Hello, and welcome. I am Dr. Javed Butler, President of the Baylor Scott & White Research Institute and Professor of Medicine at University of Mississippi Medical Center. I am excited to share the Jardine's clinical data in adults with heart failure from the EMPEROR clinical trials, including the breakthrough findings in adults with HF-PEF or heart failure with preserved ejection fraction. The clinical development of Jardine's is marked by a number of significant milestones. So before we go any further, let's talk briefly about the indications for Jardine's. As we'll review in more detail, the results of the EMPEROR clinical trials established Jardine's as the first FDA-approved heart failure therapy to demonstrate a statistically significant reduction in the risk of cardiovascular death and hospitalization for heart failure, regardless of left ventricular ejection fraction. We'll go over disease state information related to heart failure, followed by clinical data from the EMPEROR trials, and we'll conclude with practical considerations for Jardine's treatment. Jardine's is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure. To reduce the risk of sustained decline in EGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression. To reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease. As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Jardine's is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase their risk of diabetic ketoacidosis. Jardine's is not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an EGFR less than 30 milliliters per minute per 1.73 meters squared. Jardine's is likely to be ineffective in this setting based upon its mechanism of action. Jardine's is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 milligrams of prednisone or equivalent for kidney disease. Jardine's is not expected to be effective in these populations. Important safety information, contraindications, hypersensitivity to embagloflosin or any of the excipients in Jardine's, reactions such as angioedema have occurred. This presentation is supported by and made on behalf of Beringer Engelheim Pharmaceuticals and Lilly USA. The presentation content has been reviewed for consistency with FDA guidelines and is not approved for continuing medical education credit. Let's begin with a brief review of some of the challenges associated with heart failure. All subtypes of heart failure carry a high risk of mortality and hospitalization, but HFPAF in particular is associated with some unique challenges. In fact, HFPAF has long been considered one of the greatest unmet needs in cardiovascular medicine. Treatment options for HFPAF have been extremely limited and most treatments for these patients have consisted of medications that address symptoms and comorbidities. We should also note that the prevalence of comorbidities such as obesity and type 2 diabetes maladies tend to be higher in patients with HFPAF compared with HFREF. It's not surprising that we are seeing the prevalence of HFPAF increase in parallel with the rising prevalence of these comorbidities. In fact, looking at recent data, we are beginning to see the incidence of HFPAF overtake that of HFREF. HFPAF is also associated with longer average hospital stays compared with HFREF. Because of these differences, both HFPAF and HFREF are associated with similarly poor outcomes. Heart failure is associated with high rates of hospitalization and hospitalizations are associated with a substantial reduction in life expectancy. For adults 65 to 69 years old, this can translate to more than a decade of lost life. And even for octogenarians and nonagenarians, for whom there is a high competing risk of death from other causes, the decrease in life expectancy after a heart failure hospitalization is still on the order of years rather than months or days. These poor outcomes show why early and aggressive treatment should be a goal for all patients with heart failure and why we, as clinicians, need to stay appraised of new developments in treatment and incorporate them into our practice whenever possible. Jardians, as an SGLT2 inhibitor, is recommended for adults with HFREF, heart failure with mildly reduced ejection fraction, and HFPAF. Specifically, the SGLT2 inhibitor class has gained a 1A recommendation for HFREF and a 2A BR recommendation for heart failure with mildly reduced ejection fraction and HFPAF. So they should be considered for adults with heart failure, regardless of LVEF. This direction comes straight from the 2022 American Heart Association, American College of Cardiology, Heart Failure Society of America guidelines for the management of heart failure. It offers recommendation for treating all the major phenotypes of heart failure, including HFREF, HFPAF, and notably, heart failure with mildly reduced ejection fraction. The latter classification was first recognized as a distinct subtype in the 2016 European Society of Cardiology guidelines and accounts for roughly 10 to 