Randomised, blinded, cross-over evaluation of the palatability of and preference for different potassium binders in participants with chronic hyperkalaemia in the USA, Canada and Europe: the APPETIZE study.

OBJECTIVES: Traditional potassium (K+) binders for treating hyperkalaemia are unpalatable and poorly tolerated. Newer K+ binders are reportedly better tolerated; however, no published data describe their palatability, a determinant of long-term adherence. This study evaluated the palatability of and preference for three K+ binders: sodium and calcium polystyrene sulfonate (S/CPS), sodium zirconium cyclosilicate (SZC) and calcium patiromer sorbitex (patiromer). DESIGN: Phase 4, randomised, participant-blinded, cross-over study. Participants were randomised to one of six taste sequences and, using a 'sip and spit' approach, tasted each K+ binder before completing a survey. SETTING: 17 centres across the USA, Canada and European Union. PARTICIPANTS: 144 participants with chronic kidney disease, hyperkalaemia and no recent use of K+ binders. MAIN OUTCOME MEASURES: For the primary (USA) and key secondary (Canada and European Union) endpoints, participants rated palatability attributes (taste, texture, smell and mouthfeel) and willingness to take each K+ binder on a scale of 0-10 (rational evaluation). Feelings about each attribute, and the idea of taking the product once daily, were evaluated using a non-verbal, visual measure of emotional response. Finally, participants ranked the K+ binders according to palatability. RESULTS: In each region, SZC and patiromer outperformed S/CPS on overall palatability (a composite of taste, texture, smell and mouthfeel), based on rational evaluation and emotional response. Taking the product once daily was more appealing for SZC and patiromer, creating greater receptivity than the idea of taking S/CPS. The emotional response to mouthfeel had the strongest influence on feelings about taking each product. In each region, a numerically greater proportion of participants ranked SZC as the most preferred K+ binder versus patiromer or S/CPS. CONCLUSIONS: Preference for more palatable K+ binders such as SZC and patiromer may provide an opportunity to improve adherence to long-term treatment of hyperkalaemia. TRIAL REGISTRATION NUMBER: NCT04566653.

Prevalence of undiagnosed stage 3 chronic kidney disease in France, Germany, Italy, Japan and the USA: results from the multinational observational REVEAL-CKD study.

OBJECTIVES: REVEAL-CKD aims to estimate the prevalence of, and factors associated with, undiagnosed stage 3 chronic kidney disease (CKD). DESIGN: Multinational, observational study. SETTING: Data from six country-specific electronic medical records and/or insurance claims databases from five countries (France, Germany, Italy, Japan and the USA [two databases]). PARTICIPANTS: Eligible participants (≥18 years old) had ≥2 consecutive estimated glomerular filtration rate (eGFR) measurements (calculated from serum creatinine values, sex and age) taken from 2015 onwards that were indicative of stage 3 CKD (≥30 and <60 mL/min/1.73 m2). Undiagnosed cases lacked an International Classification of Diseases 9/10 diagnosis code for CKD (any stage) any time before, and up to 6 months after, the second qualifying eGFR measurement (study index). MAIN OUTCOME MEASURES: The primary outcome was point prevalence of undiagnosed stage 3 CKD. Time to diagnosis was assessed using the Kaplan-Meier approach. Factors associated with lacking a CKD diagnosis and risk of diagnostic delay were assessed using logistic regression adjusted for baseline covariates. RESULTS: The prevalence of undiagnosed stage 3 CKD was 95.5% (19 120/20 012 patients) in France, 84.3% (22 557/26 767) in Germany, 77.0% (50 547/65 676) in Italy, 92.1% (83 693/90 902) in Japan, 61.6% (13 845/22 470) in the US Explorys Linked Claims and Electronic Medical Records Data database and 64.3% (161 254/250 879) in the US TriNetX database. The prevalence of undiagnosed CKD increased with age. Factors associated with undiagnosed CKD were female sex (vs male, range of odds ratios across countries: 1.29-1.77), stage 3a CKD (vs 3b, 1.81-3.66), no medical history (vs a history) of diabetes (1.26-2.77) or hypertension (1.35-1.78). CONCLUSIONS: There are substantial opportunities to improve stage 3 CKD diagnosis, particularly in female patients and older patients. The low diagnosis rates in patients with comorbidities that put them at risk of disease progression and complications require attention. TRIAL REGISTRATION: NCT04847531.

