Empagliflozin and the Risk of Heart Failure Hospitalization in Routine Clinical Care: A First Analysis From the EMPRISE Study
VIEW EDITORIAL:Empagliflozin and Heart Failure
Abstract
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.
Clinical Perspective
What Is New?
•
A first assessment from the EMPRISE (Empagliflozin Comparative Effectiveness and Safety) study, which aims to assess the comparative effectiveness, safety, and impact on healthcare utilization of empagliflozin using real-world data, showed that compared with sitagliptin, the initiation of empagliflozin was associated with a decreased risk of hospitalization for heart failure (HHF) in routine care comparable in timing and magnitude to the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients) results.
•
The decrease in risk of HHF remained consistent among patients with and without a history of cardiovascular disease at baseline, although the number of events was still small in this interim analysis.
What Are the Clinical Implications?
•
These findings complement the EMPA-REG OUTCOME trial results and consolidate the notion that empagliflozin prevents HHF in routine care patients with an observed benefit across the spectrum of type 2 diabetes mellitus patients with and without history of cardiovascular disease.
•
Clinicians need to weigh the cardiovascular benefits of empagliflozin when prescribing glucose-lowering therapies in routine patients with type 2 diabetes mellitus.
Introduction
Editorial, see p 2831
The cardiovascular outcome trial1 EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients) showed that empagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), reduces the relative risk of cardiovascular death by 38% (hazard ratio [HR], 0.62; 95% CI, 0.49–0.77), all-cause mortality by 32% (HR, 0.68; 95% CI, 0.57–0.82), and hospitalization for heart failure (HHF) by 35% (HR, 0.65; 95% CI, 0.50–0.85) when added onto standard of care in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. However, these beneficial effects are yet to be evaluated in routine clinical care, which includes patients across a broader spectrum of cardiovascular risk, including patients without clinical evidence of cardiovascular disease.
The EMPRISE (Empagliflozin Comparative Effectiveness and Safety) study program aims to assess the comparative effectiveness, safety, and impact on healthcare utilization of empagliflozin, using real-world data from 3 databases in the United States. EMPRISE is a sequentially built new-user active-comparator cohort study of 1:1 propensity score–matched patients initiating empagliflozin or a comparator that will collect accumulating data for a period of 5 years after the date of empagliflozin’s approval in the United States (ie, August 1, 2014, through September 30, 2019); it comprises 4 planned interim analyses and a final analysis, each performed based on 12-month data updates. EMPRISE is expected to include over 200,000 1:1 propensity score–matched patients by its completion.2
In this interim analysis from EMPRISE, based on data from August 2014 through September 2016, we evaluated the risk of HHF associated with the initiation of empagliflozin compared with the initiation of sitagliptin, the most frequently prescribed dipeptidyl peptidase 4 inhibitor (DPP-4i) in the United States, which has demonstrated a neutral effect on the risk of HHF (HR, 1.00; 95% CI, 0.83–1.20).3
Methods
The authors declare that all supporting data are available within the article (and its online-only Data Supplement).
Data Source and Study Design
Within 2 commercial (Optum Clinformatics and IBM MarketScan) and 1 federal (Medicare fee-for-service) data sources in the United States, we identified a 1:1 propensity score (PS)–matched cohort of T2D patients of ≥18 years of age initiating empagliflozin or sitagliptin. Cohort entry date was the day of the first filled prescription of empagliflozin or sitagliptin, with no SGLT2i or DPP-4i use in the preceding year among patients with at least 1 year of continuous enrollment before cohort entry. The follow-up began on the day after cohort entry and continued in an “as-treated” approach until the first occurrence of treatment discontinuation or switch to a drug in the comparator class, the occurrence of an outcome, a nursing home admission, death, plan disenrollment, or September 30, 2016. In case of treatment interruption or discontinuation, we extended the exposure effect window until 30 days after the end of the last prescription’s supply. In secondary analyses, we redefined the comparator group as initiation of the overall DPP-4i class (sitagliptin, linagliptin, saxagliptin, or alogliptin) and the exposure as initiation of the overall SGLT2i class (canagliflozin, empagliflozin, or dapagliflozin).
