Impact of empagliflozin on decongestion in acute heart failure: the EMPULSE trial.

AIMS: Effective and safe decongestion remains a major goal for optimal management of patients with acute heart failure (AHF). The effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin on decongestion-related endpoints in the EMPULSE trial (NCT0415775) were evaluated. METHODS AND RESULTS: A total of 530 patients hospitalized for AHF were randomized 1:1 to either empagliflozin 10 mg once daily or placebo for 90 days. The outcomes investigated were: weight loss (WL), WL adjusted for mean daily loop diuretic dose (WL-adjusted), area under the curve of change from baseline in N-terminal pro-B-type natriuretic peptide levels, hemoconcentration, and clinical congestion score after 15, 30, and 90 days of treatment. Compared with placebo, patients treated with empagliflozin demonstrated significantly greater reductions in all studied markers of decongestion at all time-points, adjusted mean differences (95% confidence interval) at Days 15, 30, and 90 were: for WL -1.97 (-2.86, -1.08), -1.74 (-2.73, -0.74); -1.53 (-2.75, -0.31) kg; for WL-adjusted: -2.31 (-3.77, -0.85), -2.79 (-5.03, -0.54), -3.18 (-6.08, -0.28) kg/40 mg furosemide i.v. or equivalent; respectively (all P < 0.05). Greater WL at Day 15 (i.e. above the median WL in the entire population) was associated with significantly higher probability for clinical benefit at Day 90 (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline to 90 days) with the win ratio of 1.75 (95% confidence interval 1.37, 2.23; P < 0.0001). CONCLUSION: Initiation of empagliflozin in patients hospitalized for AHF resulted in an early, effective and sustained decongestion which was associated with clinical benefit at Day 90.

Renal effects of empagliflozin in patients hospitalized for acute heart failure: from the EMPULSE trial.

AIM: The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improved clinical outcomes in patients hospitalized for acute heart failure. In patients with chronic heart failure, SGLT2 inhibitors cause an early decline in estimated glomerular filtration rate (eGFR) followed by a slower eGFR decline over time than placebo. However, the effects of SGLT2 inhibitors on renal function during a hospital admission for acute heart failure remain largely unknown. METHODS AND RESULTS: Between 1 and 5 days after a hospitalization for acute heart failure, 530 patients with an eGFR >20 ml/min/1.73 m2 were randomized to 10 mg of empagliflozin or placebo and treated for 90 days. Renal function and electrolytes were measured at baseline, and after 15, 30 and 90 days. We evaluated the effect of empagliflozin on eGFR over time and the impact of baseline eGFR on the primary hierarchical outcome of death, worsening heart failure events and quality of life. Mean baseline eGFR was 52.4 ml/min/1.73 m2 in the empagliflozin group and 55.7 ml/min/1.73 m2 in the placebo group. Empagliflozin caused an initial decline in eGFR (-2 ml/min/1.73 m2 at day 15 compared to placebo). At day 90, eGFR was similar between empagliflozin and placebo. Investigator-reported acute renal failure occurred in 7.7% of empagliflozin versus 12.1% of placebo patients. The overall clinical benefit (hierarchical composite of all-cause death, heart failure events and quality of life) of empagliflozin was unaffected by baseline eGFR. CONCLUSION: In patients hospitalized for acute heart failure, empagliflozin caused an early modest decline in renal function which was no longer evident after 90 days. Acute renal events were similar in both groups. The clinical benefit of empagliflozin was consistent regardless of baseline renal function.

Biomarker-driven prognostic models in chronic heart failure with preserved ejection fraction: the EMPEROR-Preserved trial.

