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

Abstract

Open in new tabDownload slide

See page 711 for the editorial comment on this article (doi: 10.1093/eurheartj/ehaa965) 

Introduction

In type 2 diabetes (T2D), sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of both incident and recurrent heart failure (HF) hospitalization.^1–5 In addition, in patients with HF and reduced ejection fraction (HFrEF), SGLT2 inhibitors reduce risk of cardiovascular death and worsening HF, independent of the presence of T2D.⁶ Ongoing clinical trials are further assessing effects of SGLT2 inhibitors on clinical outcomes in HF across the spectrum of ejection fraction (EF).^7–9

Beyond its adverse impact on clinical outcomes, HF results in considerable symptom burden.¹⁰ Exercise intolerance, which can manifest as dyspnoea or fatigue, is a cardinal symptom of HF that affects patients regardless of underlying left ventricular ejection fraction (LVEF) and leads to the impairment of physical functioning and quality of life. Improving HF symptoms and ability to complete daily activities continue to be unmet medical needs, which are of particular importance for patients with HF, independent of EF.¹⁰ A recent trial suggests symptom improvements with SGLT2 inhibition, measured by the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS), in patients with HFrEF; however, the effect in HF with preserved EF (HFpEF) is unknown.¹¹

The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) programme was designed to prospectively evaluate the effect of the SGLT2 inhibitor empagliflozin on exercise ability and symptom burden in HF through two conceptually identical randomized trials, enrolling patients with HFrEF and HFpEF, with and without T2D.

Methods

Trial design

The detailed study design of the EMPERIAL programme has been published.¹² In brief, EMPERIAL-Reduced (ClinicalTrials.gov: NCT03448419) and EMPERIAL-Preserved (NCT03448406) were concurrently conducted, Phase 3, randomized, double-blind, placebo-controlled trials, that evaluated the effect of empagliflozin on exercise ability and patient-reported outcomes in patients with HF, with and without T2D. The participating centres are provided in the Supplementary material online.

The protocols were approved by the investigational review board at each participating centre. All patients provided written informed consent. The studies were conducted in accordance with Good Clinical Practice, International Council for Harmonisation guidelines, and the ethical principles of the Declaration of Helsinki.

Eligible patients had symptomatic (NYHA II-IV) HF diagnosed ≥3 months prior to screening with LVEF ≤40% (EMPERIAL-Reduced) or >40% (EMPERIAL-Preserved) and 6-minute walk test distance (6MWTD) of ≥100 m at baseline and ≤350 m at screening. Patients with LVEF ≤40% were required to be on guideline-directed medical therapy,^{13  ,  14} at stable doses for ≥4 weeks prior to screening. A stable dose of diuretics was required for ≥2 weeks prior to screening. Inclusion and exclusion criteria are listed in the Supplementary material online.

Participants were randomized (1:1) to empagliflozin 10 mg once daily or placebo for 12 weeks. Randomization was performed in blocks, using an interactive response technology system, without stratification. Visits were performed at screening, baseline, Week 6, Week 12 (or earlier in the case of early study discontinuation), and 7 days after treatment discontinuation. Measurements at baseline, Week 6, and Week 12 included: 6MWTD,¹⁵ Kansas City Cardiomyopathy Questionnaire (KCCQ),¹⁶ Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS),¹⁷ Clinical Congestion Score (summary score of orthopnoea, jugular venous distension, and oedema),¹⁸ and N-terminal pro-brain natriuretic peptide (NT-proBNP). At baseline and Week 12, two 6-minute walk tests (6MWTs) were performed ≥1 h apart to increase reliability and reduce variability. Distances from both tests were recorded and the larger distance measured was used for all analyses.

Endpoints

The primary endpoint was change from baseline in 6MWTD at Week 12. Key secondary endpoints were change from baseline in KCCQ-TSS and CHQ-SAS dyspnoea score at Week 12.

Additional endpoints included: change from baseline to Week 6 in 6MWTD, KCCQ-TSS responders (≥5 and ≥8 points) at Week 12, change from baseline at Week 12 in clinical congestion score, NT-proBNP, and intensification of diuretic use (defined as any new start and any dose increase).

Safety was assessed based on adverse events (AEs) reported throughout the study and up to 7 days after last dose of study medication [coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA version 22.0)], clinical laboratory tests, vital signs, 12-lead electrocardiogram, and physical examination. Data collection ended on 7 October 2019 in EMPERIAL-Reduced and 9 October 2019 in EMPERIAL-Preserved.

