Empagliflozin reduces cardiorenal events, healthcare resource use and mortality in Sweden compared to dipeptidyl peptidase-4 inhibitors: Real world evidence from the Nordic EMPRISE study.

AIMS: To evaluate effectiveness and healthcare resource utilization (HCRU) of empagliflozin versus dipeptidyl peptidase-4 inhibitors (DPP-4i) in Swedish clinical practice, as part of the EMPRISE EU study (EUPAS27606, NCT03817463). MATERIALS AND METHODS: A non-interventional, cohort study using retrospectively collected data from Swedish national registries. Adults with type 2 diabetes newly initiated on empagliflozin or DPP-4i from May 2014 to December 2018 were matched 1:1 using propensity scores based on >180 covariates. Cardiovascular outcomes included hospitalization for heart failure (HHF), all-cause mortality (ACM), myocardial infarction (MI), stroke and cardiovascular mortality (CVM), as well as their composite outcomes. Renal outcomes included end-stage renal disease (ESRD), estimated glomerular filtration rate (eGFR) decline to <60 ml/min/1.73 m2 and progression to micro/macroalbuminuria. HCRU outcomes were also assessed. Comparisons were done using Cox proportional hazards and Poisson regression models. RESULTS: Overall, 15,785 matched-pairs were identified, with a mean follow-up of 6.4 and 9.7 months for patients initiating empagliflozin versus DPP-4i, respectively. Empagliflozin was associated with significant reduction in rates of HHF (hazard ratio [HR] = 0.67; 95% confidence interval: 0.49-0.91), ACM (HR = 0.53; 0.41-0.68), HHF + ACM (HR = 0.59; 0.48-0.73), MI + stroke + ACM (HR = 0.68; 0.57-0.81), CVM (HR = 0.46; 0.29-0.73), HHF + CVM (HR = 0.61; 0.47-0.79) and MI + stroke + CVM (HR = 0.79; 0.63-0.98) versus DPP-4i. Empagliflozin also reduced the rates of ESRD (HR = 0.13; 0.03-0.57) and eGFR decline (HR = 0.83; 0.70-0.99). Regarding HCRU, empagliflozin was associated with lower risk of first inpatient stay (HR = 0.87; 0.81-0.93), and lower rate of inpatient and outpatient visits (rate ratio [RR] = 0.85; 0.80-0.89 and RR = 0.96; 0.94-0.98) than DPP-4i. CONCLUSIONS: Empagliflozin treatment compared to DPP-4i reduced cardiorenal events and overall mortality, which may explain lower HCRU among empagliflozin users in Sweden.

Healthcare Resource Utilization and Costs for Empagliflozin Versus Glucagon-Like Peptide-1 Receptor Agonists in Routine Clinical Care in Denmark.

INTRODUCTION: The sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin has shown reductions in major adverse cardiac events similar to glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, evidence is limited about how these therapies compare regarding overall healthcare resource utilization and costs in routine clinical care. METHODS: We conducted a comparative cohort study based on linked prospective healthcare databases for the entire population of Denmark during 2015-2018. We included 13,747 new users of empagliflozin and 13,249 new users of GLP-1RAs. Propensity scores were applied to balance potential confounders across the two treatment groups through inverse probability treatment weighting (IPTW). We assessed directly referable costs per person-year associated with healthcare resource utilization (inpatient, emergency room, and outpatient clinic hospital care, primary care health services, and prescription medication costs at pharmacies) among drug initiators while on-treatment. RESULTS: The two IPTW cohorts were well balanced at baseline (median age 61 years, 60% men, diabetes duration 6.7 years, 19% with pre-existing ischemic heart disease, 8% with pre-existing cerebrovascular disease), with similar healthcare costs in the previous year. During follow-up, average on-treatment costs per person-year were very similar among empagliflozin and GLP-1 RA initiators for the following services: inpatient hospitalizations (13,565 DKK versus 13,275 DKK), hospital outpatient clinic visits (12,007 DKK versus 12,152 DKK), emergency room visits (370 DKK versus 399 DKK), and primary care services (4108 DKK versus 4302 DKK). Total costs for any prescription drugs were clearly lower for empagliflozin initiators than for GLP-1 RA initiators (8946 DKK versus 14,029 DKK). In sum, overall healthcare costs on-treatment were lower for empagliflozin initiators (38,995 DKK per person-year) than for GLP-1RA initiators (44,157 DKK per person-year). CONCLUSIONS: In this nationwide population-based cohort study, average healthcare costs after drug initiation and while on treatment were lower for empagliflozin initiators than for GLP-1RAs initiators, driven by lower drug costs. REGISTRATION: The study protocol and analysis plan have been registered on the website of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) ( http://www.encepp.eu/encepp/viewResource.htm?id=37726 , first protocol registration 4 June 2019), and on clinicaltrials.gov ( https://clinicaltrials.gov/ct2/show/NCT03993132 , first posted 20 June 2019).