AIMS: Biomarker-driven prognostic models incorporating N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) in heart failure (HF) with preserved ejection fraction (HFpEF) are lacking. We aimed to generate a biomarker-driven prognostic tool for patients with chronic HFpEF enrolled in EMPEROR-Preserved. METHODS AND RESULTS: Multivariable Cox regression models were created for (i) the primary composite outcome of HF hospitalization or cardiovascular death, (ii) all-cause death, (iii) cardiovascular death, and (iv) HF hospitalization. PARAGON-HF was used as a validation cohort. NT-proBNP and hs-cTnT were the dominant predictors of the primary outcome, and in addition, a shorter time since last hospitalization, New York Heart Association (NYHA) class III or IV, history of chronic obstructive pulmonary disease (COPD), insulin-treated diabetes, low haemoglobin, and a longer time since HF diagnosis were key predictors (eight variables, all p < 0.001). The consequent primary outcome risk score discriminated well (c-statistic = 0.75) with patients in the top 10th of risk having an event rate >22× higher than those in the bottom 10th. A model for HF hospitalization alone had even better discrimination (c = 0.79). Empagliflozin reduced the risk of cardiovascular death or hospitalization for HF in patients across all risk levels. NT-proBNP and hs-cTnT were also the dominant predictors of all-cause and cardiovascular mortality followed by history of COPD, low albumin, older age, left ventricular ejection fraction ≥50%, NYHA class III or IV and insulin-treated diabetes (eight variables, all p < 0.001). The mortality risk model had similar discrimination for all-cause and cardiovascular mortality (c-statistic = 0.72 for both). External validation provided c-statistics of 0.71, 0.71, 0.72, and 0.72 for the primary outcome, HF hospitalization alone, all-cause death, and cardiovascular death, respectively. CONCLUSIONS: The combination of NT-proBNP and hs-cTnT along with a few readily available clinical variables provides effective risk discrimination both for morbidity and mortality in patients with HFpEF. A predictive tool-kit facilitates the ready implementation of these risk models in routine clinical practice.

Uric acid and sodium-glucose cotransporter-2 inhibition with empagliflozin in heart failure with reduced ejection fraction: the EMPEROR-reduced trial.

BACKGROUND: The sodium-glucose cotransporter-2 inhibitor empagliflozin decreases the risk of cardiovascular death or hospitalization for heart failure (HF) in patients with HF with reduced ejection fraction. Empagliflozin reduces serum uric acid (SUA), but the relevance of this effect in patients with HF is unclear. This study aimed to investigate the effect of empagliflozin on SUA levels and the therapeutic efficacy of empagliflozin in relation to SUA. METHODS: The association between SUA and the composite primary outcome of cardiovascular death or hospitalization for worsening HF, its components, and all-cause mortality was investigated in 3676 patients of the EMPEROR-Reduced trial (98.6% of the study cohort). The treatment effect of empagliflozin was studied in relation to SUA as continuous variable, to clinical hyperuricaemia (SUA >5.7 mg/dL for women, >7.0 mg/dL for men) and in subgroups of patients of tertiles of SUA. RESULTS: Hyperuricaemia was prevalent in 53% of patients with no sex differences. Elevated SUA (highest tertile, mean SUA 9.38 ± 1.49 mg/dL) was associated with advanced severity of HF and with worst outcome [composite outcome, hazard ratio (HR) 1.64 (95% confidence interval, CI 1.28-2.10); cardiovascular mortality, HR 1.98 (95% CI 1.35-2.91); all-cause mortality, HR 1.8 (95% CI 1.29-2.49), all P < 0.001] in multivariate adjusted analyses, as compared with the lowest tertile. SUA was reduced following treatment with empagliflozin at 4 weeks (vs. placebo: -1.12 ± 0.04 mg/dL, P < 0.0001) and remained lower throughout follow-up, with a similar reduction in all prespecified subgroups. Empagliflozin reduced events of clinically relevant hyperuricaemia (acute gout, gouty arthritis or initiation of anti-gout therapy) by 32% [HR 0.68 (95% CI 0.52-0.89), P = 0.004]. The beneficial effect of empagliflozin on the primary endpoint was independent of baseline SUA [HR 0.76 (95% CI 0.65-0.88), P < 0.001) and of the change in SUA at 4 weeks [HR 0.81 (95% CI 0.69-0.95), P = 0.012]. As a hypothesis-generating finding, an interaction between SUA and treatment effect suggested a benefit of empagliflozin on mortality (cardiovascular and all-cause mortality) in patients in elevated SUA (P for interaction = 0.005 and = 0.011, respectively). CONCLUSION: Hyperuricaemia is common in HF and is an independent predictor of advanced disease severity and increased mortality. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricaemia. The benefit of empagliflozin on the primary outcome was observed independently of SUA.

