Treatment patterns and trajectories in patients after acute heart failure hospitalization.

AIMS: The trajectories of systolic function after admission for acute heart failure (HF) and their effect on clinical outcomes have not been fully elucidated. We aimed to assess changes in left ventricular ejection fraction (LVEF) between the index and 1 year after discharge and to examine their prognostic implications. METHODS AND RESULTS: We extracted data from a prospective multicentre registry of patients hospitalized for acute HF and identified 1636 patients with LVEF data at admission and 1 year after discharge. We categorized them into five groups based on LVEF changes: HF with unchanged-preserved EF [HFunc-pEF (EF ≥ 50%); N = 527, 32.2%], unchanged-mildly reduced EF [HFunc-mrEF (EF 41-49%); N = 86, 5.3%], unchanged-reduced EF [HFunc-rEF (EF ≤ 40%); N = 377, 23.0%], worsened EF (HFworEF; N = 83, 5.1%), and improved EF (HFimpEF; N = 563, 34.4%). We then evaluated the subsequent composite outcome of cardiovascular death and HF readmission. During 1 year after discharge, 53% of patients with HF with reduced EF and 67% of those with HF with mildly reduced EF (HFmrEF) transitioned to other categories, whereas 92% of those with HF with preserved EF (HFpEF) remained within the same category. Patients with HFimpEF were more likely to be younger and had relatively preserved renal function, whereas those with HFworEF were the oldest and had more comorbidities among the five groups. After multivariable adjustment, patients with HFimpEF and HFunc-pEF had a lower risk for composite outcomes when referenced to patients with HFunc-rEF [hazard ratio (95% confidence interval), P-value: 0.28 (0.16-0.49), P < 0.001, and 0.40 (0.25-0.63), P < 0.001, respectively]. Conversely, patients with HFunc-mrEF and HFworEF had a comparable risk [0.44 (0.18-1.07), P = 0.07, and 0.63 (0.29-1.39), P = 0.26, respectively]. CONCLUSIONS: A substantial number of patients with HF experienced transitions to other categories after discharge. Notably, patients with decreased EF experienced a worse prognosis, even with slight decreases (e.g. HFpEF transitioning to HFmrEF). These findings emphasize the significance of longitudinal assessments of systolic function to better manage patients following acute decompensation.

Impact of treatment of hyperkalaemia on quality of life: design of a prospective observational cohort study of long-term management of hyperkalaemia in patients with chronic kidney disease or chronic heart failure in Japan.

INTRODUCTION: Hyperkalaemia (HK) is a frequent complication in patients with chronic kidney disease (CKD) and/or chronic heart failure (CHF). HK must be managed, both to protect patients from its direct clinical adverse outcomes and to enable treatment with disease-modifying therapies including renin-angiotensin-aldosterone system inhibitors. However, the experiences of patients undergoing treatment of HK are not clearly understood. Optimising treatment decisions and improving long-term patient management requires a better understanding of patients' quality of life (QOL). Thus, the aims of this research are: (1) to describe treatment patterns and the impact of treatment on a patient's QOL, (2) to study the relationships between treatment patterns and the impact of treatment on a patient's QOL and (3) to study the relationships between the control of serum potassium (S-K) and the impact of treatment on a patient's QOL, in patients with HK. METHODS AND ANALYSIS: This is a prospective cohort study with 6 months of follow-up in 30-40 outpatient nephrology and cardiology clinics in Japan. The participants will be 350 patients with CKD or CHF who received their first potassium binders (PB) prescription to treat HK within the previous 6 months. Medical records will be used to obtain information on S-K, on treatment of HK with PBs and with diet, and on the patients' characteristics. To assess the impact of treatment on a patient's QOL, questionnaires will be used to obtain generic health-related QOL, CKD-specific and CHF-specific QOL, and PB-specific QOL. Multivariable regression models will be used to quantify how treatment patterns and S-K control are related to the impact of treatment on a patient's QOL. ETHICS AND DISSEMINATION: Institutional review boards at all participating facilities review the study protocol. Patient consent will be obtained. The results will be published in international journals. TRIAL REGISTRATION NUMBER: NCT05297409.

Impact of chronic potassium binder treatment on the clinical outcomes in patients with hyperkalemia: Results of a nationwide hospital-based cohort study.