Epidemiology and outcomes in patients with anemia of CKD not on dialysis from a large US healthcare system database: a retrospective observational study.

BACKGROUND: Optimal management of anemia of chronic kidney disease (CKD) remains controversial. This retrospective study aimed to describe the epidemiology and selected clinical outcomes of anemia in patients with CKD in the US. METHODS: Data were extracted from Henry Ford Health System databases. Adults with stages 3a-5 CKD not on dialysis (estimated glomerular filtration rate < 60 mL/min/1.73m2) between January 1, 2013 and December 31, 2017 were identified. Patients on renal replacement therapy or with active cancer or bleeding were excluded. Patients were followed for ≥12 months until December 31, 2018. Outcomes included incidence rates per 100 person-years (PY) of anemia (hemoglobin < 10 g/dL), renal and major adverse cardiovascular events, and of bleeding and hospitalization outcomes. Adjusted Cox proportional hazards models identified factors associated with outcomes after 1 and 5 years. RESULTS: Among the study cohort (N = 50,701), prevalence of anemia at baseline was 23.0%. Treatments used by these patients included erythropoiesis-stimulating agents (4.1%), iron replacement (24.2%), and red blood cell transfusions (11.0%). Anemia incidence rates per 100 PY in patients without baseline anemia were 7.4 and 9.7 after 1 and 5 years, respectively. Baseline anemia was associated with increased risk of renal and major cardiovascular events, hospitalizations (all-cause and for bleeding), and transfusion requirements. Increasing CKD stage was associated with increased risk of incident anemia, renal and major adverse cardiovascular events, and hospitalizations. CONCLUSIONS: Anemia was a prevalent condition associated with adverse renal, cardiovascular, and bleeding/hospitalization outcomes in US patients with CKD. Anemia treatment was infrequent.

Investigating the global prevalence and consequences of undiagnosed stage 3 chronic kidney disease: methods and rationale for the REVEAL-CKD study.

Background: Timely diagnosis and treatment of stage 3 chronic kidney disease (CKD) can prevent further loss of kidney function and progression to kidney failure. However, contemporary data on the global prevalence of undiagnosed stage 3 CKD are scarce. REVEAL-CKD is a multinational, multifocal and observational study aiming to provide insights into undiagnosed stage 3 CKD in a large population. Methods: Patients (aged ≥18 years) with data in selected secondary databases from 11 countries will be included if they have at least two estimated glomerular filtration rate (eGFR) measurements from 2015 onwards that are ≥30 and <60 mL/min/1.73 m2, recorded >90 and ≤730 days apart. Undiagnosed cases are those without an International Classification of Diseases 9/10 diagnosis code for CKD (any stage) any time before and up to 6 months after the second qualifying eGFR measurement. Time to diagnosis will be assessed using a Kaplan-Meier approach; patient characteristics associated with undiagnosed CKD will be assessed using adjusted logistical regression analyses. Results: REVEAL-CKD will assess the point prevalence of undiagnosed stage 3 CKD and time to CKD diagnosis in initially undiagnosed cases overall and in individual countries. Trends in undiagnosed CKD prevalence by calendar year will be assessed. Patient characteristics, healthcare resource utilization, adverse clinical outcomes, and CKD management and monitoring practices in patients with versus without a CKD diagnosis will be compared. Conclusions: REVEAL-CKD will increase awareness of the global clinical and economic burden of undiagnosed stage 3 CKD and provide valuable insights to inform clinical practice and policy changes.

Understanding Patient Perspectives of the Impact of Anemia in Chronic Kidney Disease: A United States Patient Survey.

Anemia in chronic kidney disease (CKD) is associated with reduced health-related quality of life and physical functioning. This study investigated knowledge and awareness of anemia in patients with CKD in the United States (US) through an online, quantitative survey administered to patients aged ≥18 years with self-reported CKD, with or without anemia. Of 446 patients included, 255 (57.2%) were diagnosed with anemia and 191 (42.8%) were in the non-anemia cohort. In patients with anemia, 71.0% were aware of the relationship between CKD and anemia versus 52.9% in the non-anemia cohort. In the anemia cohort, 46.3% of patients were aware of their hemoglobin level, versus 27.2% in the non-anemia cohort. Despite 67.4% of patients with anemia believing their condition was well/very well managed, only 50% reported being informed about different treatments without prompting healthcare providers. In the US, patients with anemia and CKD perceived that anemia had a negative impact on physical health and emotional wellbeing. Results emphasize a lack of disease awareness, suggesting patients would benefit from further education on anemia in CKD.

