (AP), stroke, heart failure (HF), and atrial fibrillation (AF), which were assessed separately. BPH was observed in 48,651 (2.1%) men. During a mean (±SD) follow-up of 1,359±1,020 days, 7,638 MI, 52,167 AP, 25,355 stroke, 58,183 HF, and 16,693 AF events were detected. Hazard ratios of BPH for MI, AP, stroke, HF, and AF were 1.04 (95% confidence interval [CI] 0.92-1.18), 1.31 (95% CI 1.25-1.37), 1.26 (95% CI 1.18-1.33), 1.21 (95% CI 1.16-1.27), and 1.15 (95% CI 1.07-1.24), respectively. We confirmed the robustness of our primary findings through a multitude of sensitivity analyses. In particular, a history of BPH was associated with a higher risk of developing CVD, even in participants without obesity, hypertension, diabetes, or dyslipidemia. CONCLUSIONS: Our analysis of a nationwide epidemiological dataset demonstrated that BPH was associated with a greater risk of developing CVD in middle-aged men.

Awareness of Being Prescribed Antihypertensive Medications and Cardiovascular Outcomes.

BACKGROUND: Hypertension is a major cause of cardiovascular disease (CVD). In patients with hypertension, unawareness of the disease often results in poor blood pressure control and increases the risk of CVD. However, data in nationwide surveys regarding the proportion of unaware individuals and the implications of such on their clinical outcomes are lacking. We aimed to clarify the association between unawareness of being prescribed antihypertensive medications among individuals taking antihypertensive medications and the subsequent risk of developing CVD.Methods and Results: This retrospective cohort study analyzed data from the JMDC Claims Database, including 313,715 individuals with hypertension treated with antihypertensive medications (median age 56 years). The primary endpoint was a composite of myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation. Overall, 19,607 (6.2%) individuals were unaware of being prescribed antihypertensive medications. During the follow-up period, 33,976 composite CVD endpoints were documented. Despite their youth, minimal comorbidities, and the achievement of better BP control with a reduced number of antihypertensive prescriptions, unawareness of being prescribed antihypertensive medications was associated with a greater risk of developing composite CVD. Hazard ratios of unawareness of being prescribed antihypertensive medications were 1.16 for myocardial infarction, 1.25 for angina pectoris, 1.15 for stroke, 1.36 for heart failure, and 1.28 for atrial fibrillation. The results were similar in several sensitivity analyses, including the analysis after excluding individuals with dementia. CONCLUSIONS: Among individuals taking antihypertensive medications, assessing the awareness of being prescribed antihypertensive medications may help identify those at high risk for CVD-related events.

Myocardial Injury by COVID-19 Infection Assessed by Cardiovascular Magnetic Resonance Imaging　- A Prospective Multicenter Study.

BACKGROUND: This prospective multicenter study assessed the prevalence of myocardial injury in patients with COVID-19 using cardiac magnetic resonance imaging (CMR).Methods and Results: We prospectively screened 505 patients with moderate to severe COVID-19 disease from 7 hospitals in Japan. Of these patients, 31 (mean [±SD] age 63.5±10.4 years, 23 [74%] male) suspected of myocardial injury, based on elevated serum troponin or B-type natriuretic peptide concentrations either upon admission or 3 months after discharge, underwent CMR 3 months after discharge. The primary endpoint was the presence of myocardial injury, defined by any of the following: (1) contrast enhancement in the left or right ventricle myocardium on late gadolinium enhancement CMR; (2) left or right ventricular dysfunction (defined as <50% and <45%, respectively); and (3) pericardial thickening on contrast enhancement. The mean (±SD) duration between diagnosis and CMR was 117±16 days. The primary endpoint was observed in 13 of 31 individuals (42%), with 8 (26%) satisfying the modified Lake Louise Criteria for the diagnosis of acute myocarditis. CONCLUSIONS: This study revealed a high incidence of myocardial injury identified by CMR in patients with moderate to severe COVID-19 and abnormal findings for cardiac biomarkers.

Histological validation of atrial structural remodelling in patients with atrial fibrillation.

