New Empagliflozin Analysis Shows Consistent Cardio-Renal Benefits in Adults with HFrEF Regardless of Chronic Kidney Disease Stage

Ingelheim, Germany and Indianapolis, USANovember 2, 2020 /PRNewswire/ -- Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) announced that new exploratory subgroup analyses from the Phase III EMPEROR-Reduced trial demonstrated that empagliflozin reduces the risk of cardiovascular and renal adverse events in adults with heart failure with reduced ejection fraction, regardless of diabetes status or underlying chronic kidney disease. These results were presented today as an oral report at Kidney Week 2020, the annual meeting of the American Society of Nephrology, and published in the journal Circulation.^[1]

Dr. Faiez Zannad, an EMPEROR clinical investigator and Honorary Professor of Therapeutics at the University of Lorraine in France, stated: “Heart failure and chronic kidney disease are each independently associated with an increased risk of hospitalization and premature death from cardiovascular causes. The presence of one condition typically accelerates the onset and progression of the other, further elevating disease risk and leading to poorer prognosis. In the EMPEROR-Reduced study, empagliflozin demonstrated consistent benefits in reducing the risk of cardiovascular death and hospitalization for heart failure (the trial’s composite primary endpoint) among adult patients with heart failure with reduced ejection fraction, regardless of the presence or absence of chronic kidney disease, while also slowing the decline in renal function. This is encouraging news for the growing number of adult patients affected by both heart failure and chronic kidney disease.”

As previously reported, the EMPEROR-Reduced clinical study demonstrated that in adult patients with heart failure with reduced ejection fraction, with or without diabetes, empagliflozin reduced the relative risk of cardiovascular death or hospitalization for heart failure by 25%, and reduced the relative risk of first and subsequent hospitalizations for heart failure by 30%. Furthermore, patients experienced a slower decline in eGFR (a measure of renal function deterioration), which was part of the trial’s composite endpoint.^[1]Another exploratory analysis indicated that empagliflozin reduced the relative risk of the composite renal endpoint by 50%, including end-stage renal disease or severe loss of renal function.^[1]These benefits were observed across all endpoints in this new analysis among the subgroup of patients with or without underlying chronic kidney disease, including those with severe renal impairment.^[1]The safety profile in all patients enrolled in the EMPEROR-Reduced clinical trial was consistent with the known safety profile of empagliflozin.^[2]

Dr. Waheed Jamal, Vice President and Head of Medical Affairs for Cardiometabolic Diseases at Boehringer Ingelheim, stated, “We have a good understanding of the interplay between heart failure and chronic kidney disease, but we need deeper insights into how to treat these interconnected conditions. These new data demonstrate the benefits of comprehensive management of cardiorenal-metabolic diseases, holding the potential to improve the health of millions of people worldwide.”

Dr. Jeff Emmick, Vice President of Product Development at Eli Lilly and Company, stated, “Heart failure and chronic kidney disease are common, life-threatening conditions whose treatment regimens require improvement. The EMPOWER clinical development program, including our ongoing EMPEROR-Preserved and EMPA-KIDNEY trials, explores the potential role of empagliflozin in improving outcomes for patients with these conditions. The new findings from EMPEROR-Reduced will help us achieve our goal of redefining how these patients are treated.”

In March 2020, the U.S. Food and Drug Administration (FDA) granted fast track designation to empagliflozin for the treatment of chronic kidney disease, underscoring the urgent need for new therapeutic options in patients with this condition. The fast track designation covers the ongoing EMPA-KIDNEY trial, which is investigating the effects of empagliflozin on the progression of kidney disease and the incidence of cardiovascular death in adults with chronic kidney disease (with or without diabetes). The results of the EMPA-KIDNEY clinical trial are expected to be published in 2022.^[2]

In June 2019, the FDA also granted empagliflozin Fast Track designation for reducing the risk of cardiovascular death and heart failure hospitalization in patients with chronic heart failure. The Fast Track designation was based on the EMPEROR program, which includes the EMPEROR-Reduced and EMPEROR-Preserved clinical trials. EMPEROR-Preserved is investigating the effect of empagliflozin on cardiovascular death or hospitalization due to heart failure in adults with heart failure with preserved ejection fraction, an area where there are currently no approved treatment options. Results from EMPEROR-Preserved are expected to be announced in 2021. Empagliflozin is not yet indicated for the treatment of heart failure.

The EMPEROR and EMPA-KIDNEY studies are part of the EMPOWER clinical program, one of the most extensive and comprehensive trial programs for any SGLT2 inhibitor, designed to explore the impact of empagliflozin on the lives of patients with various cardiorenal-metabolic diseases.

On the EMPEROR Heart Failure Studies^[6],[3]

EMPEROR (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure) The chronic heart failure research program comprises two Phase III, randomized, double-blind trials evaluating the efficacy and safety of once-daily empagliflozin versus placebo, added to standard of care, in adult patients with chronic heart failure with preserved ejection fraction and reduced ejection fraction (including both patients with and without diabetes).

Primary Endpoint: Time to First Adjudicated Cardiovascular Death or Adjudicated Hospitalization for Heart Failure (HHF)
Number of enrolled patients: 3,730 cases
Completion Time: 2020
# Key Summary Link

Primary endpoint: Time to first adjudicated cardiovascular death or adjudicated hospitalization for heart failure (HHF) [Time frame: up to 38 months]
Expected number of patients to be enrolled: approximately 5,990 cases
Estimated Completion Date: 2021

*Ejection FractionIt is a measure of the percentage of blood pumped out of the left ventricle with each contraction. When the heart relaxes, the ventricles refill with blood.