Statistical considerations

Sample size assumptions and power analyses details have been published previously.¹² In each trial, a sample size of 150 patients per randomized treatment group was required to provide 90% power at a two-sided alpha level of 0.05 to detect a 30-m treatment difference between empagliflozin and placebo in change from baseline at Week 12 in 6MWTD, assuming standard deviation of 72 m and worst-case imputation of missing data for 5% of patients. Analysis of primary and both key secondary efficacy endpoints was performed using Wilcoxon rank test, including patients with missing data via a worst-case imputation.¹² If the primary endpoint was not met, tests of key secondary endpoints would be conducted in an exploratory fashion. Efficacy analyses were performed following the intention-to-treat principle. Several exploratory subgroup analyses were pre-specified in the statistical analysis plan, including analysis by diabetes status. For all KCCQ and CHQ-SAS domains, a mixed model repeated measures (MMRM) analysis was pre-specified. The model included treatment-by-visit interaction and baseline value-by-visit interaction as fixed effects. Safety was analysed descriptively in patients treated with ≥1 dose of study drug. No interim analyses were performed.

Responder analyses were conducted using a logistic regression model adjusted for baseline value of the respective score, baseline T2D status, glomerular filtration rate estimated by the Chronic Kidney Disease EPIdemiology collaboration formula with serum creatinine [eGFR (CKD-EPIcr)] at baseline, and age. Missing scores were handled as no improvement.

Statistical considerations for the other exploratory endpoints are listed in the Supplementary material online.

Results

Between March 2018 and October 2019, in the USA, Canada, Australia, and Europe, 312 patients at 109 centres participated in EMPERIAL-Reduced and 315 patients at 108 centres participated in EMPERIAL-Preserved. A total of 156 participants were randomized to empagliflozin and 156 to placebo in EMPERIAL-Reduced, and 157 to empagliflozin and 158 to placebo in EMPERIAL-Preserved (Figure 1).

Baseline demographics

Baseline characteristics are shown in Table 1. In EMPERIAL-Reduced, the mean age was 69.0 ± 10.2 years, 25.6% were women, and 13.5% were African American. The cause of HF was ischaemic in 50.6% of participants, the mean LVEF was 30.3 ± 6.7%, and diabetes was present in 59.9% of participants. The median [interquartile range (IQR)] baseline 6MWTD was 309.0 m (248.5, 332.0) with placebo and 306.0 m (260.0, 333.5) with empagliflozin. In EMPERIAL-Preserved, the mean age was 73.5 ± 8.8 years, 43.2% were women, and 10.2% were African American. The cause of HF was ischaemic in 40.6% of participants. The mean LVEF was 53.1 ± 8.0%, and diabetes was present in 51.1%. The median (IQR) 6MWTD at baseline was 299.5 m (245.0, 331.0) with placebo and 297.0 m (246.0, 326.0) with empagliflozin. Patients were treated according to guideline-recommended HF therapies; 36.5% of EMPERIAL-Reduced and 3.5% of EMPERIAL-Preserved participants were treated with angiotensin receptor neprilysin inhibitors (ARNis) at baseline (Table 1).

The number of participants who prematurely discontinued the trial medication for any reason was 13 (8.3%) with placebo and 15 (9.7%) with empagliflozin in EMPERIAL-Reduced, and 11 (7.0%) and 13 (8.3%), respectively, in EMPERIAL-Preserved.

Primary and key secondary analyses

In both EMPERIAL-Reduced and EMPERIAL-Preserved, the primary endpoint was not met (Take home figure). In EMPERIAL-Reduced, 6MWTD median (IQR) change from baseline at Week 12 was 13.5 m (−8.0, 42.0) with empagliflozin and 18.0 m (−11.5, 54.0) with placebo, with a median [95% confidence interval (CI)] difference of −4.0 m (−16.0, 6.0) (P = 0.42; Table 2). In EMPERIAL-Preserved, 6MWTD median change (IQR) was 10.0 m (−10.0, 32.0) with empagliflozin and 5.0 m (−20.0, 33.0) with placebo, with a median difference of 4.0 m (−5.0, 13.0; P = 0.37) (Table 2). Further analyses of the primary endpoint indicated consistency across subgroups (Supplementary material online, Figures S1 and S2). As the primary endpoint was not met, analyses of all secondary endpoints are considered exploratory.