Introduction: Hyperkalemia (HK) is a common disorder in patients with heart failure or chronic kidney disease, and potassium binders (PBs) are recommended to control serum potassium (S-K) levels. Although HK is often a chronic condition, short-term and intermittent PBs treatment has been largely applied to control S-K levels, and little is known about the impact of long-term and chronic PBs treatment on clinical outcomes. Method: This retrospective cohort study was conducted using a Japanese claims database (April 2008-September 2018). HK was defined as at least two S-K ≥5.1 mmol/L within a 12-month(M) interval. The index date was defined as the initial PB prescription date, and the S-K values were examined at 3M, 6M, and 12M after the index. The medication possession ratio (MPR) was used to evaluate the length of the prescribed period of PB, as prescription refill was not allowed in Japan. Clinical outcomes were analyzed by comparing MPR <80% to MPR ≥80% using Cox proportional hazards regression. Results: We found 4,321 patients with HK and were on initial PB treatments, and 993 and 3,328 patients were categorized in the MPR <80% and MPR ≥80% groups, respectively. The mean prescription days ±SD in the MPR <80% and MPR ≥80% groups were 114.7 ± 9.1 and 1151.2 ± 22.5, respectively. S-K value with adjustment by covariates in MPR <80% and MPR ≥80% groups were 5.62 (95% CI: 5.57-5.68) and 5.72 (95% CI: 5.68-5.76) at index followed by 4.65 (95% CI: 4.58-4.71) and 4.57 (95% CI: 4.51-4.62) at 3M, respectively. The hazard ratios of incidence rates in hospitalization was 1.41 (p < 0.001), introduction of renal replacement therapy was 1.25 (p < 0.003), recurrent HK was 1.67 (p < 0.001), and decreased eGFR was 1.41 (p < 0.001), respectively. Conclusion: These results indicate a higher risk of adverse outcomes when PBs were not prescribed chronically, whereas S-K levels were similarly controlled. Chronic control with continued PBs rather than temporary treatment may be associated with the reduction of adverse clinical outcomes in patients with HK.

Correction: Kohsaka et al. Risk-Benefit Balance of Renin-Angiotensin-Aldosterone Inhibitor Cessation in Heart Failure Patients with Hyperkalemia. J. Clin. Med. 2022, 11, 5828.

In the original publication [...].

Association of Hyperkalemia and Hypokalemia with Patient Characteristics and Clinical Outcomes in Japanese Hemodialysis (HD) Patients.

This study aimed to examine the characteristics and clinical outcomes of Japanese hemodialysis patients with dyskalemia. A retrospective study was conducted using a large Japanese hospital group database. Outpatients undergoing thrice-a-week maintenance hemodialysis were stratified into hyperkalemia, hypokalemia, and normokalemia groups based on their pre-dialysis serum potassium (sK) levels during the three-month baseline period. Baseline characteristics of the three groups were described and compared for the following outcomes during follow-up: all-cause mortality, all-cause hospitalization, major adverse cardiovascular events (MACE), cardiac arrest, fatal arrythmia, and death related to arrhythmia. The study included 2846 eligible patients, of which 67% were men with a mean age of 65.65 (SD: 12.63) years. When compared with the normokalemia group (n = 1624, 57.06%), patients in the hypokalemia group (n = 313, 11.00%) were older and suffered from malnutrition, whereas patients in the hyperkalemia group (n = 909, 31.94%) had longer dialysis vintage. The hazard ratios for all-cause mortality and MACE in the hypokalemia group were 1.47 (95% confidence interval [CI], 1.13-1.92) and 1.48 (95% CI, 1.17-1.86), respectively, whereas that of death related to arrhythmia in the hyperkalemia group was 3.11 (95% CI, 1.03-9.33). Thus, dyskalemia in maintenance hemodialysis patients was associated with adverse outcomes, suggesting the importance of optimized sK levels.

Evolution of sodium-glucose co-transporter 2 inhibitors from a glucose-lowering drug to a pivotal therapeutic agent for cardio-renal-metabolic syndrome.

