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dapagliflozin (Farxiga, Xigduo XR)

FDA recommends approval Dec 2013. [2] Indications: - diabetes mellitus type 2 - *for use in association with insulin - *adjunct to diet & exercise - diabetes mellitus type 1 - *for use in association with insulin [7] (industry-sponsored study) - associated with reduced risk for heart failure hospitalization [9] - FDA-approved to reduce risk of hospitalization for heart failure in adults with [12] or without [14] type 2 diabetes - lowers risk for worsening heart failure or cardiovascular death among patients with reduced LV ejection fraction, regardless of diabetes status [11,13] - risk reduction observed within 28 days [16] - risk reduction observed in both men & women [17] - greatest risk reduction among patients with reduced eGFR & albuminuria [18] - improves cardiovascular event free survival (2.1 years) & overall survival (1.7 years) in patients with HFrEF [21] - beneficial for patients with HFrEF regardless of frailty status [22] - baseline kidney function does not modify benefit of dapagliflozin in patients with heart failure & mildly reduced or preserved ejection fraction [25] - reduces days of potential full health lost due to death, hospitalizations, & impaired well-being - benefit increases over time during the first year [35] - benefits patients with HFpEF [25] - FDA-approved for treatment of heart failure for any LV ejection fraction [28] - associated with reduction in chronic kidney disease progression [10] regardless of diabetes status [15]; FDA-approved for chronic kidney disease [19] - dapagliflozin 10 mg QD slows rate of decline in eGFR vs placebo [25] - dapagliflozin 10 mg QD reduces hospitalization (all cause) & death in patients with chronic kidney disease with & without type 2 diabetes (RR ~0.8) [26] - dapagliflozin reduces risk of cardiovascular death across LVEF spectrum (HFrEF & HFpEF) with contributions from lower risk of sudden death & death from progressive heart failure [27] - dapagliflozin may favorably mitigate anemia in chronic renal failure [29] Contraindications: - moderate-to-severe renal impairment - eGFR < 45 mL/min/1.73 m2 [10,23] (consider dose reduction) - safe & effective if eGFR > 25 mL/min/1.73 m2 [32] - eGFR < 25 mL/min/1.73 m2 (do not initiate, but may continue) [28] - eGFR < 25 mL/min/1.73 m2 (contraindicated) [23] - end stage renal disease contraindicated - history of bladder cancer Dosage: - 2.5-10 mg PO QD - stop 3 days prior to surgery Dosage adjustment in renal failure: - see Contraindications: Adverse effects: - potential risks for bladder cancer, breast cancer - liver toxicity - urinary tract infection - genital infection - female genital infection, vaginal yeast infection - for a single episode of candidiasis in patient taking flozin, treat candidiasis & continue flozin [30,31 - dehydration - elderly & patients taking diuretics at higher risk - hypotension - renal failure, acute kidney injury [6] - an initial decline of eGFR of >10% in patients with mildly reduced ejection fraction or preserved ejection fraction is not associated with adverse renal outcomes [34] - ketoacidosis [5] - no increase in ketoacidosis noted when used in combination with insulin in industry-sponsored study [7] - necrotizing fasciitis, Fournier Gangrene of perineum (class effect) [33] Laboratory: - urine glucose may be elevated (glucosuria) Mechanism of action: - selective inhibitor of sodium-glucose cotransporter 2 (SGLT2) - blocks reabsorption of glucose by the renal tubules, thus decreasing plasma glucose & increasing urine glucose - lowers hemoglobin A1C by about 1% - decreases weight by ~ 4-7 pounds - lowers blood pressure (small decrease) - increases LDL cholesterol (small increase) - decreases plasma hepcidin [8] - may increase blood hemoglobin & hematocrit [8] - can lower systolic blood pressure 4-8 mm Hg [31,32] Notes: - dapagliflozin provides intermediate value compared with standard of care* * based on ACC/AHA benchmarks [20]