Contemporary outcomes of anemia in US patients with chronic kidney disease.

BACKGROUND: Long-term clinical outcome data from patients with non-dialysis-dependent (NDD) chronic kidney disease (CKD) are lacking. We characterized patients with NDD-CKD and anemia using real-world data from the USA. METHODS: This retrospective longitudinal observational study evaluated integrated Limited Claims and Electronic Health Record Data (IBM Health, Armonk, NY), including patients ≥18 years with two or more estimated glomerular filtration rate (eGFR) measures <60 mL/min/1.73 m2 ≥90 days apart. Anemia was defined as the first observed hemoglobin <10 g/dL within 6-month pre- and post-CKD index date. Data were analyzed from January 2012 to June 2018. Patients with documented iron-deficiency anemia at baseline were excluded. RESULTS: Comprising 22 720 patients (57.4% female, 63.9% CKD stage 3, median hemoglobin 12.5 g/dL), median (interquartile range) follow-up for patients with and without anemia were 2.9 (1.5-4.4) and 3.8 (2.2-4.8) years, respectively. The most prevalent comorbidities were dyslipidemia (57.6%), type 2 diabetes mellitus (38.8%) and uncontrolled hypertension (20.0%). Overall, 23.3% of patients had anemia, of whom 1.9% and <0.1% received erythropoiesis-stimulating agents (ESAs) or intravenous iron, respectively. Anemia prevalence increased with CKD stage from 18.2% (stage 3a) to 72.8% (stage 5). Patients with anemia had a higher incidence rate of hospitalizations for heart failure (1.6 versus 0.8 per 100 patient-years), CKD stage advancement (43.5 versus 27.5 per 100 patient-years), and a 40% eGFR decrease (18.1 versus 7.3 per 100 patient-years) versus those without anemia. CONCLUSIONS: Anemia, frequently observed in NDD-CKD and associated with adverse clinical outcomes, is rarely treated with ESAs and intravenous iron. These data suggest that opportunities exist for improved anemia management in patients with NDD-CKD.

Lifetime cost-effectiveness simulation of once-weekly exenatide in type 2 diabetes: A cost-utility analysis based on the EXSCEL trial.

AIMS: The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial assessed once-weekly exenatide (EQW) vs. placebo, added to usual care in 14,752 patients with type 2 diabetes mellitus (Clinicaltrials.gov: NCT01144338). We assessed the lifetime cost-effectiveness of adding EQW vs. usual care alone from a healthcare perspective. METHODS: Medical resource use and EQ-5D utilities were collected throughout the study. Within-trial results were extrapolated to a lifetime horizon using the UK Prospective Diabetes Study Outcomes Model version 2 (UKPDS-OM2), predicting predict cardiovascular and microvascular events. Cost-effectiveness was evaluated separately for US and UK settings, with outcomes measured in quality-adjusted life-years (QALYs). RESULTS: EQW plus usual care gained 0.162 QALYs at an additional cost of $41,545/patient, compared with usual care in a US setting. The incremental cost-effectiveness ratio (ICER) was $259,223/QALY. In a UK setting, the QALY gain was 0.151 at an additional cost of £6357: an ICER of £42,589/QALY. Sensitivity analyses ranged between $34,369-$269,571 and £3430-£46,560 per QALY gained. CONCLUSIONS: In a lifetime extrapolation, adding EQW to usual care increased QALYs and costs compared with usual care alone. The base-case ICERs exceeded the commonly-cited cost-effectiveness thresholds of $100,000/QALY and £20,000/QALY. However, ICERs were considerably lower in some subgroups, and in sensitivity analyses.

Treatments for Chronic Kidney Disease: A Systematic Literature Review of Randomized Controlled Trials.