Outcomes and Patient Characteristics
The HHF outcome was defined as a heart failure discharge diagnosis in the primary position (HHF-specific; positive predictive value = 84% to 100%)4; we also assessed a broader definition of HHF, defined as a heart failure discharge diagnosis in any position (HHF-broad; positive predictive value = 79% to 96%).4 Patient baseline characteristics were measured on the basis of enrollment information and claims during the 12 months before cohort entry and included demographics, calendar time (in quarters and days), comorbidities, diabetes mellitus–specific complications, use of diabetes mellitus drugs, use of other medications, indicators of health care utilization as proxy for overall disease state, care intensity and surveillance, and laboratory test results, which were available for a subset of 45% to 50% of patients in Optum and 5% to 10% in MarketScan. Particular emphasis was placed on the identification of claims-measured indicators of diabetes mellitus severity, including number of glucose-lowering medications at index date and specific past or concurrent diabetes mellitus therapy, diabetic nephropathy, neuropathy, retinopathy, diabetic foot and lower-limb amputations, and the number of hemoglobin A1c or glucose tests ordered (Table I in the online-only Data Supplement). We assessed the potential for residual confounding by unmeasured factors not included in the claims-based propensity score model by evaluating balance in laboratory test results in the subset of the population with this information available. An equivalent study design on second-line oral antidiabetic medications had shown successful balance in unmeasured patient characteristics like duration of diabetes mellitus, body mass index, hemoglobin A1c, creatinine, or lipid levels.5
Statistical Analysis
Within each data source, PSs were estimated using a multivariable logistic regression predicting the initiation of empagliflozin versus sitagliptin, conditional on over 140 predefined baseline characteristics (Table I in the online-only Data Supplement).6 Patients were 1:1 PS-matched using the nearest neighbor methodology with a maximum caliper of 0.01 of the PS.7,8 Postmatching covariate balance between treatments was assessed for each covariate by the calculation of standardized differences (ie, the difference in means or proportions divided by the pooled standard deviation), with meaningful imbalances set at values greater than 0.1.9,10 HRs and 95% CIs were estimated in each data source and pooled across the data sources using a fixed-effects meta-analysis,7 because random-effects pooling can be biased in the context of few databases.8 To address potential unmeasured confounding, we conducted the following sensitivity analyses: (1) we performed 1:1 high-dimensional PS matching, which enriched the original PS with 100 additional empirically identified covariates; and (2) we assessed the association with a control outcome with an expected null finding (ie, the occurrence of flu vaccination during follow-up). We also conducted subgroup analyses stratified by (1) the presence of cardiovascular disease at baseline, defined as a diagnosis or procedure for myocardial infarction, unstable angina, coronary atherosclerosis or other forms of chronic ischemic heart disease, coronary procedure, congestive heart failure, ischemic or hemorrhagic stroke, transient ischemic attack, peripheral arterial disease or surgery, or lower extremity amputation, recorded in the 12 months before cohort entry; (2) the presence of heart failure at baseline, defined as a diagnosis of heart failure or use of loop diuretics during the 12 months before cohort entry; (3) sex; and (4) the empagliflozin dose initiated (10 or 25 mg/day). Within each subgroup, PS was re-estimated, and PS matching and analyses were reperformed. Analyses redefining the comparator group as initiation of the overall DPP-4i class (sitagliptin, linagliptin, saxagliptin, or alogliptin) and the exposure as initiation of the overall SGLT2i class (canagliflozin, empagliflozin, or dapagliflozin) were also conducted.
All analyses were performed using Aetion platform version 3.2 with R version 3.2, which has previously been scientifically validated by accurately repeating a range of previously published studies12 and by replicating clinical trial findings.13,14 All individual data were deidentified, the study was approved by the Brigham and Women’s Hospital institutional review board, and signed data license agreements were in place for all data sources. The study was registered at EnCEPP (EUPAS20677) and at ClinicalTrials.gov (NCT03363464).