Interactions

drug adverse effects of hypoglycemic agents

General

SGLT-2 inhibitor; oral glucosuric agent; flozin

Database Correlations

PUBCHEM correlations

References

  1. Wilding JPH et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: A randomized trial. Ann Intern Med 2012 Mar 20; 156:405 PMID: 22431673
  2. Pierson R FDA panel backs Bristol diabetes drug after prior rejection. Reuters, Dec 12, 2013 http://www.reuters.com/article/2013/12/12/us-bristolmyers-astrazeneca-diabetes-idUSBRE9BB19X20131212
  3. FDA News Release: Jan. 8, 2014 FDA approves Farxiga to treat type 2 diabetes. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm380829.htm
  4. Prescriber's Letter 21(3): 2014 (subscription needed) http://www.prescribersletter.com
  5. FDA MedWatch. May 15, 2015 SGLT2 inhibitors: Drug Safety Communication - FDA Warns Medicines May Result in a Serious Condition of Too Much Acid in the Blood. https://mail.google.com/mail/u/0/?tab=wm#inbox/14d587f1089e0791
  6. FDA Safety Alert. June 14, 2016 Canagliflozin (Invokana, Invokamet) and Dapagliflozin (Farxiga, Xigduo XR): Drug Safety Communication - Strengthened Kidney Warnings. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm506554.htm
  7. Dandona P, Mathieu C, Phillip M et al Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. The Lancet Diabetes & Endocrinology. Sept 14, 2017 PMID: 2891906 http://thelancet.com/journals/landia/article/PIIS2213-8587(17)30308-X/fulltext - Petrie JR SGLT2 inhibitors in type 1 diabetes: knocked down, but up again? The Lancet Diabetes & Endocrinology. Sept 14, 2017 PMID: 28919060 http://thelancet.com/journals/landia/article/PIIS2213-8587(17)30315-7/fulltext
  8. Monaco K Dapagliflozin Tied to Drop in Hepcidin Levels. Decrease may boost hematocrit and hemoglobin after SGLT-2 inhibitor therapy. MedPage Today. May 20, 2018 https://www.medpagetoday.com/meetingcoverage/aace/72989 - Ghanim H, et al Dapagliflozin Suppresses Plasma Hepcidin Concentrations. American Association of Clinical Endocrinologists (AACE) 2018; Abstract 228
  9. Wiviott SD, Raz I, Bonaca MP et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2018 Nov 10 PMID: 30415602 https://www.nejm.org/doi/10.1056/NEJMoa1812389
  10. American Diabetes Association Issues Critical Updates to the 2019 Standards of Medical Care in Diabetes. News Release. March 27, 2019 http://www.diabetes.org/newsroom/press-releases/2019/ada-issues-critical-updates-to-2019-standards-of-care.html
  11. McMurray JJV, Solomon SF, Inzucchi SE et al Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med Sept 19, 2019 PMID: 31535829 https://www.nejm.org/doi/full/10.1056/NEJMoa1911303 - Fang JC Heart-Failure Therapy - New Drugs but Old Habits? N Engl J Med Sept 19, 2019 PMID: 31535828 https://www.nejm.org/doi/full/10.1056/NEJMe1912180
  12. Nainggolan L FDA OKs Dapagliflozin to Reduce HF Hospitalization in Diabetes. Medscape - Oct 21, 2019. https://www.medscape.com/viewarticle/920093
  13. Kosiborod M et al. Effects of dapagliflozin on symptoms, function and quality of life in patients with heart failure and reduced ejection fraction: Results from the DAPA-HF Trial. Circulation 2019 Nov 17; PMID: 31736335 Free PMC article. Clinical Trial. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.044138 - Martinez FA et al. Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age: Insights from DAPA-HF. Circulation 2019 Nov 17 PMID: 31736328 Clinical Trial. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.044133 - Petrie MC, Verma S, Docherty KF et al. Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes. JAMA 2020 Mar 27; 323:1353 PMID: 32219386 https://jamanetwork.com/journals/jama/fullarticle/2763950
  14. FDA News Release. May 5, 2020 FDA approves new treatment for a type of heart failure. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-type-heart-failure
  15. Heerspink HJL, Stefansson BV, Correa-Rotter R. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. September 24, 2020 PMID: 32970396 https://www.nejm.org/doi/full/10.1056/NEJMoa2024816
  16. Berg DD, Jhund PS, Docherty KF et al Time to Clinical Benefit of Dapagliflozin and Significance of Prior Heart Failure Hospitalization in Patients With Heart Failure With Reduced Ejection Fraction. JAMA Cardiol. Published online February 17, 2021 PMID: 33595593 https://jamanetwork.com/journals/jamacardiology/fullarticle/2776351
  17. Butt JH, Docherty KF, Petrie MC et al Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction. A Prespecified Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial. JAMA Cardiol. Published online March 31, 2021. PMID: 33787831 https://jamanetwork.com/journals/jamacardiology/fullarticle/2777811
  18. Zelniker TA, Raz I, Mosenzon O et al Effect of Dapagliflozin on Cardiovascular Outcomes According to Baseline Kidney Function and Albuminuria Status in Patients With Type 2 Diabetes. A Prespecified Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. Published online April 14, 2021 PMID: 33851953 https://jamanetwork.com/journals/jamacardiology/fullarticle/2778552
