Ertugliflozin for Heart Failure

Overseen By Veena Rao, PHD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yale University

Must be taking: Loop diuretics

Must not be taking: Thiazides

Disqualifiers: Renal replacement, Bladder dysfunction, Diabetes, others

Stay on Your Current Meds You can continue your current medications while participating

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

60 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine the effects on heart failure signs and symptoms of the use of either ertugliflozin, metolazone or placebo, in conjunction with intravenous loop diuretic use in acute settings and chronic oral loop diuretic therapy. There are two general purposes for this study. The proposed study is both larger and more rigorous than essentially all PK/PD studies that form the basis of current practice with loop diuretics as well as all studies looking at add-on thiazide therapy (current guideline-recommended adjuvant). The second is to generate a mechanistic understanding of the pleotropic cardio-renal factors with chronic therapy that differentiate ertugliflozin from traditional diuretics particularly in how they maintain reduced blood volume without the complication of over-diuresis and volume depletion.

Will I have to stop taking my current medications?

The trial requires that you stop taking thiazide or thiazide-like diuretics, including metolazone, before participating. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

What evidence supports the effectiveness of the drug Ertugliflozin for heart failure?

Research shows that Ertugliflozin, a type of SGLT2 inhibitor, can reduce the risk of hospitalization for heart failure in patients with type 2 diabetes and heart disease, suggesting potential benefits for heart failure management. ^{1 2 3 4 5}

Is Ertugliflozin safe for humans?

Ertugliflozin has been studied for safety in people with type 2 diabetes and chronic kidney disease, showing it is generally safe for these conditions. It has been approved by the US FDA and received positive opinions from the EU for use in adults with type 2 diabetes. ^{6 7 8 9 10}

How is the drug Ertugliflozin unique for treating heart failure?

Ertugliflozin is part of a unique class of drugs called SGLT2 inhibitors, which not only help lower blood sugar in people with type 2 diabetes but also provide heart and kidney benefits, making it a novel option for heart failure treatment. ^{1 11 12 13 14}

Eligibility Criteria

This trial is for adults with acute decompensated heart failure who have signs of fluid overload and need intravenous diuretics. They must be on a stable dose of oral loop diuretics, have an eGFR of at least 30 mL/min/1.73 m2, and can't be using thiazide or similar drugs. Excluded are those planning renal therapy, with significant bladder issues, history of certain diabetes complications, frequent urinary infections, severe anemia, or are pregnant/breastfeeding.

Inclusion Criteria

Your kidney function is very low, with an eGFR of 30 mL/min/1.73 m2 or less.

I have been taking a strong water pill daily for at least a month.

Signed informed consent

Exclusion Criteria

Pregnancy or breastfeeding

I have had a heart transplant or have serious heart valve disease.

I have major issues controlling my bladder.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either ertugliflozin, metolazone, or placebo in conjunction with intravenous loop diuretic use for 6 weeks

6 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ertugliflozin
• Metolazone
• Placebo

Trial Overview The study tests the effects of Ertugliflozin versus Metolazone (a type of diuretic) or placebo in managing heart failure symptoms alongside standard IV loop diuretics. It aims to understand how Ertugliflozin affects cardio-renal factors differently from traditional diuretics without causing excessive fluid loss.

Participant Groups

Group I: Metolazone Experimental Treatment 1 Intervention

Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo

Group II: Ertugliflozin Experimental Treatment 1 Intervention

Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo

Group III: Placebo Placebo Group 1 Intervention

Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo

Ertugliflozin is already approved in United States, European Union for the following indications:

Approved in United States as Steglatro for:

• Type 2 diabetes mellitus

Approved in European Union as Steglatro for:

• Type 2 diabetes mellitus

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

A meta-analysis of 10 randomized controlled trials involving 15,373 heart failure patients found no significant differences in clinical outcomes among the SGLT2 inhibitors empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin regarding heart failure hospitalizations, cardiovascular deaths, and all-cause mortality.

Despite the lack of differences in treatment effects, the analysis highlighted the need for further research due to the variability in study results and the wide confidence intervals observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing the clinical outcomes across different sodium/glucose cotransporter 2 (SGLT2) inhibitors in heart failure patients: a systematic review and network meta-analysis of randomized controlled trials. Teo, YH., Yoong, CSY., Syn, NL., et al.[2022]

In the EMPEROR-Reduced trial involving 3,730 patients with heart failure with reduced ejection fraction (HFrEF), empagliflozin significantly reduced the risk of hospitalization for heart failure or cardiovascular death, showing consistent efficacy across different levels of diuretic therapy.