Results
We identified a total of 18,880 empagliflozin and 201,839 sitagliptin initiators. Empagliflozin initiators were younger, more frequently male, less frail as measured by the Claims-Based Frailty Index,15 and had a lower general burden of comorbidities as measured by the Combined Comorbidity Score16 compared with sitagliptin. Conversely, they had higher prevalence of obesity, higher baseline use of insulin or glucagon-like peptide-1 receptor agonists, and a higher number of antidiabetic medications at cohort entry (Table 1). Of empagliflozin initiators, 87% were successfully matched to sitagliptin initiators, resulting in 16,443 patient pairs (Figure 1, Table 1). PS-matched patients showed similar distribution of characteristics at baseline. In the patient subset with laboratory test results, those values were equally balanced including hemoglobin A1c and creatinine, despite not having been included in the PS model (Table 1, Table I in the online-only Data Supplement). The average age was 59 years, and almost 54% of the participants were males. Individuals with a history of cardiovascular disease, including recent acute cardiovascular events, represented about 25% of study participants, and approximately 5% of the population had history of heart failure. The additional comparisons of empagliflozin versus the overall DPP-4i class (N=17,551 PS-matched pairs) and the overall SGLT2i class versus the DPP-4i class (N=112,264 PS-matched pairs) showed comparable characteristics and balance achievement after PS matching (Figure I and Table II in the online-only Data Supplement).
| Baseline Characteristics | Unmatched | Propensity-Score Matched | ||||
|---|---|---|---|---|---|---|
| Sitagliptin (N = 201 839) | Empagliflozin (N = 18 880) | St. Diff. | Sitagliptin (N = 16 443) | Empagliflozin (N = 16 443) | St. Diff. | |
| Demographics | ||||||
| Age, mean (SD) | 67.54 (9.46) | 58.41 (8.93) | 0.99 | 59.11 (9.11) | 59.09 (8.94) | 0.00 |
| Male, n (%) | 96 641 (47.9) | 10 168 (53.9) | −0.12 | 8777 (53.4) | 8816 (53.6) | 0.00 |
| Burden of comorbidities | ||||||
| Combined comorbidity score, mean (SD) | 2.89 (2.22) | 2.20 (1.59) | 0.36 | 2.22 (1.66) | 2.19 (1.63) | 0.02 |
| Frailty score, mean (SD) | 0.15 (0.05) | 0.13 (0.04) | 0.44 | 0.14 (0.04) | 0.14 (0.04) | 0.00 |
| Diabetes-related complications, n (%) | ||||||
| Diabetic nephropathy | 20 082 (9.9) | 1490 (7.9) | 0.07 | 1257 (7.6) | 1247 (7.6) | 0.00 |
| Diabetic retinopathy | 14 153 (7.0) | 1122 (5.9) | 0.04 | 966 (5.9) | 957 (5.8) | 0.00 |
| Diabetic neuropathy | 36 387 (18.0) | 3216 (17.0) | 0.03 | 2698 (16.4) | 2694 (16.4) | 0.00 |
| Diabetes mellitus with peripheral circulatory disorders | 12 811 (6.3) | 762 (4.0) | 0.10 | 701 (4.3) | 674 (4.1) | 0.01 |
| Diabetic foot | 4986 (2.5) | 357 (1.9) | 0.04 | 329 (2.0) | 298 (1.8) | 0.01 |
| Hypoglycemia | 14 631 (7.2) | 1160 (6.1) | 0.04 | 1060 (6.4) | 1057 (6.4) | 0.00 |
| Features of diabetes mellitus medication initiation and baseline diabetes mellitus therapy | ||||||
| No. antidiabetic drugs at cohort entry, mean (SD) | 2.16 (0.77) | 2.29 (0.95) | -0.15 | 2.21 (0.85) | 2.22 (0.90) | −0.01 |
| Naive new user, n (%)* | 27 139 (13.4) | 1380 (7.3) | 0.20 | 1294 (7.9) | 1363 (8.3) | −0.01 |
| Monotherapy, n (%) | 20 203 (10.0) | 1130 (6.0) | 0.15 | 1061 (6.5) | 1127 (6.9) | −0.02 |
| Concomitant initiation or current use of metformin, n (%) | 131 791 (65.3) | 11 305 (59.9) | 0.11 | 10 010 (60.9) | 10 092 (61.4) | −0.01 |
| Concomitant initiation or current use of sulfonylureas, n (%) | 67 409 (33.4) | 4849 (25.7) | 0.17 | 4385 (26.7) | 4378 (26.6) | 0.00 |
| Concomitant initiation or current use of insulin, n (%) | 19 559 (9.7) | 3922 (20.8) | -0.31 | 3010 (18.3) | 2954 (18.0) | 0.01 |
| Other comorbidities at baseline, n (%) | ||||||