Cardio-renal-metabolic (CRM) syndrome, which involves type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and heart failure (HF), is a serious healthcare issue globally, with high morbidity and mortality. The disorders that comprise CRM syndrome are independent can mutually affect and accelerate the exacerbation of each other, thereby substantially increasing the risk of mortality and impairing quality of life. To manage CRM syndrome by preventing vicious interactions among individual disorders, a holistic treatment approach that can simultaneously address multiple disorders underpinning CRM syndrome is of great importance. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) lower blood glucose levels by inhibiting glucose reabsorption in the renal proximal tubule and were first indicated for the treatment of T2DM. Several cardiovascular outcome trials have demonstrated that SGLT2i not only lower blood glucose but also reduce the risk of hospitalization for HF and worsening renal function in patients with T2DM. Results have also suggested that the observed cardiorenal benefits of SGLT2i may be independent of their blood glucose-lowering effects. Several randomized controlled trials subsequently assessed the efficacy and safety of SGLT2i in patients without T2DM, and revealed considerable benefits of SGLT2i treatment against HF and CKD, regardless of the presence of T2DM. Thus, SGLT2i have become an essential therapeutic option to prevent the onset, slow the progression, and improve the prognosis of CRM syndrome. This review assesses the evolution of SGLT2i from a glucose-lowering drug to a therapeutic agent for CRM syndrome by evaluating epoch-making clinical studies, including randomized control trials and real-world studies.

Clinical impact of suboptimal RAASi therapy following an episode of hyperkalemia.

BACKGROUND: Hyperkalemia (HK) is a barrier to optimization of renin-angiotensin-aldosterone system inhibitor (RAASi) therapy in heart failure (HF) and chronic kidney disease (CKD). We investigated cardiorenal risk associated with changes in RAASi regimen after an episode of HK in patients with HF and/or CKD. METHODS: This observational study utilized data from hospital records, claims, and health registers from the US (Optum's de-identified Market Clarity Data) and Japan (Medical Data Vision). Included patients had an index episode of HK between July 2019 and September 2021 (US), or May 2020 and September 2021 (Japan), with prior diagnosis of HF or CKD (stage 3 or 4), and RAASi use. Risk of a cardiorenal composite outcome (HF emergency visit, HF hospitalization, or progression to end-stage kidney disease) was determined in patients who discontinued RAASi, down-titrated their dose by > 25%, or maintained or up-titrated their dose following the HK episode. RESULTS: A total of 15,488 and 6020 patients were included from the US and Japan, respectively. Prior to the episode of HK, 59% (US) and 27% (Japan) of patients had achieved > 50% target RAASi dose. Following the episode of HK, 33% (US) and 32% (Japan) of patients did not fill a new RAASi prescription. Risk of the cardiorenal outcome at 6 months was higher in patients who discontinued or down-titrated versus maintained or up-titrated RAASi treatment both in the US (17.5, 18.3, and 10.6%; p <  0.001) and in Japan (19.7, 20.0, and 15.1%; p <  0.001). CONCLUSION: HK-related RAASi discontinuation or down-titration was associated with higher risk of cardiorenal events versus maintained or up-titrated RAASi.

[Andexanet alfa (ONDEXXYA® for Intravenous Injection 200†mg), a reversal agent for direct factor Xa inhibitors: pharmacological characteristics and clinical evidence].

Andexanet alfa is a modified recombinant human factor Xa (FXa) that was designed to serve as a binding target for FXa inhibitors as decoy protein. It sequesters FXa inhibitors from binding to endogenous FXa, thereby reversing anticoagulant effect of FXa inhibitors. Andexanet alfa has been approved in March 2022 in Japan for patients with life-threatening or uncontrolled bleeding while on treatment with a FXa inhibitor, apixaban, rivaroxaban, or edoxaban tosilate hydrate. It is administered via two dosing regimens, based on the type of FXa inhibitor, dose, and time since the last dose. In nonclinical studies, andexanet alfa significantly inhibited bleeding induced by FXa inhibitors in animal bleeding models. In the development for Japanese patients, the following two clinical studies have been conducted to confirm the efficacy and safety. First, safety and the reversal effect of andexanet alfa on the FXa inhibitor-mediated anticoagulant activity in healthy adults were confirmed in the overseas phase 2 study including Japanese subjects. Next, the reversal effect of andexanet alfa on the anticoagulation activity and the hemostasis were demonstrated in patients with acute major bleeding while on FXa inhibitor treatment in the global phase 3b/4 study (ANNEXA-4 study). The subgroup analysis of Japanese population showed that the efficacy and safety results were consistent with those of overall population. Andexanet alfa is the first approved reversal agent for FXa inhibitors in Japan and is expected to contribute to the improvement of prognosis in patients with fatal and/or uncontrolled bleeding by timely reversing anticoagulant effect of FXa inhibitors.