The safety profile of empagliflozin remained stable regardless of the baseline diuretic dose, although higher doses of diuretics were associated with increased rates of adverse events, indicating that while empagliflozin is effective, careful monitoring is needed for patients on higher diuretic doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Empagliflozin According to Background Diuretic Use in Heart Failure With Reduced Ejection Fraction: Post-Hoc Analysis of EMPEROR-Reduced. Dhingra, NK., Verma, S., Butler, J., et al.[2023]

The EMPEROR-Preserved trial demonstrated that the SGLT2 inhibitor empagliflozin significantly reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with preserved ejection fraction (HFPEF), with a hazard ratio of 0.79.

These findings suggest that SGLT2 inhibitors may become the new standard of care for patients with HFPEF, highlighting their efficacy in managing heart failure-related events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SGLT2 Inhibitors and Heart Failure with Preserved Ejection Fraction. Jhund, PS.[2022]

In a study involving 8246 patients with type 2 diabetes and cardiovascular disease, ertugliflozin significantly reduced the risk of first hospitalization for heart failure (HHF) by 30% compared to placebo, indicating its efficacy in preventing heart failure events.

Ertugliflozin also decreased the total number of HHF events and cardiovascular deaths related to heart failure, particularly benefiting patients with lower ejection fractions, reduced kidney function, albuminuria, and those on diuretics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Ertugliflozin on Heart Failure-Related Events in Patients With Type 2 Diabetes Mellitus and Established Atherosclerotic Cardiovascular Disease: Results of the VERTIS CV Trial. Cosentino, F., Cannon, CP., Cherney, DZI., et al.[2021]

Empagliflozin has been shown to significantly reduce cardiovascular mortality by 38% and heart failure hospitalizations by 35% in diabetic patients, indicating its potential effectiveness in heart failure management.

The EMPA-TROPISM clinical trial will assess the safety and efficacy of empagliflozin in 80 non-diabetic heart failure patients over 6 months, focusing on improvements in cardiac function and quality of life, while monitoring for safety issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and Design of the EMPA-TROPISM Trial (ATRU-4): Are the "Cardiac Benefits" of Empagliflozin Independent of its Hypoglycemic Activity? Santos-Gallego, CG., Garcia-Ropero, A., Mancini, D., et al.[2019]

Steglatro (ertugliflozin) has been shown to effectively improve glycemic control in adults with type-2 diabetes mellitus, making it a valuable option for managing this condition.

The efficacy of Steglatro was evaluated through clinical trials, demonstrating its ability to lower blood sugar levels in patients, which is crucial for preventing complications associated with diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ertugliflozin (Steglatro): A New Option for SGLT2 Inhibition. Kovacich, N., Chavez, B.[2020]

Ertugliflozin, a sodium glucose co-transporter type 2 inhibitor, has shown significant improvements in glycaemic control in type 2 diabetes patients during the VERTIS phase III clinical trial program.

Ertugliflozin, both as a standalone treatment and in combination with other medications like metformin and sitagliptin, has been approved by the US FDA and received positive feedback from the EU for its effectiveness in managing type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ertugliflozin: First Global Approval. Markham, A.[2019]

Sotagliflozin, the first dual inhibitor of SGLT1 and SGLT2, has shown significant efficacy in reducing cardiovascular and heart failure events in patients with type 2 diabetes, as demonstrated in the SOLOIST-WHF trial with a hazard ratio of 0.67.

While sotagliflozin expands treatment options for heart failure, existing SGLT2 inhibitors like dapagliflozin and empagliflozin have more robust evidence supporting their use, particularly in heart failure and chronic kidney disease, indicating that further research is needed to clarify sotagliflozin's role in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sotagliflozin: Efficacy, Safety, and Potential Therapeutic Applications in Heart Failure. Long, A., Salvo, M.[2023]

Ertugliflozin significantly reduced glycated hemoglobin (HbA1c) levels in patients with chronic kidney disease (CKD) stage 3, with reductions of -0.27% to -0.31% at week 18, indicating its efficacy in managing blood sugar levels in this population.

The treatment was well tolerated, showing no significant differences in adverse events, including kidney-related issues, between ertugliflozin and placebo, while also leading to reductions in body weight and systolic blood pressure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glycemic efficacy and safety of the SGLT2 inhibitor ertugliflozin in patients with type 2 diabetes and stage 3 chronic kidney disease: an analysis from the VERTIS CV randomized trial. Dagogo-Jack, S., Pratley, RE., Cherney, DZI., et al.[2021]

In the VERTIS CV trial, patients with type 2 diabetes and a history of heart failure experienced a faster decline in kidney function (eGFR) compared to those without heart failure, indicating a greater risk for kidney issues in this group.

