IN-BOEHRINGER-INGELHEIM

Full results from the EMPEROR-Reduced Phase III trial in adults with heart failure with reduced ejection fraction, with and without diabetes, showed that empagliflozin was associated with a significant 25 percent relative risk reduction in the primary endpoint of time to cardiovascular death or hospitalization due to heart failure.¹ The trial evaluated the effect of adding empagliflozin (10 mg) versus placebo to standard of care.¹ The results will be presented today at the ESC Congress 2020, the annual meeting of the European Society of Cardiology,³ and published in The New England Journal of Medicine ,¹ Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) announced.

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The findings from the primary endpoint were consistent in subgroups with and without type 2 diabetes.¹ Key secondary endpoint analyses from the trial demonstrated that empagliflozin reduced the relative risk of first and recurrent hospitalization for heart failure by 30 percent.¹ Additionally, the rate of decline in eGFR, a measure of kidney function decline, was slower with empagliflozin than with placebo.¹

"Heart failure is a devastating and debilitating cardiovascular condition. Not only does it limit quality of life, but it is also a progressive disease that requires repeated hospitalizations and is accompanied by a loss in kidney function,” said Milton Packer, M.D., Chair of the Executive Committee for the EMPEROR Program and Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center in Dallas, Texas, U.S. “Results from the EMPEROR-Reduced trial show that, when given to adults with heart failure with reduced ejection fraction, empagliflozin reduces the number of heart failure hospitalizations while slowing the decline of kidney function. These results are highly statistically significant and clinically important.”

In an exploratory analysis, the absolute risk reduction observed in the primary endpoint of EMPEROR-Reduced corresponded to a number needed to treat of 19 patients over 16 months to prevent one cardiovascular death or hospitalization for heart failure.¹ An additional exploratory analysis showed that empagliflozin decreased the relative risk of a composite kidney endpoint*, including end stage kidney disease and a profound loss of kidney function, by 50 percent.¹

In EMPEROR-Reduced, the efficacy results were achieved with a simple dosing regimen, with once daily dosing and no need for titration.¹ The safety profile was similar to the well-established safety profile of empagliflozin.¹ There were no clinically meaningful differences in adverse events including hypovolemia (decreased blood volume), hypotension (low blood pressure), volume depletion (loss of fluids), renal insufficiency (poor kidney function), hyperkalemia (high potassium levels) or hypoglycemic events (low blood sugar) compared with placebo.¹

Heart failure affects over 60 million people worldwide,4 with more than one million people being hospitalized due to the condition every year in the U.S. and Europe.² Heart failure occurs when the heart cannot pump sufficient blood to the rest of the body and is the most common and severe complication of a heart attack.^5,6 People with heart failure often experience breathlessness and fatigue, which can severely impact their quality of life.^7,8 Individuals with heart failure often also have impaired kidney function, which can have a significant negative impact on prognosis.⁹

“Heart failure can have a profound impact on people living with the condition, with the potential of life limiting consequences for the heart and the kidneys,” said Waheed Jamal, M.D., Corporate Vice President and Head of CardioMetabolic Medicine, Boehringer Ingelheim. "Empagliflozin was the first SGLT2 inhibitor to demonstrate a reduction in cardiovascular death and hospitalization due to heart failure in people with type 2 diabetes and established cardiovascular disease, based on the EMPA-REG OUTCOME^® trial. We continue to break new ground with the EMPEROR-Reduced results, which provide robust evidence that empagliflozin can transform the lives of millions of people through reducing cardiovascular outcomes and slowing the progression of kidney damage in people with heart failure. We look forward to exploring these data further and are planning regulatory submissions for later this year.”

“Tens of millions of people live with heart failure and kidney disease,” said Jeff Emmick, M.D., Ph.D., Vice President, Product Development, Lilly. “Results from EMPEROR-Reduced show that empagliflozin can help improve heart failure outcomes while also slowing kidney function decline. We are excited to share these data and, through our ongoing EMPOWER program, hope to redefine how people living with these conditions are treated.”

The U.S. Food and Drug Administration (FDA) has granted Fast Track designation to empagliflozin for the reduction of the risk of cardiovascular death and hospitalization for heart failure in people with heart failure.¹⁰ This designation is for the EMPEROR program, which consists of the EMPEROR-Reduced and EMPEROR-Preserved trials. EMPEROR-Preserved is exploring the effect of empagliflozin on cardiovascular death or hospitalization for heart failure in adults with heart failure with preserved ejection fraction,¹¹ an area that currently has no approved treatment options. EMPEROR-Preserved results are expected in 2021.

Additionally, the ongoing EMPA-KIDNEY study is evaluating the effect of empagliflozin on the progression of kidney disease and occurrence of cardiovascular death in adults with established chronic kidney disease, with and without diabetes.¹² The FDA has also granted Fast Track designation to empagliflozin for the treatment of chronic kidney disease, demonstrating the urgent need for new treatment options for people living with the condition worldwide.¹³ Results from EMPA-KIDNEY are expected in 2022.