Minimally Clinically Important Difference in Health Status Scores in Patients With HFrEF vs HFpEF.

BACKGROUND: Differences in clinically important thresholds in patient-reported outcomes measures such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) remain less well-established in patients with heart failure with preserved ejection fraction (HFpEF) versus heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: The purpose of this study was to estimate meaningful thresholds for improvement or deterioration in the KCCQ-Total Symptom Score (TSS) in patients with HFrEF versus HFpEF. METHODS: This secondary analysis of EMPERIAL program used anchor- and distribution-based approaches to estimate thresholds for improvement or deterioration in the KCCQ-TSS using Patient Global Impression of Severity (PGIS) as the primary anchor. Mean change in KCCQ-TSS from baseline to week 12 was calculated for each PGIS. RESULTS: A total of 312 HFrEF and 315 HFpEF patients were enrolled. At week 12, mean changes in KCCQ-TSS corresponding to PGIS changes of "any improvement," "1-category improvement," and "1-category deterioration" were 13 ± 17, 12 ± 17, -3 ± 16 points in HFrEF, and 15 ± 18, 13 ± 17, -7 ± 18 points in HFpEF. Threshold for meaningful within-patient change in KCCQ-TSS was ≥9 points in HFrEF and ≥7 points in HFpEF patients. Sensitivity and specificity of ≥9 points/≥7 points change was 0.65 and 0.70 for HFrEF and 0.64 and 0.66 for HFpEF. Cumulative distribution function curves of KCCQ-TSS change from baseline to week 12 showed a shift to higher scores in both HFrEF and HFpEF patients. CONCLUSIONS: In the EMPERIAL program, a change in KCCQ-TSS of ≥9 points in HFrEF and ≥7 points in HFpEF represents the minimal clinically important difference for improvement, confirming the broad range of 5-10 points as meaningful thresholds.

Effects of Empagliflozin on Symptoms, Physical Limitations, and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial.

BACKGROUND: Patients hospitalized for acute heart failure experience poor health status, including a high burden of symptoms and physical limitations, and poor quality of life. SGLT2 (sodium-glucose cotransporter 2) inhibitors improve health status in chronic heart failure, but their effect on these outcomes in acute heart failure is not well characterized. We investigated the effects of the SGLT2 inhibitor empagliflozin on symptoms, physical limitations, and quality of life, using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the EMPULSE trial (Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized). METHODS: Patients hospitalized for acute heart failure were randomized to empagliflozin 10 mg daily or placebo for 90 days. The KCCQ was assessed at randomization and 15, 30, and 90 days. The effects of empagliflozin on the primary end point of clinical benefit (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in KCCQ Total Symptom Score [TSS] change from baseline to 90 days) were examined post hoc across the tertiles of baseline KCCQ-TSS. In prespecified analyses, changes (randomization to day 90) in KCCQ domains, including TSS, physical limitations, quality of life, clinical summary, and overall summary scores were evaluated using a repeated measures model. RESULTS: In total, 530 patients were randomized (265 each arm). Baseline KCCQ-TSS was low overall (mean [SD], 40.8 [24.0] points). Empagliflozin-treated patients experienced greater clinical benefit across the range of KCCQ-TSS, with no treatment effect heterogeneity (win ratio [95% CIs] from lowest to highest tertile: 1.49 [1.01-2.20], 1.37 [0.94-1.99], and 1.48 [1.00-2.20], respectively; P for interaction=0.94). Beneficial effects of empagliflozin on health status were observed as early as 15 days and persisted through 90 days, at which point empagliflozin-treated patients experienced a greater improvement in KCCQ TSS, physical limitations, quality of life, clinical summary, and overall summary (placebo-adjusted mean differences [95% CI]: 4.45 [95% CI, 0.32-8.59], P=0.03; 4.80 [95% CI, 0.00-9.61], P=0.05; 4.66 [95% CI, 0.32-9.01], P=0.04; 4.85 [95% CI, 0.77-8.92], P=0.02; and 4.40 points [95% CI, 0.33-8.48], P=0.03, respectively). CONCLUSIONS: Initiation of empagliflozin in patients hospitalized for acute heart failure produced clinical benefit regardless of the degree of symptomatic impairment at baseline, and improved symptoms, physical limitations, and quality of life, with benefits seen as early as 15 days and maintained through 90 days. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT0415775.

