Effectiveness and safety of empagliflozin in routine care patients: Results from the EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study.

AIM: To investigate effectiveness and safety outcomes among patients with type 2 diabetes (T2D) initiating empagliflozin versus dipeptidyl peptidase-4 (DPP-4) inhibitor treatment across the broad spectrum of cardiovascular risk. METHODS: In a population-based cohort study we identified 39 072 pairs of 1:1 propensity score-matched adult patients with T2D initiating empagliflozin or DPP-4 inhibitors, using data from 2 US commercial insurance databases and Medicare between August 2014 and September 2017. The primary outcomes were a composite of myocardial infarction (MI)/stroke, and hospitalization for heart failure (HHF). Safety outcomes were bone fractures, lower-limb amputations (LLAs), diabetic ketoacidosis (DKA), and acute kidney injury (AKI). We estimated pooled hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for more than 140 baseline covariates. RESULTS: Study participants had a mean age of 60 years and only 28% had established cardiovascular disease. Compared to DPP-4 inhibitors, empagliflozin was associated with similar risk of MI/stroke (HR 0.99 [95% CI 0.81-1.21]), and lower risk of HHF (HR 0.48 [95% CI 0.35-0.67] and 0.63 [95% CI 0.54-0.74], based on a primary and any heart failure discharge diagnosis, respectively). The HR was 0.52 (95% CI 0.38-0.72) for all-cause mortality (ACM) and 0.83 (95% CI 0.70-0.98) for a composite of MI/stroke/ACM. Empagliflozin was associated with a similar risk of LLA and fractures, an increased risk of DKA (HR 1.71 [95% CI 1.08-2.71]) and a decreased risk of AKI (HR 0.60 [95% CI 0.43-0.85]). CONCLUSIONS: In clinical practice, the initiation of empagliflozin versus a DPP-4 inhibitor was associated with a lower risk of HHF, ACM and MI/stroke/ACM, a similar risk of MI/stroke, and a safety profile consistent with documented information.

Confirming diagnoses of acute pancreatitis with commonly available electronic data.

BACKGROUND: Recorded diagnoses of acute pancreatitis (AP) are often inaccurate resulting in limited utility for case identification in large data sources, especially where electronic medical records (EMR) are not available. Our objectives were to validate diagnoses of AP and to identify an algorithm using additional data to enhance the identification of AP cases in different data sources. METHODS: We randomly sampled 550 persons with an AP diagnosis from inpatient data or outpatient or emergency department diagnoses immediately preceding a hospitalization and 150 negative controls with a differential diagnosis (cholangitis or cholecystitis). We conducted an EMR review to confirm cases of AP and used logistic regression to develop EMR-based and claims-based algorithms to identify confirmed AP cases with variables typically available in electronic data sources. Algorithm performance was assessed using the C statistic, sensitivity, specificity, and positive and negative predictive value. RESULTS: Of the 550 patients with an AP diagnosis, 467 (84.9%) were confirmed cases. An AP diagnosis alone had high sensitivity (98.9%), modest specificity (63.6%), and a C statistic of 0.813. An EMR-based model using an AP diagnosis, body mass index ≥30 kg/m2 , a serum lipase >3 times upper limit of normal and diabetes attained a C-statistic of 0.914. A claims-based model attained a C-statistic of 0.892 using an AP diagnosis and dichotomous variables for whether a serum lipase test and/or an abdominal ultrasound was performed. CONCLUSIONS: Our simple algorithms increased the accuracy of identification of AP cases providing widespread applicability to epidemiological and drug safety studies.

Health Care Costs by Type of Expenditure across eGFR Stages among Patients with and without Diabetes, Cardiovascular Disease, and Heart Failure.

