Empagliflozin + Potassium Nitrate for Heart Failure

(SAK Trial)

Overseen By Melissa Fernando

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Pennsylvania

Must not be taking: Organic nitrates, PDE inhibitors

Disqualifiers: Pregnancy, Uncontrolled atrial fibrillation, Valvular disease, Cardiomyopathy, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

53 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will test whether pharmacologic agents that may improve mitochondrial function and energy fuel metabolism \[Empagliflozin (Empa)\], with and without additional supplements that increase perfusion and fatty acid oxidation \[Potassium Nitrate (KNO3)\], improve submaximal exercise endurance and skeletal muscle oxidative phosphorylation capacity (SkM OxPhos) in participants with Heart Failure with Preserved Ejection Fraction (HFpEF).

Will I have to stop taking my current medications?

The trial requires that you stop taking organic nitrates or phosphodiesterase inhibitors if they cannot be interrupted. Other medications are not specifically mentioned, so it's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug Empagliflozin for heart failure?

Empagliflozin has been shown to reduce the risk of hospitalization and death in people with heart failure, even if they don't have diabetes. It also improves quality of life for those with chronic heart failure. ^{1 2 3 4 5}

Is the combination of Empagliflozin and Potassium Nitrate safe for humans?

Empagliflozin (Jardiance) is generally safe for treating heart failure and diabetes, but it can cause side effects like fluid loss and, in rare cases, a serious condition called diabetic ketoacidosis (a dangerous buildup of acids in the blood). There is no specific safety data available for the combination with Potassium Nitrate. ^{1 2 3 6 7}

How is the drug empagliflozin unique for treating heart failure?

Empagliflozin is unique for treating heart failure because it not only helps manage blood sugar levels in diabetes but also reduces the risk of hospitalization and death in heart failure patients, even those without diabetes. It works by promoting the removal of excess glucose and fluid from the body, which can help reduce symptoms like fluid retention and high blood pressure. ^{1 2 3 8 9}

Research Team

Payman Zamani, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

Adults with Heart Failure with Preserved Ejection Fraction (HFpEF) who have been on stable heart medication for at least a month. They should show signs of high heart pressure, have an ejection fraction >= 50%, and meet specific criteria related to the function of their heart valves. Pregnant women, individuals under 18, those with severe kidney or liver issues, uncontrolled diabetes or blood pressure problems, certain allergies, and people unable to exercise are excluded.

Inclusion Criteria

You have had high pressure in your heart during previous medical tests.

There is evidence that your heart is not pumping blood effectively.

I have heart issues indicated by specific heart function tests and symptoms.

Exclusion Criteria

I have heart issues found on a stress test that haven't been fixed or shown to be minor.

My heart beats more than 100 times a minute due to atrial fibrillation.

My kidney function is reduced, with an eGFR below 45.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Empagliflozin with or without Potassium Nitrate for 6 weeks

6 weeks

Weekly visits (in-person)

Washout

A 2-week washout period following the treatment phase

2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Empagliflozin
• Potassium Nitrate

Trial Overview The trial is testing if Empagliflozin (a diabetes drug that might help the heart), alone or combined with Potassium Nitrate (which could improve blood flow and muscle energy use), can increase exercise ability in HFpEF patients compared to placebo. Participants will be randomly assigned to one of three groups: Empagliflozin + Potassium Chloride, Empagliflozin + Potassium Nitrate, or Placebo + Potassium Chloride.

Participant Groups

Group I: Empagliflozin + Potassium Chloride (KCl) Active Control 1 Intervention

Empagliflozin (10 mg daily) + Potassium Chloride (6 mmol three times daily) Active arm will be 6 weeks in duration followed by a 2 week washout period.

Group II: Empagliflozin + Potassium Nitrate (KNO3) Active Control 1 Intervention

Empagliflozin (10 mg daily) + Potassium Nitrate (6 mmol three times daily) Active arm will be 6 weeks in duration followed by a 2 week washout period.

Group III: Potassium Chloride (KCl) + Placebo for Empa Placebo Group 1 Intervention

Potassium Chloride (6 mmol three times daily) + Placebo for Empagliflozin Placebo arm will be 6 weeks in duration followed by a 2 week washout period.

Empagliflozin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Jardiance for:

• Type 2 diabetes mellitus
• Heart failure with reduced ejection fraction
• Chronic kidney disease

Approved in United States as Jardiance for:

• Type 2 diabetes mellitus
• Heart failure with reduced ejection fraction
• Chronic kidney disease
• Cardiovascular risk reduction

Approved in Canada as Jardiance for:

• Type 2 diabetes mellitus
• Heart failure with reduced ejection fraction
• Chronic kidney disease

Approved in Japan as Jardiance for:

• Type 2 diabetes mellitus
• Heart failure with reduced ejection fraction

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Findings from Research

In the EMPEROR-Reduced study involving over 3700 participants with chronic heart failure and reduced ejection fraction, empagliflozin significantly reduced the risk of hospitalization for heart failure complications (13.2% vs. 18.3% for placebo) over an average of 16 months.

Empagliflozin also showed a lower incidence of serious kidney problems (1.6% vs. 3.1% for placebo), indicating its potential safety and efficacy in managing heart failure, although it was associated with a higher rate of genital tract infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug treatment with empagliflozin lowered risk for hospitalization in people with heart failure with reduced ejection fraction: plain language summary of the EMPEROR-Reduced study. Zannad, F., Macari, S.[2023]

Empagliflozin (Jardiance) is now approved for reducing the risk of cardiovascular death and hospitalization in adults with heart failure, even in those without diabetes, highlighting its expanded therapeutic use.