The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial.

The sodium-glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751 ), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09-1.68; P = 0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment.

Impact of anaemia and the effect of empagliflozin in heart failure with reduced ejection fraction: findings from EMPEROR-Reduced.

AIMS: Anaemia is frequent among patients with heart failure (HF) and reduced ejection fraction (HFrEF) and is associated with poor outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) increase haematocrit and may correct anaemia. This study aims to investigate the impact of empagliflozin on haematocrit and anaemia, and whether anaemia influenced the effect of empagliflozin in EMPEROR-Reduced. METHODS AND RESULTS: Mixed-effects models and survival analysis. A total of 3726 patients (out of 3730) had baseline haematocrit values, 3013 (81%) had no anaemia and 713 (19%) had anaemia. Patients with anaemia were older (70.4 vs. 66.0 years), had lower body mass index (26.6 vs. 28.2 kg/m2 ), lower estimated glomerular filtration rate (54.2 vs. 63.9 ml/min/1.73 m2 ), and higher N-terminal pro-B-type natriuretic peptide (2362 vs. 1800 pg/ml). Compared to patients without anaemia, those with anaemia had 1.5 to 2.5-fold higher rates of cardiovascular and all-cause mortality, total HF hospitalizations, and kidney composite outcomes. The effect of empagliflozin to reduce the primary composite outcome of cardiovascular death or HF hospitalizations, total HF hospitalizations, and kidney composite outcome was not modified by baseline anaemia status (interaction p > 0.1 for all). Compared to placebo, empagliflozin rapidly (as early as week 4) increased haematocrit and haemoglobin and reduced the rates of new-onset anaemia throughout the follow-up (22.6% in placebo vs. 12.3% in empagliflozin; hazard ratio 0.49, 95% confidence interval 0.41-0.59; p < 0.001). CONCLUSIONS: Anaemia was associated with poor outcomes. Empagliflozin reduced new-onset anaemia throughout the follow-up and improved HF and kidney outcomes irrespective of anaemia status at baseline.

Mediators of the improvement in heart failure outcomes with empagliflozin in the EMPA-REG OUTCOME trial.

AIMS: In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of death from heart failure (HF) or hospitalization for heart failure (HHF) versus placebo in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular (CV) disease. We evaluated post hoc the degree to which covariates mediated the effects of empagliflozin on HHF or HF death. METHODS AND RESULTS: A mediator had to fulfil the following criteria: (i) affected by active treatment, (ii) associated with the outcome, and finally (iii) adjustment for it results in a reduced treatment effect compared with unadjusted analysis. Potential mediators were calculated as change from baseline or updated mean and evaluated in univariable analyses as time-dependent covariates in Cox regression of time to HHF or HF death; those with the largest mediating effects were then included in a multivariable analysis. Increases in heart rate, log urine albumin-to-creatinine ratio (UACR), waist circumference, and uric acid were associated with increased risk of HHF or HF death; increases in high-density lipoprotein cholesterol, estimated glomerular filtration rate, haematocrit, haemoglobin, and albumin were associated with reduced risk of HHF or HF death. In univariable analyses, change from baseline in haematocrit, haemoglobin, albumin, uric acid, and logUACR mediated 51%, 54%, 23%, 24%, and 27% of the risk reduction with empagliflozin versus placebo, respectively. Multivariable analysis including haemoglobin, logUACR, and uric acid mediated 85% of risk reduction with similar results when updated means were evaluated. CONCLUSIONS: Changes in haematocrit and haemoglobin were the most important mediators of the reduction in HHF and death from HF in patients with T2DM and established CV disease treated with empagliflozin. Albumin, uric acid, and logUACR had smaller mediating effects in this population.

