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.

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.

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.

Characteristics, Symptom Severity, and Experiences of Patients Reporting Chronic Kidney Disease in the PatientsLikeMe Online Health Community: Retrospective and Qualitative Study.

BACKGROUND: Chronic kidney disease (CKD) is a major global health burden, and is associated with increased adverse outcomes, poor quality of life, and substantial health care costs. While there is an increasing need to build patient-centered pathways for improving CKD management in clinical care, data in this field are scarce. OBJECTIVE: The aim of this study was to understand patient-reported experiences, symptoms, outcomes, and treatment journeys among patients with CKD through a retrospective and qualitative approach based on data available through PatientsLikeMe (PLM), an online community where patients can connect and share experiences. METHODS: Adult members (aged ≥18 years) with self-reported CKD within 30 days of enrollment, who were not on dialysis, and registered between 2011 and 2018 in the PLM community were eligible for the retrospective study. Patient demographics and disease characteristics/symptoms were collected from this retrospective data set. Qualitative data were collected prospectively through semistructured phone interviews in a subset of patients, and questions were oriented to better understand patients' experiences with CKD and its management. RESULTS: The retrospective data set included 1848 eligible patients with CKD, and median age was 56 years. The majority of patients were female (1217/1841, 66.11%) and most were US residents (1450/1661, 87.30%). Of the patients who reported comorbidities (n=1374), the most common were type 2 diabetes (783/1374, 56.99%), hypertension (664/1374, 48.33%), hypercholesterolemia (439/1374, 31.95%), and diabetic neuropathy (376/1374, 27.37%). The most commonly reported severe or moderate symptoms in patients reporting these symptoms were fatigue (347/484, 71.7%) and pain (278/476, 58.4%). In the qualitative study, 18 eligible patients (13 females) with a median age of 60 years and who were mainly US residents were interviewed. Three key concepts were identified by patients to be important to optimal care and management: listening to patient needs, coordinating health care across providers, and managing clinical care. CONCLUSIONS: This study provides a unique source of real-world information on the patient experience of CKD and its management by utilizing the PLM network. The results reveal the challenges these patients face living with an array of symptoms, and report key concepts identified by patients that can be used to further improve clinical care and management and inform future CKD studies.

Comparison of healthcare resource utilization and costs in patients with type 2 diabetes initiating dapagliflozin versus sitagliptin.

AIMS: To compare healthcare costs and utilization in patients with type 2 diabetes (T2D) who initiated dapagliflozin (DAPA) with costs and utilization in those who initiated sitagliptin (SITA) in a real-world setting. MATERIALS AND METHODS: This was a retrospective study of health plan enrollees in two US commercial claims databases or Medicare Part D. The study population comprised adult patients with T2D who initiated DAPA or SITA between January 1, 2014 and April 30, 2015. DAPA and SITA initiators were propensity-score-matched, and healthcare utilization and costs during the 1-year follow-up period were compared. Analyses were conducted separately for patients with evidence of oral antidiabetic drug (OAD) monotherapy use at baseline. RESULTS: A total of 2722 patients were included in each matched cohort. Follow-up unadjusted all-cause costs ($16 065 and $17 281; P = 0.135) and diabetes-related costs ($9697 and $9354; P = 0.539) were similar in the DAPA and SITA cohorts. Higher office and outpatient visit costs in the SITA group were offset by higher pharmacy costs in the DAPA group. In the subgroup of 1804 patients with OAD monotherapy use at baseline, patients in the SITA group had higher total all-cause costs compared with those in the DAPA group ($14 884 vs. $12 353; P = 0.026). CONCLUSION: Patients who initiated DAPA or SITA had similar all-cause and diabetes-related healthcare costs over 1 year of follow-up. In the subgroup of patients treated with OAD monotherapy at baseline (84% metformin monotherapy), those who initiated DAPA as add-on therapy had lower costs than patients who added SITA.

