Acipimox + Empagliflozin for Heart Failure and Type 2 Diabetes

Overseen By Ralph DeFronzo, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: The University of Texas Health Science Center at San Antonio

Must be taking: SGLT2 inhibitors

Must not be taking: DPP4 inhibitors, Pioglitazone

Disqualifiers: Cancer, Pregnancy, Drug use, others

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate how a combination of drugs, including empagliflozin (a medication for type 2 diabetes), affects heart function in individuals with type 2 diabetes and heart failure. Researchers seek to determine if these treatments can enhance the heart's ability to pump blood. Participants will receive either the active medication or a placebo (a pill with no active drug) for three months. Individuals with type 2 diabetes and heart failure, experiencing symptoms like shortness of breath or fatigue, may be suitable for this trial. As an Early Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants a chance to contribute to groundbreaking medical research.

Will I have to stop taking my current medications?

The trial requires participants to be on a stable dose of guideline-directed medications for heart failure, so you may need to continue your current heart failure medications. However, if you are taking Dipeptidyl Peptidase-4 Inhibitors (DPP4i) or pioglitazone for diabetes, you will need to stop those medications to participate.

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

Research has shown that empagliflozin is generally safe for people with type 2 diabetes and heart failure. Studies have found that it can reduce the risk of hospitalization for heart failure and death from heart-related issues. However, there is a higher risk of diabetic ketoacidosis (DKA), a serious condition where the body produces too many blood acids called ketones. The risks of kidney problems and low blood sugar are lower compared to some other treatments.

This trial is in its early stages, as the researchers are just beginning to test the treatment in people. They are still collecting safety information specifically for this use. However, since empagliflozin is already approved for other conditions, a basic level of safety has been established for those uses. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about empagliflozin for heart failure and type 2 diabetes because it offers a unique approach by using SGLT2 inhibition to help manage both conditions. Unlike standard treatments like ACE inhibitors or diuretics, empagliflozin not only aids in controlling blood sugar levels but also reduces the risk of heart failure by promoting better kidney function and cardiovascular health. This dual action makes it a promising option for patients who need effective management of both heart failure and diabetes, potentially improving outcomes more comprehensively than existing treatments.

What evidence suggests that this trial's treatments could be effective for heart failure and type 2 diabetes?

Research has shown that empagliflozin, which participants in this trial may receive, may help treat heart failure and type 2 diabetes. One study showed it lowered the risk of hospitalization for heart failure or death from heart-related issues by 34%. Another study found that people with type 2 diabetes who took empagliflozin had better heart health than those on a placebo. The treatment also significantly reduced deaths related to heart problems. These findings suggest that empagliflozin might improve heart function and overall health in people with these conditions. ^{1 2 5 6 7}

Who Is on the Research Team?

Ralph A DeFronzo, MD

Principal Investigator

University of Texas Health Science Center San Antonio

Are You a Good Fit for This Trial?

This trial is for high-risk individuals with type 2 diabetes and heart failure who have a reduced ability of the heart to pump blood (HFrEF). Participants should not be currently using SGLT2 inhibitors or medications affecting ketone levels.

Inclusion Criteria

BMI 23-38 kg/m2

Stable body weight (±4 pounds) over the last 3 months

Glycated hemoglobin (HbA1c) 5.5-10%

Exclusion Criteria

I have a physical disability that makes it unsafe for me to do certain exercises.

I am currently taking medication for diabetes that includes SGLT2 inhibitors, GLP-1 receptor agonists, or pioglitazone.

Systolic BP>180mmHg and/or diastolic BP >100mmHg

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive empagliflozin or placebo for 12 weeks to study the effects on plasma ketone levels and heart function

12 weeks

Regular visits for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Empagliflozin
• Ketones

Trial Overview

The study is testing if Acipimox, Empagliflozin, or a placebo can improve heart function by increasing ketone levels in the blood. The effects on the left ventricle's pumping ability are measured.

How Is the Trial Designed?

Group I: Empagliflozin Group Experimental Treatment 2 Interventions

Subjects will be randomized 2:1 to receive empagliflozin, 25mg/day for 3 months

Group II: Placebo group Placebo Group 2 Interventions

Subjects will be randomized to receive the empagliflozin placebo for 3 months

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?