| History of CV disease | 74 342 (36.8) | 4608 (24.4) | 0.27 | 4115 (25.0) | 4094 (24.9) | 0.00 |
| Ischemic heart disease | 51 715 (25.6) | 3382 (17.9) | 0.19 | 3013 (18.3) | 2980 (18.1) | 0.01 |
| Previous coronary revascularization | 15 386 (7.6) | 864 (4.6) | 0.13 | 754 (4.6) | 772 (4.7) | 0.00 |
| Ischemic or hemorrhagic stroke | 19 753 (9.8) | 997 (5.3) | 0.17 | 948 (5.8) | 913 (5.6) | 0.01 |
| Heart failure | 21 514 (10.7) | 920 (4.9) | 0.22 | 884 (5.4) | 834 (5.1) | 0.01 |
| Peripheral arterial disease or surgery | 20 610 (10.2) | 959 (5.1) | 0.19 | 863 (5.2) | 872 (5.3) | 0.00 |
| Hypertension | 166 283 (82.4) | 14 422 (76.4) | 0.15 | 12 565 (76.4) | 12 513 (76.1) | 0.01 |
| Chronic kidney disease | 31 924 (15.8) | 1268 (6.7) | 0.29 | 1203 (7.3) | 1164 (7.1) | 0.01 |
| Laboratory test results† | ||||||
| HbA1c, mean % (SD) | 8.33 (1.78) | 8.50 (1.77) | -0.10 | 8.60 (1.86) | 8.46 (1.77) | 0.08 |
| Patients with HbA1c results available, n (%) | 17 214 (19.3) | 2649 (18.4) | 0.02 | 2395 (19.7) | 2091 (17.2) | 0.06 |
| Creatinine (mg/dL), mean (SD) | 0.97 (0.33) | 0.88 (0.22) | 0.32 | 0.90 (0.26) | 0.89 (0.22) | 0.04 |
| Patients with creatinine results available, n (%) | 17 436 (19.6) | 2812 (19.5) | 0.00 | 2441 (20.1) | 2197 (18.1) | 0.05 |
| Total cholesterol (mg/dL), mean (SD) | 176.96 (45.82) | 176.69 (45.22) | 0.01 | 179.36 (47.83) | 177.42 (45.80) | 0.04 |
| Patients with total cholesterol results available, n (%) | 15 478 (17.4) | 2556 (17.8) | -0.01 | 2195 (18.1) | 2012 (16.5) | 0.04 |
| LDL level (mg/dL), mean (SD) | 89.89 (47.55) | 87.41 (39.68) | 0.06 | 91.14 (40.49) | 88.07 (39.53) | 0.08 |
| Patients with LDL results available, n (%) | 16 147 (18.1) | 2543 (17.7) | 0.01 | 2243 (18.4) | 2003 (16.5) | 0.05 |
| HDL level (mg/dL), mean (SD) | 46.32 (44.30) | 44.07 (13.07) | 0.07 | 43.98 (12.61) | 44.24 (13.16) | -0.02 |
| Patients with HDL results available, n (%) | 15 345 (17.2) | 2516 (17.5) | -0.01 | 2179 (17.9) | 1978 (16.3) | 0.04 |
CV indicates cardiovascular; HbA1c, hemoglobin A1c; HDL, high-density lipoproteins; LDL, low-density lipoprotein; and St. Diff., standardized differences (ie, the difference in means or proportions divided by the pooled SD).9
*
Defined as patients without any use of glucose-lowering medications during the 12 months before cohort entry.
†
Only available in Optum Clinformatics and Truven MarketScan.
The incidence rates/1000 person-years in empagliflozin versus sitagliptin PS-matched initiators were 2.1 versus 6.7 for HHF-specific and 10.5 versus 22.2 for HHF-broad outcomes. 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 (Table 2). Database-specific estimates suggested concordant direction of the effect (Table III in the online-only Data Supplement). Cumulative incidence plots were consistent with these findings and tended to separate within 6 months after treatment initiation (Figure 2). Further adjustment by high-dimensional PS matching produced consistent results (HR, 0.54; 95% CI, 0.29–0.98 for HHF-specific; HR, 0.54; 95% CI, 0.41–0.71 for HHF-broad), as well as stratified analyses by duration of follow-up (Tables IV and V in the online-only Data Supplement). There was no association between empagliflozin and a control outcome with an expected null finding (ie, occurrence of flu vaccination during follow-up; HR, 0.96; 95% CI, 0.90–1.02; Table VI in the online-only Data Supplement). Subgroup analyses by presence of baseline cardiovascular disease, history of heart failure, sex, and empagliflozin daily dose initiated produced consistent results (Table 2), as did analyses comparing empagliflozin versus the overall class of DPP-4i and comparing the overall SGLT2i versus the DPP-4i class (Table 3, Figure II in the online-only Data Supplement).