Healthcare resource utilization in patients treated with empagliflozin in East Asia.

AIMS/INTRODUCTION: We investigated the utilization of healthcare resources in patients with type 2 diabetes treated with empagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, versus dipeptidyl peptidase-4 (DPP-4) inhibitors in clinical practice in Japan, South Korea, and Taiwan. MATERIALS AND METHODS: We analyzed the Japanese Medical Data Vision database (December 2014-April 2018), the South Korean National Health Information Database, and the Taiwanese National Health Insurance claims database (both May 2016-December 2017). Patients with type 2 diabetes starting empagliflozin, 10 or 25 mg, or a DPP-4 inhibitor were matched 1:1 via propensity scores (PS). We compared inpatient care needs, emergency room (ER) visits, and outpatient visits between the treatment groups using Poisson regression and Cox proportional hazards models, pooled across countries by random-effects meta-analysis. RESULTS: We identified 28,712 pairs of PS-matched patients; the mean follow-up was 5.7-6.8 months. Empagliflozin-treated patients had a 27% lower risk of all-cause hospitalization compared with DPP-4 inhibitor-treated patients (rate ratio [RR] 0.73, 95% CI 0.67-0.79), and 23% reduced risk for first hospitalization (hazard ratio 0.77, 95% CI 0.73-0.81). The risk for an ER visit was 12% lower with empagliflozin than with DPP-4 inhibitors (RR 0.88, 95% CI 0.83-0.94) while the risk for outpatient visit was 4% lower (RR 0.96, 95% CI 0.96-0.97). These findings were generally consistent across countries, regardless of baseline cardiovascular disease, and in the subgroup starting empagliflozin with the 10 mg dose. CONCLUSIONS: Empagliflozin treatment was associated with lower inpatient care needs and other healthcare resource utilization than DPP-4 inhibitors in routine clinical practice in East Asia in this study.

Cost-Effectiveness of Empagliflozin in Patients With Diabetic Kidney Disease in the United States: Findings Based on the EMPA-REG OUTCOME Trial.

RATIONALE & OBJECTIVE: Benefits of sodium-glucose cotransporter 2 inhibitors on kidney outcomes have been demonstrated in clinical trials. Among patients with type 2 diabetes and established cardiovascular (CV) disease enrolled in the EMPA-REG OUTCOME study (ClinicalTrials.gov identifier NCT01131676), empagliflozin added to standard of care (SOC) reduced the risk of incident or worsening nephropathy compared with SOC alone. This analysis evaluated the cost-effectiveness of empagliflozin versus SOC alone in the subpopulation with diabetic kidney disease (DKD) from the perspective of US commercial insurers and Medicare. STUDY DESIGN: Discrete event simulation model. SETTING & POPULATION: Patients with DKD in a US health care system. INTERVENTIONS: Empagliflozin 10 or 25mg with SOC versus SOC alone. SOC included glucose-lowering therapies and medications to treat CV risk factors. OUTCOMES: Incremental cost-effectiveness ratios (2020 US dollars per quality-adjusted life-year [QALY] gained). Costs and QALYs were discounted 3.0% per year. MODEL, PERSPECTIVE, & TIME FRAME: Cost-effectiveness analysis, commercial insurers and Medicare perspective, lifetime horizon. RESULTS: The incremental cost-effectiveness ratio of empagliflozin with SOC versus SOC alone was $25,974 per QALY. Empagliflozin added 0.67 QALYs and $17,322 per patient over a lifetime horizon. Results were driven by fewer clinical events (including CV death, heart failure hospitalization, albuminuria progression, and a composite kidney outcome) experienced by patients receiving empagliflozin with SOC versus SOC alone. Results were sensitive to rates of CV death, nonfatal myocardial infarction, and heart failure hospitalization, as well as to drug costs and time horizon. Probabilistic sensitivity analyses indicated 91% of simulations at <$50,000 per QALY. LIMITATIONS: The EMPA-REG OUTCOME study was not powered to assess treatment benefits in a subgroup and excluded patients with estimated glomerular filtration rate<30mL/min/1.73m2. CONCLUSIONS: Based on the EMPA-REG OUTCOME study, this cost-effectiveness analysis suggests that, for commercial insurers and Medicare, adding empagliflozin to SOC may be a cost-effective treatment option for patients with DKD.