Rates of myocardial infarction and stroke in patients initiating treatment with SGLT2-inhibitors versus other glucose-lowering agents in real-world clinical practice: Results from the CVD-REAL study.

The multinational, observational CVD-REAL study recently showed that initiation of sodium-glucose co-transporter-2 inhibitors (SGLT-2i) was associated with significantly lower rates of death and heart failure vs other glucose-lowering drugs (oGLDs). This sub-analysis of the CVD-REAL study sought to determine the association between initiation of SGLT-2i vs oGLDs and rates of myocardial infarction (MI) and stroke. Medical records, claims and national registers from the USA, Sweden, Norway and Denmark were used to identify patients with T2D who newly initiated treatment with SGLT-2i (canagliflozin, dapagliflozin or empagliflozin) or oGLDs. A non-parsimonious propensity score was developed within each country to predict initiation of SGLT-2i, and patients were matched 1:1 in the treatment groups. Pooled hazard ratios (HRs) and 95% CIs were generated using Cox regression models. Overall, 205 160 patients were included. In the intent-to-treat analysis, over 188 551 and 188 678 person-years of follow-up (MI and stroke, respectively), there were 1077 MI and 968 stroke events. Initiation of SGLT-2i vs oGLD was associated with a modestly lower risk of MI and stroke (MI: HR, 0.85; 95%CI, 0.72-1.00; P = .05; Stroke: HR, 0.83; 95% CI, 0.71-0.97; P = .02). These findings complement the results of the cardiovascular outcomes trials, and offer additional reassurance with regard to the cardiovascular effects of SGLT-2i, specifically as it relates to ischaemic events.

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.

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.

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.

Authors' reply to "Comment on generalizability of GLP-1 RA CVOTs in US T2D population".

The authors of the manuscript "Generalizability of Glucagon-Like Peptide-1 Receptor Agonist Cardiovascular Outcome Trials Enrollment Criteria to the US Type 2 Diabetes Population" respond to a letter to the editor.

Differences in health care outcomes between postdischarge COPD patients treated with inhaled corticosteroid/long-acting ß2-agonist via dry-powder inhalers and pressurized metered-dose inhalers.

PURPOSE: The aim of this study was to examine real-world differences in health care resource use (HRU) and costs among COPD patients in the USA treated with a dry powder inhaler (DPI) or pressurized metered-dose inhaler (pMDI) following a COPD-related hospitalization. METHODS: This retrospective analysis used the Truven MarketScan® databases. Eligibility criteria included 1) age ≥40 years, 2) COPD diagnosis, 3) inpatient admission with a diagnosis of COPD exacerbation, 4) inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA) prescription within 10 days of hospital discharge (index date), and 5) continuous enrollment for 12 months preindex and 90 days postindex. Outcomes included pre- and postindex HRU and costs. DPI and pMDI groups were compared on postindex outcomes via multivariate models controlling for demographic and baseline characteristics. RESULTS: The sample included 1,960 DPI and 1,086 pMDI ICS/LABA patients. During the preindex period, pMDI patients were significantly more likely to be prescribed a short-acting ß-agonist, experienced more COPD exacerbation-related hospital days, and had a greater number of pulmonologist visits compared to DPI patients (P<0.05), all suggestive of greater disease severity. However, multivariate models revealed that pMDI patients incurred 10% lower all-cause postindex costs (predicted mean costs [2016 US dollars]: $2,673 vs $2,956) and 19% lower COPD-related costs (predicted mean costs: $138 vs $169; P<0.05). Additionally, pMDI patients were 28% less likely to experience a COPD exacerbation-related hospital readmission within 60 days postdischarge compared to the DPI patients (OR: 0.72, 95% CI: 0.52-0.99, P<0.05). CONCLUSION: Despite greater COPD-related HRU and costs preceding index hospitalization, US patients using a pMDI after hospital discharge incurred significantly lower all-cause and COPD-related health care costs compared with those using a DPI, in addition to a decreased likelihood of a COPD exacerbation-related hospital readmission. Results suggest that inhaler device type may influence COPD outcomes and that COPD patients may derive greater clinical benefit from treatment delivered via pMDI vs DPI.