BACKGROUND: CKD is associated with higher health care costs that increase with disease progression. However, research is lacking on the type of health care costs associated with CKD across all stages in a general population with a substantial comorbidity burden. METHODS: Using electronic medical records of an integrated delivery system, we evaluated health care costs by expenditure type in general and in patients with CKD by eGFR and presence of comorbidities. We categorized 146,132 patients with eGFR data in 2016 or 2017 and examined nonmutually exclusive groups according to presence of diabetes mellitus, cardiovascular disease, or heart failure. We used 1 year of follow-up data to calculate outpatient, inpatient, emergency, pharmaceutical, dialysis, and total health care costs by eGFR (Kidney Disease Improving Global Outcomes-defined eGFR categories), adjusted for age, sex, and nonwhite race. RESULTS: Mean total health care costs among patients with CKD without comorbidities were 31% higher than among patients without CKD ($7374 versus $5631, respectively). Hospitalizations accounted for 35% of total costs among those with CKD and no comorbidities but up to 55% among patients with CKD and heart failure. The proportion of costs attributable to hospitalizations accelerated with declining kidney function, reaching as high as 66%. CONCLUSIONS: Poorer kidney function and the presence of diabetes mellitus, cardiovascular disease, or heart failure drive substantial health care costs and increase the proportion of costs attributable to inpatient care. The large contribution of inpatient costs begins in earlier stages of CKD and escalates as kidney function declines. Additional therapies to reduce CKD incidence, slow CKD progression, and lower hospitalization risk are needed to benefit patients and reduce CKD's economic burden.

Empagliflozin and the Risk of Heart Failure Hospitalization in Routine Clinical Care.

BACKGROUND: The EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients) showed that empagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces the risk of hospitalization for heart failure (HHF) by 35%, on top of standard of care in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The EMPRISE (Empagliflozin Comparative Effectiveness and Safety) study aims to assess empagliflozin's effectiveness, safety, and healthcare utilization in routine care from August 2014 through September 2019. In this first interim analysis, we investigated the risk of HHF among T2D patients initiating empagliflozin versus sitagliptin, a dipeptidyl peptidase-4 inhibitor. METHODS: Within 2 commercial and 1 federal (Medicare) claims data sources in the United States, we identified a 1:1 propensity score-matched cohort of T2D patients ≥18 years old initiating empagliflozin or sitagliptin from August 2014 through September 2016. The HHF outcome was defined as a HF discharge diagnosis in the primary position (HHF-specific); a broader definition was based on a HF discharge diagnosis in any position (HHF-broad). Hazard ratios (HRs) and 95% CIs were estimated controlling for over 140 baseline characteristics in each data source and pooled by fixed-effects meta-analysis. RESULTS: After propensity-score matching, we identified 16,443 patient pairs who initiated empagliflozin or sitagliptin. Average age was approximately 59 years, almost 54% of the participants were males, and approximately 25% had records of existing cardiovascular disease. Compared with sitagliptin, the initiation of empagliflozin decreased the risk of HHF-specific by 50% (HR, 0.50; 95% CI, 0.28-0.91), and the risk of HHF-broad by 49% (HR, 0.51;95% CI, 0.39-0.68), over a mean follow-up of 5.3 months. The results were consistent in patients with and without baseline cardiovascular disease, and for empagliflozin at both the 10- and 25-mg daily doses; analyses comparing empagliflozin versus the dipeptidyl peptidase-4 inhibitor class, and comparing sodium-glucose cotransporter-2 inhibitor versus dipeptidyl peptidase-4 inhibitor classes also produced consistent findings. CONCLUSIONS: The first interim analysis from EMPRISE showed that compared with sitagliptin, the initiation of empagliflozin was associated with a decreased risk of HHF among patients with T2D as treated in routine care, with and without a history of cardiovascular disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03363464.

Incidence of lower extremity amputations among patients with type 1 and type 2 diabetes in the United States from 2010 to 2014.

AIM: To compare the incidence of lower extremity amputation (LEA) among patients with type 1 diabetes (T1D) and patients with type 2 diabetes (T2D) with those without diabetes using US commercial claims and to assess the presence of key co-morbidities and precipitating factors at the time of the LEA. METHODS: Cohorts were defined via IBM MarketScan research databases for beneficiaries with T1D and T2D during 2010-2014. For each T1D and T2D patient, one patient without a prior diabetic claim matched on calendar time, sex and age, was randomly selected. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals. RESULTS: Among the matched cohorts of 120 129 T1D patients and 1.7 million T2D patients, the incidence of LEA was higher among patients with T1D than patients with T2D, with the most frequent cases being minor LEAs (4.85 and 1.53 per 1000 patient years [PY], respectively), largely toe amputations (4.49 and 1.43 per 1000 PY, respectively). Compared with non-diabetic patients matched on age, sex and calendar time, T1D and T2D patients had more co-morbidities and a higher incidence of LEA (6.02 vs. 0.14 per 1000 PY; aHR, 22.47 [16.42-30.73] and 1.90 vs. 0.23 per 1000 PY; aHR, 4.64 [4.32-4.98]). CONCLUSIONS: Our data showed a higher incidence of LEA, especially minor LEA, in patients with T1D and T2D compared with those without diabetes, with a greater risk among patients with T1D than patients with T2D. Accounting for known and measurable risk factors for LEA reduced the relative hazard by nearly 50%; the majority of LEA cases were minor LEAs and toe amputations.

