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

introduction

Chronic heart failure is a progressive disease associated with poor quality of life if not managed appropriately. Chronic heart failure patients who are not maintained on guideline-directed medical therapy, as well as lifestyle modifications, are at a higher risk of experiencing heart failure exacerbations that can lead to hospitalization. Therefore, management of this condition is aimed at avoiding reversible precipitants and optimizing guideline-directed therapy to reduce mortality and hospitalizations.1

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Dapagliflozin (Farxiga) is a sodium glucose transporter-2 (SGLT2) inhibitor that was approved by the FDA in 2014 for the reduction of HbA1c in type 2 diabetes mellitus. cardiovascular outcomes 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 study also included a prespecified subgroup analysis of patients with heart failure.

Results showed that dapagliflozin reduced the risk of hospitalization for heart failure by 27% compared with placebo (hazard ratio, 0.73; 95% CI, 0.61 to 0.88; p=0.0008).2 This study has generated interest in conducting dedicated heart failure studies with SGLT2 inhibitors.

Approval for use in patients with heart failure with reduced ejection fraction was based on results from the DAPA-HF study. In this Phase 3, placebo-controlled study, patients with New York Heart Association II, III, or IV heart failure and an ejection fraction of 40% or less were randomized to receive dapagliflozin (10 mg once daily ) or placebo, in addition to the 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 with placebo (hazard ratio 0.74; 95% CI 0.65 to 0.85; p<0.001). Of note, the dapagliflozin benefits identified in this study were observed regardless of baseline diabetes status.3 In 2020, the FDA approved dapagliflozin for adults with heart failure with reduced ejection fraction to reduce 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. The benefit in this patient population was seen in the DELIVER study.

Patients with heart failure and left ventricular ejection fraction greater 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 19.5% of patients in the placebo group (HR: 0.74, 95 %CI: 0.65-0.85, p<0.0001). Based on the results of this study, dapagliflozin is now approved for patients with heart failure with preserved ejection fraction.5

Mechanism of action

Dapagliflozin is an inhibitor of SGLT2, expressed in the renal proximal tubules and responsible for the reabsorption of filtered glucose from the tubular lumen. By inhibiting SGLT2, dapagliflozin reduces the reabsorption of filtered glucose and increases urinary glucose excretion. Additionally, dapagliflozin decreases sodium reabsorption and increases sodium release to the distal tubule. While the mechanism of benefit in heart failure is unclear, it has been linked to a reduction in volume and sodium overload, leading to improvements in heart 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 studies, patients treated with dapagliflozin experienced increased urination, urinary tract infections, and genital fungal infections more frequently than those treated with placebo. Additionally, greater increases in low-density lipoprotein cholesterol (LDL-C) and hematocrit values ​​were observed in patients treated with dapagliflozin.6

Patients and healthcare professionals have reported cases of ketoacidosis, acute kidney injury, urosepsis, and pyelonephritis and Fourniers’s gangrene during post-marketing surveillance. Severe hypoglycemia and diabetic ketoacidosis (DKA) have only been observed in patients with diabetes mellitus.6

Warnings/Precautions

Diabetic euglycaemic ketoacidosis (DKA). Dapagliflozin may 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 immediate medical attention if they experience any of these symptoms.6

Genitourinary infections. Dapagliflozin can 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 may 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 a history of hypersensitivity reactions to the drug. Dapagliflozin is contraindicated in patients undergoing any form of dialysis.6

special populations

Pregnancy and breastfeeding. Dapagliflozin is not recommended during the second and third trimesters of pregnancy. This recommendation is based on adverse events reported in animal studies. Because of the potential for serious adverse events in breastfed infants, dapagliflozin is not recommended for use in breastfeeding women.6

Pediatric use. The safety and efficacy of dapagliflozin in patients aged less than 18 years have not been established.6

Geriatric use. No dose adjustment recommendations for dapagliflozin based on age are provided.6

Kidney failure. Of note, dapagliflozin and its metabolites are primarily eliminated renally. Dapagliflozin initiation is not recommended with an eGFR <25 mL/minute/1.73m2, but if the patient is already taking the drug, it should be continued; however, if dialysis is initiated, dapagliflozin should be discontinued.6

Liver failure.No dose adjustments are 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.Proc. Mayo Clin. 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 English 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 English 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 English J Med. 2022; 387:1089-1098
    DOI: 10.1056/NEJMoa2206286
  6. Complete Farxiga Prescribing Information. May 2020, accessed January 31, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202293s020lbl.pdf

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