Dataset Information

Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial.

ABSTRACT:

Background

Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events.

Methods

Patients with Class II-IV heart failure and a left ventricular ejection fraction ?40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes.

Results

Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60-0.87] and 0.78 [95% CI, 0.64-0.97], respectively, P-interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (P-interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia.

Conclusions

In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

SUBMITTER: Anker SD

PROVIDER: S-EPMC7834911 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial.

Anker Stefan D SD Butler Javed J Filippatos Gerasimos G Khan Muhammad Shahzeb MS Marx Nikolaus N Lam Carolyn S P CSP Schnaidt Sven S Ofstad Anne Pernille AP Brueckmann Martina M Jamal Waheed W Bocchi Edimar A EA Ponikowski Piotr P Perrone Sergio V SV Januzzi James L JL Verma Subodh S Böhm Michael M Ferreira João Pedro JP Pocock Stuart J SJ Zannad Faiez F Packer Milton M

Circulation 20201111 4

<h4>Background</h4>Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events.<h4>Methods</h4>Patients with Class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespeci ...[more]

PMID: 33175585

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Project description:BackgroundFrailty is a severe, common co-morbidity associated with heart failure (HF) with preserved ejection fraction (HFpEF). The impact of frailty on HFpEF outcomes may affect treatment choices in HFpEF. The impact of frailty on HFpEF patients and any impact on the clinical benefits of sodium glucose co-transporter 2 (SGLT2) inhibition in HFpEF have been described in only a limited number of trials. Whether the SGLT2 inhibitor empagliflozin would improve or worsen frailty status when given to HFpEF patients is also not known. The aims of this study were, therefore, to evaluate, in HFpEF patients enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), the impact of frailty on clinical outcomes, and on the effects of empagliflozin, as well as the effect of empagliflozin on frailty status during treatment period.MethodsWe calculated a cumulative deficit-derived frailty index (FI) using 44 variables including clinical, laboratory and quality of life parameters recorded in EMPEROR-Preserved. Patients were classified into four groups: non-frail (FI < 0.21), mild frailty (0.21 to <0.30), moderate frailty (0.30 to <0.40) and severe frailty (≥0.40). Clinical outcomes and health-related quality of life were evaluated according to baseline FI along with the effect of empagliflozin on chronological changes in FI (at 12, 32 and 52 weeks).ResultsThe patient distribution was 1514 (25.3%), 2100 (35.1%), 1501 (25.1%) and 873 (14.6%) in non-frail, mild frailty, moderate frailty and severe frailty, respectively. Severe frailty patients tended to be female and have low Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, more co-morbidities and more polypharmacy. Incidence rates of the primary outcome of cardiovascular death or HF hospitalization increased as frailty worsened (hazard ratio [HR] of each FI category compared with the non-frail group: 1.10 [95% confidence interval, CI, 0.89-1.35], 2.00 [1.63-2.47] and 2.61 [2.08-3.27] in the mild frailty, moderate frailty and severe frailty groups, respectively; P trend < 0.001). Compared with placebo, empagliflozin reduced the risk for the primary outcome across the four FI categories, HR: 0.59 [95% CI 0.42-0.83], 0.79 [0.61-1.01], 0.77 [0.61-0.96] and 0.90 [0.69-1.16] in non-frail to severe frailty categories, respectively (P value for trend = 0.097). Empagliflozin also improved other clinical outcomes and KCCQ score across frailty categories. Compared with placebo, empagliflozin-treated patients had a higher likelihood of being in a lower FI category at Weeks 12, 32 and 52 (P < 0.05), odds ratio: 1.12 [95% CI 1.01-1.24] at Week 12, 1.21 [1.09-1.34] at Week 32 and 1.20 [1.09-1.33] at Week 52.ConclusionsEmpagliflozin improved key efficacy outcomes with a possible diminution of effect in very frail patients. Empagliflozin also improved frailty status during follow-up.