Health Care Cost Analysis of PPI or P-CAB-First Treatment in Patients With Gastroesophageal Reflux Disease.

GOALS: The aim was to examine actual health care cost in patients with gastroesophageal reflux disease (GERD) who were initiated on proton pump inhibitor (PPI) or potassium-competitive acid blocker (P-CAB) as first-line therapy in Japanese real-world clinical settings. BACKGROUND: To date, cost-utility evaluation of acid-suppressants treatment in Japan has only been conducted by model analysis. STUDY: A cost utilization analysis was performed using a Japanese nationwide hospital-based claim database by extracting patients with GERD initiated on either PPI or P-CAB (242,102 pairs) and esomeprazole (EPZ) or P-CAB (241,825 pairs). Health care costs were compared in each comparison cohort with propensity-score matched pairs. The switching rates of initial acid-suppressants were also examined. RESULTS: Baseline characteristics were well-balanced after matching. The 3-year mean cumulative GERD-related and hospitalization costs per patient were ¥142,620 and ¥122,444 in PPI-first and P-CAB-first treatment groups, and ¥105,263 and ¥121,958 in EPZ-first and P-CAB-first treatment groups, respectively. Most hospitalization costs were non-GERD related in all the groups. The switching rates of PPI to P-CAB and P-CAB to PPI in 12 months were 7.5% and 20.2%, respectively. CONCLUSIONS: In this propensity-score matched analysis, health care cost was higher in patients with GERD initiated on PPI than in those initiated on P-CAB mainly owing to non-GERD-related hospitalization cost, whereas it was lower in those initiated on EPZ than in those initiated on P-CAB. When considering health care costs except hospitalization costs, PPI-first treatment was less expensive than P-CAB-first treatment. Low switching rate from PPI to P-CAB in the real-world practice may partially explain the discrepancy.

Validation of a new instrument for measuring disease-specific quality of life: A pilot study among patients with chronic kidney disease and hyperkalemia.

BACKGROUND: To prepare for a longitudinal study of the effects of potassium-lowering treatment on quality of life (QOL), we quantified the validity of a new disease-specific instrument for measuring QOL, using data from patients who had hyperkalemia (HK) due to chronic kidney disease (CKD) or chronic heart failure, and were also being treated with potassium binders (PBs). METHODS: In this cross-sectional study, the participants were 98 patients at five outpatient clinics in Japan. The outcome measures were the Medical Outcomes Study 36-item short-form (SF-36), a widely used generic measure of QOL, and the Quality of Life Disease-specific Impact Scale (QDIS-7), a recently-developed disease-specific measure of QOL. Internal-consistency reliability was quantified, and factor analysis was done to confirm hypothesized QOL dimensions. Validation tests used two external criteria: CKD stage, and PB formulation. PB formulation was used because different formulations are associated with different degrees of patients' burden. Using a previously-described method, we computed the relative validity (RV) of the two measures. RESULTS: Two factor scoring of the SF-36 and one factor scoring of the QDIS-7, as standardized from previous studies, were confirmed. The RVs showed that the QDIS-7 was much more valid than the SF-36, for discriminating between groups defined clinically (by CKD stage), and also between groups defined by PB formulation. Reliability was satisfactory: 0.73-0.95 for the SF-36 and 0.86 for the QDIS-7. CONCLUSIONS: The QDIS-7 with CKD or PB attributions was more valid than the SF-36 for measuring the effects of CKD and of PB formulation on QOL.

Machine learning models for prediction of HF and CKD development in early-stage type 2 diabetes patients.

