By: Jennifer Galvet, PharmD Candidate c/o 2024

              Farxiga (dapagliflozin) is a first-in-class, oral, once daily sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated for improving glycemic control in type 2 diabetes (T2D), reducing the risk of cardiovascular (CV) death and hospitalization in heart failure (HF), and reducing the risk of sustained eGFR decline in chronic kidney disease.¹ Dapagliflozin inhibits SGLT2 located in the proximal renal tubules of the kidneys. SGLT2 is responsible for the reabsorption of filtered glucose from the tubular lumen. Inhibition of SGLT2 reduces the reabsorption of filtered glucose, promoting its excretion through the urine. Additionally, dapagliflozin reduces sodium reabsorption, lowering both preload and afterload of the heart.²

Original Phase III DAPA-HF Trial

In 2020, dapagliflozin was approved in the United States to reduce the risk of CV death and hospitalization in HF with reduced ejection fraction (HFrEF), with or without T2D.³ The Food and Drug Administration (FDA) approved dapagliflozin using data from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial.⁴ In this phase III, prospective, placebo-controlled trial, 4,744 patients with New York Association class II, III, or IV HF and an ejection fraction of ≤ 40% were randomized to receive either dapagliflozin 10 mg once daily or placebo, in addition to standard recommended HF device and drug therapy.⁴

The primary outcome was a composite of worsening HF, signified by hospitalization or the need for intravenous therapy, or CV death.⁴ Over a median of 18.2 months, the primary outcome occurred in 386 patients (16.3%) in the dapagliflozin group and in 502 patients (21.2%) in the placebo group (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.65 to 0.85; p < 0.001).⁴ Dapagliflozin was superior to placebo in all individual components of the composite primary outcome. When comparing patients given dapagliflozin vs. placebo, 231 (9.7%) vs. 318 (13.4%) were hospitalized for HF (HR 0.70; 95% CI 0.59 to 0.83) and 277 (9.6%) vs. 273 (11.5%) died from CV causes (HR 0.82; 95% CI 0.69 to 0.98), respectively.⁴ During the trial period, 21 patients needed to be treated to prevent one primary outcome (95% CI 15 to 38).⁴

A secondary outcome of the DAPA-HF trial was a composite of hospitalization for HF or CV death.⁴ In the dapagliflozin group, there were 567 total first and recurrent events, including 340 hospitalizations for HF and 227 deaths from CV causes. In the placebo group, there were 742 total events, including 469 hospitalizations for HF and 273 deaths from CV causes.⁴ This data showed a relative risk (RR) of 0.75 (95% CI 0.65 to 0.88; p < 0.001).⁴ Among patients with HFrEF, it was concluded that those who received dapagliflozin had a lower risk of worsening HF or death from CV causes than those who received placebo, regardless of the patient’s diabetes condition.⁴

Dapagliflozin Demonstrates Mortality
Benefit Irrespective of Ejection Fraction

Results from a patient level pooled meta-analysis of the DAPA-HF and Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trials demonstrated that dapagliflozin, compared to placebo, showed mortality improvements in patients with HF, regardless of their left ventricle ejection fraction (LVEF) range.⁵ In this meta-analysis, 11,007 patients were included. Of these patients, 4,744 (43%) had an LVEF ≤ 40% and 5,504 (50%) were randomized to receive dapagliflozin.⁵

This meta-analysis evaluated the incidence of death from CV causes, death from all causes, total hospitalizations for HF, time to first hospitalization for HF, and death from a composite of causes. Regarding incidence of death from CV causes, dapagliflozin, compared to placebo, exhibited a HR of 0.86 (95% CI 0.76 to 0.97; p = 0.01).⁵ In a subgroup analysis of patients with a LVEF ≤ 40%, dapagliflozin exhibited a HR of 0.82 (95% CI 0.69 to 0.98). In patients with an LVEF > 40%, dapagliflozin showed a HR of 0.89 (95% CI 0.76 to 1.04).⁵ Regarding death from all causes, dapagliflozin was found to have a HR of 0.90 (95% CI 0.82 to 0.99; p = 0.03).⁵ Lastly, regarding total HF hospitalizations, dapagliflozin had a RR of 0.71 (95% CI 0.65 to 0.78; p < 0.001).⁵ These results directly reflect the valuable role dapagliflozin can play in clinical practice as treatment can be initiated while waiting for the ejection fraction to be measured.

Farxiga vs. Jardiance

Jardiance (empagliflozin) is indicated to reduce the risk of CV death and hospitalization in adults with both HF and T2D with established CV disease, as well as to improve glycemic control.⁶ Similar to dapagliflozin, empagliflozin is also a SGLT2 inhibitor that reduces sodium and glucose reabsorption in the kidney. SGLT2 is located in the early segment of the proximal tubule and is responsible for reabsorbing 80 to 90% of filtered glucose. The remaining glucose is reabsorbed by SGLT1 in the latter portions of the proximal tubule.⁷ In terms of their selectivity for these transporters, dapagliflozin approximately has a 1200-fold higher potency for SGLT2 than SGLT1, whereas empagliflozin approximately has a 2700-fold higher potency.⁷ In addition to their ability to improve glycemic control, both dapagliflozin and empagliflozin provide cardioprotective effects and reductions in adverse CV outcomes.⁷