Resource use and costs associated with opioid-induced constipation following total hip or total knee replacement surgery.

PURPOSE: Constipation is a well-known complication of surgery that can be exacerbated by opioid analgesics. This study evaluated resource utilization and costs associated with opioid-induced constipation (OIC). PATIENTS AND METHODS: This retrospective, observational, and propensity-matched cohort study utilized the Premier Healthcare Database. The study included adults ≥18 years of age undergoing total hip or total knee replacement as inpatients who received an opioid analgesic and were discharged between January 1, 2012, and June 30, 2015. Diagnosis codes identified patients with OIC who were then matched 1:1 to patients without OIC. Generalized linear and logistic regression models were used to compare inpatient resource utilization, total hospital costs, inpatient mortality, and 30-day all-cause readmissions and emergency department visits. RESULTS: Of 788,448 eligible patients, 40,891 (5.2%) had OIC. Covariates were well balanced between matched patients with and without OIC (n=40,890 each). In adjusted analyses, patients with OIC had longer hospital lengths of stay (3.6 versus 3.3 days; p<0.001), higher total hospital costs (US$17,479 versus US$16,265; p<0.001), greater risk of intensive care unit admission (odds ratio [OR]=1.12, 95% CI: 1.01-1.24), and increased likelihood of 30-day hospital read-missions (OR=1.16, 95% CI: 1.11-1.22) and emergency department visits (OR=1.38, 95% CI: 1.07-1.79) than patients without OIC. No statistically significant difference was found with inpatient mortality (OR=0.89, 95% CI: 0.59-1.35). CONCLUSION: OIC was associated with greater resource utilization and hospital costs for patients undergoing primarily elective total hip or total knee replacement surgery. These results support OIC screening and management strategies as part of perioperative care management.

Comparison of low-dose liraglutide use versus other GLP-1 receptor agonists in patients without type 2 diabetes.

OBJECTIVES: The objective was to compare the use of low-dose liraglutide (LD-L) (Victoza) to the other glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients without a type 2 diabetes (T2D) diagnosis in the post approval period for high-dose liraglutide (HD-L) (Saxenda), which is not indicated for T2D. STUDY DESIGN: This was a retrospective, repeated cross-sectional, cohort study. METHODS: Adult patients with T2D with more than 1 prescription for a GLP-1 RA in the Optum Humedica database between December 2014 and March 2016 were included. The proportions of patients without a T2D diagnosis who were prescribed L-DL versus the other GLP-1 RAs and within each cohort were computed. Logistic regression models estimated the predictive value of either treatment in those without a T2D diagnosis, controlling for multiple factors. To supplement these findings, administrative claims data were extracted from the Truven Health MarketScan database. RESULTS: Analyses identified 11,245 patients prescribed LD-L and 4134 patients prescribed other GLP-1 RAs. For the entire study period, Humedica data revealed that patients without T2D accounted for 2.7% of the GLP-1 RA cohort and 17.5% of the LD-L cohort. Multivariable logistic regression analyses identified that patients receiving LD-L were more than 6 times likely to have no indication of T2D relative to patients taking other GLP-1 RAs. Claims data from MarketScan corroborated the Humedica results. CONCLUSIONS: In patients without a T2D diagnosis, LD-L use was significantly greater than that with other GLP-1 RAs within 6 months after approval of HD-L; differences persisted until the end of the study. Increased payer scrutiny of appropriate LD-L use is warranted.

Eligibility varies among the 4 sodium-glucose cotransporter-2 inhibitor cardiovascular outcomes trials: implications for the general type 2 diabetes US population.