Cost-effectiveness of empagliflozin in patients with type 2 diabetes and established cardiovascular disease in China.

BACKGROUND: In several cardiovascular outcome trials (CVOTs), empagliflozin (SGLT-2 inhibitor), sitagliptin (DPP-4 inhibitor) and liraglutide (GLP-1 receptor agonist) + standard of care (SoC) were compared to SoC in patients with type 2 diabetes and established cardiovascular disease (CVD). This study assessed the cost-effectiveness (CE) of empagliflozin + SoC in comparison to sitagliptin + SoC and liraglutide + SoC based on the respective CVOT. METHODS: The IQVIA Core Diabetes Model (CDM) was calibrated to reproduce the CVOT outcomes. EMPA-REG OUTCOME baseline characteristics and CVOT specific treatment effects on risk factors for cardiovascular disease (HbA1c, BMI, blood pressure, lipids) were applied. Three-year observed cardiovascular events of empagliflozin + SoC versus sitagliptin + SoC and liraglutide + SoC were derived from EMPA-REG OUTCOME and an indirect treatment comparison. Relative risk adjustments to calibrate the CDM were obtained after a trial and error process to match as closely the observed and CDM-predicted outcomes. The drug-specific treatment effects were considered up until HbA1c reached 8.5% and treatment switch occurred. After this switch, the United Kingdom Prospective Diabetes Study 82 risk equations predicted events based on co-existing risk factors and treatment intensification to basal bolus insulin were applied. The analysis was conducted from the perspective of the Chinese healthcare system applying 3% discounting. The time horizon was lifelong. RESULTS: Empagliflozin + SoC provides additional Quality Adjusted Life years (QALY + 0.564) for an incremental cost of 42,497RMB (US$6053) compared to sitagliptin + SoC, resulting in an Incremental Cost Utility Ratio of 75,349RMB (US$10,732), thus below the willingness-to-pay threshold of 212,676RMB, corresponding to three times the Gross Domestic Product in China (2019). Compared to liraglutide + SoC, empagliflozin + SoC use leads to 0.211QALY gained and cost savings of 71,427RMB (US$10,173) and is as such dominant. Scenario and probabilistic sensitivity analyses demonstrated the robustness of the results. CONCLUSION: Results suggest that empagliflozin + SoC is cost-effective compared to sitagliptin + SoC and liraglutide + SoC at a willingness-to-pay threshold of 212,676RMB ($30,292)/QALY.

Cardiovascular Events, Acute Hospitalizations, and Mortality in Patients With Type 2 Diabetes Mellitus Who Initiate Empagliflozin Versus Liraglutide: A Comparative Effectiveness Study.