Ertugliflozin treatment slowed the rate of eGFR decline in both patients with and without heart failure, showing its potential to benefit kidney health regardless of heart failure status, with similar protective effects observed in both subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Ertugliflozin on Kidney Outcomes in Patients With Heart Failure at Baseline in the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes (VERTIS CV) Trial. Cherney, DZI., Cosentino, F., McGuire, DK., et al.[2023]

SGLT2 inhibitors (SGLT2i) showed a trend towards reducing the risk of cardiovascular death or heart failure hospitalization compared to sacubitril/valsartan and vericiguat, indicating their potential effectiveness in heart failure treatment.

SGLT2i demonstrated the greatest reduction in heart failure hospitalization rates compared to standard care and vericiguat, suggesting they may be the most effective therapy among the treatments analyzed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative Efficacy of Sacubitril-Valsartan, Vericiguat, and SGLT2 Inhibitors in Heart Failure with Reduced Ejection Fraction: a Systematic Review and Network Meta-Analysis. Aimo, A., Pateras, K., Stamatelopoulos, K., et al.[2022]

SGLT2 inhibitors, a new class of glucose-lowering medications, have been shown to significantly reduce the risk of heart failure events in patients with type 2 diabetes, as demonstrated in three large cardiovascular trials.

Canagliflozin, an SGLT2 inhibitor, also effectively reduced heart failure events in patients with type 2 diabetes and chronic kidney disease, highlighting its potential as a preventive treatment for heart failure in at-risk populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventing and Treating Heart Failure with Sodium-Glucose Co-Transporter 2 Inhibitors. Vaduganathan, M., Januzzi, JL.[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]

The ongoing CANDLE trial is evaluating the safety and non-inferiority of canagliflozin, an SGLT2 inhibitor, compared to glimepiride in 250 patients with type 2 diabetes and chronic heart failure over a 24-week period.

This trial aims to assess not only the change in NT-proBNP levels, a marker for heart failure, but also the effects on glycemic control, blood pressure, body weight, and overall quality of life, potentially providing important insights into the management of heart failure in diabetic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial. Tanaka, A., Inoue, T., Kitakaze, M., et al.[2018]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Comparing the clinical outcomes across different sodium/glucose cotransporter 2 (SGLT2) inhibitors in heart failure patients: a systematic review and network meta-analysis of randomized controlled trials. [2022]

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

Efficacy and Safety of Empagliflozin According to Background Diuretic Use in Heart Failure With Reduced Ejection Fraction: Post-Hoc Analysis of EMPEROR-Reduced. [2023]

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

SGLT2 Inhibitors and Heart Failure with Preserved Ejection Fraction. [2022]

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

Efficacy of Ertugliflozin on Heart Failure-Related Events in Patients With Type 2 Diabetes Mellitus and Established Atherosclerotic Cardiovascular Disease: Results of the VERTIS CV Trial. [2021]

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

Rationale and Design of the EMPA-TROPISM Trial (ATRU-4): Are the "Cardiac Benefits" of Empagliflozin Independent of its Hypoglycemic Activity? [2019]

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

Ertugliflozin (Steglatro): A New Option for SGLT2 Inhibition. [2020]

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

Ertugliflozin: First Global Approval. [2019]

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

Sotagliflozin: Efficacy, Safety, and Potential Therapeutic Applications in Heart Failure. [2023]

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

Glycemic efficacy and safety of the SGLT2 inhibitor ertugliflozin in patients with type 2 diabetes and stage 3 chronic kidney disease: an analysis from the VERTIS CV randomized trial. [2021]

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

Effects of Ertugliflozin on Kidney Outcomes in Patients With Heart Failure at Baseline in the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes (VERTIS CV) Trial. [2023]

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

Relative Efficacy of Sacubitril-Valsartan, Vericiguat, and SGLT2 Inhibitors in Heart Failure with Reduced Ejection Fraction: a Systematic Review and Network Meta-Analysis. [2022]

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

Preventing and Treating Heart Failure with Sodium-Glucose Co-Transporter 2 Inhibitors. [2020]

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

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

14. England pubmed.ncbi.nlm.nih.gov

Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial. [2018]