Kidney disease progression and all-cause mortality across estimated glomerular filtration rate and albuminuria categories among patients with vs. without type 2 diabetes.

BACKGROUND: Studies of progression of kidney dysfunction typically focus on renal replacement therapy or percentage decline in estimated glomerular filtration rate (eGFR) as outcomes. Our aim was to compare real-world patients with and without T2D to estimate progression from and to clinically defined categories of kidney disease and all-cause mortality. METHODS: This was an observational cohort study of 31,931 patients with and 33,201 age/sex matched patients without type 2 diabetes (T2D) who had a serum creatinine and urine albumin-to-creatinine ratio (UACR) or dipstick proteinuria (DP) values. We used the first available serum creatinine value between 2006 and 2012 to calculate baseline eGFR and categorized them and the corresponding UACR/DP values using the Kidney Disease Improving Global Outcomes (KDIGO) categories. To assess our primary outcomes, we extracted probabilities of eGFR progression or mortality from life-table analyses and conducted multivariable Cox regression analyses of relative risk adjusted for age, sex, race/ethnicity, smoking, ischemic heart disease, heart failure, and use of renal-angiotensin-aldosterone system inhibitors. RESULTS: Patterns of eGFR decline were comparable among patients with vs. without T2D with larger percentage declines at higher albuminuria levels across all eGFR categories. eGFR decline was generally larger among T2D patients, particularly in those with severely increased albuminuria. Across all CKD categories, risk of progression to the next higher category of eGFR was substantially increased with increasing albuminuria. For example, the risk was 23.5, 36.2, and 65.1% among T2D patients with eGFR 30-59 ml/min/1.73m2 and UACR < 30, 30-299, and > 300 mg/dL, respectively (p < 0.001). Other comparisons were similarly significant. Among patients with low eGFR and normal to mildly increased albuminuria, the relative risk was up to 8-fold greater for all-cause mortality compared with the non-CKD subgroup (eGFR> 60 ml/min/1.73m2 with normal to mildly increased albuminuria). CONCLUSIONS: Presence of albuminuria was associated with accelerated eGFR decline independent of T2D. Risk for adverse outcomes was remarkably high among patients with CKD and normal to mildly increased albuminuria levels. Independent of T2D or albuminuria, a substantial risk for adverse outcomes exists for CKD patients in a routine care setting.

Correction to: Kidney disease progression and all-cause mortality across estimated glomerular filtration rate and albuminuria categories among patients with vs. without type 2 diabetes.

An amendment to this paper has been published and can be accessed via the original article.

Cardiovascular safety of linagliptin compared with other oral glucose-lowering agents in patients with type 2 diabetes: A sequential monitoring programme in routine care.

AIM: To evaluate the safety of linagliptin versus other glucose-lowering medications in a multi-year monitoring programme using insurance claims data. METHODS: In two commercial US claims databases, we identified three pairwise 1:1 propensity-score (PS)-matched cohorts of patients with type 2 diabetes (T2D) aged ≥18 years initiating linagliptin or a comparator (other dipeptidyl peptidase-4 [DPP-4] inhibitors [n = 31 492 pairs], pioglitazone [n = 23 316 pairs], or second-generation sulphonylureas [n = 19 731 pairs]) between May 2011 and December 2015. The primary endpoint was the risk of a composite cardiovascular (CV) outcome (hospitalization for myocardial infarction, stroke, unstable angina, or coronary revascularization). We estimated pooled hazard ratios (HRs) and 95% confidence intervals (CIs), controlling for >100 baseline characteristics. RESULTS: Patient characteristics were well balanced after PS-matching. The mean age was 55 years and mean follow-up was 0.8 years. Linagliptin conferred a similar risk of the composite CV outcome compared to other DPP-4 inhibitors (HR 0.91, 95% CI 0.79-1.05) and pioglitazone (HR 0.98, 95% CI 0.84-1.15), and showed a reduced risk of CV outcomes compared to second-generation sulphonylureas (HR 0.76, 95% CI 0.64--0.92). Key findings were signalled at the first interim analysis in June 2013 and solidified during ongoing monitoring until 2015. CONCLUSION: Analyses from a large monitoring programme in routine care of patients with T2D, showed that linagliptin had similar CV safety compared to other DPP-4 inhibitors and pioglitazone, and a reduced CV risk compared to sulphonylureas.

