Dapagliflozin for Coronary Artery Disease

(SMILE Trial)

Overseen By Nicole J Sprouse, RN

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: University of Virginia

Disqualifiers: Cardiomyopathy, Heart failure, Stroke, others

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

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

Compensation: Varies

Number of Visits: 3

Duration: 12 weeks

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called dapagliflozin (also known as Farxiga) to determine if it can improve blood flow in the heart for women with symptoms of ischemic heart disease, a condition where the heart receives insufficient blood. Participants will take either dapagliflozin or a placebo (a pill resembling the drug but without an active ingredient) for 12 weeks. Researchers will compare heart blood flow between the two groups using special imaging tests. Women with heart symptoms but without major artery blockages might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that dapagliflozin is generally safe for people. Studies have found that it does not increase the risk of major heart problems compared to a placebo (a pill with no active ingredients). Some evidence even suggests it might benefit heart health. For instance, one study found that people taking dapagliflozin had fewer hospital visits for heart failure.

While this trial tests dapagliflozin for coronary artery disease, it is already approved for other conditions, like type 2 diabetes. This approval provides some reassurance about its safety. However, since this trial is in an early stage, more research is needed to fully understand its effectiveness for coronary artery disease specifically. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for coronary artery disease, which typically include statins, beta-blockers, and ACE inhibitors, dapagliflozin offers a novel approach by targeting and inhibiting the sodium-glucose co-transporter 2 (SGLT2). This mechanism is primarily used in managing diabetes, but researchers are excited about its potential cardiovascular benefits, such as improving heart function and reducing heart failure risk. Additionally, dapagliflozin is administered as a simple oral tablet, making it convenient for patients. Its ability to potentially address both blood sugar levels and heart health could set it apart from traditional heart disease treatments.

What evidence suggests that dapagliflozin might be an effective treatment for ischemic heart disease?

Research has shown that dapagliflozin, which participants in this trial may receive, can improve heart health. Studies have found that this drug lowers the risk of dying from heart problems and reduces hospital visits for heart failure. Specifically, it decreased the chances of heart-related deaths or nonfatal heart attacks in some patients. Dapagliflozin belongs to a group of drugs that enhance heart conditions by aiding blood flow and heart function. These findings suggest that dapagliflozin might improve blood flow in the heart, which is the focus of the current trial. This makes it an appealing option for people with heart disease symptoms. ^{1 2 6 7 8}

Who Is on the Research Team?

Patricia Rodriguez-Lozano, MD

Principal Investigator

University of Virginia Health System

Are You a Good Fit for This Trial?

This trial is for women with symptoms of ischemic heart disease but no major blockages in their heart arteries. They must have suspected ischemia, a decent kidney function, and if diabetic, approval from their diabetes doctor. It's not for those with severe heart failure, recent acute coronary syndrome or stroke, certain chronic diseases, low blood pressure, frequent urinary infections, type 1 diabetes or active cancer.

Inclusion Criteria

Willing to provide written informed consent

I was referred for a heart check-up due to suspected blockage signs within the last 2 years.

My kidney function is at a safe level for the trial.

Exclusion Criteria

I have a serious heart valve condition.

I often feel faint due to low blood pressure below 95 mmHg.

I have type 2 diabetes and have had diabetic ketoacidosis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a 12-week course of dapagliflozin 10mg or placebo. Blood flow in the heart is assessed using stress cardiac magnetic resonance imaging at baseline and 12 weeks.

12 weeks

3 visits (in-person) at baseline, 6 weeks, and 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dapagliflozin 10mg Tab
• Placebo

Trial Overview The study tests whether Dapagliflozin improves blood flow in the heart compared to a placebo over 12 weeks. Women will be randomly given either the drug or placebo and monitored using stress cardiac MRI at the start and end of the trial to measure any changes in heart blood flow.

How Is the Trial Designed?

Group I: Dapagliflozin Experimental Treatment 1 Intervention

Dapagliflozin 10mg oral tablet.

Group II: Placebo Placebo Group 1 Intervention

Placebo matching tablet.

Dapagliflozin 10mg Tab is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Farxiga for:

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

Approved in United States as Farxiga for:

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

Approved in Canada as Farxiga for:

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

Approved in Japan as Farxiga for:

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

Who Is Running the Clinical Trial?