Potential contribution of haemoconcentration to changes in lipid variables with empagliflozin in patients with type 2 diabetes: A post hoc analysis of pooled data from four phase 3 randomized clinical trials.

AIM: To examine the association between changes in lipids and markers of haemoconcentration (haematocrit and serum albumin) with empagliflozin, a sodium-glucose co-transporter-2 inhibitor, in patients with type 2 diabetes (T2D) using pooled data from four phase 3 randomized trials. MATERIALS AND METHODS: Patients with T2D received placebo (n = 825), empagliflozin 10 mg (n = 830) or 25 mg (n = 822) for 24 weeks. In post hoc mediation analyses, we assessed total changes in LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoprotein (Apo) B, and Apo A-I, and changes in these variables associated with, and independent of, changes in haematocrit and serum albumin at week 24 using ANCOVA models. RESULTS: Empagliflozin versus placebo increased serum LDL-cholesterol, HDL-cholesterol, and Apo A-I, decreased triglycerides (empagliflozin 10 mg only), and (non-significantly) increased Apo B. Empagliflozin modestly increased haematocrit and serum albumin. In mediation analyses, haematocrit changes (increases) with empagliflozin were associated with significant changes (increases) in all lipid variables, including Apo B. Except for triglycerides (non-significant), similar lipid variable associations were observed with serum albumin changes. Haematocrit- and serum albumin-independent changes in lipids with empagliflozin were significant for HDL-cholesterol (increases), mostly significant for triglycerides (decreases), and less so for other lipid fractions. CONCLUSION: Haematocrit and serum albumin increases were associated with increases in lipid fractions with empagliflozin. Empagliflozin-associated changes in serum lipids, particularly LDL-cholesterol increases, may be partly attributable to haemoconcentration resulting from increased urinary volume and subsequent volume contraction.

Sodium-glucose co-transporter 2 inhibition in patients hospitalized for acute decompensated heart failure: rationale for and design of the EMPULSE trial.

AIMS: Treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors improves outcomes in patients with chronic heart failure (HF) with reduced ejection fraction. There is limited experience with the in-hospital initiation of SGLT2 inhibitors in patients with acute HF (AHF) with or without diabetes. EMPULSE is designed to assess the clinical benefit and safety of the SGLT2 inhibitor empagliflozin compared with placebo in patients hospitalized with AHF. METHODS: EMPULSE is a randomized, double-blind, parallel-group, placebo-controlled multinational trial comparing the in-hospital initiation of empagliflozin (10 mg once daily) with placebo. Approximately 500 patients admitted for AHF with dyspnoea, signs of fluid overload, and elevated natriuretic peptides will be randomized 1:1 stratified to HF status (de-novo and decompensated chronic HF) to either empagliflozin or placebo at approximately 165 sites across North America, Europe and Asia. Patients will be enrolled regardless of ejection fraction and diabetes status and will be randomized during hospitalization and after stabilization (between 24 h and 5 days after admission), with treatment continued up to 90 days after initiation. The primary outcome is clinical benefit at 90 days, consisting of a composite of all-cause death, HF events, and ≥5 point change from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), assessed using a 'win-ratio' approach. Secondary outcomes include assessments of safety, change in KCCQ-TSS from baseline to 90 days and change in natriuretic peptides from baseline to 30 days. CONCLUSION: The EMPULSE trial will evaluate the clinical benefit and safety of empagliflozin in patients hospitalized for AHF.

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.

Evaluation of the effect of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced trial.