Delaying disease progression and reducing the risk of mortality are key goals in the treatment of chronic kidney disease (CKD). New drug classes to augment renin-angiotensin-aldosterone system (RAAS) inhibitors as the standard of care have scarcely met their primary endpoints until recently. This systematic literature review explored treatments evaluated in patients with CKD since 1990 to understand what contemporary data add to the treatment landscape. Eighty-nine clinical trials were identified that had enrolled patients with estimated glomerular filtration rate 13.9-102.8 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) 29.9-2911.0 mg/g, with (75.5%) and without (20.6%) type 2 diabetes (T2D). Clinically objective outcomes of kidney failure and all-cause mortality (ACM) were reported in 32 and 64 trials, respectively. Significant reductions (P < 0.05) in the risk of kidney failure were observed in seven trials: five small trials published before 2008 had evaluated the RAAS inhibitors losartan, benazepril, or ramipril in patients with (n = 751) or without (n = 84-436) T2D; two larger trials (n = 2152-2202) published onwards of 2019 had evaluated the sodium-glucose co-transporter 2 (SGLT2) inhibitors canagliflozin (in patients with T2D and UACR > 300-5000 mg/g) and dapagliflozin (in patients with or without T2D and UACR 200-5000 mg/g) added to a background of RAAS inhibition. Significant reductions in ACM were observed with dapagliflozin in the DAPA-CKD trial. Contemporary data therefore suggest that augmenting RAAS inhibitors with new drug classes has the potential to improve clinical outcomes in a broad range of patients with CKD.

Adverse clinical outcomes associated with RAAS inhibitor discontinuation: analysis of over 400 000 patients from the UK Clinical Practice Research Datalink (CPRD).

BACKGROUND: Users of guideline-recommended renin-angiotensin-aldosterone system (RAAS) inhibitors may experience disruptions to their treatment, e.g. due to hyperkalaemia, hypotension or acute kidney injury. The risks associated with treatment disruption have not been comprehensively assessed; therefore, we evaluated the risk of adverse clinical outcomes in RAAS inhibitor users experiencing treatment disruptions in a large population-wide database. METHODS: This exploratory, retrospective analysis utilized data from the UK's Clinical Practice Research Datalink, linked to Hospital Episodes Statistics and the Office for National Statistics databases. Adults (≥18 years) with first RAAS inhibitor use (defined as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) between 1 January 2009 and 31 December 2014 were eligible for inclusion. Time to the first occurrence of adverse clinical outcomes [all-cause mortality, all-cause hospitalization, cardiac arrhythmia, heart failure hospitalization, cardiac arrest, advancement in chronic kidney disease (CKD) stage and acute kidney injury] was compared between RAAS inhibitor users with and without interruptions or cessations to treatment during follow-up. Associations between baseline characteristics and adverse clinical outcomes were also assessed. RESULTS: Among 434 027 RAAS inhibitor users, the risk of the first occurrence of all clinical outcomes, except advancement in CKD stage, was 8-75% lower in patients without interruptions or cessations versus patients with interruptions/cessations. Baseline characteristics independently associated with increased risk of clinical outcomes included increasing age, smoking, CKD, diabetes and heart failure. CONCLUSIONS: These findings highlight the need for effective management of factors associated with RAAS inhibitor interruptions or cessations in patients for whom guideline-recommended RAAS inhibitor treatment is indicated.

Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors vs other glucose-lowering drugs in 13 countries across three continents: analysis of CVD-REAL data.

BACKGROUND: Randomized, controlled cardiovascular outcome trials may not be fully representative of the management of patients with type 2 diabetes across different geographic regions. We conducted analyses of data from the multinational CVD-REAL consortium to determine the association between initiation of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and cardiovascular outcomes, including subgroup analyses based on patient characteristics. METHODS: De-identified health records from 13 countries across three continents were used to identify patients newly-initiated on SGLT-2i or other glucose-lowering drugs (oGLDs). Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching for oGLD initiation. In the matched groups hazard ratios (HRs) for hospitalization for heart failure (HHF), all-cause death (ACD), the composite of HHF or ACD, myocardial infarction (MI) and stroke were estimated by country, and pooled using a weighted meta-analysis. Multiple subgroup analyses were conducted across patient demographic and clinical characteristics to examine any heterogeneity in treatment effects. RESULTS: Following matching, 440,599 new users of SGLT-2i and oGLDs were included in each group. Mean follow-up time was 396 days for SGLT-2i initiation and 406 days for oGLDs initiation. SGLT-2i initiation was associated with a lower risk of HHF (HR: 0.66, 95%CI 0.58-0.75; p < 0.001), ACD (HR: 0.52, 95%CI 0.45-0.60; p < 0.001), the composite of HHF or ACD (HR: 0.60, 95%CI 0.53-0.68; p < 0.001), MI (HR: 0.85, 95%CI 0.78-0.92; p < 0.001), and stroke (HR: 0.78, 95%CI 0.72-0.85; p < 0.001); regardless of patient characteristics, including established cardiovascular disease, or geographic region. CONCLUSIONS: This CVD-REAL study extends the findings from the SGLT-2i clinical trials to the broader setting of an ethnically and geographically diverse population, and across multiple subgroups. Trial registration NCT02993614.