AboutEMPOWERItem

The Consortium developed the EMPOWER project, which aims to explore the impact of empagliflozin on major clinical cardiovascular and renal outcomes in a range of cardiorenal-metabolic diseases. Cardiorenal-metabolic diseases are a leading cause of death globally, resulting in up to 20 million deaths annually.^[9]Through the EMPOWER program, Boehringer Ingelheim and Eli Lilly are working to increase awareness of these interconnected systems and develop therapies that provide comprehensive, multi-organ benefits.^[10]EMPOWER comprises nine studies and one real-world study, reinforcing the alliance’s long-term commitment to improving clinical outcomes in patients with cardiorenal-metabolic diseases. With global enrollment of more than 257,000 adult patients in its clinical trials, EMPOWER is one of the most extensive and comprehensive clinical programs conducted to date for SGLT2 inhibitors.

Development projects include the following trials:

[1]Composite exploratory endpoint included chronic dialysis or renal transplant or sustained reduction of  ≥40% in eGFR (CKD-EPI) or a sustained eGFR <15 mL/min/1.73 m2 (for patients with baseline eGFR ≥30) or sustained eGFR <10 mL/min/1.73 m2 (for patients with baseline eGFR <30 mL/min/1.73 m2).

[1] Packer M, Anker SD, Butler J, et al. Cardiac and Renal Outcomes With Empagliflozin in Heart Failure With a Reduced Ejection Fraction. N Engl J Med. 2020;10.1056/NEJMoa2022190.

[2] ClinicalTrials.gov. EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin). Available at: https://clinicaltrials.gov/ct2/show/NCT03594110. Accessed October 2020.

[3] ClinicalTrials.gov. EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced). Available at: https://clinicaltrials.gov/ct2/show/NCT03057977. Accessed October 2020.

[4] ClinicalTrials.gov. EMPagliflozin initiated in patients hospitalised for acUte heart faiLure (de novo or decompensated chronic HF) who have been StabilisEd (EMPULSE) Available at: https://www.clinicaltrials.gov/ct2/show/NCT04157751. Accessed October 2020.

[5] Boehringer Ingelheim Pharmaceuticals, Inc. Press release. 2020. Available at: https://www.boehringer-ingelheim.com/press-release/dcri-collaboration-empact-mi. Accessed October 2020.

[6] ClinicalTrials.gov. A phase III randomised, double-blind trial to evaluate the effect of 12 weeks treatment of once daily EMPagliflozin 10 mg compared with placebo on ExeRcise ability and heart failure symptoms, In patients with chronic HeArt FaiLure with reduced Ejection Fraction (HFrEF) (EMPERIAL - reduced). Available at: https://clinicaltrials.gov/ct2/show/NCT03448419. Accessed October 2020.

[7] ClinicalTrials.gov. A phase III randomised, double-blind trial to evaluate the effect of 12 weeks treatment of once daily EMPagliflozin 10 mg compared with placebo on ExeRcise ability and heart failure symptoms, in patients with chronic HeArt FaiLure with preserved Ejection Fraction (HFpEF) (EMPERIAL - preserved). Available at: https://clinicaltrials.gov/ct2/show/NCT03448406. Accessed October 2020.

[8] Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373:2117-28.

[9] Kim DJ, Sheu WH-H, Seino Y, et al. Cardiovascular Effectiveness and Safety of Empagliflozin in Routine Care in East Asia: Results from the EMPRISE study. Presented at IDF Congress 2019. 2-6 December 2019, Busan, Korea.

[10] Patorno E, Pawar A, Franklin J, et al. Empagliflozin and the risk of heart failure hospitalization in routine clinical care: a first analysis from the EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) Trial. Circulation. 2019;139:2822-30.

[11] American Heart Association. What is Heart Failure? Available at: https://www.heart.org/en/health-topics/heart-failure/what-is-heart-failure. Accessed: August 2020.

[12] GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-1858.

[13] Suskin N, McKelvie RS, Burns RJ, et al. Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure. Eur Heart J. 2000;21:1368-75.

[14] Ronco C, McCullough P, Anker SD, et al. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J. 2010;31(6):703-11.

[15] Lazzeri C, Valente S, Tarquini R, et al. Cardiorenal syndrome caused by heart failure with preserved ejection fraction. Int J Nephrol. 2011;2011:634903.

[16] Jardiance® (empagliflozin) tablets, U.S. Prescribing Information. Available at: http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Jardiance/jardiance.pdf. Accessed: May 2020.

[17] European Summary of Product Characteristics Jardiance^®, approved May 2018. Data on file.

[18] Jardiance^® (Full Prescribing Information). Mexico; Boehringer Ingelheim Pharmaceuticals, Inc; 2017.

[19] Jardiance^® (empagliflozin) tablets, U.S. Prescribing Information. Available at: http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Jardiance/jardiance.pdf. Accessed: August 2020.

[20] Jardiance^® (empagliflozin) tablets. European Product Information; approved April 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/jardiance-epar-product-information_en.pdf. Accessed October 2020.

[21] Jardiance^® (Full Prescribing Information). Mexico; Boehringer Ingelheim Pharmaceuticals, Inc; 2017.

[22] Vallon V and Thompson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017;60(2):215–25.