OBJECTIVES: Guidance to industry from the FDA requires studies to evaluate the cardiovascular safety of novel type 2 diabetes (T2D) medications. Although the objectives of such cardiovascular outcomes trials (CVOTs) are similar, differences in features such as enrollment criteria present a challenge when trying to assess the applicability of these studies to real-world T2D populations. This study evaluated the proportions of US adults with T2D who met the eligibility criteria for each of the 4 sodium-glucose cotransporter-2 (SGLT2) inhibitor CVOTs. STUDY DESIGN: A cross-sectional retrospective study was conducted using data from the National Health and Nutrition Examination Survey (NHANES) and published patient eligibility criteria for completed or ongoing SGLT2 inhibitor CVOTs. METHODS: Data on T2D diagnosis and other relevant clinical and demographic characteristics were extracted from the NHANES (2009-2010 and 2011-2012). Weighted analysis of these data was used to estimate the percentage of US adults with T2D who met the eligibility criteria for the CANVAS program (CANagliflozin cardioVascular Assessment Study) (canagliflozin; NCT01032629, NCT01989754), and the DECLARE-TIMI 58 (dapagliflozin; NCT01730534), EMPA-REG OUTCOME (empagliflozin; NCT01131676), and VERTIS-CV (ertugliflozin; NCT01986881) trials. RESULTS: The weighted analysis identified a population of 23,941,512 US adults from data on key inclusion criteria and information indicating a diagnosis of T2D. Of these, 4.1% met the criteria for EMPA-REG OUTCOME, 4.8% for VERTIS-CV, 8.8% for the CANVAS program, and 39.8% for the DECLARE-TIMI 58 trial. CONCLUSIONS: There were considerable differences in the proportions of US adults with T2D who met the eligibility criteria for these studies.The DECLARE-TIMI 58 trial criteria were the most generalizable to the US T2D population.

Generalizability of glucagon-like peptide-1 receptor agonist cardiovascular outcome trials enrollment criteria to the US type 2 diabetes population.

OBJECTIVES: Cardiovascular outcomes trials (CVOTs) for evaluating the safety of novel antidiabetic agents are required by the FDA. CVOTs vary in their design and inclusion criteria, making it difficult to evaluate their applicability to the general population. This study examined the proportion of adults eligible for 7 ongoing or completed glucagon-like peptide-1 receptor agonist (GLP-1 RA) CVOTs. STUDY DESIGN: This cross-sectional, retrospective, cohort study compared data from the National Health and Nutrition Examination Survey (NHANES) with published eligibility criteria from GLP-1 RA CVOTs. METHODS: Patient information on T2D status and other relevant characteristics were extracted from the 2009 to 2010 and the 2011 to 2012 NHANES. Weighted analyses of these data were used to calculate the numbers of adults with T2D in the US population who would have met eligibility criteria for enrollment in the following published or ongoing CVOTs: ELIXA (lixisenatide; NCT01147250), EXSCEL (Exenatide Study of Cardiovascular Event Lowering) (exenatide once weekly; NCT01144338), FREEDOM-CVO (exenatide via ITCA 650 miniature osmotic pump; NCT01455896), HARMONY Outcomes (albiglutide; NCT02465515), LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results) (liraglutide; NCT01179048), REWIND (Researching Cardiovascular Events With a Weekly INcretin in Diabetes) (dulaglutide; NCT01394952), and SUSTAIN-6 (semaglutide; NCT01720446). RESULTS: The proportion of adults with T2D eligible for enrollment varied substantially among CVOTs (6.4%-47.2%); EXSCEL, which had a pragmatic study design, had the most generalizable inclusion criteria. More than 60% of patients with T2D would have qualified for enrollment into at least 1 GLP-1 RA CVOT. CONCLUSIONS: Most adults with T2D in the United States would have qualified for enrollment into at least 1 of the GLP-1 RA CVOTs evaluated. EXSCEL had the most generalizable eligibility criteria of these trials and ELIXA the least.

Sitaxsentan for treatment of pulmonary hypertension.