Exploratory analysis results for the key secondary endpoints are shown in Table 2.

The median (95% CI) difference from baseline to Week 12, empagliflozin vs. placebo, in KCCQ-TSS was 3.13 (0.00, 7.29) and 2.08 (−2.08, 6.25) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. The median difference, empagliflozin vs. placebo, in CHQ-SAS dyspnoea score was 0.10 (−0.20, 0.40) and −0.07 (−0.35, 0.20) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively.

Further exploratory analyses

In addition to the primary non-parametric analyses (Wilcoxon rank test), a parametric approach (MMRM analysis) was used to allow comparability with outcomes from other trials, such as DEFINE-HF and PARADIGM-HF.^{6  ,  19} Exploratory MMRM analyses of KCCQ-TSS showed between-group differences in mean (95% CI) change from baseline at Week 12 of 4.55 (1.18, 7.93) favouring empagliflozin vs. placebo in EMPERIAL-Reduced, and 0.58 (−2.97, 4.13) in EMPERIAL-Preserved (Supplementary material online, Figure S7).

More participants showed KCCQ-TSS improvements in pre-specified clinically meaningful thresholds of ≥5 and ≥8 points with empagliflozin than placebo, with adjusted odds ratios (OR) (95% CI) 1.83 (1.12, 2.98) and 1.66 (1.02, 2.72), respectively, in EMPERIAL-Reduced (Figure 2). Analyses assessing the same cut-offs did not suggest treatment difference in EMPERIAL-Preserved.

Open in new tabDownload slide

Open in new tabDownload slide

Figure 1

CONSORT 2010 flow diagram—EMPERIAL-Reduced (A) and EMPERIAL-Preserved (B).

Figure 2

Exploratory KCCQ-TSS responder rate analyses of the pre-specified thresholds ≥5 and ≥8 points, suggested improvement, empagliflozin vs. placebo, in EMPERIAL-Reduced, but not EMPERIAL-Preserved. Conducted using an adjusted logistic regression model. Missing data handled as no improvement. Brackets contain 95% confidence intervals. KCCQ-TSS, Kansas City Cardiomyopathy Questionnaire-Total System Score; OR, odds ratio.

Open in new tabDownload slide

Congestion score reduction at Week 12, empagliflozin vs. placebo, was observed in EMPERIAL-Reduced: −0.31 (95% CI −0.53, −0.09); but not EMPERIAL-Preserved [−0.09 (−0.31, 0.14)] (Figure 3). No significant changes in Patient Global Impression of Severity or Change in HF symptoms or dyspnoea were observed in either study (Supplementary material online, Tables S10 and S11). No notable change in NT-proBNP was observed in either study (Table 2, Supplementary material online, Tables S12 and S13). Seven (4.5%) empagliflozin vs. 25 (16.1%) placebo participants required intensification of diuretic therapy in EMPERIAL-Reduced, and 17 (11.0%) vs. 24 (15.4%), respectively, in EMPERIAL-Preserved (Figure 4).

Figure 3

Exploratory MMRM analyses of change in clinical congestion score^a from baseline at Week 12 suggest empagliflozin treatment effect in EMPERIAL-Reduced (A), but not in EMPERIAL-Preserved (B). ^aSummary score of orthopnoea, jugular venous distension, and oedema. Mixed model repeated measures analysis using all data up to individual trial completion in randomized patients who had a baseline and post-baseline measurement for the respective outcome. Model included treatment-by-visit interaction and baseline value-by-visit interaction as fixed effects. Unstructured covariance was used to fit the mixed model. Brackets show 95% confidence intervals. CIs, confidence intervals.

Open in new tabDownload slide

Figure 4

Exploratory analyses of intensification of diuretic therapy suggest empagliflozin treatment effect at Week 12 in EMPERIAL-Reduced but not in EMPERIAL-Preserved. Based on a Cox regression model. CI, confidence interval; HR, hazard ratio.

Open in new tabDownload slide

Safety

In both trials, there was no notable difference for empagliflozin vs. placebo regarding the overall frequencies of any AE or any AE leading to treatment discontinuation (Table 4). Serious AEs (SAEs) were less frequently reported with empagliflozin than placebo and frequencies of AEs of interest were low. Decreased kidney function was reported with similar frequencies in both groups. No ketoacidosis or confirmed hypoglycaemic events occurred in participants without T2D. No new safety concerns were identified.