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

Published Research Related to This Trial

In a study involving 949 patients with type 2 diabetes and chronic stable angina, ranolazine significantly reduced the average weekly frequency of angina episodes compared to placebo (3.8 vs. 4.3 episodes), indicating its efficacy in managing angina in this high-risk population.

Ranolazine also decreased the use of sublingual nitroglycerin (1.7 doses vs. 2.1 doses), and it was well tolerated with no difference in serious adverse events compared to placebo, suggesting it is a safe option for patients who remain symptomatic despite other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina). Kosiborod, M., Arnold, SV., Spertus, JA., et al.[2022]

Dapagliflozin (Farxiga) is approved for reducing the risk of declining kidney function and kidney failure in adults with chronic kidney disease, regardless of whether they have type 2 diabetes.

It also helps lower the risk of cardiovascular death and hospitalization for heart failure, highlighting its efficacy in managing both kidney and heart health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antidiabetic Drug Approved to Reduce Risk of Kidney Disease. Aschenbrenner, DS.[2023]

Dapagliflozin is an effective treatment for type 2 diabetes, proven through multiple controlled clinical trials that assess its efficacy, safety, and tolerability.

It is approved by the FDA for use as a standalone therapy or in combination with other glucose-lowering medications, including insulin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin: A Sodium Glucose Cotransporter 2 Inhibitor for the Treatment of Diabetes Mellitus. Davis, PN., Ndefo, UA., Oliver, A.[2021]

Dapagliflozin is an effective SGLT2 inhibitor for managing type 2 diabetes, showing consistent reductions in blood glucose levels and body weight over long-term follow-up periods of 1-4 years across various clinical trials.

It has a low risk of causing hypoglycemia and is generally well tolerated, although it can lead to genital infections, particularly in women, and is not recommended for patients with moderate to severe renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin: a review of its use in patients with type 2 diabetes. Plosker, GL.[2022]

Dapagliflozin is an effective treatment for type 2 diabetes, showing noninferiority to metformin and glimepiride in clinical trials involving 9 studies, indicating it can be a reliable option for patients.

While generally safe, dapagliflozin is associated with an increased risk of urinary infections and other side effects, suggesting it may be best used as an add-on therapy for patients not adequately controlled on other diabetes medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin for the Treatment of Type 2 Diabetes Mellitus. Aylsworth, A., Dean, Z., VanNorman, C., et al.[2019]

In a study involving 32 patients with stable angina and 17 with acute myocardial infarction, the esophageal electrostimulation test was found to effectively assess the efficiency of antianginal medications by measuring increases in anginal threshold.

The long-acting nitrate Isomak R (forte) demonstrated significant efficacy as an antianginal drug, improving physical stress tolerance and reducing angina attacks without major side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Use of transesophageal electrostimulation of the heart for evaluating the effectiveness of anti-anginal therapy]. Makolkin, VI., Petriĭ, VV.[2017]

Dapagliflozin effectively lowers blood sugar levels and glycated hemoglobin (HbA1c) in patients with type 2 diabetes, with a low risk of hypoglycemia and additional benefits like weight loss and reduced blood pressure.

While it is generally safe, dapagliflozin can increase the risk of genital infections, particularly in women, and its efficacy may be reduced in patients with kidney issues; ongoing trials are investigating its potential cardiovascular and renal protective effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Dapagliflozin (forxiga®) : SGLT 2 cotransporter inhibitor as glucose-lowering agent in type 2 diabetes]. Scheen, AJ.[2021]

Dapagliflozin, an SGLT2 inhibitor, effectively improves glycemic control, reduces body weight, and lowers blood pressure in adults with type 2 diabetes, heart failure, and chronic kidney disease, starting at an estimated glomerular filtration rate of 25 mL/min/1.73 m².

In addition to its primary benefits, dapagliflozin positively affects cardiovascular health by improving arterial stiffness and lipid profiles, thereby reducing the risk of cardiovascular complications, although it is underused in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beyond the Glycaemic Control of Dapagliflozin: Impact on Arterial Stiffness and Macroangiopathy. González-Clemente, JM., García-Castillo, M., Gorgojo-Martínez, JJ., et al.[2022]

Dapagliflozin, an SGLT2 inhibitor, has been shown to significantly reduce the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF), regardless of whether they have type 2 diabetes.