Background In cardiovascular outcome trials, the sodium glucose cotransporter 2 inhibitor empagliflozin and glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide caused similar reductions in major adverse cardiac events (MACE). We compared clinical outcomes in routine clinical care. Methods and Results EMPLACE (Cardiovascular and Renal Outcomes, and Mortality in Danish Patients with Type 2 Diabetes Who Initiate Empagliflozin Versus GLP-1RA: A Danish Nationwide Comparative Effectiveness Study) is an ongoing nationwide population-based comparative effectiveness cohort study in Denmark. For the present study, we included 14 498 new users of empagliflozin and 12 706 new users of liraglutide, 2015 to 2018. Co-primary outcomes were expanded major adverse cardiac events (stroke, myocardial infarction, unstable angina, coronary revascularization, hospitalization for heart failure [HHF], or all-cause death); HHF or all-cause death; and first HHF or first initiation of loop-diuretic therapy. Secondary outcomes included all-cause hospitalization or death. We applied propensity score balancing and Cox regression to compute adjusted hazard ratios (aHRs) in on-treatment (OT) and intention-to-treat (ITT) analyses. Cohorts were well balanced at baseline (median age 61 years, 59% men, diabetes mellitus duration 6.6 years, 30% with preexisting cardiovascular disease). During mean follow-up of 1.1 years in OT and 1.5 years in ITT analyses, empagliflozin versus liraglutide was associated with a similar rate of expanded major adverse cardiac events (OT aHR, 1.02; 95% CI, 0.91-1.14; ITT aHR, 1.06; 95% CI, 0.96-1.17), and HHF or all-cause death (OT aHR, 0.97; 95% CI, 0.85-1.11; ITT aHR, 1.02; 95% CI, 0.91-1.14); and a decreased rate of a first incident HHF or loop-diuretic initiation (OT aHR, 0.80; 95% CI, 0.68-0.94; ITT aHR, 0.87; 95% CI, 0.76-1.00), and of all-cause hospitalization or death (OT aHR, 0.93; 95% CI, 0.89-0.98; ITT aHR, 0.93; 95% CI, 0.90-0.97). Conclusions Empagliflozin and liraglutide initiators had comparable rates of expanded major adverse cardiac events, and HHF or all-cause death, whereas empagliflozin initiators had a lower rate of a first HHF or loop-diuretic initiation.

Cost-effectiveness of empagliflozin versus canagliflozin, dapagliflozin, or standard of care in patients with type 2 diabetes and established cardiovascular disease.

INTRODUCTION: Empagliflozin, a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, is approved in the USA to reduce risk of cardiovascular (CV) death in adults with type 2 diabetes mellitus (T2DM) and established CV disease, based on EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial results. Empagliflozin reduced major adverse CV event (MACE) by 14%, CV death by 38%, and hospitalization for heart failure (HHF) by 35% vs placebo, each on top of standard of care (SoC). SGLT-2 inhibitors canagliflozin and dapagliflozin have also been compared with placebo, all on top of SoC, in CV outcome trials. In the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program, canagliflozin reduced MACE by 14% and HHF by 33%. Dapagliflozin reduced HHF by 27% in the DECLARE-TIMI 58 trial (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events). This analysis estimated the cost-effectiveness of empagliflozin versus canagliflozin, dapagliflozin, or SoC, in US adults with T2DM and established CV disease. RESEARCH DESIGN AND METHODS: Individual patient-level discrete-event simulation was conducted to predict time-to-event for CV and renal outcomes, and specific adverse events over patients' lifetimes. Occurrence of events in EMPA-REG OUTCOME was estimated based on event-free survival curves with time-dependent covariates. An HR for canagliflozin or dapagliflozin versus empagliflozin on each clinical event was estimated from published CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME data using indirect treatment comparison. Public sources provided US costs and utilities. RESULTS: The model predicted longer survival for empagliflozin versus canagliflozin, dapagliflozin, and SoC mainly due to direct reduction in CV death. Empagliflozin dominated canagliflozin, yielding more quality-adjusted life years (QALYs; 0.38) at a lower cost (-US$306). Compared with dapagliflozin and SoC, empagliflozin yielded 0.50 and 0.84 incremental QALYs at US$1517 and US$27 539 incremental costs, yielding incremental cost-effectiveness ratios of US$3054/QALY and US$32 848/QALY, respectively. CONCLUSIONS: Empagliflozin was projected to dominate canagliflozin and be highly cost-effective compared with dapagliflozin and SoC using US healthcare costs.

Cost-effectiveness analysis of empagliflozin compared with glimepiride in patients with Type 2 diabetes in China.

Aim: The study assesses the cost-effectiveness of empagliflozin versus glimepiride in patients with Type 2 diabetes and uncontrolled by metformin alone in China, based on the EMPA-REG H2H-SU trial. Materials & methods: A calibrated version of the IQVIA Core Diabetes Model was used. Cost of complications and utility were taken from literature. The Chinese healthcare system perspective and 5% discounting rates were applied. Results: Empagliflozin+metformin provides additional quality-adjusted life-years (0.317) driven by a reduction in the number of cardiovascular and renal events, for an additional cost of $1382 (CNY9703) compared with glimepiride+metformin. Conclusion: Empagliflozin is cost-effective treatment versus glimepiride applying a threshold of $30,290 (CNY212,676).

Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes.