The EMPEROR and EMPA-KIDNEY studies are part of the EMPOWER clinical program, the broadest and most comprehensive of any SGLT2 inhibitor, exploring the impact of empagliflozin on the lives of people across the spectrum of cardio-renal-metabolic conditions. The program also includes the EMPACT-MI study, which will investigate the effect of empagliflozin on all-cause mortality and hospitalization for heart failure in adults, with and without diabetes, who have had a heart attack¹⁴ , and the EMPULSE study, which is exploring empagliflozin in adults, with and without diabetes, who are hospitalized for acute heart failure and have been stabilized.¹⁵

* 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/1.73m² (for patients with baseline eGFR ≥ 30) or sustained eGFR < 10 mL/min/1.73m² (for patients with baseline eGFR < 30 mL/min/1.73m² ).

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About the EMPEROR Heart Failure Studies^11,16

The EMPEROR (EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure) heart failure studies are two Phase III, randomized, double-blind trials investigating once-daily empagliflozin compared with placebo in adults with heart failure with preserved or reduced ejection fraction*, both with and without diabetes, who are receiving current standard of care:

• EMPEROR-Reduced [NCT03057977 ] investigated the safety and efficacy of empagliflozin in patients with chronic heart failure with reduced ejection fraction (HFrEF).

• Primary endpoint: time to first event of adjudicated cardiovascular death or adjudicated hospitalization for heart failure
• Number of patients: 3,730
• Completion: 2020
• Link to lay summary

• EMPEROR-Preserved [NCT03057951 ] investigates the safety and efficacy of empagliflozin in patients with chronic heart failure with preserved ejection fraction (HFpEF).

• Primary endpoint: time to first event of adjudicated cardiovascular death or adjudicated hospitalization for heart failure [Time Frame: up to 38 months]
• Anticipated number of patients: approx. 5,990
• Estimated completion: 2021

*Ejection fraction is a measurement of the percentage of blood the left ventricle pumps out with each contraction.¹⁷ When the heart relaxes, the ventricle refills with blood.

• HFrEF occurs when the heart muscle does not contract effectively, and less blood is pumped out to the body compared with a normally functioning heart.¹⁷
• HFpEF occurs when the heart muscle contracts normally but the ventricle does not fill with enough blood, so less blood can enter the heart compared with a normally functioning heart.¹⁷

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.¹⁸ 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 eight 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 257,000 adults studied worldwide in clinical studies, it is the broadest and most comprehensive clinical program for an SGLT2 inhibitor to date.

The development program encompasses:

• EMPEROR-Reduced, in adults with chronic heart failure with reduced ejection fraction to reduce the risk of cardiovascular death or hospitalization due to heart failure¹
• EMPEROR-Preserved, in adults with chronic heart failure with preserved ejection fraction to reduce the risk of cardiovascular death or hospitalization due to heart failure¹¹
• EMPULSE, in adults hospitalized for acute heart failure to improve clinical and patient reported outcomes¹⁵
• EMPACT-MI, to evaluate all-cause mortality and hospitalization for heart failure in adults with and without type 2 diabetes who have had an acute myocardial infarction, with the aim to prevent heart failure and improve outcomes¹⁴
• EMPA-KIDNEY, in adults with established chronic kidney disease to reduce the progression of kidney disease and the occurrence of cardiovascular death¹²
• EMPERIAL-Reduced, in adults with chronic heart failure with reduced ejection fraction to evaluate functional ability and patient reported outcomes¹⁹
• EMPERIAL-Preserved, in adults with chronic heart failure with preserved ejection fraction to evaluate functional ability and patient-reported outcomes²⁰
• EMPA-REG OUTCOME^® , in adults with type 2 diabetes and established cardiovascular disease to prevent major adverse cardiovascular events, including cardiovascular death²¹
• EMPRISE, a non-interventional study of the effectiveness, safety, healthcare utilization and cost of care of empagliflozin in routine clinical practice in adults with type 2 diabetes across the cardiovascular risk continuum^22,23

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.⁵ It is a widespread condition affecting over 60 million people worldwide and expected to increase as the population ages.⁴ Heart failure is highly prevalent in people with diabetes;²⁴ however, approximately half of all people with heart failure do not have diabetes.^4,25

The empagliflozin heart failure program was initiated based on data from the EMPA-REG OUTCOME^® trial, which assessed the effect of empagliflozin (10 mg or 25 mg once daily) in adults with type 2 diabetes and established cardiovascular disease when added to standard of care, compared with placebo.²¹

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.¹⁸

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, improving the health of one system can lead to positive effects throughout the others.^26,27

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.^28,29,30

Inhibition of SGLT2 with empagliflozin in people with type 2 diabetes and high blood sugar levels prevents sugar being re-absorbed by the kidneys, leading to the excretion of excess sugar in the urine. In addition, initiation of empagliflozin also prevents salt being re-absorbed, leading to increased excretion of salt from the body and reducing the fluid load of the body’s blood vessel system (i.e. intravascular volume). Empagliflozin induces changes to the sugar, salt and water metabolism in the body that may contribute to the reductions in cardiovascular death observed in the EMPA-REG OUTCOME^® trial.³¹

Please click on the following link for ‘Notes to Editors’ and ‘References’ https://www.boehringer-ingelheim.com/press-release/emperor-reduced-heart-failure-full-data

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