dapagliflozin (Farxiga, Xigduo XR)
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Introduction
FDA recommends approval Dec 2013.[2]
Indications
- diabetes mellitus type 2
- diabetes mellitus type 1
- 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
- history of bladder cancer
Dosage
- 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]
- drug adverse effects of hypoglycemic agents
- drug adverse effects of oral glucosuric agent; SGLT-2 inhibitor; flozin
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]
More general terms
Component of
References
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/22431673
- ↑ 2.0 2.1 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
- ↑ FDA News Release: Jan. 8, 2014 FDA approves Farxiga to treat type 2 diabetes. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm380829.htm
- ↑ Prescriber's Letter 21(3): 2014 (subscription needed) http://www.prescribersletter.com
- ↑ 5.0 5.1 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
- ↑ 6.0 6.1 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
- ↑ 7.0 7.1 7.2 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/2891906 <Internet> 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28919060 <Internet> http://thelancet.com/journals/landia/article/PIIS2213-8587(17)30315-7/fulltext - ↑ 8.0 8.1 8.2 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 - ↑ 9.0 9.1 Wiviott SD, Raz I, Bonaca MP et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2018 Nov 10 PMID: https://www.ncbi.nlm.nih.gov/pubmed/30415602 https://www.nejm.org/doi/10.1056/NEJMoa1812389
- ↑ 10.0 10.1 10.2 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
- ↑ 11.0 11.1 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/31535828 https://www.nejm.org/doi/full/10.1056/NEJMe1912180 - ↑ 12.0 12.1 Nainggolan L FDA OKs Dapagliflozin to Reduce HF Hospitalization in Diabetes. Medscape - Oct 21, 2019. https://www.medscape.com/viewarticle/920093
- ↑ 13.0 13.1 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/32219386 https://jamanetwork.com/journals/jama/fullarticle/2763950 - ↑ 14.0 14.1 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
- ↑ 15.0 15.1 Heerspink HJL, Stefansson BV, Correa-Rotter R. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. September 24, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32970396 https://www.nejm.org/doi/full/10.1056/NEJMoa2024816
- ↑ 16.0 16.1 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: https://www.ncbi.nlm.nih.gov/pubmed/33595593 https://jamanetwork.com/journals/jamacardiology/fullarticle/2776351
- ↑ 17.0 17.1 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: https://www.ncbi.nlm.nih.gov/pubmed/33787831 https://jamanetwork.com/journals/jamacardiology/fullarticle/2777811
- ↑ 18.0 18.1 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: https://www.ncbi.nlm.nih.gov/pubmed/33851953 https://jamanetwork.com/journals/jamacardiology/fullarticle/2778552
- ↑ 19.0 19.1 Jeffry S FDA Approves Dapagliflozin (Farxiga) for Chronic Kidney Disease. Medscape - Apr 30, 2021. https://www.medscape.com/viewarticle/950329
- ↑ 20.0 20.1 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/34037664 https://jamanetwork.com/journals/jamacardiology/fullarticle/2780365 - ↑ 21.0 21.1 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/34319362 https://jamanetwork.com/journals/jamacardiology/fullarticle/2782407 - ↑ 22.0 22.1 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: https://www.ncbi.nlm.nih.gov/pubmed/35467935 https://www.acpjournals.org/doi/10.7326/M21-4776
- ↑ 23.0 23.1 23.2 Medical Knowledge Self Assessment Program (MKSAP) 19 American College of Physicians, Philadelphia 2022
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/36027570 https://www.nejm.org/doi/10.1056/NEJMoa2206286
- ↑ 25.0 25.1 25.2 25.3 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: https://www.ncbi.nlm.nih.gov/pubmed/36326604 https://jamanetwork.com/journals/jamacardiology/fullarticle/2798233
- ↑ 26.0 26.1 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: https://www.ncbi.nlm.nih.gov/pubmed/36469914 https://www.acpjournals.org/doi/10.7326/M22-2115
- ↑ 27.0 27.1 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: https://www.ncbi.nlm.nih.gov/pubmed/36189985 PMCID: PMC9531084 Free PMC article https://jamanetwork.com/journals/jamacardiology/fullarticle/2796866
- ↑ 28.0 28.1 28.2 Brooks M FDA Expands Use of Dapagliflozin to Broader Range of HF. Medscape. May 9, 2023 https://www.medscape.com/viewarticle/991736
- ↑ 29.0 29.1 Koshino A et al. Dapagliflozin and anemia in patients with chronic kidney disease. NEJM Evid 2023 Jun; 2:EVIDoa2300049. PMID: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/32948397 - ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/32808541 Review.
- ↑ 31.0 31.1 NEJM Knowledge+ Endocrinology
- ↑ 32.0 32.1 32.2 NEJM Knowledge+ Nephrology/Urology
- ↑ 33.0 33.1 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: https://www.ncbi.nlm.nih.gov/pubmed/31060053 https://annals.org/aim/article-abstract/2732837/fournier-gangrene-associated-sodium-glucose-cotransporter-2-inhibitors-review-spontaneous
- ↑ 34.0 34.1 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: https://www.ncbi.nlm.nih.gov/pubmed/37952176 https://jamanetwork.com/journals/jamacardiology/fullarticle/2811979
- ↑ 35.0 35.1 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: https://www.ncbi.nlm.nih.gov/pubmed/38537918 Free article. Clinical Trial.
- ↑ 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
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