AIMS: The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF). METHODS AND RESULTS: HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were -4.0 m (-16.0, 6.0; P = 0.42) and 4.0 m (-5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported. CONCLUSION: The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.

Cost-effectiveness of empagliflozin in the UK in an EMPA-REG OUTCOME subgroup with type 2 diabetes and heart failure.

AIMS: Heart failure (HF) and type 2 diabetes (T2D), common co-morbidities, translate into worse patient prognoses and higher direct costs than for either condition alone. Empagliflozin has been shown to markedly reduce cardiovascular (CV) deaths and HF hospitalizations (HHF) in HF patients with T2D. This study evaluated the lifetime cost-effectiveness of supplementing standard of care (SoC) with empagliflozin, relative to SoC alone, in HF patients with T2D from the UK payer perspective. METHODS AND RESULTS: An existing discrete-event simulation model was adapted for the economic evaluation. Risk equations developed from time-dependent parametric survival analyses using patient-level HF subpopulation data from the EMPA-REG OUTCOME trial were employed to predict CV and renal events. Non-CV death, utility weights, and costs were drawn from UK sources. Quality-adjusted life years (QALYs) and costs were discounted at 3.5% per annum. Relative to SoC, empagliflozin with SoC yielded fewer first HHF, recurrent HHF, CV death, and non-fatal myocardial infarction but more non-fatal stroke events. Empagliflozin with SoC vs. SoC alone was associated with increased average life expectancy (10.80 vs. 9.59 LYs) and quality of life (6.27 vs. 5.62 QALYs), though at higher lifetime cost (£18 197 vs. £16 829) per person, resulting in an incremental cost-effectiveness ratio of £2093 per QALY. The probability of empagliflozin being cost-effective in the HF subpopulation at a £20 000 per QALY willingness-to-pay threshold was 91%. CONCLUSIONS: This analysis suggests that adding empagliflozin to SoC in HF patients with T2D constitutes a cost-effective use of UK healthcare resources and may provide long-term health benefits to patients.

Long-Term Cost-Effectiveness Analyses of Empagliflozin Versus Oral Semaglutide, in Addition to Metformin, for the Treatment of Type 2 Diabetes in the UK.

INTRODUCTION: International guidelines recommend treatment with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist for treatment intensification in type 2 diabetes mellitus (T2DM) patients with progression on metformin. In the randomised, controlled, Peptide Innovation for Early Diabetes Treatment (PIONEER) 2 trial, the SGLT-2 inhibitor empagliflozin was compared with the GLP-1 receptor agonist oral semaglutide, in addition to metformin. The aim of the current study was to assess the long-term cost-effectiveness of empagliflozin 25 mg versus oral semaglutide 14 mg, in addition to metformin, for T2DM patients in the UK. METHODS: Analyses were conducted from the UK healthcare payer perspective, using the IQVIA Core Diabetes model, with a time horizon of 50 years. Patients received either empagliflozin or oral semaglutide, in addition to metformin, until Hba1c threshold of 7.5% (58 mmol/mol) was exceeded, following which treatment intensification with insulin glargine in addition to empagliflozin or oral semaglutide plus metformin was assumed. Baseline cohort characteristics and 52-week treatment effects were derived from the PIONEER 2 trial. Treatment effects of empagliflozin and GLP-1 receptor agonists on hospitalisation for heart failure (hHF) were based on the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) real-world study. Utilities, treatment costs and costs of diabetes-related complications were obtained from published sources. RESULTS: Direct costs for empagliflozin plus metformin were considerably lower than those for oral semaglutide plus metformin (by more than GBP 6000). Compared with oral semaglutide plus metformin, empagliflozin plus metformin was a cost-effective treatment for T2DM patients in all scenarios tested. Probabilistic sensitivity analysis showed cost-effectiveness in > 95% of the iterations using a threshold of 20,000 GBP/QALY. CONCLUSION: Empagliflozin 25 mg is a cost-effective treatment option versus oral semaglutide 14 mg, when used in addition to metformin, for the treatment of T2DM patients in the UK.

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.

Cost-effectiveness of empagliflozin compared with liraglutide based on cardiovascular outcome trials in Type II diabetes.