Methods and rationale of the DISCOVER CKD global observational study.

BACKGROUND: Real-world data for patients with chronic kidney disease (CKD), specifically pertaining to clinical management, metabolic control, treatment patterns, quality of life (QoL) and dietary patterns, are limited. Understanding these gaps using real-world, routine care data will improve our understanding of the challenges and consequences faced by patients with CKD, and will facilitate the long-term goal of improving their management and prognosis. METHODS: DISCOVER CKD follows an enriched hybrid study design, with both retrospective and prospective patient cohorts, integrating primary and secondary data from patients with CKD from China, Italy, Japan, Sweden, the UK and the USA. Data will be prospectively captured over a 3-year period from >1000 patients with CKD who will be followed up for at least 1 year via electronic case report form entry during routine clinical visits and also via a mobile/tablet-based application, enabling the capture of patient-reported outcomes (PROs). In-depth interviews will be conducted in a subset of ∼100 patients. Separately, secondary data will be retrospectively captured from >2 000 000 patients with CKD, extracted from existing datasets and registries. RESULTS: The DISCOVER CKD program captures and will report on patient demographics, biomarker and laboratory measurements, medical histories, clinical outcomes, healthcare resource utilization, medications, dietary patterns, physical activity and PROs (including QoL and qualitative interviews). CONCLUSIONS: The DISCOVER CKD program will provide contemporary real-world insight to inform clinical practice and improve our understanding of the epidemiology and clinical and economic burden of CKD, as well as determinants of clinical outcomes and PROs from a range of geographical regions in a real-world CKD setting.

Cardiovascular and mortality benefits of sodium-glucose co-transporter-2 inhibitors in patients with type 2 diabetes mellitus: CVD-Real Catalonia.

BACKGROUND: Evidence from prospective cardiovascular (CV) outcome trials in type 2 diabetes (T2DM) patients supports the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) to reduce the risk of CV events. In this study, we compared the risk of several CV outcomes between new users of SGLT2i and other glucose-lowering drugs (oGLDs) in Catalonia, Spain. METHODS: CVD-REAL Catalonia was a retrospective cohort study using real-world data routinely collected between 2013 and 2016. The cohorts of new users of SGLT2i and oGLDs were matched by propensity score on a 1:1 ratio. We compared the incidence rates and hazard ratio (HR) for all-cause death, hospitalization for heart failure, chronic kidney disease, and modified major adverse CV event (MACE; all-cause mortality, myocardial infarction, or stroke). RESULTS: After propensity score matching, 12,917 new users were included in each group. About 27% of users had a previous history of CV disease. In the SGLT2i group, the exposure time was 60% for dapagliflozin, 26% for empagliflozin and 14% for canagliflozin. The use of SGLT2i was associated with a lower risk of heart failure (HR: 0.59; 95% confidence interval [CI] 0.47-0.74; p < 0.001), all-cause death (HR = 0.41; 95% CI 0.31-0.54; p < 0.001), all-cause death or heart failure (HR = 0.55; 95% CI 0.47-0.63; p < 0.001), modified MACE (HR = 0.62; 95% CI 0.52-0.74; p < 0.001), and chronic kidney disease (HR = 0.66; 95% CI 0.54-0.80; p < 0.001). CONCLUSIONS: In this large, retrospective observational study of patients with T2DM from a Catalonia, initiation of SGLT-2i was associated with lower risk of mortality, as well as heart failure and CKD.

Understanding Patient Perspectives and Awareness of the Impact and Treatment of Anemia with Chronic Kidney Disease: A Patient Survey in China.