Development and validation of algorithms to identify newly diagnosed type 1 and type 2 diabetes in pediatric population using electronic medical records and claims data.

PURPOSE: To develop and validate algorithms to classify diabetes type in newly diagnosed pediatric patients with DM. METHOD: Data from the United States Department of Defense health system were used to identify patients aged 10 to 18 years with incident DM. Two independent sets of 200 children were randomly sampled for algorithm development and validation. Algorithms were developed based on clinical insight, published literature, and quantitative approaches. The actual DM type was ascertained via chart review. Finally, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were evaluated. RESULTS: Among the 400 patients, mean age was 14.2 (±2.5 years), and 50% were female. The best performing algorithms were based on data available in claims. They consisted of several logical expressions based on one predictor or more, which classified patients by use of glucose-lowering drugs or testing, DM ICD-9 diagnosis codes, and comorbidities. The best performing T2DM and T1DM algorithms achieved 90% and 98% sensitivity, 95% and 95% specificity, 87% and 98% PPV, and 96% and 96% NPV, respectively. CONCLUSIONS: Our results suggest that claims algorithms can accurately identify newly diagnosed T1DM and T2DM pediatric patients, which can facilitate large database studies in children with T1DM and T2DM. However, external validation in other data sources is needed.

Safety of non-insulin glucose-lowering drugs in pregnant women with pre-gestational diabetes: A cohort study.

AIMS: To evaluate the association between use of non-insulin antidiabetics in early pregnancy and the risk of miscarriages, stillbirths and major structural malformations. MATERIALS AND METHODS: A cohort of 1511 pregnant women with pre-gestational diabetes linked to live births was identified using electronic medical records from The Health Improvement Network (THIN) for the period 1995 to 2012. Information on prescriptions, foetal outcomes and potential confounders was ascertained from both codes and free text in the THIN database. Odds ratios (OR) and 95% confidence intervals (CI) of adverse foetal outcomes in women treated with non-insulin antidiabetics during the first trimester compared to those on insulin were estimated using logistic regression to adjust for type of diabetes, glycaemic control and other maternal characteristics. RESULTS: Among 311 pregnant women on non-insulin antidiabetics, 21.9% had a miscarriage and 1.6% a stillbirth; 1.9% of live births had major malformations. The corresponding frequencies for the 883 women on insulin were 13.3%, 1.7% and 9.6%. Insulin users more often had type 1 diabetes and poor glycaemic control. Compared to women with type 1 diabetes, those with type 2 diabetes had a higher risk of miscarriages (20.5% vs 12.8%) but a lower prevalence of malformations (4.0% vs 9.2%). Compared to women with HbA1c ≤7%, those with HbA1c >7% had a higher prevalence of malformations (12.6% vs 2.7%). After adjustment for diabetes type and glycaemic control, compared to insulin, non-insulin antidiabetic patients were associated with an OR for miscarriage of 1.19 (95% CI, 0.75-1.89), for stillbirths of 0.65 (95% CI, 0.16-2.58), and for major malformations of 0.25 (95% CI, 0.08-0.84). CONCLUSION: Among women with diabetes, use of non-insulin antidiabetics early in pregnancy was not associated with greater risks of foetal losses or major malformations than was insulin.

Claims-based studies of oral glucose-lowering medications can achieve balance in critical clinical variables only observed in electronic health records.