Aim: Cost-effectiveness (CE) analysis of empagliflozin+standard of care (SoC) compared with SoC and liraglutide+SoC, in patients with Type II diabetes and established cardiovascular disease, was conducted using evidence from cardiovascular outcomes trials. Methods: The IQVIA Core Diabetes Model was calibrated to predict same outcomes observed in EMPA-REG OUTCOME and LEADER trials. Three-year observed cardiovascular events of SoC, empagliflozin+SoC and liraglutide+SoC were derived from EMPA-REG OUTCOME trial and an indirect comparison. Time horizon was 50 years and the UK payer perspective was taken. Results: Empagliflozin+SoC dominated liraglutide+SoC with greater quality-adjusted life years and reduced costs. Base-case incremental CE ratio of 6428 GBP/QALY was observed for empagliflozin+SoC versus SoC. Conclusion: Results suggest that empagliflozin+SoC is cost effective versus SoC and liraglutide+SoC.

Changes in SGLT2i and GLP-1RA real-world initiator profiles following cardiovascular outcome trials: A Danish nationwide population-based study.

BACKGROUND: We investigated changes in clinical characteristics of SGLT2i and GLP-1RA real-world initiators in Denmark before/after landmark cardiovascular outcome trials. METHODS: We compared first-time SGLT2i (25,070) and GLP-1RA (14,671) initiators to initiators of DPP-4i (n = 34,079), a class without proven cardiovascular benefits. We used linked population-based healthcare data to examine initiation incidence, medication patterns, and pre-existing atherosclerotic cardiovascular disease (ASCVD) during 2014-2017. RESULTS: Nationwide incidence of SGLT2i initiators increased 3.6-fold (53/100,000 to 172/100,000 per year) vs. a 1.5-fold increase for GLP-1RA. DPP-4i initiation remained stable. From the end of 2015, SGLT2i was increasingly used as 2nd-line therapy, while medication patterns were much more stable for GLP-1RA. Among SGLT2i users, ASCVD increased slightly from 28% to 30%; age- and gender-adj. prevalence ratio (aPR) = 1.03 (95% CI:0.97-1.10). In contrast, among GLP-1RA initiators, baseline ASCVD declined from 29% to 27% (aPR: 0.90 (95% CI:0.84-0.97)), and in DPP-4i initiators from 31% to 29% (aPR: 0.91 (95% CI:0.88-0.96)). CONCLUSIONS: Following the EMPA-REG OUTCOME trial in 2015, SGLT2i have become increasingly used as 2nd-line treatment in everyday clinical practice, with only minor increases in patient proportions with ASCVD. For GLP-1RA, we observed more stable therapy lines and slightly decreasing ASCVD in new users despite the LEADER trial.

Cost-Effectiveness Analysis of Empagliflozin in Comparison to Sitagliptin and Saxagliptin Based on Cardiovascular Outcome Trials in Patients with Type 2 Diabetes and Established Cardiovascular Disease.

INTRODUCTION: In the cardiovascular outcome trials (CVOT) EMPA-REG OUTCOME, TECOS and SAVOR-TIMI 53, empagliflozin [sodium/glucose cotransporter 2 (SGLT2) inhibitor], sitagliptin and saxagliptin [both dipeptidyl peptidase 4 (DPP4) inhibitors] + standard of care (SoC) were compared to SoC in patients with type 2 diabetes and established cardiovascular disease (CVD). This study assessed the cost-effectiveness (CE) of empagliflozin + SoC in comparison to sitagliptin + SoC and saxagliptin + SoC based on the respective CVOT. METHODS: The IQVIA Core Diabetes Model (CDM) was calibrated to reproduce the CVOT outcomes. EMPA-REG OUTCOME baseline characteristics and CVOT specific treatment effects on risk factors for cardiovascular disease [glycated haemogloblin A1c (HbA1c), body mass index (BMI), blood pressure, lipids] were applied. Three-year observed cardiovascular events of empagliflozin + SoC versus sitagliptin + SoC and saxagliptin + SoC were derived from EMPA-REG OUTCOME and an indirect treatment comparison. Relative risk (RR) adjustments to calibrate the CDM were estimated after consecutive attempts of running the model until the observed and CDM-predicted outcomes matched closely. The drug-specific treatment effects were considered up until treatment switch (when HbA1c reached 8.5%), after which, the United Kingdom Prospective Diabetes Study (UKPDS) 82 risk equations predicted events based on co-existing risk factors and treatment intensification to basal-bolus insulin were applied. The analysis was conducted from the perspective of the UK National Health Service. Costs and quality of life data were derived from UK national sources and published literature. A 50-year time horizon and discount rate of 3.5% were applied. RESULTS: The CDM projected quality-adjusted life years (QALYs) of 6.408, 5.917 and 5.704 and total costs of 50,801 GBP, 47,627 GBP and 48,071 GBP for empagliflozin + SoC, sitagliptin + SoC and saxagliptin + SoC, respectively. The incremental CE ratio (ICER) of empagliflozin + SoC versus sitagliptin + SoC and saxagliptin + SoC was 6464 GBP/QALY and 3878 GBP/QALY, respectively. One-way and probabilistic sensitivity analyses demonstrated the robustness of the results. CONCLUSION: Results suggest that empagliflozin + SoC is cost-effective compared to sitagliptin + SoC and saxagliptin + SoC at a willingness to pay threshold of 20,000 GBP/QALY. FUNDING: Boehringer Ingelheim International GmbH.