BACKGROUND AND AIMS: This study aimed to histologically validate atrial structural remodelling associated with atrial fibrillation. METHODS AND RESULTS: Patients undergoing atrial fibrillation ablation and endomyocardial atrial biopsy were included (n = 230; 67 ± 12 years old; 69 women). Electroanatomic mapping was performed during right atrial pacing. Voltage at the biopsy site (Vbiopsy), global left atrial voltage (VGLA), and the proportion of points with fractionated electrograms defined as ≥5 deflections in each electrogram (%Fractionated EGM) were evaluated. SCZtotal was calculated as the total width of slow conduction zones, defined as regions with a conduction velocity of <30 cm/s. Histological factors potentially associated with electroanatomic characteristics were evaluated using multiple linear regression analyses. Ultrastructural features and immune cell infiltration were evaluated by electron microscopy and immunohistochemical staining in 33 and 60 patients, respectively. Fibrosis, intercellular space, myofibrillar loss, and myocardial nuclear density were significantly associated with Vbiopsy (P = .014, P < .001, P < .001, and P = .002, respectively) and VGLA (P = .010, P < .001, P = .001, and P < .001, respectively). The intercellular space was associated with the %Fractionated EGM (P = .001). Fibrosis, intercellular space, and myofibrillar loss were associated with SCZtotal (P = .028, P < .001, and P = .015, respectively). Electron microscopy confirmed plasma components and immature collagen fibrils in the increased intercellular space and myofilament lysis in cardiomyocytes, depending on myofibrillar loss. Among the histological factors, the severity of myofibrillar loss was associated with an increase in macrophage infiltration. CONCLUSION: Histological correlates of atrial structural remodelling were fibrosis, increased intercellular space, myofibrillar loss, and decreased nuclear density. Each histological component was defined using electron microscopy and immunohistochemistry studies.

Feedbacks Using behaviOral econOmic theories on STEP countS in Cardiovascular Disease Patients (FOOTSTEPS) Using Novel Daily Step Counts Retrieving System.

The effectiveness of gamification-based feedback systems that utilize non-monetary points to promote exercise among cardiovascular disease (CVD) patients has not been fully evaluated. This study aimed to evaluate the effectiveness of a gamification program using non-monetary points on the daily step counts in CVD patients. We collected 30 patients with a history of heart failure or myocardial infarction at a single tertiary center between January 9, 2023, and April 13, 2023. The primary outcome was the change in daily step counts. The baseline step counts were compared with those during the 4-week gamification and the 1-week follow-up period. A total of 29 participants with a mean age of 64.6 years were finally enrolled, and 8 (27.6%) were female. Among them, 23 (79.3%) had a history of old myocardial infarction, and 9 (31.0%) had a history of chronic heart failure. During the intervention period, the average daily step counts increased significantly from baseline in weeks 1-5 (week 1: 1165 steps; 95% CI, 319-2011; P = 0.009, week 2: 1508; 635-2382; P = 0.001, week 3: 1321; 646-1996; P < 0.001, week 4: 1436; 791-2081; P < 0.001, week 5:1148; 436-1860; P < 0.001). Higher body mass index was statistically associated with the smaller difference in step counts from the baseline, and the lower proportion of achievement of step count goals. Female sex was significantly associated with the higher proportion of achievement of step count goals. In conclusion, this pilot prospective interventional study demonstrated the effectiveness of gamification-based feedback systems that utilize non-monetary points to increase daily step counts in CVD patients.

[Development of a new method for assessing the availability of low-sodium foods in Japan].

Objectives　Food environment improvement involving salt reduction requires improving access to and labeling low-sodium foods. Assessing the implementation status of these measures is also necessary. However, to date, no established methods exist for assessing the availability of low-sodium foods in communities. In this study, we aimed to devise a survey on the availability of low-sodium foods as a community food environment assessment method in order to establish common assessment methods, criteria, and practical measures, as well as standardization nationwide.Methods　A preliminary survey on the availability of low-sodium foods was conducted in Kitakyushu City in four stores with nationwide representation. Consent for providing information on handled product lists was obtained. The on-site lists collected through direct investigation by surveyors were compared with the handled product lists provided by the stores and analyzed to identify survey challenges and examine feasibility and the potential for accuracy. The definition of low-sodium foods, which emerged as a challenge in the preliminary survey, was confirmed. Preliminary survey data were carefully reviewed to establish classification criteria for low-sodium foods and create a low-sodium food list to serve as a reference for on-site surveys. Forms for recording the results of on-site surveys and a survey manual were developed. Registered dietitians conducted on-site surveys using the manual to confirm its applicability.Results　The preliminary survey results revealed that the on-site lists had fewer omissions and greater feasibility than store-provided lists. After clearly defining low-sodium foods, we established classification criteria (three major categories, seven subcategories, and 37 minor categories) considering the ease of on-site investigations and purchases. Three forms for recording survey results were developed, including a standard input form allowing detailed documentation of the availability of individual low-sodium foods, an aggregation form for a quantitative assessment of low-sodium foods availability, and a display form visualizing the availability of low-sodium foods by store. Furthermore, a survey manual was developed explaining the purpose and approach of the low-sodium foods availability survey, definition and classification criteria for low-sodium foods, and the three forms for recording survey results. Findings indicated that all registered dietitians could conduct on-site surveys using the manual and successfully collect and organize data.Conclusion　On-site surveys using the manual and documentation forms enabled easy and accurate assessments of low-sodium foods availability. Thus, this standardized method to assess the availability of low-sodium foods could be a food environment assessment method for regional salt reduction initiatives.

