Empagliflozin + Carvedilol for Cardiotoxicity

Overseen By Sang Gune Yoo, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must be taking: Beta blockers, SGLT2 inhibitors

Must not be taking: Non-dihydropyridine calcium blockers

Disqualifiers: Untreated brain metastases, Prior anthracyclines, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking any SGLT2 inhibitors or beta blockers if you are currently on them and cannot stop during the study. If you are on a non-dihydropyridine calcium channel blocker, it must be transitioned to or used with carvedilol.

What data supports the effectiveness of the drug combination Empagliflozin and Carvedilol for cardiotoxicity?

Empagliflozin has been shown to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with heart failure and type 2 diabetes. It also improves heart function and reduces kidney problems, which can be beneficial for heart health. While specific data on the combination with Carvedilol for cardiotoxicity is not provided, these benefits suggest potential effectiveness. ^{1 2 3 4 5}

Is the combination of Empagliflozin and Carvedilol safe for humans?

Carvedilol is generally considered safe for humans and is used to treat heart conditions like heart failure and high blood pressure. It has been shown to reduce mortality and hospitalizations in heart failure patients, with common side effects including dizziness and fatigue. However, specific safety data for the combination of Empagliflozin and Carvedilol is not available in the provided research. ^{6 7 8 9 10}

How does the drug combination of Empagliflozin and Carvedilol differ from other treatments for cardiotoxicity?

The combination of Empagliflozin and Carvedilol is unique because Empagliflozin, a medication typically used for diabetes, may offer heart protection by reducing blood sugar and potentially improving heart function, while Carvedilol, a beta-blocker, protects heart mitochondria from stress and has favorable effects on heart rhythm and metabolism, making this combination potentially beneficial for heart health in ways other treatments may not address. ^{6 11 12 13 14}

What is the purpose of this trial?

Ten to 15% of patients with breast cancer are HER2 positive, with treatment focused on targeting the HER2 receptor. Although these treatments are generally well tolerated, they are associated with an increased risk of cardiomyopathy. There are currently no treatments proven to prevent the cardiotoxicities associated with HER2-targeted therapy, but there is convincing preclinical data demonstrating that prophylactic treatment with a beta blocker (BB) and/or an SGLT2 inhibitor (SGLT2i) may each independently prevent cardiotoxicity and HER-targeted treatment interruptions. The proposed pilot study will assess the feasibility and preliminary efficacy and safety of therapy with both a beta blocker (carvedilol) and an SGLT2 inhibitor (empagliflozin), alone and in combination, in a population initiating HER2-directed therapy for HER2+ breast cancer. The hypotheses being tested in this study are: 1. It is feasible to recruit 20-40 patients over 6 months 2. There are no differences in tolerability and safety between participants taking carvedilol and/or empagliflozin and those receiving usual care.

Research Team

Joshua Mitchell, M.D., MSCI, FAC, FICOS

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for breast cancer patients who are HER2 positive and starting HER2-directed therapy. It aims to prevent heart damage from these treatments. Participants should be willing to take either a beta blocker, an SGLT2 inhibitor, or both.

Inclusion Criteria

Systolic blood pressure ≥ 100 mmHg and resting heart rate ≥ 60 bpm

My kidney function is above the minimum level required.

Women of childbearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately

Exclusion Criteria

Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of study entry

I have had radiation therapy for mantle cell lymphoma.

I am allergic to medications similar to carvedilol or empagliflozin.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive carvedilol and/or empagliflozin for 12 weeks to assess feasibility and preliminary efficacy and safety

12 weeks

Regular visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Carvedilol
• Empagliflozin

Trial Overview The study tests the safety and potential benefits of carvedilol (a beta blocker) and empagliflozin (an SGLT2 inhibitor), alone or together, in preventing heart issues during HER2-targeted breast cancer treatment.

Participant Groups

Group I: Arm 3: Carvedilol BID + Empagliflozin QD Experimental Treatment 2 Interventions

Carvedilol by mouth twice per day (BID) for 12 weeks and empagliflozin by mouth daily (QD) for 12 weeks.

Group II: Arm 2: Empagliflozin QD Experimental Treatment 1 Intervention

Empagliflozin by mouth daily (QD) for 12 weeks.

Group III: Arm 1: Carvedilol BID Experimental Treatment 1 Intervention

Carvedilol by mouth twice per day (BID) for 12 weeks.

Group IV: Arm 4: Usual Care Active Control 1 Intervention

No medications.

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Findings from Research

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 3730 patients with heart failure and reduced ejection fraction, empagliflozin significantly reduced the combined risk of death, hospitalization for heart failure, and urgent heart failure visits, showing benefits as early as 12 days after starting treatment.

Empagliflozin also led to fewer hospitalizations requiring intensive care and reduced the need for diuretic intensification, while improving patients' functional class, demonstrating its efficacy in managing worsening heart failure events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial. Packer, M., Anker, SD., Butler, J., et al.[2023]

The EmDia trial is investigating the short-term effects of empagliflozin on left ventricular diastolic function in patients with type 2 diabetes, focusing on the E/E' ratio as a key measure over a 12-week period.

This study aims to provide insights into how empagliflozin may improve cardiovascular outcomes by assessing not only diastolic function but also other cardiovascular measures and molecular biomarkers, enhancing our understanding of its mechanisms of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and design of the effects of EMpagliflozin on left ventricular DIAstolic function in diabetes (EmDia) study. Jünger, C., Prochaska, JH., Gori, T., et al.[2023]

In a multicenter trial with 345 participants, carvedilol significantly improved left ventricular (LV) function and reduced mortality rates in patients with mild to moderate chronic heart failure, with a 73% lower risk of all-cause mortality compared to placebo.

Carvedilol also decreased hospitalization rates by 58% to 64% and was generally well tolerated, indicating its efficacy and safety as a treatment for chronic heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Bristow, MR., Gilbert, EM., Abraham, WT., et al.[2022]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial. [2023]

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

Rationale and design of the effects of EMpagliflozin on left ventricular DIAstolic function in diabetes (EmDia) study. [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

Effects of empagliflozin on left ventricular diastolic function in addition to usual care in individuals with type 2 diabetes mellitus-results from the randomized, double-blind, placebo-controlled EmDia trial. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Empagliflozin and Cardio-renal Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease - Implications for Clinical Practice. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Long-Term Mortality Associated With Use of Carvedilol Versus Metoprolol in Heart Failure Patients With and Without Type 2 Diabetes: A Danish Nationwide Cohort Study. [2022]

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

Carvedilol. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders. [2018]

8. Singapore pubmed.ncbi.nlm.nih.gov

Carvedilol: beta-blockade and beyond. [2018]

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

Carvedilol: molecular and cellular basis for its multifaceted therapeutic potential. [2022]

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

Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. [2022]

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

Carvedilol's antiarrhythmic properties: therapeutic implications in patients with left ventricular dysfunction. [2020]

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

Safety and efficacy of carvedilol in very elderly diabetic patients with heart failure. [2018]

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

Effects of carvedilol on isolated heart mitochondria: evidence for a protonophoretic mechanism. [2018]

14. Netherlands pubmed.ncbi.nlm.nih.gov

Carvedilol in heart mitochondria: protonophore or opener of the mitochondrial K(ATP) channels? [2019]