Empagliflozin provided a significant clinical benefit in adults stabilized in hospital following acute heart failure in EMPULSE Phase III trial

Ingelheim, Germany and Indianapolis, U.S., 1 March 2022 – Adults hospitalized for acute heart failure were 36 percent more likely to experience a clinical benefit over 90 days if initiated on empagliflozin following stabilization and prior to discharge compared with placebo in the Phase III EMPULSE trial, Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) announced today. Clinical benefit reflected a composite primary endpoint that included all-cause mortality, frequency of heart failure events, time to first heart failure event, and symptoms as measured by the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS). The findings were published today in Nature Medicine and were recently presented at the American Heart Association’s Late-Breaking Scientific Sessions 2021.^1,2 

“The first months following hospitalization for heart failure are a particularly vulnerable time for patients,” said Adriaan Voors, Professor of Cardiology, University Medical Center, Groningen, Netherlands, and EMPULSE Principal Investigator. “Current outcomes are poor, underscoring the urgent need for improved in-patient clinical management to prevent further hospitalizations or death. This significant clinical benefit with empagliflozin compared with placebo will advance our understanding of the treatment of heart failure during the early discharge phase.”

Heart failure is a leading cause of hospitalizations, accounting for more than one million per year in the U.S. and Europe.³ Outcomes for those who have been admitted to the hospital for heart failure are poor, with over 30 percent of patients readmitted within 90 days between 2010 and 2017, according to the U.S.-based National Readmission Database.⁴

The overall clinical benefit with empagliflozin was consistent for those with either new or pre-existing heart failure, for those with or without diabetes and for those with either preserved or reduced ejection fraction.¹ In an exploratory secondary endpoint, empagliflozin significantly improved KCCQ-TSS from baseline to day 90 by 4.5 points versus placebo.¹ 

The EMPULSE safety results were consistent with the well-established safety profile of empagliflozin. Investigator-reported acute renal failure rates were 7.7 percent for empagliflozin versus 12.1 percent for placebo, and there was a similar low incidence of hypoglycemia in both groups (1.9 percent for empagliflozin versus 1.5 percent for placebo). Volume depletion rates were 12.7 percent versus 10.2 percent respectively.¹

“The EMPULSE trial shows that adults hospitalized for acute heart failure and treated with empagliflozin on top of standard of care after stabilization are more likely to experience improvements in an endpoint combining mortality, hospitalizations and quality of life, compared to those receiving placebo. Additionally, the mean increase in KCCQ-TSS score suggested an overall improvement for patients in their self-reported symptom burden,” said Waheed Jamal, M.D., Corporate Vice President and Head of CardioMetabolic Medicine, Boehringer Ingelheim. “These data show a clinical benefit in those with de novo and pre-existing heart failure, supporting a wide range of adults with the condition.”

“The EMPULSE results add to the growing weight of evidence from our EMPOWER program supporting the potential role of empagliflozin in a range of conditions affecting the heart, kidneys and metabolic system,” said Jeff Emmick, M.D., Ph.D., Vice President, Product Development, Lilly. “The clinical benefit and consistent safety results demonstrated in the vulnerable phase following hospital discharge suggest that in-hospital initiation with empagliflozin for appropriate patients can improve outcomes during these critical months.”

This data publication follows the recent marketing authorization of empagliflozin for the treatment of adults with symptomatic chronic heart failure in the U.S. In 2021, empagliflozin was approved in the European Union and U.S. for the treatment of adults with heart failure with reduced ejection fraction.^5,6 The expanded indication now includes people with heart failure with preserved ejection fraction, a population that previously had no approved treatment option. 

Additionally, empagliflozin is currently indicated for the treatment of adults with insufficiently controlled type 2 diabetes.^5,6,7 Research is ongoing regarding the effects of empagliflozin on hospitalization for heart failure and mortality in post-myocardial infarction (heart attack) patients with high risk of heart failure.⁸ Empagliflozin is also currently being investigated in chronic kidney disease.⁹

About EMPULSE
The EMPULSE trial is a multicenter, randomized, double-blind, 90-day superiority trial to evaluate the effect on clinical benefit, safety and tolerability of once-daily empagliflozin 10 mg compared with placebo, initiated in 530 patients hospitalized for acute heart failure (de novo or decompensated chronic heart failure) who have been stabilized. The primary endpoint was based on clinical benefit, a hierarchical composite endpoint of all-cause mortality, frequency of heart failure events, time to first heart failure event, and symptoms as measured by the KCCQ-TSS after 90 days of treatment, assessed by the win ratio.¹⁰