AIM: To evaluate the extent to which balance in unmeasured characteristics of patients with type 2 diabetes (T2DM) was achieved in claims data, by comparing against more detailed information from linked electronic health records (EHR) data. METHODS: Within a large US commercial insurance database and using a cohort design, we identified patients with T2DM initiating linagliptin or a comparator agent within class (ie, another dipeptidyl peptidase-4 inhibitor) or outside class (ie, pioglitazone or a sulphonylurea) between May 2011 and December 2012. We focused on comparators used at a similar stage of diabetes to linagliptin. For each comparison, 1:1 propensity score (PS) matching was used to balance >100 baseline claims-based characteristics, including proxies of diabetes severity and duration. Additional clinical data from EHR were available for a subset of patients. We assessed representativeness of the claims-EHR-linked subset, evaluated the balance of claims- and EHR-based covariates before and after PS-matching via standardized differences (SDs), and quantified the potential bias associated with observed imbalances. RESULTS: From a claims-based study population of 166 613 patients with T2DM, 7219 (4.3%) patients were linked to their EHR data. Claims-based characteristics in the EHR-linked and EHR-unlinked patients were similar (SD < 0.1), confirming the representativeness of the EHR-linked subset. The balance of claims-based and EHR-based patient characteristics appeared to be reasonable before PS-matching and generally improved in the PS-matched population, to be SD < 0.1 for most patient characteristics and SD < 0.2 for select laboratory results and body mass index categories, which was not large enough to cause meaningful confounding. CONCLUSION: In the context of pharmacoepidemiological research on diabetes therapy, choosing appropriate comparison groups paired with a new-user design and 1:1 PS matching on many proxies of diabetes severity and duration improves balance in covariates typically unmeasured in administrative claims datasets, to the extent that residual confounding is unlikely.

Real world management of pregestational diabetes not achieving glycemic control for many patients in the UK.

PURPOSE: Our goal was to describe the management of pregestational diabetes in pregnant women in the United Kingdom. METHODS: We used electronic medical records from The Health Improvement Network database between January 1995 and June 2012 to identify the first pregnancy in women 15 to 45 years of age with pregestational diabetes type 1 or type 2. Information on lifestyle factors, demographic characteristics, prescription of specific antidiabetic medications, and glycemic control measures (HbA1c) was obtained from primary care provider records. We evaluated treatment patterns and HbA1c levels within 90 days before the last menstrual period (prepregnancy period) and within each trimester of pregnancy. RESULTS: In a cohort of 1511 pregnant women with pregestational diabetes, 60% had type 1 and 40% type 2 diabetes. Among women with type 1 diabetes, 90% received antidiabetic medication (primarily insulin) prepregnancy and 92% during the first trimester. Among women with type 2 diabetes, 54% received antidiabetic medication (primarily metformin) during the prepregnancy period and 60% during the first trimester. Among women with nontreated diabetes type 2 before pregnancy, 22% initiated treatment by the first trimester (primarily insulin); those on noninsulin antidiabetic medications often switched to insulin. The proportion of women with at least 1 HbA1c value recorded within the prepregnancy period was 33% for type 1 (n = 299) and 31% for type 2 diabetes (n = 189); the corresponding proportions within the first trimester were 48% and 40%, respectively. Among women with recorded HbA1c, the prevalence of HbA1c > 7% prepregnancy was 70% for type 1 and 52% for type 2 diabetes; the proportions within the first trimester were 73% and 46%, respectively. CONCLUSIONS: Management of pregnant women with diabetes seems to follow recommendations for pharmacological treatment. However, there is substantial room for improvement in HbA1c control, that is, in the planning of pregnancy in women with diabetes, in the initiation of antidiabetic medication among women with diabetes type 2 who may need it, and likely in the compliance with treatments in women with type 2 and type 1 diabetes.

Identification of impaired fasting glucose, healthcare utilization and progression to diabetes in the UK using the Clinical Practice Research Datalink (CPRD).

PURPOSE: Few studies have examined patients with prediabetes in usual, "real-world" clinical practice settings. Among patients with impaired fasting glucose (IFG), we aimed to describe the rates of progression to diabetes and to examine the long-term reduction in diabetes risk associated with regression to normoglycemia at 1 year. METHODS: The UK-based study included 120 055 non-diabetic patients in Clinical Practice Research Datalink from 2001 to 2012 aged 25+ years and with ≥1 fasting plasma glucose (FPG) test between ≥6.1 and <7.0 mmol/l indicating IFG who were followed for progression to diabetes. In a subgroup of 45 167 patients with IFG with subsequent FPG results 1 year later, we assessed the 1-year glycemic status change and estimated the relative hazard of diabetes comparing patients with regression to normoglycemia (IFG-normoglycemia) to those who remained in IFG (IFG-IFG) using a multivariable Cox model. RESULTS: Among patients with IFG with over 414 649 person-years of follow-up, 52% received a subsequent FPG test, and 10% developed diabetes within 1 year after recognition of IFG. The incidence rate of diabetes was 5.86 (95% CI: 5.78 to 5.93) per 100 person-years. In the subgroup analysis, 31% of these patients remained in IFG, while 53% and 16% converted to normoglycemia or diabetes, respectively. The adjusted hazard ratio of developing diabetes was 0.33 (95% CI: 0.31 to 0.35) comparing IFG-normoglycemia to IFG-IFG. CONCLUSIONS: IFG is a high-risk state for diabetes. Regression to normoglycemia from IFG strongly reduces the long-term risk of developing diabetes. Our study also shows the feasibility of identifying patients with IFG in the Clinical Practice Research Datalink. Copyright © 2016 John Wiley & Sons, Ltd.