OBJECTIVE: To review the literature pertinent to the efficacy and safety of sitaxsentan, a selective endothelin (ET)-A receptor antagonist under evaluation for the treatment of pulmonary arterial hypertension (PAH). DATA SOURCES: Articles were identified through searches of the MEDLINE (1966-November 2006) and International Pharmaceutical Abstracts (1970-November 2006) databases, using the key words endothelin antagonist, pulmonary arterial hypertension, pulmonary hypertension, sitaxsentan, and TBC11251. Searches were limited to articles published in English. STUDY SELECTION AND DATA EXTRACTION: Due to the limited number of articles on sitaxsentan, all studies captured in the search results were evaluated. DATA SYNTHESIS: Four studies of sitaxsentan in humans with PAH have been published to date. An uncontrolled open-label study and a randomized placebo-controlled study (STRIDE-1; Sitaxsentan to Relieve Impaired Exercise-1) showed sitaxsentan to improve exercise tolerance in patients with PAH, as evidenced by significant increases in the distance walked in 6 minutes. Significant hepatotoxicity developed in patients receiving sitaxsentan 300 mg. The benefits of sitaxsentan with respect to exercise tolerance and hemodynamics were sustained in a one year extension of the placebo-controlled study. The results of a multicenter, randomized, placebo-controlled trial of 2 doses of sitaxsentan with an open-label bosentan arm (STRIDE-2) suggested that only the 100 mg dose provided superior benefit in exercise tolerance and improvement in functional class. Treatment-related adverse effects were similar for all groups. CONCLUSIONS: Sitaxsentan appears to be superior to placebo in improving exercise tolerance in patients with PAH but may produce therapeutic outcomes similar to those of bosentan, a comparator agent. The optimal dose of sitaxsentan appears to be 100 mg once daily. Information about the use of sitaxsentan in a greater number of patients with PAH for longer periods is necessary to further define its place in the treatment of PAH.

Glucagon-like peptide-1 receptor agonists: a systematic review of comparative effectiveness research.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) act by increasing insulin secretion, decreasing glucagon secretion, slowing gastric emptying, and increasing satiety. OBJECTIVE: Published evidence directly comparing GLP-1RAs with other approved treatments for type 2 diabetes (T2D) was systematically reviewed. METHODS: A literature search was performed using MEDLINE and Embase databases to identify papers comparing GLP-1RAs with other classes of glucose-lowering therapy in patients with T2D. RESULTS: Of the 1303 papers identified, 57 met the prespecified criteria for a high-quality clinical trial or retrospective study. The efficacy and tolerability of approved GLP-1RAs (exenatide twice daily or once weekly, dulaglutide, liraglutide, lixisenatide, and albiglutide) were compared with insulin products (23 prospective studies + seven retrospective studies), dipeptidyl peptidase-4 inhibitors (11 prospective studies + three retrospective studies), sulfonylureas (nine prospective studies + one retrospective study), thiazolidinediones (five prospective studies), and metformin (two prospective studies). GLP-1RAs are effective as a second-line therapy in improving glycemic parameters in patients with T2D. Reductions in glycated hemoglobin from baseline with GLP-1RAs tended to be greater or similar compared with insulin therapy. GLP-1RAs were consistently more effective in reducing body weight than most oral glucose-lowering drugs and insulin and were associated with lower hypoglycemia risk versus insulin or sulfonylureas. GLP-1RAs improved cardiovascular risk factors, and preliminary data suggest they improve cardiovascular outcomes in patients with T2D compared with oral glucose-lowering drugs. However, results from ongoing studies are awaited to confirm these early findings. CONCLUSION: This systematic review found that GLP-1RAs are an effective class of glucose-lowering drugs for T2D.

Cost Comparison of Urate-Lowering Therapies in Patients with Gout and Moderate-to-Severe Chronic Kidney Disease.

BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk for developing gout and having refractory disease. Gout flare prevention relies heavily on urate-lowering therapies such as allopurinol and febuxostat, but clinical decision making in patients with moderate-to-severe CKD is complicated by significant comorbidity and the scarcity of real-world cost-effectiveness studies. OBJECTIVE: To compare total and disease-specific health care expenditures by line of therapy in allopurinol and febuxostat initiators after diagnosis with gout and moderate-to-severe CKD. METHODS: A retrospective observational cohort study was conducted to compare mean monthly health care cost (in 2012 U.S. dollars) among gout patients with CKD (stage 3 or 4) who initiated allopurinol or febuxostat. The primary outcome was total mean monthly health care expenditures, and the secondary outcome was disease-specific (gout, diabetes, renal, and cardiovascular disease [CVD]) expenditures. Gout patients (ICD-9-CM 274.xx) aged ≥ 18 years with concurrent CKD (stage 3 or 4) were selected from the MarketScan databases (January 2009-June 2012) upon allopurinol or febuxostat initiation. Patients were followed until disenrollment, discontinuation of the qualifying study agent, or use of the alternate study agent. Patients initiating allopurinol were subsequently propensity score-matched (1:1) to patients initiating febuxostat. Five generalized linear models (GLMs) were developed, each controlling for propensity score, to identify the incremental costs (vs. allopurinol) associated with febuxostat initiation in first-line (without prior allopurinol exposure) and second-line (with prior allopurinol exposure) settings. RESULTS: Propensity score matching yielded 2 cohorts, each with 1,486 patients (64.6% male, mean [SD] age 67.4 [12.8] years). Post-match, 74.6% of patients had stage 3 CKD; 82.9% had CVD; and 42.1% had diabetes. The post-match sample was well balanced on numerous comorbidities and medication exposures with the following exception: 50.0% of febuxostat initiators were treated in the second-line setting; that is, they had baseline exposure to allopurinol, whereas only 4.2% of allopurinol initiators had baseline exposure to febuxostat. Unadjusted mean monthly cost was $1,490 allopurinol and $1,525 febuxostat (P = 0.809). GLM results suggest that first-line febuxostat users incurred significantly (P = 0.009) lower cost than allopurinol users ($1,299 vs. $1,487), whereas second-line febuxostat initiators incurred significantly (P = 0.001) higher cost ($1,751 vs. $1,487). Febuxostat initiators in both settings had significantly (P < 0.001) higher gout-specific cost, due to higher febuxostat acquisition cost. Increased gout-specific cost in the first-line febuxostat cohort was offset by significantly (P < 0.001) lower CVD ($288 vs. $459) and renal-related cost ($86 vs. $216). There were no significant differences in either renal or CVD costs (adjusted) between allopurinol initiators treated almost exclusively in the first-line setting and second-line febuxostat patients. CONCLUSIONS: Gout patients with concurrent CKD, initiating treatment with febuxostat in a first-line setting, incurred significantly less total cost than patients initiating allopurinol during the first exposure to each agent. Conversely, patients treated with second-line febuxostat following allopurinol incurred significantly higher total cost than patients initiating allopurinol. There was no significant difference in total cost between the agents across line of therapy. Although study findings suggest the potential for CVD and renal-related savings to offset febuxostat's higher acquisition cost in gout patients with moderate-to-severe CKD, this is the first such retrospective evaluation. Future research is warranted to both demonstrate the durability of study findings and to better elucidate the mechanism by which associated cost offsets occur. DISCLOSURES: No outside funding supported this study. Turpin is an employee of Takeda Pharmaceuticals U.S.A. Mitri and Wittbrodt were employees of Takeda Pharmaceuticals U.S.A. at the time of this study. Tidwell and Schulman are employees of Outcomes Research Solutions, consultants to Takeda Pharmaceuticals U.S.A. All authors contributed to the design of the study and to the writing and review of the manuscript. All authors read and approved the final manuscript. Tidwell and Schulman collected the data, and all authors participated in data interpretation.