Chronic kidney disease (CKD) and heart failure (HF) are the first and most frequent comorbidities associated with mortality risks in early-stage type 2 diabetes mellitus (T2DM). However, efficient screening and risk assessment strategies for identifying T2DM patients at high risk of developing CKD and/or HF (CKD/HF) remains to be established. This study aimed to generate a novel machine learning (ML) model to predict the risk of developing CKD/HF in early-stage T2DM patients. The models were derived from a retrospective cohort of 217,054 T2DM patients without a history of cardiovascular and renal diseases extracted from a Japanese claims database. Among algorithms used for the ML, extreme gradient boosting exhibited the best performance for CKD/HF diagnosis and hospitalization after internal validation and was further validated using another dataset including 16,822 patients. In the external validation, 5-years prediction area under the receiver operating characteristic curves for CKD/HF diagnosis and hospitalization were 0.718 and 0.837, respectively. In Kaplan-Meier curves analysis, patients predicted to be at high risk showed significant increase in CKD/HF diagnosis and hospitalization compared with those at low risk. Thus, the developed model predicted the risk of developing CKD/HF in T2DM patients with reasonable probability in the external validation cohort. Clinical approach identifying T2DM at high risk of developing CKD/HF using ML models may contribute to improved prognosis by promoting early diagnosis and intervention.

Machine Learning Models Predicting Cardiovascular and Renal Outcomes and Mortality in Patients with Hyperkalemia.

Hyperkalemia is associated with increased risks of mortality and adverse clinical outcomes. The treatment of hyperkalemia often leads to the discontinuation or restriction of beneficial but potassium-increasing therapy such as renin-angiotensin-aldosterone inhibitors (RAASi) and high-potassium diet including fruits and vegetables. To date, limited evidence is available for personalized risk evaluation in this heterogeneous and multifactorial pathophysiological condition. We developed risk prediction models using extreme gradient boosting (XGB), multiple logistic regression (LR), and deep neural network. Models were derived from a retrospective cohort of hyperkalemic patients with either heart failure or chronic kidney disease stage ≥3a from a Japanese nationwide database (1 April 2008−30 September 2018). Studied outcomes included all-cause death, renal replacement therapy introduction (RRT), hospitalization for heart failure (HHF), and cardiovascular events within three years after hyperkalemic episodes. The best performing model was further validated using an external cohort. A total of 24,949 adult hyperkalemic patients were selected for model derivation and internal validation. A total of 1452 deaths (16.6%), 887 RRT (10.1%), 1,345 HHF (15.4%), and 621 cardiovascular events (7.1%) were observed. XGB outperformed other models. The area under receiver operator characteristic curves (AUROCs) of XGB vs. LR (95% CIs) for death, RRT, HHF, and cardiovascular events were 0.823 (0.805−0.841) vs. 0.809 (0.791−0.828), 0.957 (0.947−0.967) vs. 0.947 (0.936−0.959), 0.863 (0.846−0.880) vs. 0.838 (0.820−0.856), and 0.809 (0.784−0.834) vs. 0.798 (0.772−0.823), respectively. In the external dataset including 86,279 patients, AUROCs (95% CIs) for XGB were: death, 0.747 (0.742−0.753); RRT, 0.888 (0.882−0.894); HHF, 0.673 (0.666−0.679); and cardiovascular events, 0.585 (0.578−0.591). Kaplan−Meier curves of the high-risk predicted group showed a statistically significant difference from that of the low-risk predicted groups for all outcomes (p < 0.005; log-rank test). These findings suggest possible use of machine learning models for real-world risk assessment as a guide for observation and/or treatment decision making that may potentially lead to improved outcomes in hyperkalemic patients while retaining the benefit of life-saving therapies.

Risk-Benefit Balance of Renin-Angiotensin-Aldosterone Inhibitor Cessation in Heart Failure Patients with Hyperkalemia.

Background: Whether to continue renin−angiotensin−aldosterone system inhibitor (RAASi) therapy in patients with hyperkalemia remains a clinical challenge, particularly in patients with heart failure (HF), where RAASis remain the cornerstone of treatment. We investigated the incidence of dose reduction or the cessation of RAASis and evaluated the threshold of serum potassium at which cessation alters the risk−benefit balance. Methods: This retrospective analysis of a Japanese nationwide claims database investigated treatment patterns of RAASis over 12 months after the initial hyperkalemic episode. The incidences of the clinical outcomes of patients with RAASi (all ACEi/ARB/MRA) or MRA-only cessation (vs. non-cessation) were compared via propensity score-matched patients. A cubic spline regression analysis assessed the hazard of death resulting from treatment cessation vs. no cessation at each potassium level. Results: A total of 5059 hyperkalemic HF patients were identified; most received low to moderate doses of ACEis and ARBs (86.9% and 71.5%, respectively) and low doses of MRAs (76.2%). The RAASi and MRA cessation rates were 34.7% and 52.8% at 1 year post-diagnosis, while the dose reduction rates were 8.4% and 6.5%, respectively. During the mean follow-up of 2.8 years, patients who ceased RAASi or MRA therapies were at higher risk for adverse outcomes; cubic spline analysis found that serum potassium levels of <5.9 and <5.7 mmol/L conferred an increased mortality risk for RAASi and MRA cessation, respectively. Conclusions: Treatment cessation/dose reduction of RAASis are common among HF patients. The risks of RAASi/MRA cessation may outweigh the benefits in patients with mild to moderate hyperkalemia.