Potential negative effect of total parenteral nutrition on the human circadian clock.

When patients cannot eat on their own, total parenteral nutrition (TPN) is a clinically beneficial method of maintaining nutrition. However, many animal studies have demonstrated that circadian rhythms are strongly affected by feeding time, raising the concern that continuous TPN around the clock may have an unexpected negative impact on the circadian clock of patients. To investigate this concern, we compared clock gene expression of aged subjects with or without TPN using hair follicle cells and found that while none of the non-TPN subjects showed any obvious defects in circadian rhythms of peripheral clock gene expression, a portion of aged subjects receiving continuous TPN showed abnormal circadian rhythms in peripheral clocks. Continuous TPN around the clock may therefore potentially perturb peripheral circadian rhythms, giving rise to the proposal that TPN needs to be administered with consideration to time factors.

Lack of impact of ipragliflozin on endothelial function in patients with type 2 diabetes: sub-analysis of the PROTECT study.

BACKGROUND: We assessed the impact of 24 months of treatment with ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on endothelial function in patients with type 2 diabetes as a sub-analysis of the PROTECT study. METHODS: In the PROTECT study, patients were randomized to receive either standard antihyperglycemic treatment (control group, n = 241 ) or add-on ipragliflozin treatment (ipragliflozin group, n = 241) in a 1:1 ratio. Among the 482 patients in the PROTECT study, flow-mediated vasodilation (FMD) was assessed in 32 patients in the control group and 26 patients in the ipragliflozin group before and after 24 months of treatment. RESULTS: HbA1c levels significantly decreased after 24 months of treatment compared to the baseline value in the ipragliflozin group, but not in the control group. However, there was no significant difference between the changes in HbA1c levels in the two groups (7.4 ± 0.8% vs. 7.0 ± 0.9% in the ipragliflozin group and 7.4 ± 0.7% vs. 7.3 ± 0.7% in the control group; P = 0.08). There was no significant difference between FMD values at baseline and after 24 months in both groups (5.2 ± 2.6% vs. 5.2 ± 2.6%, P = 0.98 in the ipragliflozin group; 5.4 ± 2.9% vs. 5.0 ± 3.2%, P = 0.34 in the control group). There was no significant difference in the estimated percentage change in FMD between the two groups (P = 0.77). CONCLUSIONS: Over a 24-month period, the addition of ipragliflozin to standard therapy in patients with type 2 diabetes did not change endothelial function assessed by FMD in the brachial artery. TRIAL REGISTRATION: Registration Number for Clinical Trial: jRCT1071220089 ( https://jrct.niph.go.jp/en-latest-detail/jRCT1071220089 ).

Rationale and design of an investigator-initiated, multicenter, prospective, placebo-controlled, double-blind, randomized trial to evaluate the effects of finerenone on vascular stiffness and cardiorenal biomarkers in type 2 diabetes and chronic kidney disease (FIVE-STAR).