Sensitivity analysis of methods for active surveillance of acute myocardial infarction using electronic databases.

BACKGROUND: The validity of conclusions from observational studies depends on decisions regarding design, analysis, data quality, and implementation. Through sensitivity analyses, we explored the impact of such decisions on balance control and risk estimates. METHODS: Using as a template the Mini-Sentinel protocol for the active surveillance of acute myocardial infarction (MI) in association with use of antidiabetic agents, we defined cohorts of new users of metformin and second-generation sulfonylureas, baseline covariates and acute MI events using three combinations of washout and baseline periods. Using propensity-score matching, we assessed balance control and risk estimates using cumulative data for matching all patients compared with not rematching prior matches in quarterly analyses over the follow-up period. RESULTS: A longer washout period increased the confidence in new-user status, but at the expense of sample size; a longer baseline period improved capture of covariates related to pre-existing chronic conditions. When all patients were matched each quarter, balance was improved and risk estimates were more robust, especially in the later quarters. CONCLUSIONS: Durations of washout and baseline periods influence the likelihood of new-user status and sample size. Matching all patients tends to result in better covariate balance than matching only new patients. Decisions regarding the durations of washout and baseline periods depend on the specific research question and availability of longitudinal patient data within the database. This paper demonstrates the importance and utility of sensitivity analysis of methods for evaluating the robustness of results in observational studies.

Assessing the impact of propensity score estimation and implementation on covariate balance and confounding control within and across important subgroups in comparative effectiveness research.

PURPOSE: Researchers are often interested in estimating treatment effects in subgroups controlling for confounding based on a propensity score (PS) estimated in the overall study population. OBJECTIVE: To evaluate covariate balance and confounding control in sulfonylurea versus metformin initiators within subgroups defined by cardiovascular disease (CVD) history comparing an overall PS with subgroup-specific PSs implemented by 1:1 matching and stratification. METHODS: We analyzed younger patients from a US insurance claims database and older patients from 2 Medicare (Humana Medicare Advantage, fee-for-service Medicare Parts A, B, and D) datasets. Confounders and risk factors for acute myocardial infarction were included in an overall PS and subgroup PSs with and without CVD. Covariate balance was assessed using the average standardized absolute mean difference (ASAMD). RESULTS: Compared with crude estimates, ASAMD across covariates was improved 70%-94% for stratification for Medicare cohorts and 44%-99% for the younger cohort, with minimal differences between overall and subgroup-specific PSs. With matching, 75%-99% balance improvement was achieved regardless of cohort and PS, but with smaller sample size. Hazard ratios within each CVD subgroup differed minimally among PS and cohorts. CONCLUSIONS: Both overall PSs and CVD subgroup-specific PSs achieved good balance on measured covariates when assessing the relative association of diabetes monotherapy with nonfatal myocardial infarction. PS matching generally led to better balance than stratification, but with smaller sample size. Our study is limited insofar as crude differences were minimal, suggesting that the new user, active comparator design identified patients with some equipoise between treatments.

Economic burden related to fistulas or strictures among commercially insured patients with Crohn's disease in the United States.