Healthcare providers, including nurses and nurse practitioners, should closely monitor patients for potential adverse effects, particularly fluid deficits, to ensure patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diabetes Drug Now Approved for Heart Failure. Aschenbrenner, DS.[2023]

Empagliflozin (EMPA) significantly reduced the induction of ventricular fibrillation (VF) in an ex-vivo model of ischemia-reperfusion, with only 16.7% of EMPA-treated hearts experiencing VF compared to 60% in control hearts.

EMPA improved cardiac contractility, as shown by a higher left ventricular developed pressure (LVDP) and enhanced calcium cycling, indicating its potential to protect heart function during ischemic events through mechanisms that do not involve sodium-glucose co-transporter-2 (SGLT2).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-arrhythmic and inotropic effects of empagliflozin following myocardial ischemia. Azam, MA., Chakraborty, P., Si, D., et al.[2021]

In a study of 7020 patients with type 2 diabetes and established cardiovascular disease, empagliflozin significantly reduced the risk of cardiovascular death and heart failure hospitalizations, showing consistent benefits across different levels of heart failure risk.

The majority of patients without heart failure at baseline were still at risk for heart failure outcomes, highlighting the importance of monitoring and treating these patients with empagliflozin to improve their heart health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME® trial. Fitchett, D., Butler, J., van de Borne, P., et al.[2022]

Empagliflozin, originally developed for type 2 diabetes, has been shown to significantly reduce the risk of cardiovascular death and hospitalization for heart failure in patients with symptomatic chronic heart failure, regardless of their left ventricular ejection fraction, based on pivotal phase III trials.

The treatment not only improved cardiovascular outcomes but also enhanced health-related quality of life and was well tolerated, with a safety profile similar to that observed in diabetes patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Empagliflozin: A Review in Symptomatic Chronic Heart Failure. Frampton, JE.[2022]

A study involving 60 healthy Chinese subjects demonstrated that the test formulation of empagliflozin is bioequivalent to the brand-name drug Jardiance, showing similar pharmacokinetic properties under both fasting and fed conditions.

Both formulations of empagliflozin were generally well tolerated, indicating a good safety profile for the drug in the tested populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Safety, and Bioequivalence of Two Empagliflozin Formulations after Single Oral Administration under Fasting and Fed Conditions in Healthy Chinese Subjects: An Open-label Randomized Single-dose Two-sequence, Two-treatment, Two-period Crossover Study. Chen, G., Zhang, D., Du, A., et al.[2021]

A 56-year-old man with type 2 diabetes presented in diabetic ketoacidosis (DKA) despite only mild hyperglycemia, highlighting a rare complication associated with the use of empagliflozin (Jardiance®).

This case emphasizes the need for emergency physicians to recognize that DKA can occur in patients on SGLT-2 inhibitors like empagliflozin, even when blood sugar levels are not severely elevated, which can complicate diagnosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium-glucose Cotransporter-2 Induced Diabetic Ketoacidosis with Minimal Hyperglycemia. Gammons, DT., Counselman, FL.[2020]

Empagliflozin effectively lowers blood sugar levels in patients with type 2 diabetes by inhibiting glucose reabsorption in the kidneys, resulting in an average reduction of HbA1c by approximately 0.8% without causing hypoglycemia, except in those already on insulin or sulphonylureas.

In addition to improving glycemic control, empagliflozin promotes weight loss (about 2 kg) and lowers blood pressure (systolic by approximately 4 mm Hg), while also providing cardiovascular protection, as demonstrated in the EMPA-REG OUTCOME trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[EMPAGLIFLOZIN (JARDIANCE) :Nw SGLT2 COTRANSPORTER INHIBITOR FOR TREATING TYPE 2 DIABETES]. Scheen, AJ.[2022]

In the EMPEROR-Preserved study involving nearly 6000 participants, empagliflozin significantly reduced the risk of hospitalization for heart failure complications by about 30% after an average treatment duration of 26 months.

While side effects were generally similar between empagliflozin and placebo groups, there was a higher incidence of genital infections in those taking empagliflozin (2.2% vs. 0.7%), indicating a need for monitoring but overall suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug treatment with empagliflozin was beneficial in people with heart failure with preserved ejection fraction: plain language summary of the EMPEROR-Preserved study. Zannad, F., Macari, S.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Drug treatment with empagliflozin lowered risk for hospitalization in people with heart failure with reduced ejection fraction: plain language summary of the EMPEROR-Reduced study. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Diabetes Drug Now Approved for Heart Failure. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Anti-arrhythmic and inotropic effects of empagliflozin following myocardial ischemia. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME® trial. [2022]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Empagliflozin: A Review in Symptomatic Chronic Heart Failure. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Safety, and Bioequivalence of Two Empagliflozin Formulations after Single Oral Administration under Fasting and Fed Conditions in Healthy Chinese Subjects: An Open-label Randomized Single-dose Two-sequence, Two-treatment, Two-period Crossover Study. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Sodium-glucose Cotransporter-2 Induced Diabetic Ketoacidosis with Minimal Hyperglycemia. [2020]

8. Belgium pubmed.ncbi.nlm.nih.gov

[EMPAGLIFLOZIN (JARDIANCE) :Nw SGLT2 COTRANSPORTER INHIBITOR FOR TREATING TYPE 2 DIABETES]. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Drug treatment with empagliflozin was beneficial in people with heart failure with preserved ejection fraction: plain language summary of the EMPEROR-Preserved study. [2023]