Changes in Treatment Satisfaction Over 3 Years in Patients With Type 2 Diabetes After Initiating Second-line Treatment.

CONTEXT: J-DISCOVER is a prospective observational cohort study aiming to understand the current management of patients with early-stage type 2 diabetes mellitus (T2DM) in Japan, enrolling patients initiating second-line treatment. OBJECTIVE: The current analysis examined the change in treatment satisfaction during the study period and factors affecting this change among patients in J-DISCOVER. METHODS: We used data from the J-DISCOVER study, in which 1798 patients with T2DM aged ≥ 20 years were enrolled from 142 sites across Japan. Treatment satisfaction was assessed using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). RESULTS: The mean DTSQ treatment satisfaction score increased from 25.9 points at baseline to 27.3 points at 6 months, which was maintained through 36 months. Among the baseline characteristics examined, higher baseline DTSQ treatment satisfaction scores (P < 0.0001), older age (≥ 75 vs < 65 years, P = 0.0096), living alone (P = 0.0356), and type of facility (clinics vs hospitals, P = 0.0044) had a significantly negative impact on the changes in DTSQ treatment satisfaction scores. Improvement in mean glycated hemoglobin (HbA1c) from baseline (7.7%) to 36 months (7.1%) was associated with positive changes in the DTSQ treatment satisfaction score (P = 0.0003). CONCLUSION: Changes in DTSQ treatment satisfaction scores were related to HbA1c improvement, suggesting that the management strategy was appropriately planned for each patient. The results also suggest that the availability of social support for patients with T2DM who are elderly or living alone may be an important factor affecting treatment satisfaction, adherence, and clinical outcomes.

Cost-Effectiveness Analysis of Initiating Type 2 Diabetes Therapy with a Sodium-Glucose Cotransporter 2 Inhibitor Versus Conventional Therapy in Japan.

INTRODUCTION: Many patients with type 2 diabetes mellitus (T2DM) suffer from complications that impose substantial burdens on prognosis and medical costs. Accumulating evidence has demonstrated the clinical benefit of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular and renal complications. However, the health economic impact of SGLT2i remains unclear. The aim of this study was to evaluate the cost-effectiveness of initiating antidiabetic therapy with an SGLT2i using Japanese real-world data. METHODS: We constructed a natural history model incorporating heart failure (HF), myocardial infarction, stroke, chronic kidney disease, and end-stage renal disease (ESRD) as complications. The target population comprised patients with T2DM who newly initiated their first oral glucose-lowering drugs. By using a population-based microsimulation, we estimated the 10-year medical costs in Japanese yen (JPY) and outcomes (hospitalization for/development of complications and quality-adjusted life years [QALY]) for patients who initiated antidiabetic therapy with an SGLT2i or conventional therapy. Sensitivity analyses included a probabilistic sensitivity analysis (PSA) with 1,000,000 iterations. RESULTS: In the base-case analysis, the total medical cost per person was JPY 1,638,806 versus JPY 1,825,033 and the QALYs were 8.732 versus 8.513 for the SGLT2i strategy versus the conventional strategy, respectively. Thus, initiating treatment with an SGLT2i was dominant, more effective (QALY gain), and lower cost. When treating 10,000 patients, the SGLT2i strategy would reduce all-cause deaths by 410 (552 vs 962), HF events by 201 (897 vs 1098), and ESRD events by 16 (16 vs 32) versus the conventional strategy. The PSA revealed that the probability of dominance for initiating SGLT2i therapy was 90.5%, demonstrating the robustness of the results. CONCLUSION: Our results suggest that initiating T2DM treatment with SGLT2i, aimed at managing cardiovascular and renal complications from the early stages of diabetes, can improve the clinical outcome and reduce cost burden of T2DM.