Project description:BackgroundEmpagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, with or without diabetes, but additional data are needed about the effect of the drug on inpatient and outpatient events that reflect worsening heart failure.MethodsWe randomly assigned 3730 patients with class II to IV heart failure with an ejection fraction of ≤40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to recommended treatments for heart failure, for a median of 16 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points.ResultsEmpagliflozin reduced the combined risk of death, hospitalization for heart failure or an emergent/urgent heart failure visit requiring intravenous treatment (415 versus 519 patients; empagliflozin versus placebo, respectively; hazard ratio [HR], 0.76; 95% CI, 0.67-0.87; P<0.0001). This benefit reached statistical significance at 12 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (HR, 0.67; 95% CI, 0.50-0.90; P=0.008) and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention (HR, 0.64; 95% CI, 0.47-0.87; P=0.005). As compared with placebo, fewer patients in the empagliflozin group reported intensification of diuretics (297 versus 414 [HR, 0.67; 95% CI, 0.56-0.78; P<0.0001]). Additionally, patients assigned to empagliflozin were 20% to 40% more likely to experience an improvement in New York Heart Association functional class and were 20% to 40% less likely to experience worsening of New York Heart Association functional class, with statistically significant effects that were apparent 28 days after randomization and maintained during long-term follow-up. The risk of any inpatient or outpatient worsening heart failure event in the placebo group was high (48.1 per 100 patient-years of follow-up), and it was reduced by empagliflozin (HR, 0.70; 95% CI, 0.63-0.78; P<0.0001).ConclusionsIn patients with heart failure and a reduced ejection fraction, empagliflozin reduced the risk and total number of inpatient and outpatient worsening heart failure events, with benefits seen early after initiation of treatment and sustained for the duration of double-blind therapy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Project description:BackgroundThe 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.MethodsThe 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.ResultsHyperuricaemia 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).ConclusionHyperuricaemia 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.