BACKGROUND: The overactivation of mineralocorticoid receptor (MR) plays a key pathological role in the progression of cardiovascular and renal diseases by promoting pro-inflammatory and pro-fibrotic signaling. Recently, it has been found that finerenone, a novel nonsteroidal selective MR antagonist, can robustly improve cardiorenal outcomes in patients with type 2 diabetes (T2D) and a wide spectrum of chronic kidney disease (CKD). However, the mechanisms underlying the cardiorenal benefits of finerenone are poorly understood. Further, whether the clinical benefits are mediated by an improvement in vascular stiffness is not confirmed. Therefore, the current study aims to evaluate the effects of finerenone on vascular stiffness as assessed using cardio ankle vascular index (CAVI) and relevant cardiorenal biomarkers in patients with T2D and CKD. METHODS: The Effects of Finerenone on Vascular Stiffness and Cardiorenal Biomarkers in Type 2 Diabetes and Chronic Kidney Disease (FIVE-STAR) is an ongoing, investigator-initiated, multicenter, prospective, placebo-controlled, double-blind, randomized clinical trial in Japan. Its target sample size is 100 subjects. Recruitment will be performed from September 2023 to July 2024. After obtaining informed consent, eligible participants with T2D and CKD (25 mL/min/1.73 m2 ≤ estimated glomerular filtration ratio [eGFR] < 90 mL/min/1.73 m2 and 30 mg/g Cr ≤ urinary albumin-to-creatinine ratio [UACR] < 3500 mg/g Cr) will be equally randomized to receive 24-week treatment with either finerenone (starting dose at 10 mg once daily in participants with a baseline eGFR < 60 mL/min/1.73 m2 or at 20 mg once daily in those with a baseline eGFR ≥ 60 mL/min/1.73 m2) or dose-matched placebo. The primary endpoint is the change from baseline in CAVI at 24 weeks. The secondary endpoints are changes from baseline in UACR at 12 and 24 weeks and relevant serum and urinary biomarkers at 24 weeks. As an exploratory endpoint, proteomic analysis using the Olink® Target 96 panels will be also performed. DISCUSSION: FIVE-STAR is the first trial evaluating the therapeutic impact of finerenone on vascular stiffness and relevant cardiorenal biomarkers in patients with T2D and CKD. This study will provide mechanistic insights on the clinical benefits of finerenone based on recent cardiovascular and renal outcome trials. Trial registration Unique Trial Number, NCT05887817 ( https://clinicaltrials.gov/ct2/show/NCT05887817 ) and jRCTs021230011 ( https://jrct.niph.go.jp/latest-detail/jRCTs021230011 ).

Sex-Specific Differences in the Risk of Heart Failure following Anti-HER2 Monoclonal Antibody Therapy.

BACKGROUND: Anti-HER2 monoclonal antibody is associated with a greater risk of heart failure (HF) in female breast cancer patients. In recent years, the indication of anti-HER2 monoclonal antibodies was further expanded to stomach, colorectal, and salivary gland cancers regardless of sex in Japan. However, there have been no data on sex difference in the risk of HF after the anti-HER2 monoclonal antibody treatment. OBJECTIVES: We compared the risk of HF between male and female cancer patients treated with anti-HER2 monoclonal antibody using a nationwide population-based database. METHOD: We analyzed 4,608 cancer patients (230 men, median age; 52 years, breast cancer; 4,333) treated with HER2 monoclonal antibody enrolled in the JMDC Claims Database. The primary outcome was the incidence of HF. RESULTS: Over a mean follow-up of 917 ± 835 days, 559 HF events were documented. Kaplan-Meier curves showed no significant difference in the incidence of HF between men and women. Multivariable Cox regression analysis showed that male sex was not associated with a risk of HF compared with women (HR, 0.76; 95% CI: 0.39-1.49). CONCLUSIONS: Our analysis of a nationwide population-based database firstly revealed that no significant sex difference existed in the risk of HF among cancer patients treated with anti-HER2 monoclonal antibody. Our findings suggest that the use of anti-HER2 monoclonal antibodies in male patients may be associated with similar risks observed in female patients.

Canagliflozin reduces proteinuria by targeting hyperinsulinaemia in diabetes patients with heart failure: A post hoc analysis of the CANDLE trial.