| Patient Population | N Events (IR/1000 PY) | Hazard Ratio (95% CI) | |
|---|---|---|---|
| Empagliflozin | Sitagliptin | ||
| All patients | 16 443 | 16 443 | |
| HHF-specific* | 16 (2.1) | 48 (6.7) | 0.50 (0.28–0.91) |
| HHF-broad† | 78 (10.5) | 158 (22.2) | 0.51 (0.39–0.68) |
| Patients with CV history‡ | 4034 | 4034 | |
| HHF-specific* | 12 (7.0) | 30 (16.9) | 0.55 (0.27–1.10) |
| HHF-broad† | 60 (35.1) | 106 (60.7) | 0.60 (0.44–0.83) |
| Patients without CV history‡ | 12 342 | 12 342 | |
| HHF-specific* | <11 (0.5)§ | 14 (2.6) | 0.41 (0.10–1.68) |
| HHF-broad† | 16 (2.8) | 40 (7.4) | 0.40 (0.22–0.73) |
| Patients with HF history¶ | 1934 | 1934 | |
| HHF-specific* | 12 (14.5) | 25 (29.4) | 0.54 (0.27–1.09) |
| HHF-broad† | 51 (62.7) | 87 (104.7) | 0.61 (0.43–0.86) |
| Patients without HF history¶ | 14 405 | 14 405 | |
| HHF-specific* | <11 (0.6)§ | 11 (1.7) | 0.60 (0.18–2.07) |
| HHF-broad† | 25 (3.8) | 50 (7.9) | 0.52 (0.32–0.85) |
| Gender, male | 8690 | 8690 | |
| HHF-specific* | <11 (2.5)§ | 26 (6.7) | 0.48 (0.23–1.02) |
| HHF-broad† | 48 (11.8) | 89 (23.0) | 0.56 (0.40–0.80) |
| Gender, female | 7637 | 7637 | |
| HHF-specific* | <11 (1.8)§ | 17 (5.2) | 0.67 (0.25–1.83) |
| HHF-broad† | 31 (9.4) | 58 (17.7) | 0.57 (0.37–0.89) |
| Empagliflozin 10 mg | 10 204 | 10 204 | |
| HHF-specific* | 11 (2.6) | 28 (6.2) | 0.66 (0.32–1.39) |
| HHF-broad† | 45 (10.8) | 99 (22.0) | 0.53 (0.37–0.75) |
| Empagliflozin 25 mg | 7396 | 7396 | |
| HHF-specific* | <11 (1.8)§ | 23 (7.2) | 0.48 (0.18–1.26) |
| HHF-broad† | 34 (10.3) | 73 (22.8) | 0.49 (0.32–0.74) |
CV indicates cardiovascular; HF indicates heart failure; HHF, hospitalization for heart failure; IR, incidence rate; and PY, person-years.
*
Discharge diagnosis of HF in the primary position.
†
Discharge diagnosis of HF in any position.
‡
Defined as a history of myocardial infarction, unstable angina, coronary atherosclerosis and other forms of chronic ischemic heart disease, coronary procedure, heart failure, ischemic or hemorrhagic stroke, transient ischemic attack, peripheral arterial disease or surgery, or lower-extremity amputation.
§
In accordance with the data use agreement, we do not report information for frequency cells with fewer than 11 cases. These are noted as <11.
¶
Defined as history of heart failure or use of loop diuretics.