20% of heart failure cases. For patients with HFREF, we can see that SGLT2 inhibitors are now recognized as a core component of guideline-directed medical care, with the same class of recommendations as beta blockers, MRAs, and RAS inhibitors, with or without a neprilysin inhibitor. For patients with preserved or mildly reduced ejection fraction, SGLT2 inhibitors are given a class 2A recommendation, which is stronger than the level of recommendation given for ARNI, ACE inhibitor, ARB, and MRA in these patients. Now let's look into some of the clinical trial data that led to the recent inclusion of SGLT2 inhibitors in treatment guidelines for adults with heart failure. The EMPR clinical trials consisted of two similarly designed clinical trials, EMPR-preserved and EMPR-reduced. EMPR-preserved and EMPR-reduced for phase 3, randomized, double-blind, placebo-controlled studies that investigated the effects of Jardians on major heart failure outcomes in patients with HFPEF and HFREF, respectively. The trials were designed to answer three questions. First, how does treatment with Jardians affect the occurrence of a composite outcome of cardiovascular death or heart failure hospitalization? And second, how does it affect the occurrence of total hospitalization for heart failure that prevents both first and recurrent and the rate of decline in EGFR during treatment? In both trials, patients were randomized one-to-one to receive placebo or Jardians 10 milligrams. All patients were also receiving usual treatment for patients with heart failure, including diuretics, RAS inhibitors with and without a neprilysin inhibitor, beta blockers, MRAs, and when indicated, cardiac devices. The key differences between the trials lie in the inclusion criteria. EMPR-preserved enrolled patients with chronic heart failure and left ventricular ejection fraction above 40%, whereas EMPR-reduced enrolled heart failure patients with LVEF of 40% or less. Because the patient population in EMPR-reduced was enriched for patients who were at an increased risk for heart failure events, patients with an LVEF above 30% were required to have particularly high anti-probiotic levels or a history of hospitalization for heart failure within the previous 12 months. Patients with an EGFR as low as 20 were eligible for inclusion in both trials. Now we'll review results from the EMPR clinical trials, starting with the breakthrough data from EMPR-preserved. These data establish EMPR-preserved as the first trial assessing morbidity and mortality to meet its primary endpoint in adults with HFPEF. In EMPR-preserved, Jardians proved a statistically significant and clinically relevant 21% relative risk reduction in the risk of cardiovascular death or hospitalization for heart failure with a corresponding absolute risk reduction of 3.3%. This benefit translates into a number needed to treat a 31 over the median duration of follow-up of 26 months. Jardians is the first FDA-approved heart failure therapy to demonstrate a statistically significant risk reduction in cardiovascular death and hospitalization for heart failure regardless of LVEF. Another striking finding from the trial was how rapidly the benefits were observed. In fact, the benefit of Jardians achieved statistical significance by day 18 and it was sustained throughout the duration of the study. For me, this early benefit we see with Jardians speaks a sense of urgency and underscores the potential benefit for patients if we intervene early. We also saw that Jardians reduced the risk of cardiovascular death and hospitalization for heart failure in EMPR-preserved regardless of LVEF, medication use at baseline, or diabetes status. Now, taking a look at the key secondary endpoint of total heart failure hospitalization events, Jardians was associated with a significant 27% relative risk reduction in total hospitalizations for heart failure, including both first and recurrent hospitalizations. Among the absolute event rates, there were 407 events in the Jardians group and 541 events in the placebo group. There was also a separate analysis of EMPR-preserved that examined time to a worsening heart failure event, defined in this case as cardiovascular death, heart failure hospitalization, or an emergency or urgent heart failure visit requiring intravenous treatment for worsening heart failure. A benefit with Jardians was observed within days following randomization. Once again, this speaks to the early benefit we see with Jardians in patients with HFPAF. Let's turn our attention to some of the safety data from EMPR-preserved. The safety profile of Jardians in EMPR-preserved was largely consistent with what was observed in previous trials. In EMPR-preserved, rates of serious adverse events were generally comparable between the Jardians and the placebo groups. Uncomplicated genital and urinary tract infections and hypotension were more common with Jardians than with placebo. Hypoglycemia rates were similar between the Jardians and the placebo