BACKGROUND: Anemia is a common complication of chronic kidney disease (CKD) that may reduce patients' health-related quality of life (HRQoL). This study explored the experience and knowledge of patients with CKD, with and without anemia, in China. METHODS: A quantitative online survey was administered to 500 consenting Chinese patient volunteers aged ≥18 years with self-reported CKD, with or without anemia, between August 29, and September 17, 2018. Patients with cancer were excluded. The 27-question survey explored knowledge of anemia, HRQoL, anemia management, and interactions with healthcare providers. RESULTS: Of 456 evaluable patients, 148 (32.5%) reported having anemia and 262 (57.5%) did not. Knowledge of anemia and its symptoms varied, and approximately half of all patients did not know their hemoglobin level. Patients with anemia expressed an adverse impact of anemia on HRQoL, most commonly lack of energy (65.5%), sadness/depression (54.1%), and feeling ill (50.0%). The most frequently reported treatments among these patients were dietary advice (68.9%), iron supplements (63.5%), and oral medications (53.4%). Although 89.2% of patients with anemia trusted their healthcare providers above other information sources, only 29.0% reported seeking information from them; this was despite 92.6% reporting wanting further information and support about managing conditions like anemia. CONCLUSION: Our findings suggest that patients with CKD, both with and without anemia, would benefit from increased awareness of anemia and more in-depth discussions with healthcare providers in order to facilitate better management of CKD and optimization of treatment plans.

Association of sodium-glucose cotransporter-2 inhibitors with outcomes in type 2 diabetes with reduced and preserved left ventricular ejection fraction: Analysis from the CVD-REAL 2 study.

This study of real-world data from the Maccabi database in Israel compared the risk of heart failure hospitalization (HHF) or death in patients with type 2 diabetes (T2D) initiating sodium-glucose cotransporter-2 (SGLT2) inhibitors versus other glucose-lowering drugs (OGLDs) according to baseline left ventricular (LV) ejection fraction (EF). After propensity-matching patients by baseline EF there were 10 614 episodes of treatment initiation; 57% had diabetes for >10 years, the mean glycated haemoglobin level was 66 mmol/mol (8.2%), ∼43% had cardiovascular disease, ∼7% had heart failure and ∼ 20% had chronic kidney disease. A total of 2876 patients (∼9%) had reduced EF (<50%). Over a mean follow-up of 1.5 years there were 371 HHFs or deaths, 88 (23.7%) in patients with reduced EF. Initiation of SGLT2 inhibitors versus OGLDs was associated with lower risk of HHF or death overall (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.46-0.70]; P < 0.001) and in patients with both reduced EF (HR 0.61, 95% CI 0.40-0.93) and preserved EF (HR 0.55, 95% CI 0.43-0.70), with no significant heterogeneity (Pinteraction = 0.72). Our findings from real-world clinical practice show that the lower risk of HHF and death associated with use of SGLT2 inhibitors versus OGLDs is consistent in T2D patients with both reduced and preserved EF.

Assessment of The High risk and unmEt Need in patients with CAD and type 2 diabetes (ATHENA): US healthcare resource use, cost, and burden of illness in a commercially insured population.

AIMS: THEMIS (NCT01991795) demonstrated cardioprotective benefits of ticagrelor plus acetylsalicylic acid (ASA) compared with placebo plus ASA in patients with type 2 diabetes (T2D), stable coronary artery disease (CAD) and no history of myocardial infarction (MI) or stroke. To complement these findings, we assessed clinical outcomes and healthcare costs in commercially insured US patients similar to those in THEMIS. METHODS: This retrospective, observational study used data from Optum. The T2D-CAD cohort (n = 154,369) included patients (≥50 years old) either with high cardiovascular risk or taking a P2Y12 inhibitor. The THEMIS-like cohort (n = 126,938) comprised patients (≥50 years old) at high cardiovascular risk; the THEMIS-PCI-like cohort comprised a subset of these patients with prior percutaneous coronary intervention (PCI) (n = 18,394). RESULTS: Mean follow-up was 2.4-2.5 years. Incidence rates of the composite outcome (death, MI, and stroke) were 6.56 (95% CI 6.50-6.63), 6.21 (6.14-6.28), and 5.57 (5.39-5.74) per 100 person-years, and annualized healthcare costs per patient were US$15,848, US$16,044, and US$20,934 for the T2D-CAD, THEMIS-like, and THEMIS-PCI-like cohorts, respectively. CONCLUSIONS: Commercially insured patients similar to those in THEMIS had high cardiovascular event rates and healthcare costs, highlighting a need for improved preventive strategies.