Cost-effectiveness Analysis of Empagliflozin in Japan Based on Results From the Asian subpopulation in the EMPA-REG OUTCOME Trial.

PURPOSE: The goal of this study was to assess the cost-effectiveness of empagliflozin in Japan based on the Asian subpopulation in the EMPA-REG OUTCOME trial. METHODS: The trial has shown a reduction in the risk for cardiovascular (CV) and renal events with empagliflozin in patients with type 2 diabetes mellitus and established CV disease. A cost-effectiveness analysis based on the overall population of the EMPA-REG OUTCOME trial was reported previously by using a lifetime discrete event simulation model. The same modeling frame was adapted to evaluate the cost-effectiveness of treatment with empagliflozin added to standard of care (SoC) compared with SoC alone in Japan. The time to relevant clinical events and the hazard ratios were derived from an Asian subpopulation in the EMPA-REG OUTCOME trial. The costs for each event were estimated from a Japanese medical claims database. Direct medical costs, life expectancy, and quality-adjusted life years (QALYs) were calculated from the public health care perspective. FINDINGS: Treatment with empagliflozin was estimated to increase life expectancy by 6.2 years and 2.7 QALYs, whereas total cost increased by 1,115,475 yen compared with treatment with SoC alone. The incremental cost-effectiveness ratio was 415,849 yen/QALY. In the sensitivity analysis, there was no case that was in excess of the reference value of the incremental cost-effectiveness ratio in the pilot introduction for price revision in Japan (ie, 5 million yen/QALY). IMPLICATIONS: Based on the Asian subpopulation in the EMPA-REG OUTCOME trial, our results suggest that empagliflozin added to SoC is highly cost-effective compared with SoC alone in Japan.

Rationale and design of the EMPERIAL-Preserved and EMPERIAL-Reduced trials of empagliflozin in patients with chronic heart failure.

AIMS: Heart failure (HF) is associated with considerable symptom burden and impairment in physical functioning and quality of life. The sodium-glucose co-transporter 2 inhibitor empagliflozin reduced the risk of HF hospitalisation and cardiovascular death in patients with type 2 diabetes and established cardiovascular disease in the EMPA-REG OUTCOME trial, and could potentially improve congestion symptoms and exercise capacity in patients with HF. We describe the designs of the EMPERIAL-Preserved and EMPERIAL-Reduced trials of empagliflozin in patients with chronic stable HF, with or without type 2 diabetes. METHODS: EMPERIAL-Preserved and EMPERIAL-Reduced are randomised, placebo-controlled trials designed to investigate the effects of empagliflozin on exercise capacity and patient-reported outcomes in patients with chronic stable HF with preserved ejection fraction [HFpEF; left ventricular ejection fraction (LVEF) > 40%] and HF with reduced ejection fraction (HFrEF; LVEF ≤ 40%), respectively. In each trial, approximately 300 patients will be randomised 1:1 to receive empagliflozin 10 mg or placebo once daily for 12 weeks. In both trials, the primary endpoint is the change from baseline in 6-min walk test distance at week 12. Key secondary endpoints are the change from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score and change from baseline in dyspnoea score of the Chronic Heart Failure Questionnaire at week 12. CONCLUSION: The EMPERIAL-Preserved and EMPERIAL-Reduced trials will determine the effects of empagliflozin on exercise capacity and patient-reported outcomes in patients with HFpEF and HFrEF, respectively, and provide insight into the potential of empagliflozin in the treatment of patients with HF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03448406 (EMPERIAL-Preserved), NCT03448419 (EMPERIAL-Reduced).