  19. Jeffry S FDA Approves Dapagliflozin (Farxiga) for Chronic Kidney Disease. Medscape - Apr 30, 2021. https://www.medscape.com/viewarticle/950329
  20. Parizo JT, Goldhaber-Fiebert JD, Salomon JA et al Cost-effectiveness of Dapagliflozin for Treatment of Patients With Heart Failure With Reduced Ejection Fraction. JAMA Cardiol. Published online May 26, 2021. PMID: 34037681 https://jamanetwork.com/journals/jamacardiology/fullarticle/2780359 - Chew DS, Mark DB Dapagliflozin - Does Cost Make 4-Pillar Heart Failure Therapy Too Herculean a Labor for Medicine? JAMA Cardiol. Published online May 26, 2021. PMID: 34037664 https://jamanetwork.com/journals/jamacardiology/fullarticle/2780365
  21. Docherty KF, Jhund PS, Claggett B et al Extrapolating Long-term Event-Free and Overall Survival With Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction. An Exploratory Analysis of a Phase 3 Randomized Clinical Trial. JAMA Cardiol. Published online July 28, 2021 PMID: 34319398 https://jamanetwork.com/journals/jamacardiology/fullarticle/2782405 - Thomas LE, Navar AM, Pencina MJ Extrapolating Survival From Randomized Clinical Trial Data - Possibilities and Caution. JAMA Cardiol. Published online July 28, 2021 PMID: 34319362 https://jamanetwork.com/journals/jamacardiology/fullarticle/2782407
  22. Butt JH et al. Efficacy and safety of dapagliflozin according to frailty in heart failure with reduced ejection fraction: A post hoc analysis of the DAPA-HF trial. Ann Intern Med 2022 Apr 26 PMID: 35467935 https://www.acpjournals.org/doi/10.7326/M21-4776
  23. Medical Knowledge Self Assessment Program (MKSAP) 19 American College of Physicians, Philadelphia 2022
  24. Solomon SD et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 2022 Aug 27; [e-pub]. PMID: 36027570 https://www.nejm.org/doi/10.1056/NEJMoa2206286
  25. McCausland FR, Claggett BL, Vaduganathan M et al Dapagliflozin and Kidney Outcomes in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction. A Prespecified Analysis of the DELIVER Randomized Clinical Trial. JAMA Cardiol. Published online November 3, 2022. PMID: 36326604 https://jamanetwork.com/journals/jamacardiology/fullarticle/2798233
  26. Schechter M et al. Effects of dapagliflozin on hospitalizations in patients with chronic kidney disease: A post hoc analysis of DAPA-CKD. Ann Intern Med 2022 Dec 6 PMID: 36469914 https://www.acpjournals.org/doi/10.7326/M22-2115
  27. Desai AS et al Effect of Dapagliflozin on Cause-Specific Mortality in Patients With Heart Failure Across the Spectrum of Ejection Fraction. A Participant-Level Pooled Analysis of DAPA-HF and DELIVER. JAMA Cardiol. 2022;7(12):1227-1234 PMID: 36189985 PMCID: PMC9531084 Free PMC article https://jamanetwork.com/journals/jamacardiology/fullarticle/2796866
  28. Brooks M FDA Expands Use of Dapagliflozin to Broader Range of HF. Medscape. May 9, 2023 https://www.medscape.com/viewarticle/991736
  29. Koshino A et al. Dapagliflozin and anemia in patients with chronic kidney disease. NEJM Evid 2023 Jun; 2:EVIDoa2300049. PMID: 38320128 Clinical Trial. https://evidence.nejm.org/doi/10.1056/EVIDoa2300049 - Stefansson BV, Heerspink HJL, Wheeler DC et al Correction of anemia by dapagliflozin in patients with type 2 diabetes. J Diabetes Complications. 2020 Dec;34(12):107729. PMID: 32948397
  30. Engelhardt K, Ferguson M, Rosselli JL. Prevention and Management of Genital Mycotic Infections in the Setting of Sodium-Glucose Cotransporter 2 Inhibitors. Ann Pharmacother. 2021 Apr;55(4):543-548. PMID: 32808541 Review.
  31. NEJM Knowledge+ Endocrinology
  32. NEJM Knowledge+ Nephrology/Urology
  33. Bersoff-Matcha SJ, Chamberlain C, Cao C et al Fournier Gangrene Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Review of Spontaneous Postmarketing Cases. Ann Intern Med. 2019. May 7 PMID: 31060053 https://annals.org/aim/article-abstract/2732837/fournier-gangrene-associated-sodium-glucose-cotransporter-2-inhibitors-review-spontaneous
  34. Mc Causland FR, Claggett BL, Vaduganathan M et al Decline in Estimated Glomerular Filtration Rate After Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction. A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial. JAMA Cardiol. Published online November 12, 2023. PMID: 37952176 https://jamanetwork.com/journals/jamacardiology/fullarticle/2811979
  35. Kondo T, Mogensen UM, Talebi A et al Dapagliflozin and Days of Full Health Lost in the DAPA-HF Trial. J Am Coll Cardiol. 2024 May 21;83(20):1973-1986. PMID: 38537918 Free article. Clinical Trial.
  36. Highlights of Prescribing Information FARXIGA (dapagliflozin) tablets, for oral use https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/0be9cb1b-3b33-41c7-bfc2-04c9f718e442/0be9cb1b-3b33-41c7-bfc2-04c9f718e442_viewable_rendition__v.pdf

Component-of

dapagliflozin/metformin