Drugs that inhibit the sodium-glucose co-transporter 2 (SGLT2) have been shown to reduce the risk of hospitalizations for heart failure in patients with type 2 diabetes. In populations that largely did not have heart failure at the time of enrolment, empagliflozin, canagliflozin and dapagliflozin decreased the risk of serious new-onset heart failure events by ≈30%. In addition, in the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of both pump failure and sudden deaths, the two most common modes of death among patients with heart failure. In none of the three trials could the benefits of SGLT2 inhibitors on heart failure be explained by the actions of these drugs as diuretics or anti-hyperglycaemic agents. These observations raise the possibility that SGLT2 inhibitors could reduce morbidity and mortality in patients with established heart failure, including those without diabetes. The EMPEROR-Reduced trial is enrolling ≈3600 patients with heart failure and a reduced left ventricular ejection fraction (≤ 40%), half of whom are expected not to have diabetes. Patients are being randomized to placebo or empagliflozin 10 mg daily, which is added to all appropriate treatment with inhibitors of the renin-angiotensin system and neprilysin, beta-blockers and mineralocorticoid receptor antagonists. The primary endpoint is the time-to-first event analysis of the combined risk of cardiovascular death and hospitalization for heart failure, but the trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality, and recurrent hospitalization events. By adjusting eligibility based on natriuretic peptide levels to the baseline ejection fraction, the trial will preferentially enrol high-risk patients. A large proportion of the participants is expected to have an ejection fraction < 30%, and the estimated annual event rate is expected to be at least 15%. The EMPEROR-Reduced trial is well-positioned to determine if the addition of empagliflozin can add meaningfully to current approaches that have established benefits in the treatment of chronic heart failure with left ventricular systolic dysfunction.

Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial.

BACKGROUND: The principal biological processes that characterize heart failure with a preserved ejection fraction (HFpEF) are systemic inflammation, epicardial adipose tissue accumulation, coronary microcirculatory rarefaction, myocardial fibrosis and vascular stiffness; the resulting impairment of left ventricular and aortic distensibility (especially when accompanied by impaired glomerular function and sodium retention) causes increases in cardiac filling pressures and exertional dyspnoea despite the relative preservation of left ventricular ejection fraction. Independently of their actions on blood glucose, sodium-glucose co-transporter 2 (SGLT2) inhibitors exert a broad range of biological effects (including actions to inhibit cardiac inflammation and fibrosis, antagonize sodium retention and improve glomerular function) that can ameliorate the pathophysiological derangements in HFpEF. Such SGLT2 inhibitors exert favourable effects in experimental models of HFpEF and have been found in large-scale trials to reduce the risk for serious heart failure events in patients with type 2 diabetes, many of whom were retrospectively identified as having HFpEF. STUDY DESIGN: The EMPEROR-Preserved Trial is enrolling ≈5750 patients with HFpEF (ejection fraction >40%), with and without type 2 diabetes, who are randomized to receive placebo or empagliflozin 10 mg/day, which is added to all appropriate treatments for HFpEF and co-morbidities. STUDY AIMS: The primary endpoint is the time-to-first-event analysis of the combined risk for cardiovascular death or hospitalization for heart failure. The trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality and recurrent hospitalization events, and will assess a wide range of biomarkers that reflect important pathophysiological mechanisms that may drive the evolution of HFpEF. The EMPEROR-Preserved Trial is well positioned to determine if empagliflozin can have a meaningful impact on the course of HFpEF, a disorder for which there are currently few therapeutic options.

Effect of Empagliflozin on Free Fatty Acids and Ketone Bodies in Japanese Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Trial.