Sodium-glucose cotransporter 2 inhibitors compared with other glucose-lowering drugs in Japan: Subanalyses of the CVD-REAL 2 Study.

There are limited data on cardiovascular efficacy and safety of type 2 diabetes therapies in Japan, where treatments are characterized by lower metformin use and higher dipeptidyl peptidase-4 inhibitor (DPP4i) use versus other countries. We investigated the cardiovascular outcomes in Japanese patients with type 2 diabetes initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) matched 1:1 to patients initiating other glucose-lowering drugs (33,890 patients/group) or DPP4i (9,876 patients/group). SGLT2i initiation was associated with lower risks (hazard ratio of in-hospital death [death] 0.56, 95% confidence interval [CI] 0.47-0.67; hospitalization for heart failure 0.75, 95% CI 0.64-0.89; composite of hospitalization for heart failure or death 0.65, 95% CI 0.58-0.74 and stroke 0.66, 95% CI 0.52-0.84 versus other glucose-lowering drugs and lower risks of death 0.52, 95% CI 0.36-0.73) and composite of hospitalization for heart failure or death (0.65, 95% CI 0.51-0.83) versus DPP4i. In conclusion, SGLT2i initiators had lower risks of cardiovascular events versus other glucose-lowering drug initiators and, uniquely, versus DPP4i initiators in Japanese real-world practice.

Burden of Chronic Kidney Disease by KDIGO Categories of Glomerular Filtration Rate and Albuminuria: A Systematic Review.

INTRODUCTION: The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines recommend classifying patients by glomerular filtration rate (GFR) and albuminuria to predict chronic kidney disease (CKD) prognosis. The aim of this systematic review was to explore the epidemiological burden of CKD stratified by the KDIGO 2012 categories. METHODS: MEDLINE® and Embase were searched for observational studies of patients with CKD with results stratified according to the KDIGO 2012 classification. Investigated outcomes were prevalence, incidence, and risk factors and complications of CKD, including mortality. RESULTS: The review included ten observational studies with 3033 to 46,949 participants, conducted in the USA, China, France, Italy and Spain. The most frequently reported outcome was the prevalence of CKD (GFR categories G3-5), ranging from 2% to 17%. Most participants were normoalbuminuric, with 0.4-3.2% macroalbuminuric, and most fell within the KDIGO 2012 low-risk or moderate-risk groups, with 0.9-5.6% in the high-risk and 0.3-4.8% in the very high-risk groups. Although scarce, data on the prevalence of comorbidities in CKD according to the KDIGO classification suggest that they increase with albuminuria severity. CONCLUSIONS: Patients with CKD frequently have complications, but only a small proportion have severely increased albuminuria or fall within the KDIGO high-risk or very high-risk groups. These groups, however, are associated with the highest burden of disease, as comorbidities are more prevalent with increasing albuminuria severity. New studies framed by the KDIGO 2012 classification are needed to address key gaps in the understanding of CKD burden and outcomes.

Renal outcomes and all-cause death associated with sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL 3 Korea).

AIMS: To investigate the effectiveness of sodium-glucose co-transporter-2 (SGLT2) inhibitors on the risk of progression to end-stage renal disease (ESRD) and all-cause mortality in a broad range of patients with type 2 diabetes (T2D) using a Korean nationwide cohort. MATERIALS AND METHODS: Using data from the Korean National Health Insurance Service database from January 2014 to December 2017, a total of 701 674 patients were identified with T2D. We divided these patients into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs (oGLDs). Using propensity scores, patients in the two groups were matched 1:1. We assessed the risk of ESRD and all-cause death. RESULTS: There were 45 016 patients in each group, and baseline characteristics were well balanced between the groups. The patients' mean age was 58.1 ± 10.6 years and mean estimated glomerular filtration rate (eGFR) was 89.2 ± 27.4 mL/min/1.73m2 , and 8% of patients had proteinuria. We identified 167 incident ESRD cases and 1070 all-cause deaths during follow-up. Use of SGLT2 inhibitors versus oGLDs was associated with a lower risk of ESRD (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.34 to 0.65) and all-cause death (HR 0.82, 95% CI 0.73 to 0.93). In a subgroup analysis by eGFR, initiation of SGLT2 inhibitor treatment, compared with oGLD treatment, was associated with lower risk of progression to ESRD among patients with eGFR 60 to 90 mL/min/1.73m2 and those with eGFR < 60 mL/min/1.73m2 , and a lower risk of all-cause death was associated with SGLT2 inhibitors versus oGLDs in patients with eGFR ≥90 and 60 to 90 mL/min/1.73m2 . CONCLUSION: In this large nationwide study of Korean patients with T2D, initiation of SGLT2 inhibitors versus oGLDs was associated with lower risk of ESRD and all-cause death.