groups. The use of Jardians in combination with insulin or insulin secretogogues can increase the risk of hypoglycemia. The risk of hypoglycemia may be lowered by a reduction in the dose of safonuria or other concomitantly administered insulin secretogogues or insulin. Let's now look at EMPR-reduced, the sister trial of EMPR-preserved that enrolled patients with heart failure and reduced ejection fraction. In EMPR-reduced, Jardians significantly reduced the relative risk of cardiovascular death or heart failure hospitalization by 25% with a corresponding absolute risk reduction of 5.3%. This benefit translated into a number needed to treat of 19 over the median follow-up of 16 months to prevent one cardiovascular death or hospitalization for heart failure. Like in EMPR-preserved, the benefit with Jardians and EMPR-reduced was observed early and was sustained throughout the study period. The effect of Jardians on the primary outcome in EMPR-reduced was consistent across major subgroups, including baseline medication use and diabetes status. And because the primary endpoint was met, we went on to examine the results of the first secondary endpoint. We found that Jardians was associated with a 30% relative risk reduction in the secondary endpoint of total hospitalizations for heart failure. There were 388 events in the Jardians group and 553 events in the placebo group. In this analysis of time-to-worsening heart failure events during the first 40 days following randomization in EMPR-reduced, we once again see an early benefit with Jardians. These data reinforce the urgency to intervene early, and they remind us that every day counts for our patients. Now let's examine some safety data from EMPR-reduced. Many of the trends we observed in patients with HEF-PEF and EMPR-preserved were also evident here in patients with HEF-REF. Rates of serious adverse events were generally comparable between the Jardians and placebo groups, as were the rates of hypoglycemic events. The use of Jardians in combination with insulin or insulin secretagogues can increase the risk of hypoglycemia. The risk of hypoglycemia may be lowered by a reduction in the dose of safonuria or other concomitantly administered insulin secretagogues or insulin. We can see that uncomplicated genital and urinary tract infections and hypotension were more common with Jardians than with placebo, which is consistent with the results from the EMPR-preserved as well as previous trials of Jardians. We have covered a lot of important data today, so let's take a moment to summarize the key findings from the EMPR clinical trials. Jardians reduced the relative risk of cardiovascular death and hospitalization for heart failure by 25% in adults with HEF-REF and EMPR-reduced and by 21% in adults with HEF-PEF and EMPR-preserved, corresponding to an absolute risk reduction of 5.3% and 3.3% respectively. Together, these data established Jardians as the first FDA-approved heart failure therapy to demonstrate a statistically significant reduction in the risk of cardiovascular death and hospitalization for heart failure, regardless of LVEF. Now let's turn our attention to some practical consideration for initiating Jardians in adults with heart failure. Jardians can be used in adults with heart failure, regardless of their left ventricular ejection fraction. In addition, Jardians offers once-daily oral dosing without any need for titration. The starting dose of 10 mg is identical to the target dose. Jardians can be used with or without other common heart failure therapies. In summary, Jardians has proven efficacy in adults with heart failure as well as simple dosing and a well-established safety profile. Jardians is the first FDA-approved heart failure therapy to demonstrate a statistically significant risk reduction in cardiovascular death and hospitalization for heart failure, regardless of LVEF. Jardians offer convenient once-daily dosing and there is no dose titration required for adults with heart failure. In addition, the safety profile of Jardians has been evaluated across multiple clinical trials and indications. Jardians as an SGLT2 inhibitor is recommended by the 2022 American Heart Association, American College of Cardiology and Heart Failure Society of America guidelines for the management of heart failure for adults with HFREF, heart failure with mildly reduced ejection fraction and HFPEF. Now, we'll conclude the presentation with the important safety information for Jardians, starting with the warnings and precautions. Diabetic ketoacidosis in patients with type 1 diabetes mellitus and other ketoacidosis. Jardians increases the risk of life-threatening ketoacidosis in patients with type 1 diabetes and fatal ketoacidosis has occurred with Jardians. Type 2 diabetes and pancreatic disorders are also risk factors for ketoacidosis and fatal events of ketoacidosis have been reported in patients with type 2 diabetes using Jardians. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include elevated levels or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse. Signs and symptoms of diabetic ketoacidosis are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Assess patients who present with signs and symptoms of metabolic ketoacidosis regardless of blood glucose levels. If suspected, discontinue Jardians, treat promptly, and monitor for resolution before restarting. Consider keto monitoring in patients with type 1 diabetes mellitus as well as in others at risk for ketoacidosis. Withhold Jardians in clinical situations known to predispose to ketoacidosis and resume when clinically stable. Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue Jardians and seek medical attention immediately if signs and symptoms occur. Volume depletion Jardians can cause intravascular volume depletion, which may manifest as symptomatic hypotension or acute transient changes in creatinine. Acute kidney injury requiring hospitalization and dialysis has been reported in patients with type 2 diabetes receiving SGLT2 inhibitors, including Jardians. Before initiating, assess volume status and renal function in patients with impaired renal function, eGFR less than 60 milliliters per minute per 1.73 meters squared, elderly patients, or patients on loop diuretics. In patients with volume depletion, correct this condition before initiating Jardians. After initiating, monitor for signs and symptoms of volume depletion and renal function. Urosepsis and pyelonephritis Serious urinary tract infections, including urosepsis and pyelonephritis requiring hospitalization, have been identified in patients receiving Jardians. Treatment with Jardians increases the risk for urinary tract infections. Evaluate for signs and symptoms of urinary tract infections and treat promptly. Hypoglycemia In adult patients, the use of Jardians in combination with insulin or insulin secretogogues can increase the risk of hypoglycemia. In pediatric patients aged 10 years and older, the risk of hypoglycemia was higher with Jardians regardless of insulin use. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea or other concomitantly administered insulin secretogogues or insulin. Necrotizing fasciitis of the perineum, Fournier's gangrene Serious life-threatening cases requiring urgent surgical intervention have occurred in both females and males receiving Jardians. Serious outcomes have included hospitalization, multiple surgeries, and death. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment and discontinue Jardians. Genital mycotic infections Jardians increases the risk for genital mycotic infections, especially in patients with prior infections. Monitor and treat as appropriate. Lower-limb amputation Lower-limb amputations have been observed in patients with chronic kidney disease taking Jardians, peripheral artery disease, and diabetic foot infection, including osteomyelitis, with the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of diabetic foot, peripheral artery disease, including previous amputation, or diabetes. Counsel patients receiving Jardians about the importance of routine preventative foot care and monitor for signs and symptoms of diabetic foot infection, including osteomyelitis, new pain or tenderness, sores or ulcers involving the lower limbs, and institute appropriate treatment. Hypersensitivity reactions Serious hypersensitivity reactions have occurred with Jardians and geoedema. If hypersensitivity reactions occur, discontinue Jardians, treat promptly, and monitor until signs and symptoms resolve. Most common adverse reactions Greater than or equal to 5%, urinary tract infections, and female genital mycotic infections. Drug interactions Diuretics Co-administration with diuretics may enhance the potential for volume depletion. Monitor for signs and symptoms. Lithium Concomitant use with lithium may decrease serum lithium concentrations. Monitor more frequently during Jardians initiation and dosage changes. Use in special populations Pregnancy Jardians is not recommended during the second and third trimesters. Lactation Jardians is not recommended while breastfeeding. Geriatric use Jardians is expected to have diminished glycemic efficacy in elderly patients with renal impairment. Assess renal function more frequently in elderly patients. The incidence of volume depletion-related adverse reactions and urinary tract infections increased in type 2 diabetes patients greater than or equal to 75 years treated with embagloflozin. I want to conclude by acknowledging what an exciting time this is for cardiovascular medicine. These data from Jardians are truly groundbreaking. And with the guidance for SGLT2 inhibitors from the AHA, ACC, HF, SA guideline, we can see how they are already helping adults with heart failure. Thank you for joining me today with this important discussion about improving outcomes for patients with heart failure.

Javed Butler

EMPEROR clinical trials

Jardiance

heart failure therapy

cardiovascular death

hospitalization