In the DAPA-HF trial, dapagliflozin was well tolerated and demonstrated a lower risk of worsening heart failure or cardiovascular death compared to placebo, making it a valuable treatment option for adults with symptomatic HFrEF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin: A Review in Symptomatic Heart Failure with Reduced Ejection Fraction. Blair, HA.[2022]

Beta-receptor blockers are the first-line therapy for treating coronary artery disease, effectively reducing symptoms and improving patient prognosis, while calcium channel blockers and nitrates are alternatives for those who cannot tolerate beta-blockers.

Aspirin is recommended for all patients with coronary artery disease to lower the risk of future cardiac events, with clopidogrel as an alternative for those who cannot take aspirin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Risk management of coronary artery disease--pharmacological therapy]. Hofmann, T.[2019]

Calcium antagonists, particularly 1,4-dihydropyridines like nifedipine, are effective in treating myocardial ischaemia by reducing afterload and inducing coronary vasodilation, but their short action can lead to reflex tachycardia, limiting their effectiveness.

Newer DHPs such as amlodipine and lacidipine offer longer-lasting effects with less impact on heart rate, and lacidipine also provides vascular protection and reduces atheroma plaque formation, likely due to its antioxidant properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent developments in the use of calcium antagonists in myocardial protection. Gaviraghi, G., Micheli, D., Trist, DG.[2019]

Stable angina, a common symptom of coronary artery disease, is primarily managed through lifestyle changes and a combination of medications, including antianginal drugs and disease-modifying agents.

Recent advancements have introduced new treatment options like nicorandil, ivabradine, trimetazidine, and ranolazine, which are being used as second-line therapies, although their long-term effects are still being studied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stable angina pectoris: current medical treatment. Siama, K., Tousoulis, D., Papageorgiou, N., et al.[2018]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa1812389

Dapagliflozin and Cardiovascular Outcomes in Type 2 ... With respect to efficacy, dapagliflozin resulted in a lower rate of cardiovascular death or hospitalization for heart failure than placebo (4.9 ...

2. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2022/new-data-show-farxiga-significantly-lowers-the-risk-of-cardiovascular-death-in-patients-with-heart-failure.html

New data show FARXIGA significantly lowers the risk of ... Pre-specified pooled analysis from Phase III trials demonstrated reduction in CV death by 14% and reduction in death from any cause by 10% in patients with ...

3. ahajournals.org ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.039996

Dapagliflozin and Cardiovascular Outcomes in Patients ... In addition, we observed lower rates of the exploratory composite outcome of coronary heart disease death or nonfatal MI with dapagliflozin (HR ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10910463/

Cardiovascular outcomes between dapagliflozin versus ... Dapagliflozin and empagliflozin showed no significant difference of real‐world clinical cardiovascular outcomes in patients with DM over a 3‐year period.

5. sciencedirect.com sciencedirect.com/science/article/pii/S0147956323000365

SGLT2 inhibitors for prevention of primary and secondary ... SGLT2i significantly reduced major adverse cardiovascular events (MACE) in patients with prior myocardial infarction (MI) (OR 0.83, 95% CI 0.73–0.94, p = 0.004) ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4761166/

Cardiovascular effects of dapagliflozin in patients with type ... Dapagliflozin is not associated with increased CV risk and results further suggest the potential for a beneficial effect both in the overall population.

7. ajconline.org ajconline.org/article/S0002-9149%2824%2900161-9/fulltext

Cardiovascular Outcomes With Empagliflozin and ... The primary outcome of CV death, hospitalization for HF, or an urgent HF visit was found to be lower in the dapagliflozin group as compared with ...

8. acc.org acc.org/Latest-in-Cardiology/Clinical-Trials/2018/11/08/23/09/DECLARE-TIMI-58

Dapagliflozin Effect on Cardiovascular Events ... The DECLARE–TIMI 58 trial showed that dapagliflozin is superior to placebo in improving glycemic control and noninferior but not superior for reducing MACE.