Project description:BackgroundIn EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin reduced cardiovascular death or heart failure (HF) hospitalization and total HF hospitalizations, and slowed the progressive decline in kidney function in patients with HF and a reduced ejection fraction, with and without diabetes. We aim to study the effect of empagliflozin on cardiovascular and kidney outcomes across the spectrum of kidney function.MethodsIn this prespecified analysis, patients were categorized by the presence or absence of chronic kidney disease (CKD) at baseline (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2 or albumin-to-creatine ratio >300 mg/g). The primary and key secondary outcomes were: (1) a composite of cardiovascular death or HF hospitalization (primary outcome); (2) total HF hospitalizations; and (3) eGFR slope. The direct impact on kidney events was investigated by a prespecified composite kidney outcome (defined as a sustained profound decline in eGFR, chronic dialysis, or transplant). The median follow-up was 16 months.ResultsOf 3730 patients who were randomized to empagliflozin or placebo, 1978 (53%) had CKD. Empagliflozin reduced the primary outcome and total HF hospitalizations in patients with and without CKD: hazard ratio (HR)=0.78 (95% CI, 0.65-0.93) and HR=0.72 (95% CI, 0.58-0.90), respectively (interaction P=0.63). Empagliflozin slowed the slope of eGFR decline by 1.11 (0.23-1.98) ml/min/1.73 m2/yr in patients with CKD and by 2.41 (1.49-3.32) ml/min/1.73 m2/yr in patients without CKD. The risk of the composite kidney outcome was reduced similarly in patients with and without CKD: HR=0.53 (95% CI, 0.31-0.91) and HR=0.46 (95% CI, 0.22-0.99), respectively. The effect of empagliflozin on the primary composite outcome and key secondary outcomes was consistent across a broad range of baseline kidney function, measured by clinically relevant eGFR subgroups or by albuminuria, including patients with eGFR as low as 20 ml/min/1.73 m2. Empagliflozin was well tolerated in CKD patients.ConclusionsIn EMPEROR-Reduced, empagliflozin had a beneficial effect on the key efficacy outcomes and slowed the rate of kidney function decline in patients with and without CKD, and regardless of the severity of kidney impairment at baseline. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Project description:BackgroundPatients with heart failure with preserved ejection fraction have significant impairment in health-related quality of life. In the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), we evaluated the efficacy of empagliflozin on health-related quality of life in patients with heart failure with preserved ejection fraction and whether the clinical benefit observed with empagliflozin varies according to baseline health status.MethodsHealth-related quality of life was measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and 12, 32, and 52 weeks. Patients were divided by baseline KCCQ Clinical Summary Score (CSS) tertiles, and the effect of empagliflozin on outcomes was examined. The effect of empagliflozin on KCCQ-CSS, Total Symptom Score, and Overall Summary Score was evaluated. Responder analyses were performed to compare the odds of improvement and deterioration in KCCQ related to treatment with empagliflozin.ResultsThe effect of empagliflozin on reducing the risk of time to cardiovascular death or heart failure hospitalization was consistent across baseline KCCQ-CSS tertiles (hazard ratio, 0.83 [95% CI, 0.69-1.00], 0.70 [95% CI, 0.55-0.88], and 0.82 [95% CI, 0.62-1.08] for scores <62.5, 62.5-83.3, and ≥83.3, respectively; P trend=0.77). Similar results were seen for total heart failure hospitalizations. Patients treated with empagliflozin had significant improvement in KCCQ-CSS versus placebo (+1.03, +1.24, and +1.50 at 12, 32, and 52 weeks, respectively; P<0.01); similar results were seen for Total Symptom Score and Overall Summary Score. At 12 weeks, patients on empagliflozin had higher odds of improvement ≥5 points (odds ratio, 1.23 [95% CI, 1.10-1.37]), ≥10 points (odds ratio, 1.15 [95% CI, 1.03-1.27]), and ≥15 points (odds ratio, 1.13 [95% CI, 1.02-1.26]) and lower odds of deterioration ≥5 points in KCCQ-CSS (odds ratio, 0.85 [95% CI, 0.75-0.97]). A similar pattern was seen at 32 and 52 weeks, and results were consistent for Total Symptom Score and Overall Summary Score.ConclusionsIn patients with heart failure with preserved ejection fraction, empagliflozin reduced the risk for major heart failure outcomes across the range of baseline KCCQ scores. Empagliflozin improved health-related quality of life, an effect that appeared early and was sustained for at least 1 year. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057951.

Project description:BackgroundEmpagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with preserved ejection fraction, but additional data are needed about its effect on inpatient and outpatient heart failure events.MethodsWe randomly assigned 5988 patients with class II through IV heart failure with an ejection fraction of >40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to usual therapy, for a median of 26 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points.ResultsEmpagliflozin reduced the combined risk of cardiovascular death, hospitalization for heart failure, or an emergency or urgent heart failure visit requiring intravenous treatment (432 versus 546 patients [empagliflozin versus placebo, respectively]; hazard ratio, 0.77 [95% CI, 0.67-0.87]; P<0.0001). This benefit reached statistical significance at 18 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (hazard ratio, 0.71 [95% CI, 0.52-0.96]; P=0.028) and the total number of all hospitalizations that required a vasopressor or positive inotropic drug (hazard ratio, 0.73 [95% CI, 0.55-0.97]; P=0.033). Compared with patients in the placebo group, fewer patients in the empagliflozin group reported outpatient intensification of diuretics (482 versus 610; hazard ratio, 0.76 [95% CI, 0.67-0.86]; P<0.0001), and patients assigned to empagliflozin were 20% to 50% more likely to have a better New York Heart Association functional class, with significant effects at 12 weeks that were maintained for at least 2 years. The benefit on total heart failure hospitalizations was similar in patients with an ejection fraction of >40% to <50% and 50% to <60%, but was attenuated at higher ejection fractions.ConclusionsIn patients with heart failure with preserved ejection fraction, empagliflozin produced a meaningful, early, and sustained reduction in the risk and severity of a broad range of inpatient and outpatient worsening heart failure events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Dataset Information

Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial.

Background

Methods

Results

Conclusions

Publications

Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial.

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