The win ratio estimates the odds that a participant in the empagliflozin arm will have a better clinical benefit than a participant in the placebo group; higher win ratios suggest a greater clinical benefit with empagliflozin. For EMPULSE, patients were stratified by de novo versus decompensated chronic heart failure. Within each stratum, every individual in the empagliflozin group was compared with every individual in the placebo group. The win ratio was determined by the total number of wins for empagliflozin divided by the total number of losses. The components of the primary endpoint were evaluated in order of clinical importance, so that deaths are prioritized over heart failure events and symptoms.¹ 

About the EMPOWER program
The Alliance has developed the EMPOWER program to explore the impact of empagliflozin on major clinical cardiovascular and renal outcomes in a spectrum of cardio-renal-metabolic conditions. Cardio-renal-metabolic conditions are the leading cause of mortality worldwide and account for up to 20 million deaths annually.¹¹ Through the EMPOWER program, Boehringer Ingelheim and Lilly are working to advance knowledge of these interconnected systems and create care which offers integrated, multi-organ benefits. Comprised of nine clinical trials and two real-world evidence studies, EMPOWER reinforces the long-term commitment of the Alliance to improve outcomes for people living with cardio-renal-metabolic conditions. With more than 400,000 adults enrolled worldwide in clinical trials, it is one of the broadest and most comprehensive clinical programs for an SGLT2 inhibitor to date. 

About Heart Failure 
Heart failure is a progressive, debilitating and potentially fatal condition that occurs when the heart cannot supply adequate circulation to meet the body’s demands for oxygenated blood, or to do so, requires increased blood volume leading to fluid accumulation (congestion) in the lungs and peripheral tissues.^12,13 It is a widespread condition affecting over 60 million people worldwide and expected to increase as the population ages.^14,15 Heart failure is highly prevalent in people with diabetes; however, approximately half of all people with heart failure do not have diabetes.^16,17

About cardio-renal-metabolic conditions
Boehringer Ingelheim and Lilly are driven to transform care for people with cardio-renal-metabolic conditions, a group of interconnected disorders that affect more than one billion people worldwide and are a leading cause of death.^11,15 

The cardiovascular, renal and metabolic systems are interconnected, and share many of the same risk factors and pathological pathways along the disease continuum. Dysfunction in one system may accelerate the onset of others, resulting in progression of interconnected diseases such as type 2 diabetes, cardiovascular disease, heart failure, and kidney disease, which in turn leads to an increased risk of cardiovascular death. Conversely, improvements in one system can lead to positive effects throughout the others.^18,19,20

Through our research and treatments, our goal is to support people’s health, restoring the balance between the interconnected cardio-renal-metabolic systems and reducing their risk of serious complications. As part of our commitment to those whose health is jeopardized by cardio-renal-metabolic conditions, we will continue embracing a multidisciplinary approach towards care and focusing our resources on filling treatment gaps.

About empagliflozin
Empagliflozin (marketed as Jardiance^®) is an oral, once-daily, highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor and the first type 2 diabetes medicine to include cardiovascular death risk reduction data in its label in several countries.^4,5,6 

 
Boehringer Ingelheim and Eli Lilly and Company
In January 2011, Boehringer Ingelheim and Eli Lilly and Company announced an Alliance that centers on compounds representing several of the largest diabetes treatment classes. Depending on geographies, the companies either co-promote or separately promote the respective molecules each contributing to the Alliance. The Alliance leverages the strengths of two of the world’s leading pharmaceutical companies to focus on patient needs. By joining forces, the companies demonstrate their commitment, not only to the care of people with diabetes, but also to investigating the potential to address areas of unmet medical need. Clinical trials have been initiated to evaluate the impact of empagliflozin on people living with heart failure or chronic kidney disease.

About Boehringer Ingelheim 
Boehringer Ingelheim is working on breakthrough therapies that improve the lives of humans and animals. As a leading research-driven biopharmaceutical company, the company creates value through innovation in areas of high unmet medical need. Founded in 1885 and family-owned ever since, Boehringer Ingelheim takes a long-term perspective. Around 52,000 employees serve more than 130 markets in the three business areas, Human Pharma, Animal Health, and Biopharmaceutical Contract Manufacturing. Learn more at www.boehringer-ingelheim.com.

About Eli Lilly and Company
Lilly is a global health care leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at lilly.com and lilly.com/newsroom.

