Clinical Overview: Dapagliflozin for Patients with Heart Failure, Reduced Ejection Fraction and Preserved Ejection Fraction

Introduction

Chronic heart failure is a progressive disease that is associated with a poor quality of life if not managed appropriately. Patients with chronic heart failure who are not maintained on guideline directed medical therapy, in addition to lifestyle modifications, have an increased risk of experiencing heart failure exacerbations than can lead to hospitalization. Thus, management of this condition is aimed at avoidance of reversible precipitants and optimizing guideline-directed therapy to reduce mortality and hospitalizations.¹

Credit: tashatuvango - stock.adobe.com

Dapagliflozin (Farxiga) is a sodium glucose transporter-2 (SGLT2) inhibitor that was FDA-approved in 2014 for HbA1c reduction in type 2 diabetes mellitus. For continued approval, the medication was required to show cardiovascular outcomes data to ensure safety.

The DECLARE-TIMI 58 trial investigated the use of dapagliflozin in patients with type 2 diabetes and multiple cardiovascular risk factors. This trial also included a prespecified subgroup analysis of patients with heart failure.

The results showed that dapagliflozin reduced the risk of hospitalization for heart failure by 27% compared to placebo (hazard ratio 0.73; 95% CI 0.61 to 0.88; p=0.0008).² This trial prompted interest in conducting dedicated heart failure trials with SGLT2 inhibitors.

Approval for use in patients with heart failure with reduced ejection fraction was based on findings from the DAPA-HF trial. In this phase 3, placebo-controlled trial, patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less were randomized to receive either dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy.

The primary outcome was a composite of worsening heart failure or cardiovascular death. Dapagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure by 26% compared to placebo (hazard ratio 0.74; 95% CI 0.65 to 0.85; p<0.001). Of note, the benefits of dapagliflozin identified in this study were seen irrespective of baseline diabetes status.³ In 2020, the FDA approved dapagliflozin for adults with heart failure with reduced ejection fraction to lower the risk of cardiovascular death and hospitalizations.⁴

In addition to the indication for use in reduced ejection fraction, dapagliflozin has been studied in patients with preserved ejection fraction. Benefit in this patient population was observed in the DELIVER trial.

Patients with heart failure and a left ventricular ejection fraction of more than 40% were randomized to receive dapagliflozin (10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure or cardiovascular death, which occurred in 16.4% of patients in the dapagliflozin group and in 19.5% of patients in the placebo group (HR: 0.74, 95% CI: 0.65-0.85, p<0.0001). Based on results from this trial, dapagliflozin is now approved for patients with heart failure with preserved ejection fraction.⁵

Mechanism of action

Dapagliflozin is an inhibitor of SGLT2, which is expressed in the proximal renal tubules and responsible for reabsorbing filtered glucose from the tubular lumen. By inhibiting SGLT2, dapagliflozin reduces the reabsorption of filtered glucose and increases urinary glucose excretion. In addition, dapagliflozin lowers sodium reabsorption and increases the delivery of sodium to the distal tubule. Although the mechanism of benefit in heart failure is unclear, it has been linked to a reduction in sodium and volume overload, leading to improvements in cardiac function.⁶

Dosage and administration

To reduce the risk of hospitalization for heart failure in patients with type 2 diabetes mellitus and established CVD or multiple CV risk factors, the recommended dose of dapagliflozin is 10 mg orally once daily. The recommended dose of dapagliflozin for the treatment of heart failure, regardless of ejection fraction (with or without diabetes mellitus), is 10 mg orally once daily.⁶

Adverse events (AEs)

During clinical trials, patients on dapagliflozin experienced increased urination, urinary tract infections, and genital mycotic infections more frequently than those on placebo. Additionally, a greater increase in low-density lipoprotein cholesterol (LDL-C) and hematocrit values in patients treated with dapagliflozin has been observed.⁶

Patients and health care professionals have reported occurrences of ketoacidosis, acute kidney injury, urosepsis and pyelonephritis, and Fournier’s Gangrene during postmarketing surveillance. Severe hypoglycemia and diabetic ketoacidosis (DKA) were observed only in patients with diabetes mellitus.⁶

Warnings/Precautions

Euglycemic Diabetic Ketoacidosis (DKA). Dapagliflozin can increase the risk of DKA, a serious condition that occurs when the body produces high levels of ketones. Symptoms of DKA include difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue. Patients taking dapagliflozin should be advised to seek medical attention immediately if they experience any of these symptoms.⁶

Genitourinary infections. Dapagliflozin may increase the risk of genital infections, such as yeast infections or urinary tract infections, in both men and women. Patients should be instructed to report any signs or symptoms of genital infection to their provider.⁶

Dehydration. Dapagliflozin can increase the risk of dehydration, particularly in patients who are elderly or have kidney problems.⁶

Contraindications

Dapagliflozin should not be used in patients with previous hypersensitivity reaction to the medication. Dapagliflozin is contraindicated in patients undergoing any form of dialysis.⁶

Special Populations

Pregnancy & Lactation. Dapagliflozin is not recommended during the second and third trimesters of pregnancy. This recommendation is based on AEs reported in animal studies.Due to the potential for serious AEs in breastfed infants, the use of dapagliflozin is not recommended in women who are breastfeeding.⁶

Pediatric Use. The safety and efficacy of dapagliflozin in patients under 18 years of age have not been established.⁶

Geriatric Use. The are no dose adjustment recommendations provided for dapagliflozin based on age.⁶

Renal Impairment. Of note, dapagliflozin and its metabolites are primarily renally eliminated. Initiation of dapagliflozin is not recommended with an eGFR <25 mL/minute/1.73 m², but if the patient is already on the medication, it should be continued; however, if dialysis is started, dapagliflozin should be discontinued.⁶

Hepatic Impairment.There are no dose adjustments necessary for patients with mild, moderate, or severe hepatic impairment.⁶

References

1. Ramani GV, Uber PA, Mehra MR. Chronic heart failure: contemporary diagnosis and management. Mayo Clin Proc. 2010;85(2):180-195. doi:10.4065/mcp.2009.0494
2. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(4):347-357. doi:10.1056/NEJMoa1812389.
3. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019; 381:1995-2008.
4. FDA approves new treatment for a type of heart failure. HFSA. Published 2020. Accessed January 28, 2023. https://hfsa.org/fda-approves-new-treatment-type-heart-failure.
5. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022; 387:1089-1098
   DOI: 10.1056/NEJMoa2206286
6. Farxiga full prescribing information. May 2020, Accessed January 31, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202293s020lbl.pdf