Assessing the cost-effectiveness of sodium-glucose cotransporter-2 inhibitors in type 2 diabetes mellitus: A comprehensive economic evaluation using clinical trial and real-world evidence.

AIMS: The economic burden of diabetes is driven by the management of vascular complications. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated reductions in cardiovascular and renal complications, including hospitalization for heart failure (HHF) and renal disease progression, in randomized clinical trials. The objective of this study was to evaluate the cost-effectiveness of the SGLT2i class versus standard of care in type 2 diabetes mellitus (T2DM), using evidence from both clinical trial and real-world studies. METHODS: An established T2DM model was adapted to use contemporary outcomes evidence from real-world studies and randomized controlled trial evaluations of SGLT2i, and extrapolated over a lifetime for HHF, myocardial infarction, stroke, end-stage renal disease and all-cause mortality. The economic analysis considered adults with T2DM, with and without established cardiovascular disease, and was conducted over a lifetime from the perspective of the health care payer in the United Kingdom, United States and China, discounted at country-specific rates. RESULTS: SGLT2i were consistently associated with increased treatment costs, reduced complication costs and gains in quality-adjusted life years driven by differences in projected life expectancy, cardiovascular and microvascular morbidity and weight loss. SGLT2i were estimated to be cost-saving or cost-effective at relevant thresholds for the overall population in the United Kingdom, United States and China, with cost-effectiveness being the greatest in higher risk subgroups. CONCLUSIONS: The findings highlight the need to take into account cost savings from reducing common, morbid and preventable T2DM complications when considering the cost of diabetes medications.

Assessment of the high risk and unmet need in patients with CAD and type 2 diabetes (ATHENA): US healthcare resource utilization, cost and burden of illness in the Diabetes Collaborative Registry.

BACKGROUND: THEMIS (NCT01991795) showed that in patients with type 2 diabetes (T2D) and stable coronary artery disease (CAD) but with no prior myocardial infarction (MI) or stroke, ticagrelor plus acetylsalicylic acid (ASA) decreased the incidence of ischaemic cardiovascular events compared with placebo plus ASA. To complement these findings, we assessed disease burden and healthcare resource utilization (HRU) in US patients with CAD and T2D, but without a prior MI or stroke. METHODS: This observational study used 2013-2014 data from the Diabetes Collaborative Registry linked to Medicare administrative claims. Two cohorts of patients with T2D were studied: patients at high cardiovascular risk (THEMIS-like cohort; N = 56 040) and patients at high cardiovascular risk or taking P2Y12 inhibitors (CAD-T2D cohort; N = 69 790). Outcomes included the composite of all-cause death, MI and stroke; the individual events from the composite endpoint; HRU; and costs. RESULTS: Median age was 73.0 years, and median follow-up was 1.3 years in both cohorts. Event rates of the composite outcome were 16.34 (95% confidence interval: 16.31-16.37) and 17.64 (17.61-17.67) per 100 person-years for the THEMIS-like and CAD-T2D cohorts, respectively. The incidence rate of bleeding events was 0.13 events per 100 person-years in both cohorts. Healthcare costs per patient-year were USD 8741 and USD 9150 in the THEMIS-like and CAD-T2D cohorts, respectively. CONCLUSIONS: Patients in the THEMIS-like cohort and the broader CAD-T2D population had similarly substantial cardiovascular event rates and healthcare costs, indicating that patients with CAD and T2D similar to the THEMIS population are at an increased cardiovascular risk.