Cost of healthcare utilization associated with incident cardiovascular and renal disease in individuals with type 2 diabetes: A multinational, observational study across 12 countries.

AIM: To examine how the development of cardiovascular and renal disease (CVRD) translates to hospital healthcare costs in individuals with type 2 diabetes (T2D) initially free from CVRD. METHODS: Data were obtained from the digital healthcare systems of 12 nations using a prespecified protocol. A fixed country-specific index date of 1 January was chosen to secure sufficient cohort disease history and maximal follow-up, varying between each nation from 2006 to 2017. At index, all individuals were free from any diagnoses of CVRD (including heart failure [HF], chronic kidney disease [CKD], coronary ischaemic disease, stroke, myocardial infarction [MI], or peripheral artery disease [PAD]). Outcomes during follow-up were hospital visits for CKD, HF, MI, stroke, and PAD. Hospital healthcare costs obtained from six countries, representing 68% of the total study population, were cumulatively summarized for CVRD events occurring during follow-up. RESULTS: In total, 1.2 million CVRD-free individuals with T2D were identified and followed for 4.5 years (mean), that is, 4.9 million patient-years. The proportion of individuals indexed before 2010 was 18% (n = 207 137); 2010-2015, 31% (361 175); and after 2015, 52% (609 095). Overall, 184 420 (15.7%) developed CVRD, of which cardiorenal disease was most frequently the first disease to develop (59.7%), consisting of 23.0% HF and 36.7% CKD, and more common than stroke (16.9%), MI (13.7%), and PAD (9.7%). The total cumulative cost for CVRD was US$1 billion, of which 59.0% was attributed to cardiorenal disease, 3-, 5-, and 6-fold times greater than the costs for stroke, MI, and PAD, respectively. CONCLUSION: Across all nations, HF or CKD was the most frequent CVRD manifestation to develop in a low-risk population with T2D, accounting for the highest proportion of hospital healthcare costs. These novel findings highlight the importance of cardiorenal awareness when planning healthcare.

Manifestation of Heart Failure and Chronic Kidney Disease are Associated with Increased Mortality Risk in Early Stages of Type 2 Diabetes Mellitus: Analysis of a Japanese Real-World Hospital Claims Database.

INTRODUCTION: To assess the initial manifestation of comorbidities and their impact on mortality risk in patients with type 2 diabetes mellitus (T2DM) without a history of cardiovascular or renal complications (i.e., in the early stages of T2DM) compared with patients without T2DM. METHODS: We performed a retrospective cohort study using a Japanese hospital claims database. The incidence rates of comorbidities (chronic kidney disease [CKD], heart failure [HF], myocardial infarction [MI], peripheral arterial disease [PAD], and stroke) and mortality risk were compared between patients with T2DM and age-/sex-matched patients without T2DM (matched 1:2). RESULTS: Among the comorbidities assessed in this study, CKD and/or HF was the most frequent initial manifestation in the patients with T2DM (n = 426,186) with an incidence rate 2.02 times greater than that in matched patients without T2DM (n = 1,018,609). The mortality risk was also greater in patients with T2DM than in patients without T2DM with a hazard ratio of 1.73. In both patients with and without T2DM, the presence of CKD or HF was associated with greater mortality risks compared with the presence of MI, PAD, or stroke. CONCLUSIONS: The high incidence of CKD or HF manifestation can contribute to the augmented mortality risk in patients in the early stages of T2DM compared with patients without T2DM. These findings highlight the importance of early interventions for preventing/treating CKD and HF to improve the prognosis of patients with T2DM.

Three-Year Glycaemic Control and Management in Patients with Type 2 Diabetes Initiating Second-Line Treatment in Japan: A Prospective Observational Study, J-DISCOVER.