Correction to: Cardiovascular Safety of Empagliflozin Versus Dipeptidyl Peptidase-4 (DPP-4) Inhibitors in Type 2 Diabetes: Systematic Literature Review and Indirect Comparisons.

The authors have updated Fig. 3 which was incorrectly published in the original publication.

Cardiovascular Safety of Empagliflozin Versus Dipeptidyl Peptidase-4 (DPP-4) Inhibitors in Type 2 Diabetes: Systematic Literature Review and Indirect Comparisons.

INTRODUCTION: Clinical trials conducted in patients with type 2 diabetes (T2DM) treated with glucose-lowering drugs and examining cardiovascular-related outcomes have yielded mixed results. In this work, we aimed to assess the relative treatment effects of empagliflozin versus sitagliptin and saxagliptin (dipeptidyl peptidase-4 (DPP-4) inhibitors) on cardiovascular-related outcomes in patients with T2DM. METHODS: We conducted a systematic literature review to identify clinical trials assessing cardiovascular-related outcomes for sitagliptin-, saxagliptin-, and empagliflozin-treated patients with T2DM. A network meta-analysis of indirect treatment comparisons was conducted in a Bayesian framework. Hazard ratios (HR) and 95% credible intervals (CrI) were computed for six cardiovascular-related outcomes to estimate the relative efficacies of these agents. RESULTS: Empagliflozin showed a statistically significant superiority over saxagliptin (HR 0.60; 95% CrI 0.46-0.80) and sitagliptin (HR 0.60; 95% CrI 0.46-0.79) to reduce the risk for cardiovascular-related mortality. For all-cause mortality, empagliflozin showed a statistically significant risk reduction compared to saxagliptin (HR 0.61; 95% CrI 0.49-0.76) and sitagliptin (HR 0.67; 95% CrI 0.54-0.83). A similar pattern was observed in the risk reduction for hospitalization due to heart failure, where empagliflozin was found to be statistically significantly superior to saxagliptin (HR 0.51; 95% CrI 0.37-0.70) and sitagliptin (HR 0.65; 95% CrI 0.47-0.90). Empagliflozin was not statistically significantly different to sitagliptin and saxagliptin with regard to the risk of a composite endpoint composed of death, stroke or myocardial infarction. CONCLUSION: In this indirect comparison to the DPP-4 inhibitors saxagliptin and sitagliptin, empagliflozin significantly lowered the risk of cardiovascular-related mortality, all-cause mortality and hospitalizations due to heart failure. FUNDING: Boehringer Ingelheim GmbH.

Cost-effectiveness analysis of dabigatran versus rivaroxaban for stroke prevention in patients with non-valvular atrial fibrillation using real-world evidence in elderly US Medicare beneficiaries.

OBJECTIVE: Dabigatran and rivaroxaban have been approved by the US FDA to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation (NVAF) patients. Newly published real-world evidence based on the US population found that elderly Medicare patients with NVAF treated with rivaroxaban experienced statistically significant increases in intracranial hemorrhage (ICH) and major extracranial bleeding, and statistically nonsignificant decreases in thromboembolic stroke and acute myocardial infarction (AMI) compared with dabigatran. This study assessed the cost-effectiveness of dabigatran vs. rivaroxaban for the treatment of US Medicare NVAF patients. METHODS: A previously published Markov model was adapted to compare dabigatran and rivaroxaban. The model considered thromboembolic stroke, bleeding events, and AMI based on the published real-world event risks. Model outputs included clinical event rates, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: Dabigatran patients experienced fewer ICH and major extracranial bleeding events than rivaroxaban patients, but more stroke and AMI events. Dabigatran was found to yield lower costs and higher QALYs than rivaroxaban, with incremental costs of -$3534 and incremental QALYs of 0.004. Results remained consistent in sensitivity analyses, with a positive net monetary benefit (willingness-to-pay thresholds of $50,000 and $100,000 per QALY) for dabigatran over rivaroxaban for all model inputs tested. CONCLUSIONS: In this study using US Medicare real-world data, dabigatran was found to dominate rivaroxaban. The analyses were limited by the short follow-up period of the real-world data and results may not be generalizable to other patient populations.