AIM: To investigate factors associated with proteinuria regression in patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin. MATERIALS AND METHODS: This study was a post hoc analysis of the CANDLE trial (UMIN000017669), which compared the effect of 24 weeks of treatment with canagliflozin or glimepiride for changes in N-terminal pro-brain natriuretic peptide in patients with T2DM and chronic heart failure (CHF). Factors associated with regression of proteinuria at 24 weeks were evaluated with multivariate logistic models. RESULTS: The rate of regression of proteinuria was higher (28/102, 27.5% vs. 12/112, 10.7%), and that of progression was lower (9/102, 8.8% vs. 26/112, 23.2%), in the canagliflozin versus the glimepiride group (P = .0001). There were no differences in the change in the estimated glomerular filtration rate category between groups. Insulin level, homeostatic model assessment of ß-cell function, homeostatic model assessment for insulin resistance and estimated plasma volume were decreased at 24 weeks in the regression subclass but not in the progression subclass, suggesting that regression of proteinuria is associated with the declines in these values in the canagliflozin group. Higher insulin level at baseline was solely associated with proteinuria regression in the multivariate logistic regression model (baseline insulin, as per a 1-mlU/L increase, odds ratio 1.24 [1.05-1.47], P = .011). CONCLUSIONS: In patients with T2DM and CHF, regression of proteinuria with canagliflozin treatment was associated with the pretreatment insulin level. These results may provide clinicians with novel mechanistic insights into the beneficial effects of canagliflozin on renal outcomes and may warrant discussion for selecting preferred patient profiles, including pretreatment insulin levels.

Association of four health behaviors in Life's Essential 8 with the incidence of hypertension and diabetes mellitus.

BACKGROUND: The association between health behaviors and the risk of developing hypertension and diabetes is not fully understood. We aimed to examine the association between four health behaviors involved in Life's Essential 8, the American Heart Association's key measures for improving and maintaining cardiovascular health, and the incidence of hypertension and diabetes. METHODS: This observational cohort study used the JMDC Claims Database between 2005 and 2021, which is a health check-up and claims database. We analyzed 2,912,183 participants without a history of hypertension, diabetes, cardiovascular disease, or renal failure. Non-ideal health behaviors included smoking, slow gait speed, eating fast, and poor sleep quality. RESULTS: During 1140 ± 877 days, 201,385 hypertension and 142,156 diabetes events were recorded. In a multivariable Cox regression analysis, the risk of hypertension and diabetes increased with an increasing number of non-ideal health behaviors. The hazard ratios (HRs) (95% confidence interval [CI]) per 1-point increase in non-ideal health behavior components for hypertension and diabetes were 1.11 (1.10-1.11) and 1.08 (1.08-1.09), respectively. Each health behavior was independently associated with the incidence of hypertension and diabetes. A 1-point improvement in health behaviors was associated with a lower risk of developing hypertension (HR 0.94, 95% CI 0.93-0.95) and diabetes (HR 0.95, 95% CI 0.94-0.96). CONCLUSION: Factors that can be substituted for the four health behaviors involved in Life's Essential 8 can stratify the risk of hypertension and diabetes, and improving these health behaviors is useful in preventing hypertension and diabetes in general population.

Relationship Between Canagliflozin, Sodium Glucose Cotransporter 2 Inhibitor, and Hematopoietic Effects in Patients With Diabetes and Mild Heart Failure: Results From the CANDLE Trial.

ABSTRACT: There were few clinical studies on the relationship between sodium glucose cotransporter 2 inhibitors (SGLT2i) and hematopoiesis in patients with diabetes (DM) and heart failure (HF) with consideration of systemic volume status. A total of 226 DM patients with HF enrolled in the CANDLE trial, a multicenter, prospective, randomized open-label blinded-endpoint trial, were studied. Estimated plasma volume status (ePVS) was calculated based on a weight- and hematocrit-based formula. At baseline, there was no significant difference in hematocrit and hemoglobin between the canagliflozin (n = 109) and glimepiride (n = 116) groups. Hematocrit and hemoglobin at 24 weeks, changes in hematocrit and hemoglobin difference (24 weeks-baseline), and hematocrit and hemoglobin ratio (24 weeks/baseline) were significantly higher in the canagliflozin than in the glimepiride group, respectively. There was no significant difference in ePVS at baseline and 24 weeks between the 2 groups. After adjustment for baseline parameters, canagliflozin correlated positively with changes in hematocrit and hemoglobin difference, and hematocrit and hemoglobin ratio by multivariate linear regression analyses. The difference in hematocrit and hemoglobin between the 2 groups became statistically significant at 3 and 6 months after randomization. There was no heterogeneity between canagliflozin and the characteristics of the patients for hematocrit and hemoglobin difference and ratio. A correlation of the changes in hematocrit and hemoglobin with cardiac and renal improvement was not observed. In conclusion, canagliflozin was associated with an increased hematocrit and hemoglobin in patients with diabetes and HF regardless of their volume status and characteristics.