BACKGROUND: Crohn's disease (CD) is a chronic, progressive, immune-mediated gastrointestinal condition that can lead to fistulizing or stricturing complications. OBJECTIVE: To quantify the burden of illness related to fistulas and/or strictures in patients with CD. METHODS: Using the Optum Research Database from October 2015 to December 2019, patients with CD were classified according to 1 of 3 condition cohorts: CD with fistula (CD-F), CD with stricture (CD-S), or CD with fistula and stricture (CD-FS). Each cohort was matched to a nonfistula, nonstricture CD cohort. Postdiagnosis per patient per year (PPPY) costs and health care resource utilization were assessed, accounting for variable lengths of follow-up periods. Multivariable generalized linear models were used to estimate the adjusted mean costs in each cohort. RESULTS: The CD-F, CD-S, and CD-FS cohorts included 1,317; 4,650; and 894 patients, respectively. The mean age of patients within the CD-S and their comparator cohorts was higher than in the CD-F or CD-FS cohorts (59.9 vs 49.5 vs 49.6 years). At baseline, cardiovascular disease was the most common comorbidity across all condition and comparator cohorts. Condition cohorts had 2-4 times more inpatient visits, 5-8 times more surgical visits, and 2-3 times more endoscopies PPPY than comparator cohorts. Compared with their respective comparator cohort, patients in the 3 condition cohorts had higher medication, medical, and total health care costs. CONCLUSIONS: This study demonstrates a significant economic burden related to fistulas and/or strictures among patients with CD, highlighting the importance of prevention, early recognition, and appropriate management of CD-related complications. DISCLOSURES: Yanni Fan, Ling Zhang, Jennifer S Thompson, and Kimberly G Brodovicz are employees of Boehringer Ingelheim. Rhonda L Bohn, Monik C Jiménez, and Stephani Gray (Bohn Epidemiology, LLC) are paid consultants to Boehringer Ingelheim. Gil Y Melmed reports receiving grants from Pfizer; consulting fees from Boehringer Ingelheim, AbbVie, Arena, BMS, Celgene, Entasis, Ferring Lilly, Fresenius Kabi, Medtronic, Samsung Bioepis, Janssen, Takeda, Pfizer, Prometheus Labs, and TechLab. We conducted a retrospective study using administrative claims data from the Optum Research Database, a database of a commercially insured population in the United States. All patient data were anonymized and deidentified; therefore, informed consent was not necessary. Restrictions apply to the availability of these data because of a contract between Optum and Boehringer Ingelheim, and data are thus unavailable to the public. For enquiries on the dataset analyzed in this study, please contact Optum (https://www.optum.com).

Patients With Stricturing or Penetrating Crohn's Disease Phenotypes Report High Disease Burden and Treatment Needs.

BACKGROUND: Crohn's disease (CD) is a chronic autoimmune disease in which inflammation can progress to complications of stricturing and/or penetrating disease. Real-world data on burden of complicated CD phenotypes are limited. METHODS: We analyzed cross-sectional data from the SPARC IBD (Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease) registry from 2016 to 2020. Four mutually exclusive phenotype cohorts were created: inflammatory CD (CD-I), complicated CD (stricturing CD, penetrating CD, and stricturing and penetrating CD [CD-SP]). Statistical analyses were performed using CD-I as the reference. RESULTS: A total of 1557 patients were identified: CD-I (n = 674, 43.3%), stricturing CD (n = 457, 29.4%), penetrating CD (n = 166, 10.7%), and CD-SP (n = 260, 16.7%). Patients with complicated phenotypes reported significantly greater use of tumor necrosis factor inhibitors (84.2%-86.7% vs 66.0%; P < .001) and corticosteroids (75.3%-82.7% vs 68.0%; P < .001). Patients with CD-SP reported significantly more aphthous ulcer (15.4% vs 10.5%; P < .05), erythema nodosum (6.5% vs 3.6%; P < .05), inflammatory bowel disease-related arthropathy (25.8% vs 17.2%; P < .01), liquid stools (24.2% vs 9.3%; P < .001), nocturnal fecal incontinence (10.8% vs 2.5%; P < .001), and CD-related surgery (77.7% vs 12.2%; P < .001). CONCLUSIONS: Patients with complicated CD phenotypes reported higher rates of active CD-related luminal and extraintestinal manifestations, and underwent more surgeries, despite being more likely to have received biologics than those with CD-I. The potential for early recognition and management of CD-I to prevent progression to complicated phenotypes should be explored in longitudinal studies.

Patients with complicated (stricturing and/or penetrating) Crohn's disease (CD) phenotypes have a higher disease burden, despite greater use of biologics, than patients with inflammatory CD. Early recognition and optimized management of CD may prevent progression to complicated phenotypes.

Palmoplantar Pustulosis has a Greater Disease Burden than Plaque Psoriasis: Real-World Evidence From the CorEvitas Psoriasis Registry.