In 2022, Shi et al. published a meta-analysis comparing the efficacy of dapagliflozin 10 mg and empagliflozin 10 mg in HF.⁸ Databases were searched up to October, 2021, resulting in the inclusion of 11 randomized controlled trials. The primary outcomes were hospitalization for HF and exacerbation of HF. When individually compared to placebo for risk of hospitalization from HF, empagliflozin had an odds ratio (OR) of 0.76 (95% CI 0.69 to 0.84) while dapagliflozin had an OR of 0.68 (95% CI 0.58 to 0.80). The network meta-analysis comparing both agents together showed that the OR of dapagliflozin vs. empagliflozin was 0.90 (95% CI 0.75 to 1.10).⁸ Regarding risk of exacerbation of HF, empagliflozin, when compared to placebo, showed an OR of 0.68 (95% CI 0.62 to 0.74) while dapagliflozin showed an OR of 0.70 (95% CI 0.59 to 0.84).⁸ When comparing both agents, the OR of empagliflozin vs. dapagliflozin was found to be 0.70 (95% CI 0.59 to 0.84).⁸

Additional outcomes of interest included CV death/hospitalization for HF, all-cause death, and hypoglycemia. When individually compared to placebo for the risk of CV death/hospitalization from HF, dapagliflozin showed an OR of 0.71 (95% CI 0.62 to 0.82) while empagliflozin showed an OR of 0.74 (95% CI 0.64 to 0.87).⁸ The network meta-analysis of dapagliflozin vs. empagliflozin demonstrated an OR of 0.95 (95% CI 0.78 to 1.17).⁸ In the analysis of all-cause death, the OR of dapagliflozin, compared to placebo, was 0.77 (95% CI 0.66 to 0.91) whereas the OR of empagliflozin was 0.96 (95% CI 0.86 to 1.08).⁸ When comparing dapagliflozin vs. empagliflozin, the OR was 0.80 (95% CI 0.66 to 0.98).⁸ Lastly, when comparing each agent individually to placebo to look at the risk of hypoglycemia, dapagliflozin showed an OR of 0.85 (95% CI 0.40 to 1.83) while empagliflozin had an OR of 0.92 (95% CI 0.67 to 1.27).⁸ The OR of dapagliflozin vs. empagliflozin was 0.92 (95% CI 0.40 to 2.12).⁸ Overall, the results from this meta-analysis show that both dapagliflozin 10 mg and empagliflozin 10 mg had comparable results when evaluating their efficacy in reducing mortality, hospitalizations, and risk of adverse effects like hypoglycemia.

Conclusion

The results from the above studies help show the cardioprotective role of SGLT2 inhibitors, supporting their place in treatment guidelines for HF. The American College of Cardiology (ACC), American Heart Association (AHA), and Heart Failure Society of America (HFSA) released a joint guideline updating recommendations for preventing, diagnosing, and managing HF.⁹ The new guidelines recommend that patients at risk for HF with T2D and either CV disease or high CV risk should initiate SGLT2 inhibitor therapy. For patients with HFrEF, the guidelines recommend pharmacological intervention with SGLT2 inhibitors regardless of whether they have T2D. For patients with HF with mildly reduced ejection fraction (HFmrEF) or HF with preserved ejection fraction (HFpEF), initial treatment with SGLT2 inhibitors are now deemed potentially beneficial in decreasing CV mortality and hospitalization risk.⁹ Overall, these updated guidelines increase the recommended uses for dapagliflozin, allowing for improved prevention and delay of HF and CV disease.

References

1. Farxiga (dapagliflozin) [package insert]. Princeton, NJ; Bristol-Myers Squibb Company; Revised 08/01/2014.
2. Wanner C, Marx N. SGLT2 inhibitors: the future for treatment of type 2 diabetes mellitus and other chronic diseases. Diabetologia. 2018;61(10):2134-2139. doi: 10.1007/s00125-018-4678-z
3. FDA approves new treatment for a type of heart failure. US Food & Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-type-heart-failure. Published 05/05/2020.
4. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008. doi: 10.1056/NEJMoa1911303
5. Jhund PS, Kondo T, Butt JH, et al. Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER. Nat Med. 2022. doi: 10.1038/s41591-022-01971-4
6. Jardiance (empagliflozin) [package insert]. Ridgefield, CT; Boehringer Ingelheim Pharmaceuticals, Inc.; Revised 12/01/2016
7. Tentolouris A, Vlachakis P, Tzeravini E, Eleftheriadou I, Tentolouris N. SGLT2 Inhibitors: A Review of Their Antidiabetic and Cardioprotective Effects. Int J Environ Res Public Health. 2019;16(16):2965. Published 2019 Aug 17. doi:10.3390/ijerph16162965
8. Shi Z, Gao F, Liu W, He X. Comparative Efficacy of Dapagliflozin and Empagliflozin of a Fixed Dose in Heart Failure: A Network Meta-Analysis. Front Cardiovasc Med. 2022;9:869272. doi: 10.3389/fcvm.2022.869272
9. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi: 10.1161/CIR.0000000000001063.

Published by Rho Chi Post