No increase in AE rates were observed with empagliflozin. The spectrum of AEs was consistent with the known safety profile of empagliflozin in patients with T2D, and safety was also demonstrated in patients without T2D for the first time (Supplementary material online, Table S1).

Discussion

The EMPERIAL trials did not demonstrate improvement in the primary endpoint of exercise ability, irrespective of LVEF, as measured by 6MWTD over 12 weeks. The key secondary endpoints of KCCQ-TSS and CHQ-SAS dyspnoea were analysed in an exploratory manner. Non-parametric estimates of the Week 12 difference in medians, empagliflozin vs. placebo, were inconclusive, whereas the exploratory responder analysis and parametric analysis of the difference in means suggest a possible favourable effect of empagliflozin on KCCQ-TSS and CHQ-SAS in HFrEF, but not HFpEF patients. The indication of effect on KCCQ-TSS, but not 6MWTD, is not necessarily unexpected, as the 6MWT assesses physical performance, whereas the KCCQ-TSS reflects symptom burden and symptom frequency, rather than physical limitation. Furthermore, cardiac performance and exercise capacity are disassociated due to multiple factors.²⁰

No notable NT-proBNP change was observed in either study, despite the empagliflozin-associated improvement in clinical congestion score and patient-reported outcomes in HFrEF.

The exploratory KCCQ-TSS MMRM analyses are comparable with exploratory observations from the DEFINE-HF trial, which showed a neutral effect of dapagliflozin on 6MWTD.²¹ Furthermore, the KCCQ-TSS between-group difference of 4.55 at Week 12, favouring empagliflozin, in EMPERIAL-Reduced is similar to the between-group difference of 4.8 seen in DEFINE-HF, which enrolled exclusively patients with HF and EF ≤40%.²¹

The magnitude of effect of empagliflozin on KCCQ-TSS (MMRM analysis) in EMPERIAL-Reduced (9.0 ± 1.2 empagliflozin vs. 4.5 ± 1.2 placebo) was similar to the magnitude of effect of dapagliflozin on KCCQ-CSS (Kansas City Cardiomyopathy Questionnaire clinical summary score) (8-month observations) in the DAPA-HF trial (6.1 ± 18.6 dapagliflozin vs. −3.3 ± 19.2 placebo).⁶ This is in contrast to the smaller magnitude of effect on KCCQ-CSS observed in PARADIGM-HF, with 8-month differences of −3.0 ± 0.4 with sacubitril/valsartan and −4.6 ± 0.4 with enalapril.²² EMPERIAL-Reduced ≥5-point KCCQ-TSS responder analysis indicated a favourable effect of empagliflozin over placebo, with OR (95% CI) 1.83 (1.12, 2.98) (Figure 3), which was also comparable with DAPA-HF observations, with dapagliflozin vs. placebo OR of 1.15 (1.08, 1.23).⁶

Consistent with the possible benefits seen in KCCQ-TSS, exploratory analyses of additional secondary endpoints suggested favourable effects on symptoms, clinical congestion score and diuretic use with empagliflozin in EMPERIAL-Reduced but not EMPERIAL-Preserved. It may be that the effects of empagliflozin on the exploratory endpoints of congestion and volume homeostasis were more pronounced in HFrEF than in HFpEF, or that the observation period was too short to see effects in EMPERIAL-Preserved. Heterogeneity among the HFpEF participants may have contributed to the lack of uniform observations between the trials. Furthermore, this type of dichotomy, with respect to mortality and morbidity, between HFrEF and HFpEF patients has been observed with other drugs.^23–25

Various HFrEF trials have shown correlation between KCCQ improvement, or prevention of deterioration, and a lower mortality risk or decline in rate of HF hospitalization.^{26  ,  27} Despite no significant difference in 6MWTD, the KCCQ-TSS improvement in EMPERIAL-Reduced may suggest future improvement in mortality and HF hospitalization, as recently shown with empagliflozin in EMPEROR-Reduced,⁹ and dapagliflozin in the DAPA-HF trial.¹¹ Mortality and HF hospitalization in patients with HFpEF treated with empagliflozin are being evaluated in the ongoing EMPEROR-Preserved trial.⁷ The absence of KCCQ-TSS improvement in EMPERIAL-Preserved does not necessarily imply that there may also be an absence of benefit in EMPEROR-Preserved, as effects on mortality may also not be uniformly accompanied by effects on quality of life scores.