| Patient Population | N Events (IR/1000 PY) | |||||
|---|---|---|---|---|---|---|
| Empagliflozin | DPP-4i | HR (95% CI) | SGLT2 | DPP-4i | HR (95% CI) | |
| All patients | 17 551 | 17 551 | 112 264 | 112 264 | ||
| HHF-specific* | 16 (2.0) | 42 (5.6) | 0.49 (0.27–0.89) | 175 (2.7) | 414 (6.9) | 0.42 (0.35–0.50) |
| HHF-broad† | 82 (10.3) | 146 (19.6) | 0.56 (0.43–0.73) | 1055 (16.2) | 1486 (24.9) | 0.70 (0.65–0.75) |
| Patients with CV history‡ | 4245 | 4245 | 29 941 | 29 941 | ||
| HHF-specific* | 13 (7.1) | 42 (23.5) | 0.34 (0.18–0.63) | 149 (8.9) | 319 (19.6) | 0.48 (0.39–0.58) |
| HHF-broad† | 64 (35.4) | 115 (65.0) | 0.56 (0.41–0.76) | 841 (51.2) | 1117 (69.6) | 0.75 (0.68–0.82) |
| Patients without CV history‡ | 13 238 | 13 238 | 82 089 | 82 089 | ||
| HHF-specific* | <11 (0.5)§ | <11§ (1.7) | 0.49 (0.12–2.03) | 36 (0.7) | 90 (2.1) | 0.37 (0.25–0.54) |
| HHF-broad† | 17 (2.8) | 36 (6.3) | 0.46 (0.26–0.83) | 217 (4.5) | 358 (8.3) | 0.57 (0.48–0.68) |
| Patients with HF history¶ | 2051 | 2051 | 15 105 | 15 105 | ||
| HHF-specific* | 13 (14.7) | 22 (24.7) | 0.78 (0.37–1.63) | 136 (16.4) | 304 (36.3) | 0.46 (0.38–0.57) |
| HHF-broad† | 54 (62.1) | 96 (110.2) | 0.56 (0.41–0.78) | 755 (93.1) | 1012 (124.5) | 0.77 (0.70–0.84) |
| Patients without HF history¶ | 15 421 | 15 421 | 96 734 | 96 734 | ||
| HHF-specific* | <11 (0.6)§ | 13 (2.0) | 0.35 (0.11–1.12) | 46 (0.8) | 96 (1.9) | 0.46 (0.32–0.66) |
| HHF-broad† | 27 (3.8) | 41 (6.2) | 0.65 (0.40–1.06) | 315 (5.6) | 472 (9.2) | 0.64 (0.55–0.73) |
| Gender, male | 9347 | 9347 | 59 788 | 59 788 | ||
| HHF-specific* | <11 (2.3)* | 26 (6.3) | 0.43 (0.20–0.92) | 100 (2.7) | 207 (6.4) | 0.47 (0.36–0.60) |
| HHF-broad† | 49 (11.1) | 91 (22.0) | 0.53 (0.37–0.74) | 571 (15.7) | 789 (24.4) | 0.69 (0.62–0.77) |
| Gender, female | 8131 | 8131 | 52 023 | 52 023 | ||
| HHF-specific* | <11 (1.7)§ | 14 (4.1) | 0.52 (0.20–1.39) | 80 (2.8) | 195 (7.2) | 0.43 (0.33–0.55) |
| HHF-broad† | 33 (9.4) | 56 (16.6) | 0.58 (0.37–0.91) | 480 (16.9) | 744 (27.6) | 0.67 (0.60–0.75) |
| Empagliflozin 10 mg | 10 620 | 10 620 | Not applicable | |||
| HHF-specific* | 11 (2.5) | 19 (4.1) | 0.83 (0.38–1.80) | |||
| HHF-broad† | 46 (10.5) | 95 (20.6) | 0.55 (0.39–0.78) | |||
| Empagliflozin 25 mg | 7744 | 7744 | ||||
| HHF-specific* | <11 (1.7)§ | 19 (5.8) | 0.40 (0.16–1.02) | |||
| HHF-broad† | 35 (10.1) | 56 (17.3) | 0.62 (0.41–0.95) | |||
CV indicates cardiovascular; HF, heart failure; DPP-4i, dipeptidyl peptidase-4 inhibitors (alogliptin=3.1%,linagliptin=19.1%, sitagliptin=66.5%, saxagliptin=11.3%); HF, heart failure; HHF, hospitalization for heart failure; IR, incidence rate; PS, propensity-score; PY, person-years; and SGLT2i, sodium-glucose cotransporter-2 inhibitors (canagliflozin=68.6%, dapagliflozin=18.6%, empagliflozin=12.8%).
*
Discharge diagnosis of HF in the primary position.
§
In accordance with the data use agreement, we do not report information for frequency cells with fewer than 11 cases. These are noted as <11.
†
Discharge diagnosis of HF in any position.