INTRODUCTION: We report a randomized, double-blind, placebo-controlled, 4-week study to investigate the effect of empagliflozin on free fatty acids and blood ketone bodies in Japanese patients with type 2 diabetes mellitus. METHODS: Patients (baseline mean [standard deviation] glycated hemoglobin 7.91% [0.80%]; body mass index 24.3 [3.2] kg/m2) were randomized to empagliflozin 10 mg (n = 20), empagliflozin 25 mg (n = 19), or placebo (n = 21) daily as monotherapy for 28 days. Meal tolerance tests (MTTs; breakfast, lunch, dinner) were performed on day - 1, day 1 (first day of treatment), and day 28. On day 1 and day 28, study drug was administered 1 h before breakfast. Free fatty acids and blood ketone bodies were measured before and 1, 2, and 3 h after each MTT, and the next morning (overnight fast). RESULTS: Empagliflozin significantly reduced plasma glucose and insulin and reduced body weight vs. placebo. Empagliflozin increased free fatty acids and total ketones bodies at day 1 and day 28. At day 28, the adjusted mean (95% confidence interval) difference vs. placebo in the time-corrected area under curve over 24 h for total ketone bodies was 67.1 (12.3, 121.8) µmol·h/L·h (P = 0.017) with empagliflozin 10 mg and 178.1 (123.9, 232.2) µmol·h/L·h (P < 0.001) with empagliflozin 25 mg. Increases in ketones with empagliflozin vs. placebo peaked just before and declined after meals, with the highest peak before breakfast. Changes in total ketone bodies appeared to be associated with changes in plasma glucose, insulin, and free fatty acids. CONCLUSION: Empagliflozin modestly increased free fatty acids and blood ketone bodies after a single dose and 28 days' treatment. Increases in ketones appeared to be related to the duration of fasting and were most pronounced before breakfast. Increases in ketones appeared to be associated with changes in well-known metabolic determinants of ketone production. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01947855. FUNDING: Boehringer Ingelheim & Eli Lilly and Company.

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).

Antihyperglycemic and Blood Pressure Effects of Empagliflozin in Black Patients With Type 2 Diabetes Mellitus and Hypertension.

BACKGROUND: Empagliflozin, a sodium-glucose cotransporter 2 inhibitor indicated for type 2 diabetes mellitus (T2DM), can lower blood pressure (BP) and reduce cardiovascular mortality in patients with T2DM and preexisting cardiovascular disease. Its effects in blacks have been understudied. METHODS: In this 24-week study, 150 blacks with T2DM and hypertension had glycohemoglobin (primary end point), office and 24-hour ambulatory BP, body weight, and safety assessments. After a 2-week, open-label, placebo run-in, patients were randomly assigned to once daily empagliflozin (10 mg for the first 4 weeks, then force-titrated to 25 mg until week 24) or placebo. A mixed-effects model for repeated measures was performed on the primary and 2 key secondary end points, and an analysis of covariance for nonrepeated measures with last observation carried forward was performed for 2 other key secondary end points. Hierarchical testing was applied for these end points. RESULTS: Overall, 52.7% of participants were men, mean (SD) age, 56.8 (9.3) years; mean duration of T2DM, 9.3 (7.1) years. The baseline values of key parameters (mean [SD]) were as follows: glycohemoglobin, 8.59 (1.02)%; ambulatory systolic BP, 146.3 (11.0) mm Hg; and ambulatory diastolic BP, 89.4 (8.1) mm Hg. By week 24, the mean (standard error) change in glycohemoglobin in the empagliflozin group was -0.77 (0.15%) in comparison with an increase of 0.07 (0.16%) in the placebo group; placebo-corrected difference, -0.78% (95% CI, -1.18 to -0.38; P=0.0002). Reductions in body weight by week 24 were -2.38 (0.38) empagliflozin and -0.80 (0.47) placebo; the placebo-corrected difference was -1.23 kg (95% CI, -2.39 to -0.07; P=0.0382). Empagliflozin significantly reduced 24-hour ambulatory systolic BP versus placebo by weeks 12 and 24 (placebo-corrected difference, -5.21 mm Hg [95% CI, -9.24 to -1.18; P=0.0117] and -8.39 mm Hg [95% CI, -13.74 to -3.04; P=0.0025], respectively). Diastolic BP was also reduced. CONCLUSIONS: In blacks with T2DM, empagliflozin reduced glycohemoglobin, body weight, and BP. The effect of empagliflozin on BP increased from 12 to 24 weeks, suggesting a full antihypertensive effect takes ≥6 months to be fully realized. At week 24, the placebo-subtracted BP effect was similar to standard antihypertensive monotherapies, suggesting that empagliflozin may be beneficial for this high-risk population. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02182830.

