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empagliflozin (Jardiance)

Indications: - diabetes mellitus type 2 alone or in combination with other hypoglycemic agents - may reduce cardiovascular risk in patients with type 2 diabetes - reduces cardiovascular death (3.7% vs 5.9%), overall mortality (5.7% vs 8.3%) & hospitalization for heart failure (2.7% vs 4.1%) relative to placebo [4] - benefits same at 10 mg & 25 mg doses [4] - FDA approves use for cardiovascular risk reduction [6] - in combination with metformin only if a sulfonylurea is not an option, or the person is at risk of hypoglycemia (NICE) - may help slow progression of diabetic nephropathy in patients with type 2 diabetes at high cardiovascular risk [5] - reduces progression of kidney disease & cardiovascular death independent of diabetes [24] - benefit most pronounced in patients with significant albuminuria [25] - lowers risk of cardiovascular death or hospitalization for heart failure among patients with systolic heart failure (HFrEF), regardless of diabetes status [8] - benefit of empagliflozin for HFrEF regardless of dose of ACE inhibitor or ARB used in combination [14] - improves functional capacity & quality of life after 6 months of treatment for systolic heart failure in patients without diabetes mellitus [9] - effective for systolic heart failure with or without volume overload [10] - reduces combined risk of cardiovascular death or hospitalization for heart failure in patients with HFpEF, regardless of diabetes status [12] - modest improvement in health-related quality of life for patients with HFpEF [13] - provides low economic value compared with standard of care for HFpEF, largely due to lack of efficacy on mortality & small benefit on quality of life [18] - increases urine output 25% over 5 days in patients with acute heart failure without adverse renal effects; eGFR not affected [16] - improves health-related quality of life at 90 days after acute heart failure [15] - benefits begin at day 15 - reduces macro-albuminuria [19] Contraindications: - diabetes mellitus type 1 - diabetic ketoacidosis - renal impairment: GFR < 30 ml/min/1.73 m2 [16] - end-stage renal disease * among patients with eGFR of 20-45 mL/min, empaglifozin 10 mg QD decreased risk of progression of kidney disease or death from cardiovascular causes [17] Dosage: - 10-25 mg PO QD - stop 3 days prior to surgery * in patients with HFpEF, need for diuretics generally less in patients also using empagliflozin [20] Adverse effects: - urinary tract infection - genital infection (RR=3) [4] - female genital infection, vaginal yeast infection [3] - for a single episode of candidiasis in patient taking flozin, treat candidiasis & continue flozin [21,22] - ketoacidosis [2] - dehydration [3] - necrotizing fasciitis, Fournier Gangrene of perineum (class effect) [23] Drug interactions: - little influence of aldosterone antagonists spironolactone or eplerenone on SGLT2-inhibitor empagliflozin benefits for patients with left ventricular systolic dysfunction [11] Mechanism of action: - inhibits sodium glucose cotransporter 2 (SGLT2) - increases glucosuria - may reduce intraglomerular pressure & hyperfiltration in patients with type 2 diabetes [5] - can lower systolic blood pressure 4-8 mm Hg [22] Notes: - efficacy of empagliflozin in reducing HbA1c in clinical trials translates into real-world effectiveness [7] - empagliflozin more effective than dapagliflozin in reducing hospitalization or all-cause mortality [26] or compared with patients who started dapagliflozin