The University of Texas Health Science Center at San Antonio

Lead Sponsor

Trials

486

Recruited

92,500+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

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 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]

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 (Jardiance) has been associated with a significant reduction in cardiovascular mortality among patients with type 2 diabetes and established cardiovascular disease, although the exact mechanism for this benefit is not yet understood.

There is uncertainty regarding whether empagliflozin may also increase the risk of fractures, a concern raised with another SGLT2 inhibitor, canagliflozin (Invokana), and all SGLT2 inhibitors are noted to have only modest effectiveness in managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SGLT2 inhibitors: new reports. [2019]

Empagliflozin, an SGLT2 inhibitor, is effective in managing blood glucose levels and reducing cardiovascular risks in patients with type 2 diabetes, but it can also lead to euglycemic diabetic ketoacidosis under certain conditions, such as acute illness or reduced carbohydrate intake.

A case study of a 23-year-old female with poorly controlled diabetes on empagliflozin revealed severe euglycemic metabolic acidosis and elevated urine ketones during a COVID-19 infection, highlighting the need for careful monitoring in patients using this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Case of Severe Metabolic Acidosis due to Jardiance-Induced Euglycemic Diabetic Ketoacidosis. Dyatlova, N., Omotosho, YB., Sherchan, R., et al.[2021]

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]

In a 52-week phase 4 trial involving Japanese patients with type 2 diabetes, empagliflozin as an add-on to liraglutide was well tolerated, with 59.4% to 66.7% of patients reporting at least one adverse event, indicating a manageable safety profile.

The combination therapy resulted in significant improvements in glycaemic control (reduction in HbA1c), body weight, and blood pressure, demonstrating its efficacy in enhancing diabetes management compared to liraglutide alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Empagliflozin as Add-On Therapy to GLP-1 Receptor Agonist (Liraglutide) in Japanese Patients with Type 2 Diabetes Mellitus: A Randomised, Double-Blind, Parallel-Group Phase 4 Study. Terauchi, Y., Utsunomiya, K., Yasui, A., et al.[2020]

Empagliflozin has been shown to improve cardiorenal outcomes and reduce hospitalization risk for heart failure in patients with diabetes, as demonstrated in the EMPA-REG OUTCOME study.

Clinical studies (EMPEROR-Preserved, EMPEROR-Reduced, EMPULSE) indicate that empagliflozin provides significant benefits over traditional heart failure therapies, including reduced mortality and hospitalizations, and improved quality of life for patients with various heart failure phenotypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CLINICAL EFFECTIVENESS OF EMPAGLIFLOZIN IN PATIENTS WITH HEART FAILURE. Rоsul, ММ., Bletskan, ММ., Ivano, NV., et al.[2023]

Citations

1.

pmc.ncbi.nlm.nih.gov

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

Heart failure outcomes with empagliflozin in patients ...

In this trial, empagliflozin reduced the risk of hospitalization for heart failure or cardiovascular death by 34%, corresponding to a number needed to treat to ...

2.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa1504720

Empagliflozin, Cardiovascular Outcomes, and Mortality in ...

Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC5253088/

Impact of Empagliflozin in Patients with Diabetes and Heart ...

In the recent EMPA-REG OUTCOME trial, empagliflozin was shown to improve cardiovascular outcomes in patients with T2DM and established cardiovascular risk where ...

4.

ahajournals.org

ahajournals.org/doi/10.1161/CIRCULATIONAHA.124.068613

Comparative Cardiovascular Effectiveness of Empagliflozin ...

Empagliflozin and dapagliflozin initiators had no differences in 6-year cardiovascular outcomes in adults with treated type 2 diabetes.

5.

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 ...

Treatment with empagliflozin led to a significant reduction in cardiovascular mortality (HR: 0.86; 95% CI: 0.78-0.96). Additionally, ...

6.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/38509341/

Effectiveness and safety of empagliflozin: final results from ...

Empagliflozin was associated with an increased risk of DKA and lower risks of AKI, hypoglycaemia and progression to proliferative retinopathy.

7.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2022190

Cardiovascular and Renal Outcomes with Empagliflozin in ...

The risk of cardiovascular death was 8% lower with empagliflozin than with placebo in our trial (hazard ratio, 0.92; 95% CI, 0.75 to 1.12) and ...