Empagliflozin compared with glimepiride in metformin-treated patients with type 2 diabetes: 208-week data from a masked randomized controlled trial.

AIM: To report results at week 208, including a 104-week masked extension, of the EMPA-REG H2H-SU trial in patients with type 2 diabetes with inadequate glycaemic control on metformin, in which empagliflozin 25 mg given for 104 weeks provided a sustained reduction in glycated haemoglobin (HbA1c) with a small but statistically significant benefit vs glimepiride, sustained reductions in weight and blood pressure, and low risk of hypoglycaemia. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes and HbA1c 53-86 mmol/mol (7% to 10%) were randomized to empagliflozin 25 mg or glimepiride 1 to 4 mg for 104 weeks as add-on to metformin. Patients who completed the randomized treatment period could participate in a 104-week extension in which they continued the double-blind treatment allocated at randomization. RESULTS: Of 765 and 780 patients treated with empagliflozin and glimepiride, 576 and 549 patients, respectively, entered the extension period of the study. At week 208, the adjusted mean difference in change from baseline in HbA1c with empagliflozin vs glimepiride was -1.96 mmol/mol, 95% CI -3.57, -0.35 (-0.18%, 95% CI -0.33, -0.03); P = 0.0172. Rescue therapy was given to 23% of patients on empagliflozin and 34% on glimepiride (odds ratio 0.56 [95% CI 0.45, 0.71]; P < 0.0001). Confirmed hypoglycaemic adverse events (plasma glucose ≤3.9 mmol/L and/or requiring assistance) occurred in 3% of patients on empagliflozin and 28% on glimepiride (odds ratio 0.08 [95% CI 0.05, 0.13]; P < 0.0001). CONCLUSIONS: In patients with type 2 diabetes, empagliflozin 25 mg as add-on to metformin for 208 weeks reduced HbA1c with a significantly lower risk of hypoglycaemia and a significantly smaller proportion of patients receiving rescue therapy compared with glimepiride.

Analysis of Fractures in Patients With Type 2 Diabetes Treated With Empagliflozin in Pooled Data From Placebo-Controlled Trials and a Head-to-Head Study Versus Glimepiride.

OBJECTIVE: To assess the effect of empagliflozin on bone fractures and bone mineral density in patients with type 2 diabetes in pooled placebo-controlled trial data and a head-to-head study versus glimepiride. RESEARCH DESIGN AND METHODS: Pooled data were analyzed from patients who were randomized 1:1:1 to empagliflozin 10 mg, empagliflozin 25 mg, or placebo in phase I-III clinical trials. Data were also analyzed from the EMPA-REG H2H-SU trial in which patients received empagliflozin 25 mg or glimepiride as an add-on to metformin for 104 weeks with a 104-week extension. Bone fracture adverse events (AEs) were evaluated through a search of investigator-reported (nonadjudicated) events. RESULTS: In the pooled analysis, bone fracture AEs were reported in 119 of 4,221 (2.8%), 105 of 4,196 (2.5%), and 123 of 4,203 (2.9%) patients in the empagliflozin 10 mg, empagliflozin 25 mg, and placebo groups, respectively (rates of 1.55, 1.36, and 1.69/100 patient-years, respectively). In the EMPA-REG H2H-SU trial, bone fracture AEs were reported in 31 of 765 (4.1%) patients receiving empagliflozin 25 mg and in 33 of 780 (4.2%) patients receiving glimepiride (rates of 1.28 and 1.40/100 patient-years, respectively). CONCLUSIONS: Empagliflozin did not increase the risk of bone fracture compared with placebo in a pooled analysis of >12,000 patients or compared with glimepiride in a 4-year head-to-head study.