Intended audiences

This press release is issued from Boehringer Ingelheim Corporate Headquarters in Ingelheim, Germany and is intended to provide information about our global business. Please be aware that information relating to the approval status and labels of approved products may vary from country to country, and a country-specific press release on this topic may have been issued in the countries where Boehringer Ingelheim and Eli Lilly and Company do business. This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Jardiance as a treatment for adults with type 2 diabetes, to reduce the risk of cardiovascular death in adults with type 2 diabetes and known cardiovascular disease, and to reduce the risk of cardiovascular death plus hospitalization for heart failure in adults with heart failure with reduced ejection fraction, and as a potential treatment for adults with cardio-renal-metabolic conditions and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there can be no guarantee that planned or ongoing studies will be completed as planned, that future study results will be consistent with the results to date or that Jardiance will receive additional regulatory approvals. For a further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, please see Lilly's most recent Forms 10-K and 10-Q filed with the U.S. Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release. 

CONTACTS:

Stefanie Molkenthin
Product Communication Manager
Boehringer Ingelheim 
Email: press@boehringer-ingelheim.com    
Phone: +49 (6132) 77 172 209

Stephan Thalen 
Global Business Communications 
Eli Lilly and Company
Email: stephan.thalen@lilly.com
Phone: (317) 903-5640
 

 References

¹ Voor AA, Angermann CE, Teerlink JR, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. (2022). DOI:10.1038/s41591-021-01659-1
² Voors AA, Angermann CE, Teerlink JR, et al., for the EMPULSE Trial Investigators. Empagliflozin in patients hospitalized for acute heart failure: the EMPULSE trial. Presented at the 2021 American Heart Association Scientific Sessions, Virtual; November 14, 2021. Late-breaking session 5.
³ Ambrosy AP, Fonarow GC, Butler J, et al. The gloal health and economic burden of hospitilizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardio. 2015;63;1123-1133.  
⁴ Khan MS, Sreenivasan J, Lateef N, et al. Trends in 30- and 90-Day Readmission Rates for Heart Failure. Circ Heart Fail. 2021 Apr;14(4):e008335. 
⁵ 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: November 2021.
⁶ Jardiance® (empagliflozin) tablets, U.S. Prescribing Information. Available at: http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Jardiance/jardiance.pdf. Accessed: November 2021.
⁷ Jardiance® (Full Prescribing Information). Mexico; Boehringer Ingelheim Pharmaceuticals, Inc; 2017.
⁸ ClinicalTrials.gov. EMPACT-MI: A Study to Test Whether Empagliflozin Can Lower the Risk of Heart Failure and Death in People Who Had a Heart Attack (Myocardial Infarction). Available at: https://clinicaltrials.gov/ct2/show/NCT04509674. Accessed: November 2021.
⁹ ClinicalTrials.gov. EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin). Available at: https://www.clinicaltrials.gov/ct2/show/NCT03594110. Accessed: November 2021.
¹⁰ ClinicalTrials.gov. A Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure. Available at: https://clinicaltrials.gov/ct2/show/NCT04157751. Accessed: November 2021. ¹¹ GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016; 388(10053):1459–544.
¹² American Heart Association. What is Heart Failure? Available at: https://www.heart.org/en/health-topics/heart-failure/what-is-heart-failure. Accessed: November 2021.
¹³ American Heart Association. Types of Heart Failure. Available at: https://www.heart.org/en/health-topics/heart-failure/what-is-heart-failure/types-of-heart-failure. Accessed: November 2021.
¹⁴ Andersen MJ, Borlaug BA. Heart failure with preserved ejection fraction: current understandings and challenges. Curr Cardiol Rep. 2014;16(7):501.
¹⁵ 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):1789–858.
¹⁶ Kenny HC, Abel ED. Heart Failure in Type 2 Diabetes Mellitus. Circ Res. 2019;124(1):121–41.
¹⁷ Dunlay SM, Givertz MM, Aguilar D, et al. Type 2 Diabetes Mellitus and Heart Failure: A Scientific Statement From the American Heart Association and the Heart Failure Society of America. Circulation. 2019;140:e294–e324.
¹⁸ García-Donaire JA, Ruilope LM. Cardiovascular and Renal Links along the Cardiorenal Continuum. Int J Nephrol. 2011;2011:975782.
¹⁹ Leon BM, Maddox TM. Diabetes and cardiovascular disease: Epidemiology, biological mechanisms, treatment recommendations and future research. World J Diabetes. 2015;6(13):1246–58.
²⁰ Thomas M, Cooper M, Zimmet P. Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat Rev Nephrol. 2015;12:73–81.