‡
Defined as history of myocardial infarction, unstable angina, coronary atherosclerosis and other forms of chronic ischemic heart disease, coronary procedure, heart failure, ischemic or hemorrhagic stroke, transient ischemic attack, peripheral arterial disease or surgery, or lower extremity amputation.
¶
Defined as history of heart failure or use of loop diuretics.
Discussion
A first assessment from EMPRISE showed that compared with sitagliptin, the initiation of empagliflozin was associated with a decreased risk of HHF in routine care comparable in timing and magnitude to the EMPA-REG OUTCOME trial results.1 The results remained consistent among patients with and without a history of cardiovascular disease at baseline, although the number of events was still small in this interim analysis.
These findings complement the EMPA-REG OUTCOME trial results and support the notion that empagliflozin prevents HHF in routine care patients with a possible benefit across the spectrum of T2D people with and without a history of cardiovascular disease. It has been proposed that 1 of the main mechanisms that may explain the cardioprotective benefits of empagliflozin and other SGLT2is17,18 is via improvement in ventricular loading conditions through a reduction in preload (secondary to natriuresis and osmotic diuresis) and afterload (through a reduction in blood pressure and improvement in vascular function). Other postulated mechanisms include the improvement in cardiac metabolism and bioenergetics leading to enhanced cardiac efficiency and cardiac output; the inhibition of the myocardial Na+/H+ exchange, which would restore whole-body sodium homeostasis and ultimately reduce cardiac failure; the reduction of necrosis and cardiac fibrosis, a common pathway through which heart failure develops; and an alteration in adipokines, cytokine production, and epicardial adipose tissue mass, a common mechanism through which cardiovascular disease and insulin resistance develops.19
The EMPRISE study was designed to enhance clinical equipoise across treatment groups and minimize chances of confounding and time-related biases.20–22 Specifically,1 EMPRISE did not implement a hierarchical exposure definition allowing patients who started sitagliptin and then switched to empagliflozin to be included as empagliflozin initiators, resulting in possible immortal time bias,20,21 but instead it included new users of either empagliflozin or sitagliptin, without any use of either SGLT2is or DPP-4is during the year before cohort entry;2,23 EMPRISE did not compare empagliflozin to diabetes mellitus agents used at the extremes of the treatment pathway for T2D (eg, metformin or insulin, but it used comparators; ie, sitagliptin or overall DPP-4is) that represented comparable therapeutic alternatives for patients with T2D at the time,24 thus enhancing clinical equipoise for diabetes mellitus severity and duration between exposure groups and reducing chances of time-lag bias16; and3 EMPRISE implemented an extensive propensity-score adjustment on many proxies of diabetes mellitus severity and duration, including baseline use of insulin and other specific diabetes mellitus agents, diabetes mellitus–related complications, and healthcare utilization, which have demonstrated success in confounding control in studies of patients with T2D5 and which can also reduce time-lag bias.16 Furthermore, the inclusion of patients as treated in routine care without restrictions enabled assessment of the effects of empagliflozin across T2D patients with and without history of cardiovascular disease, and head-to-head comparisons of specific alternative diabetes mellitus treatment options allowed answering the clinically relevant question of which medication to choose for optimal diabetes mellitus care. Finally, observed absolute rates of HHF among EMPRISE patients were comparable with those previously reported among real-world T2D patients as captured in healthcare utilization data sources.25,26
Residual confounding by some unmeasured characteristics cannot be entirely ruled out, although it is unlikely to be consequential. A high-dimensional PS–matched analysis, which enriched the original PS with 100 additional empirically identified covariates, produced results consistent with the main analysis, and we were able to reproduce a null finding in an analysis evaluating the association between empagliflozin and a control neutral outcome. In addition, selected laboratory test results, including hemoglobin A1c, were balanced after propensity-score adjustment, despite not having been included in the propensity-score model, suggesting that we were able to successfully balance key unmeasured factors. Even though heart failure outcomes were defined using previously validated claims-based algorithms with high positive predictive value,4 some extent of outcome misclassification remains a possibility. At this stage of EMPRISE, the short duration of follow-up, mainly driven by the availability for analysis of only 2 years of empagliflozin use, limits the assessment of the long-term effects of empagliflozin. However, the decreased risk of HHF observed in RCTs appeared equally early1,17,18; thus, the short follow-up observed in the current study is not expected to affect the assessment of HHF. The subgroup of patients without cardiovascular disease at baseline is of specific interest, although the number of events is still small. We excluded all patients from this subgroup analysis who had a cardiovascular diagnosis or procedure coded during an encounter with the professional healthcare system in the 12 months before cohort entry. We cannot fully rule out that some patients have undiagnosed or low severity cardiovascular disease that was not recorded. As more data from EMPRISE become available over the study period, analyses will be conducted to test the robustness of such a definition.