Interactions

drug adverse effects of hypoglycemic agents

General

SGLT-2 inhibitor; oral glucosuric agent; flozin

Database Correlations

PUBCHEM cid=11949646

References

  1. Medscape: August 1, 2014 Diabetes Drug Empagliflozin (Jardiance) Wins FDA OK on Second Try. http://www.medscape.com/viewarticle/829326
  2. 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
  3. Lily News Release. Aug. 20, 2015 Jardiance demonstrated cardiovascular (CV) risk reduction in people with type 2 diabetes at high risk for CV events. https://investor.lilly.com/releasedetail.cfm?ReleaseID=928280
  4. Zinman B et al Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. Sept 17, 2015 PMID: 26378978 http://www.nejm.org/doi/full/10.1056/NEJMoa1504720
  5. Wanner C et al Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. June 14, 2016 PMID: 27299675 http://www.nejm.org/doi/full/10.1056/NEJMoa1515920 - Ingelfinger JR, Rosen CJ Cardiac and Renovascular Complications in Type 2 Diabetes - Is There Hope? N Engl J Med. June 14, 2016 PMID: 26605932 http://www.nejm.org/doi/full/10.1056/NEJMe1607413
  6. Gever J Jardiance Wins CV Prevention Indication. FDA approves claim that diabetes drug reduces cardiovascular death risk. Medpage Today. December 02, 2016 http://www.medpagetoday.com/Cardiology/Prevention/61822 - Tucker ME FDA Approves Empagliflozin for Reducing CVD Death. Medscape. Dec 02, 2016. http://www.medscape.com/viewarticle/872697 - FDA News Release. Dec 2, 2016 FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm531517.htm
  7. Munk NE, Knudsen JS, Pottegard A, Witte DR, Thomsen RW. Differences Between Randomized Clinical Trial Participants and Real-World Empagliflozin Users and the Changes in Their Glycated Hemoglobin Levels. JAMA Netw Open. 2020;3(2):e1920949. Feb 7. PMID: 32031651 Free Article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2760444
  8. Phend C Second SGLT2 Drug Scores for HFrEF, Regardless of Diabetes Status. - EMPEROR-Reduced trial "exceptionally concordant" with DAPA-HF results. MedPage Today August 28, 2020 https://www.medpagetoday.com/meetingcoverage/esc/88346 - Packer M, Anker S, Butler J et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020 Aug 29; [e-pub]. PMID: 32865377 https://www.nejm.org/doi/10.1056/NEJMoa2022190
  9. Santos-Gallego CG et al. Randomized trial of empagliflozin in nondiabetic patients with heart failure and reduced ejection fraction. J Am Coll Cardiol 2021 Jan 26; 77:243 PMID: 33197559. https://www.sciencedirect.com/science/article/abs/pii/S0735109720377536 - Goldberg LR. The pleiotropic effects of SGLT2 inhibitors: Remodeling the treatment of heart failure. J Am Coll Cardiol 2021 Jan 26; 77:256. PMID: 33478648 https://www.sciencedirect.com/science/article/abs/pii/S0735109720378931
  10. Packer M et al. Empagliflozin in patients with heart failure, reduced ejection fraction, and volume overload: EMPEROR-Reduced trial. J Am Coll Cardiol 2021 Mar 23; 77:1381. PMID: 33736819 https://www.sciencedirect.com/science/article/pii/S0735109721002023 - Kosiborod M, Vaduganathan M. SGLT-2 inhibitors in heart failure: Volume or value? J Am Coll Cardiol 2021 Mar 23; 77:1393. PMID: 33736820 https://www.sciencedirect.com/science/article/abs/pii/S0735109721003090
  11. Ferreira JP et al. Interplay of mineralocorticoid receptor antagonists and empagliflozin in heart failure: EMPEROR-Reduced. J Am Coll Cardiol 2021 Mar 23; 77:1397 PMID: 33736821 Free article https://www.sciencedirect.com/science/article/pii/S0735109721002394
  12. Anker SD, Butler J, Filippatos G et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021. Oct 14;385(16):1451-1461. Aug 27; [e-pub] PMID: 34449189 https://www.nejm.org/doi/10.1056/NEJMoa2107038
  13. Butler J, Filippatos G, Siddiqi TJ et al Empagliflozin, health status, and quality of life in patients with heart failure and preserved ejection fraction: The EMPEROR-Preserved Trial. Circulation 2021 Nov 15; [e-pub]. PMID: 34779658 Free article https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.057812
  14. Verma S, Dhingra NK, Butler J et al. Empagliflozin in the treatment of heart failure with reduced ejection fraction in addition to background therapies and therapeutic combinations (EMPEROR-Reduced): A post-hoc analysis of a randomised, double-blind trial. Lancet Diabetes Endocrinol 2022 Jan; 10:35. PMID: 34861154 https://www.thelancet.com/journals/landia/article/PIIS2213-8587(21)00292-8/fulltext - Ryden L, Ferrannini G. Is the impact of add on heart failure therapy influenced by background therapy? Lancet Diabetes Endocrinol 2022 Jan; 10:3 PMID: 34861151 https://www.thelancet.com/journals/landia/article/PIIS2213-8587(21)00311-9/fulltext
  15. Kosiborod MN et al. Effects of empagliflozin on symptoms, physical limitations and quality of life in patients hospitalized for acute heart failure - Results from the EMPULSE trial. Circulation 2022 Apr 4; [e-pub] PMID: 35377706 https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.059725
  16. Schulze PC et al. Effects of early empagliflozin initiation on diuresis and kidney function in patients with acute decompensated heart failure (EMPAG-HF). Circulation 2022 Jun 29; PMID: 35766022 Free article https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.059038
  17. The EMPA-KIDNEY Collaborative Group Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2022. Nov 4 PMID: 36331190 https://www.nejm.org/doi/full/10.1056/NEJMoa2204233
  18. Zheng J, Parizo JT, Spertus JA et al Cost-effectiveness of Empagliflozin in Patients With Heart Failure With Preserved Ejection Fraction. JAMA Intern Med. Published online November 7, 2022 PMID: 36342696 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2797773
  19. Ferreira JP, Zannad F, MD, Butler J et al Association of Empagliflozin Treatment With Albuminuria Levels in Patients With Heart Failure. A Secondary Analysis of EMPEROR-Pooled. JAMA Cardiol. 2022;7(11):1148-1159 PMID: 36129693 PMCID: PMC9494272 Free PMC article https://jamanetwork.com/journals/jamacardiology/fullarticle/2796744
  20. Butler J, Shariq Usman M, Filippatos G et al Safety and Efficacy of Empagliflozin and Diuretic Use in Patients with Heart Failure and Preserved Ejection Fraction. A Post Hoc Analysis of the EMPEROR- Preserved Trial. JAMA Cardiol. Published online May 24, 2023. PMID: 37223933 https://jamanetwork.com/journals/jamacardiology/fullarticle/2805335
  21. 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.
  22. NEJM Knowledge+ Endocrinology
  23. 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
  24. EMPA-KIDNEY Collaborative Group Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial. Lancet Diabetes Endocrinol. 2024 Jan;12(1):51-60 PMID: 38061372 Free article https://www.thelancet.com/journals/landia/article/PIIS2213-8587(23)00322-4/fulltext
  25. Alexander JT, Singh SK, Shah SD, Lambert B, Smith JP. 2023 Update in ambulatory general internal medicine Cleveland Clinic Journal of Medicine January 2024, 91 (1) 40-46 PMID: 38167397 Free article. Review. https://www.ccjm.org/content/91/1/40
  26. Modzelewski KL, Pipilas A, Bosch NA Comparative Outcomes of Empagliflozin to Dapagliflozin in Patients With Heart Failure. JAMA Netw Open. 2024;7(5):e249305 PMID: 38696170 PMCID: PMC11066699 Free PMC article. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2818219
  27. Highlights of Prescribing Information JARDIANCE (empagliflozin tablets), for oral use https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Jardiance/jardiance.pdf

Component-of

empagliflozin/linagliptin empagliflozin/linagliptin/metformin (Trijardy XR)