Background: Palmoplantar pustulosis (PPP) is a rare skin disease characterized by episodes of neutrophilic pustules on the palms of the hands and soles of the feet. Current treatments for PPP have limited efficacy, and there is little real-world evidence characterizing the disease burden of PPP in patients. Objective: To describe and compare the clinical characteristics and patient-reported outcomes (PROs) of patients with PPP with those of patients with plaque psoriasis. Methods: This real-world study used data from patients with PPP or plaque psoriasis enrolled in the CorEvitas Psoriasis Registry. Disease characteristics, historical medical data, PROs, and quality-of-life measures were compared between patients with PPP and those with plaque psoriasis. These measures were also compared following patient stratification by body surface area involvement or Psoriasis Area and Severity Index. This study is purely descriptive; no hypothesis testing was performed. Results: In this data set, patients with PPP (n = 64) reported higher mean overall pain, using the visual analog scale, relative to those with plaque psoriasis (n = 4894). Patients with PPP also reported a greater proportion of work hours missed or affected; greater impairment of work; and greater impairment of daily activity than patients with plaque psoriasis. Similar effects were observed irrespective of patient stratification. Conclusion: Generally, PPP was associated with worse PROs and a greater impact on quality of life compared with plaque psoriasis. These findings highlight a need to develop effective therapies for PPP to improve disease management.

Cardiovascular and renal effectiveness of empagliflozin in routine care in East Asia: Results from the EMPRISE East Asia study.

Aim: To evaluate the effectiveness of empagliflozin in clinical practice in East Asia in the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) East Asia study. Materials and methods: Data were obtained from the Medical Data Vision database (Japan), National Health Insurance Service database (South Korea) and National Health Insurance database (Taiwan). Patients aged ≥ 18 years with type 2 diabetes initiating empagliflozin or a dipeptidyl peptidase-4 (DPP-4) inhibitor were 1:1 propensity score (PS) matched into sequentially built cohorts of new users naïve to both drug classes. This design reduces confounding due to switching treatments, time lag and immortal time biases. Outcomes included hospitalization for heart failure (HHF), end-stage renal disease (ESRD) and all-cause mortality. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional models, controlling for > 130 baseline characteristics in each data source and pooled by random-effects meta-analysis. Results: Overall, 28 712 pairs of PS-matched patients were identified with mean follow-up of 5.7-6.8 months. Compared with DPP-4 inhibitors, the risk of HHF was reduced by 18% and all-cause mortality was reduced by 36% with empagliflozin (HR 0.82; 95% CI 0.71-0.94, and HR 0.64; 95% CI 0.50-0.81, respectively). Reductions were consistent across countries, and in patients with and without baseline cardiovascular disease. ESRD was also significantly reduced with empagliflozin versus DPP-4 inhibitors (HR 0.37; 95% CI 0.24-0.58). Conclusions: Empagliflozin treatment was associated with reduced risk for HHF, all-cause mortality and ESRD compared with DPP-4 inhibitors in routine clinical practice in Japan, South Korea and Taiwan.

The EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study programme: Design and exposure accrual for an evaluation of empagliflozin in routine clinical care.

BACKGROUND: The EMPA-REG OUTCOME trial showed that empagliflozin reduced the risk of cardiovascular death and hospitalization for heart failure (HHF) in diabetic patients with cardiovascular disease. EMPRISE is a study programme on the effectiveness, safety and healthcare utilization of empagliflozin in routine care, leveraging real-world data from two commercial and one federal US data sources from 2014 to 2019. OBJECTIVES: To describe rationale and design of EMPRISE, assess ability to minimize confounding and evaluate the time to reach sufficient statistical power for a key study outcome, HHF, using baseline information from the first year of EMPRISE. METHODS: In 3 claims data sets, we identified a 1:1 propensity score (PS)-matched cohort of diabetic patients ≥18 years initiating empagliflozin or a dipeptidyl peptidase-4 inhibitor (DPP4i), resulting in 6643 total pairs. The PS model included >140 baseline covariates. We measured covariate balance via standardized differences (SD) and postmatching c-statistic. We computed the incidence rate (IR) of HHF, predicted exposure accrual over time and calculated expected power. RESULTS: After PS matching, patient characteristics were balanced with SD <0.1 and c-statistic between 0.54 and 0.59. The population IR of HHF was 4.4 per 1000 person-years using a specific HHF definition and 14.8 using a broader HHF definition. In our projection, 80%-powered analyses would require a minimum of 169 HHF events, expected to accumulate by year 3 (specific definition) or year 2 (broader definition). CONCLUSION: Baseline information from EMPRISE provided evidence of solid confounding control and adequate exposure accrual with expected powered analyses for the primary outcomes.