In conclusion, this first interim analysis of the EMPRISE study 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. Future analyses will include increasing numbers of patients to study additional outcomes and more patient subgroups.
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© 2019 American Heart Association, Inc.
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History
Received: 5 December 2018
Accepted: 11 March 2019
Published online: 8 April 2019
Published in print: 18 June 2019
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Disclosures
Dr Patorno was supported by career development Grant K08AG055670 from the National Institute on Aging and is an investigator of investigator-initiated grants to the Brigham and Women’s Hospital from GSK, not directly related to the topic of the submitted work. Dr Déruaz-Luyet, Dr Brodovicz, and Dr Sambevski are employed by Boehringer Ingelheim. Dr Kulldorff was supported by National Institute of General Medical Sciences Grant RO1GM108999. Dr Schneeweiss was principal investigator of investigator-initiated grants to the Brigham and Women’s Hospital from Bayer and Vertex unrelated to the topic of this study and is a consultant to WHISCON and to Aetion, a software manufacturer in which he owns equity; his interests were declared, reviewed, and approved by the Brigham and Women’s Hospital and Partners HealthCare System in accordance with their institutional compliance policies. The other authors report no conflicts of interest.
Sources of Funding
This work was supported by a research grant to the Brigham and Women’s Hospital from Boehringer–Ingelheim. The study was conducted by the authors independent of the sponsor. The authors retained the right of publication and determined the final wording of the manuscript.
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- Comparative effects of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors on heart failure with preserved ejection fraction in diabetic patients: a meta-analysis, Cardiovascular Diabetology, 23, 1, (2024).https://doi.org/10.1186/s12933-024-02415-8
- Key results from observational studies and real‐world evidence of sodium‐glucose cotransporter‐2 inhibitor effectiveness and safety in reducing cardio‐renal risk, Diabetes, Obesity and Metabolism, 26, S5, (35-57), (2024).https://doi.org/10.1111/dom.15696
- Effectiveness and safety of empagliflozin: final results from the EMPRISE study, Diabetologia, 67, 7, (1328-1342), (2024).https://doi.org/10.1007/s00125-024-06126-3
- Empagliflozin, a sodium‐glucose cotransporter inhibitor enhancing mitochondrial action and cardioprotection in metabolic syndrome, Journal of Cellular Physiology, 239, 6, (2024).https://doi.org/10.1002/jcp.31264
- Sodium-Glucose Cotransporter-2 Inhibitors vs Sulfonylureas for Gout Prevention Among Patients With Type 2 Diabetes Receiving Metformin, JAMA Internal Medicine, 184, 6, (650), (2024).https://doi.org/10.1001/jamainternmed.2024.0376
- Comparative Effectiveness of Sodium–Glucose Cotransporter-2 Inhibitors for Recurrent Gout Flares and Gout-Primary Emergency Department Visits and Hospitalizations, Annals of Internal Medicine, 176, 8, (1067-1080), (2023).https://doi.org/10.7326/M23-0724
- Cardiovascular Diseases: Therapeutic Potential of SGLT-2 Inhibitors, Biomedicines, 11, 7, (2085), (2023).https://doi.org/10.3390/biomedicines11072085
- A Novel Chronic Kidney Disease Phenotyping Algorithm Using Combined Electronic Health Record and Claims Data, Clinical Epidemiology, Volume 15, (299-307), (2023).https://doi.org/10.2147/CLEP.S397020
- Empagliflozin is associated with lower cardiovascular risk compared with dipeptidyl peptidase-4 inhibitors in adults with and without cardiovascular disease: EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study results from Europe and Asia, Cardiovascular Diabetology, 22, 1, (2023).https://doi.org/10.1186/s12933-023-01963-9
- Promising Administrative Measures of Heart Failure and Future Directions, Circulation: Cardiovascular Quality and Outcomes, 16, 2, (e009833), (2023)./doi/10.1161/CIRCOUTCOMES.122.009833
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