Limitations of the EMPERIAL trials include the enrolment of relatively frail HF patients, with baseline 6MWTD <350 m, which is in contrast to DEFINE-HF. In addition, while powered to detect a 30 m 6MWTD improvement, the sample size was relatively small.

The EMPERIAL trials support the safety of SGLT2 inhibition with empagliflozin in HF patients, with and without T2D. Given the growing body of evidence demonstrating improved clinical outcomes with SGLT2 inhibitors in HF, these reassuring data on safety are noteworthy. These preliminary suggestions of benefit on congestion, diuretic use, and quality of life in HFrEF are supportive of the impact on hard clinical outcomes observed in the recently reported EMPEROR-Reduced trial.⁹

Supplementary material

Supplementary material is available at European Heart Journal online.

Acknowledgements

The EMPERIAL trials were sponsored by Boehringer Ingelheim. The authors thank the patients who participated in these trials. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Sally Neath of Elevate Scientific Solutions, Wilmslow, UK, during the preparation of this article. The authors were fully responsible for all content and editorial decisions and were involved at all stages of manuscript development and have approved the final version. The protocols were designed by the principal investigators and the sponsor, and the sponsor participated in site selection and management and in data analysis. The principal investigators had unrestricted access to the data, wrote the manuscript, and vouch for the accuracy and completeness of the data and analyses and for the fidelity of the trial to the protocol.

Funding

Boehringer Ingelheim.

Data sharing

The sponsor of the EMPERIAL trials (Boehringer Ingelheim) is committed to responsible sharing of clinical study reports, related clinical documents, and patient-level clinical study data. Researchers are invited to submit inquiries via the following website: https://trials.boehringer-ingelheim.com.

Conflict of interest: W.T.A. reports personal fees from Boehringer Ingelheim (BI), consulting fees from Abbott, Respicardia, Sensible Medical, CVRx, and Impulse Dynamics and salary support from V-Wave Ltd. J.L. reports personal fees from BI, Abbott, AstraZeneca, CVRx, Edwards Lifesciences, Impulse Dynamics, and V-Wave Ltd and grants from AstraZeneca, Sensible Medical, Volumetrix. P.P. reports personal fees from BI, Astra Zeneca, Servier, BMS, Amgen, Novartis, Merck, Pfizer, and Berlin Chemie and grants and personal fees from Vifor Pharma. P.A. reports non-financial support from Menarini, Novartis, and BI, non-financial support and grants from Actelion, and grants from Daiichi Sankyo, and Bayer. J.B. reports consulting fees from BI, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd, and Vifor. A.S.D. reports personal fees from BI, grants and personal fees from Abbott, Alnylam, AstraZeneca, and Novartis, personal fees from Amgen, Biofourmis, Boston Scientific, DalCor Pharma, Merck, Relypsa, Cytokinetics, and Regeneron, and grants from Bayer. G.F. reports Committee Member contributions in trials sponsored by Medtronic, Vifor, Servier, Novartis, and BI. J.G. reports nothing to disclose. M.F. reports nothing to disclose. L.G. reports nothing to disclose. J.G.H. reports consulting fees from AstraZeneca, Amgen, Janssen, Bayer, BI, Novartis, Merck, Akcea, Alnylam, Pfizer, Servier, and Cardiol and grants from AstraZeneca, Amgen, Janssen, Bayer, BI, Novartis, Pfizer, Servier, and Medtronic. S.J.N. reports grants from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience and personal fees from AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and BI. J.R. reports nothing to disclose. I.S. reports nothing to disclose. J.S.-C. reports fees for consulting and lectures from Boehringer Ingelheim. S.S. reports non-financial support and personal fees from BI, grants from German Ministry for Education & Research and BI, and personal fees from Bayer, Pfizer, Novartis, and AstraZeneca. J.K.W. reports nothing to report. G.S. reports grants and personal fees from Vifor and AstraZeneca, grants and non-financial support from BI, personal fees from Societá Prodotti Antibiotici, Roche, Servier, GENESIS, Cytokinetics, and Medtronic, and grants from MSD and Novartis. M.B., W.J., M.N., B.P., I.R., A.U., C.Z., and A.S. are employees of BI. S.D.A. reports grants and personal fees from Vifor Int. and Abbott Vascular and personal fees from Bayer, BI, Novartis, Servier, ID, and Cardiac Dimensions.

References