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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if Empagliflozin (also known as Jardiance), alone or combined with Potassium Nitrate, can enhance exercise endurance and muscle function in individuals with a specific type of heart failure. Participants will test different combinations, including a placebo, to identify the most effective treatment. This trial may suit those with stable heart failure with preserved ejection fraction, who experience symptoms like shortness of breath or fatigue with mild activity, and who are not currently facing uncontrolled heart conditions or severe lung issues. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that empagliflozin, one of the treatments under study, is generally safe and well-tolerated. Studies have found that it can lower the risk of hospitalization and death from heart failure, suggesting that many people can use it without serious side effects. Another study found that empagliflozin significantly reduces major heart-related events, indicating it may help maintain heart health.

Regarding potassium nitrate, clear information about its safety when used with empagliflozin is limited. However, since this study is in an early phase, researchers are closely monitoring its safety and checking for any side effects. If major safety concerns existed, the study likely would not have reached this phase.

Overall, while the combination of these treatments is still under study, empagliflozin has shown safety in other settings. Potassium nitrate's safety is still being evaluated, but no major issues have been reported so far in these trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for heart failure focus on improving heart function or managing symptoms, but the combination of empagliflozin with potassium nitrate stands out because it targets both heart and vascular health in an innovative way. Empagliflozin, traditionally used for diabetes, helps the heart by reducing fluid overload and improving heart efficiency, while potassium nitrate could enhance blood vessel function by increasing nitric oxide levels, potentially improving circulation. This dual approach not only addresses heart symptoms but also aims to enhance overall cardiovascular health, which is why researchers are particularly excited about its potential benefits.

What evidence suggests that this trial's treatments could be effective for heart failure?

Research has shown that empagliflozin can lower the risk of hospitalization for heart failure and death from heart-related issues. In earlier studies, about one-third of participants reported feeling better after taking empagliflozin. Potassium nitrate may help muscles use energy more efficiently, potentially making daily activities easier for those with heart failure. This trial will investigate whether combining empagliflozin and potassium nitrate can improve exercise ability and muscle function in people with heart failure. Early results appear promising, but further research is needed to confirm these benefits. Participants in this trial may receive empagliflozin with potassium nitrate, empagliflozin with potassium chloride, or a placebo for empagliflozin with potassium chloride. ^{2 3 6 7 8}

Who Is on the Research Team?

Payman Zamani, MD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

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

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

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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, 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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9375711/

Empagliflozin and serum potassium in heart failure Empagliflozin reduced the incidence of hyperkalemia without increasing the risk of hypokalemia. This pooled analysis from the EMPEROR trials ...

2. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/75/NCT05138575/Prot_SAP_000.pdf

Protocol – SGLT2i and KNO3 in HFpEF This study will test whether Empagliflozin (Empa), with and without. Potassium Nitrate (KNO3), improves submaximal exercise endurance and skeletal muscle ...

3. boehringer-ingelheim.com boehringer-ingelheim.com/us/media/press-releases/new-jardiance-empagliflozin-data-show-improved-cv-outcomes-regardless-heart-failure-status-baseline

New Jardiance® (empagliflozin) data show improved CV ... Data shows reduction in risk of hospitalization for heart failure or CV death with JARDIANCE compared with placebo.

4. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK601683/

Clinical Review - Empagliflozin (Jardiance) - NCBI - NIH According to the HeartLife Foundation survey (N = 12), approximately 33.3% of respondents felt better after taking empagliflozin, while 8.3% reported they felt ...

5. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2797498

Comparative Effectiveness of Empagliflozin vs Liraglutide ... This comparative effectiveness study evaluates the association of empagliflozin with cardiovascular outcomes compared with liraglutide and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4872285/

Heart failure outcomes with empagliflozin in patients ... Empagliflozin improved other heart failure outcomes, including hospitalization for or death from heart failure [2.8 vs. 4.5%; HR: 0.61 (0.47–0.79); P < 0.001] ...

7. cureus.com cureus.com/articles/394397-empagliflozin-and-cardiovascular-outcomes-a-systematic-review-of-randomized-controlled-trials-in-populations-with-diabetes-and-heart-failure

Empagliflozin and Cardiovascular Outcomes: A Systematic ... Empagliflozin was consistently associated with significant reductions in major adverse cardiovascular events, notably a 14-38% reduction in ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S0270929523001390

Management of Heart Failure With Reduced Ejection ... In the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction, empagliflozin was shown to significantly reduce the ...