INTRODUCTION: J-DISCOVER is a prospective, observational cohort study that aimed to understand characteristics, glycaemic control, comorbidities and real-world management of patients with early-stage type 2 diabetes mellitus (T2DM) in Japan, by enrolling patients initiating second-line treatment from both diabetes specialist and non-specialist care settings. METHODS: As part of the global DISCOVER programme, J-DISCOVER enrolled 1798 patients with T2DM aged at least 20 years old from 142 sites across Japan, from September 2014 to December 2015, and followed these patients for 3 years. Glycaemic control, body mass index (BMI), blood pressure, lipid profiles, treatment patterns, and prevalence of CKD and retinopathy were examined from baseline to 6, 12, 24 and 36 months, stratified by class of second-line treatment. RESULTS: At baseline, the median time after T2DM diagnosis was 3.1 years and mean glycated haemoglobin (HbA1c) was 7.7%. The mean individualized HbA1c target was 6.7 ± 0.5%, and 55.3% of patients were set the target of < 7.0%. HbA1c reductions were noted from 6 months and mean HbA1c was 7.1% at 36 months. The proportion of patients with HbA1c < 7.0% increased from 28.8% at baseline to 53.3% at 36 months, and the achievement rate of individualized HbA1c targets increased from 6.1% to 30.3%. Only two cases of severe hypoglycaemia occurred during the study. No major changes in BMI, blood pressure, lipid profile or prescription of antihypertensive or dyslipidaemia medications were observed. The frequencies of screening to detect retinopathy and chronic kidney disease (CKD) were 17.0-21.0% and 14.5-16.0%, respectively, during the follow-up period. The prevalence of CKD, but not retinopathy, increased over the follow-up period. CONCLUSIONS: This study provided an overview of the 3-year management of early-stage T2DM in patients initiating second-line treatment. Contemporary management improved glycaemic control with an acceptable risk-benefit balance, although hurdles remain to sufficient implementation of guideline-recommended treatments in current clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02226822.

Cardiovascular and Renal Outcomes Associated With Hyperkalemia in Chronic Kidney Disease: A Hospital-Based Cohort Study.

OBJECTIVE: To examine the association between hyperkalemia and long-term cardiovascular and renal outcomes in patients with chronic kidney disease. PATIENTS AND METHODS: An observational retrospective cohort study was performed using a Japanese hospital claims registry, Medical Data Vision (April 1, 2008, to September 30, 2018). Of 1,208,894 patients with at least 1 potassium measurement, 167,465 patients with chronic kidney disease were selected based on International Classification of Diseases, Tenth Revision codes or estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2. Hyperkalemia was defined as at least 2 potassium measurements of 5.1 mmol/L or greater within 12 months. Normokalemic controls were patients without a record of potassium levels of 5.1 mmol/L or greater and 3.5 mmol/L or less. Changes in eGFRs and hazard ratios of death, hospitalization for cardiac events, heart failure, and renal replacement therapy introduction were assessed between propensity score-matched hyperkalemic patients and normokalemic controls. RESULTS: Of 16,133 hyperkalemic patients and 11,898 normokalemic controls eligible for analyses, 5859 (36.3%) patients and 5859 (49.2%) controls were selected after propensity score matching. The mean follow-up period was 3.5 years. The 3-year eGFR change in patients and controls was -5.75 and -1.79 mL/min/1.73 m2, respectively. Overall, hyperkalemic patients had higher risks for death, hospitalization for cardiac events, heart failure, and renal replacement therapy introduction than controls, with hazard ratios of 4.40 (95% CI, 3.74 to 5.18), 1.95 (95% CI, 1.59 to 2.39), 5.09 (95% CI, 4.17 to 6.21), and 7.54 (95% CI, 5.73 to 9.91), respectively. CONCLUSION: Hyperkalemia was associated with significant risks for mortality and adverse clinical outcomes, with more rapid decline of renal function. These findings underscore the significance of hyperkalemia as a predisposition to future adverse events in patients with chronic kidney disease.

Current trends in diabetes mellitus database research in Japan.

With the widespread use of electronic medical records and administrative claims databases, analytic results from so-called real-world data have become increasingly important in healthcare decision-making. Diabetes mellitus is a heterogeneous condition that involves a broad spectrum of patients. Real-world database studies have been recognised as a powerful tool to understand the impact of current practices on clinical courses and outcomes, such as long-term glucose control, development of microvascular or macro-vascular diseases, and mortality. Diabetes is also a major global health issue and poses a significant social and economic burden worldwide. Therefore, it is critical to understand the epidemiology, clinical course, treatment reality, and long-term outcomes of diabetes to determine realistic solutions to a variety of disease-related issues that we are facing. In the present review, we summarise the healthcare system and large-scale databases currently available in Japan, introduce the results from recent database studies involving Japanese patients with diabetes, and discuss future opportunities and challenges for the use of databases in the management of diabetes.