Empagliflozin Explained

Empagliflozin, sold under the brand name Jardiance, among others, is an antidiabetic medication used to improve glucose control in people with type2 diabetes.[1] [2] It is taken by mouth.[1]

Common side effects include hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status changes, hypotension, acute kidney injury, and vaginal yeast infections.[1] Rarer but more serious side effects include a skin infection of the groin called Fournier's gangrene and a form of diabetic ketoacidosis with normal blood sugar levels.[1] [3] Use during pregnancy or breastfeeding is not recommended.[4] Empagliflozin sometimes causes a transient decline in kidney function, and on rare occasions causes acute kidney injury, so use should be monitored in those with kidney dysfunction. But some trials have indicated that empagliflozin can be used in people with an eGFR as low as 20 mL/min/1.73 m², without increasing adverse kidney outcomes.[5]

The use of empagliflozin has been shown to improve outcomes in people with established cardiovascular disease.[6] [7] There is evidence from high quality studies that empagliflozin can also help to slow the rate of kidney function decline. Irrespective of diabetes status, benefit was observed in those with mild, moderate or severe loss of kidney function.[8] [9]  People started on empagliflozin may first see a decrease in kidney function before their glomerular filtration rate stabilises.[10] Greatest benefit was demonstrated in those who had severe loss of kidney function, higher risk of kidney function worsening and background of diabetes.

Empagliflozin is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2), and works by increasing sugar loss in urine.

Empagliflozin was approved for medical use in the United States and in the European Union in 2014.[11] It is on the World Health Organization's List of Essential Medicines.[12] In 2022, it was the 56th most commonly prescribed medication in the United States, with more than 12million prescriptions.[13] [14] It has received approval as a generic medication from the US Food and Drug Administration (FDA).[15]

Medical uses

In the United States, empagliflozin is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure; to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression; to reduce the risk of cardiovascular death in adults with type2 diabetes and established cardiovascular disease; and as an adjunct to diet and exercise to improve glycemic control in people aged ten years of age and older with type2 diabetes.

In the European Union, empagliflozin is indicated in people aged ten years of age and older for the treatment of insufficiently controlled type 2 diabetes as an adjunct to diet and exercise; as monotherapy when metformin is considered inappropriate due to intolerance; in addition to other medicinal products for the treatment of diabetes. It is indicated in adults for the treatment of symptomatic chronic heart failure; and it is indicated in adults for the treatment of chronic kidney disease.

Empagliflozin lowers risk of hospitalization and death in people with reduced heart function, when added to standard heart failure treatment with or without type2 diabetes.[16] [17] [18] It is indicated in adults with type2 diabetes and established cardiovascular disease to reduce the risk of cardiovascular death; and as an adjunct to diet and exercise to improve glycemic control in adults with type2 diabetes.[19] [20] [21]

In June 2023, the US Food and Drug Administration (FDA) expanded the indication, as an addition to diet and exercise, to improve blood sugar control in children 10 years and older with type2 diabetes.[22]

Contraindications

Side effects

Common

Serious

Mechanism of action

Empagliflozin is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2), which is found almost exclusively in the proximal tubules of nephronic components in the kidneys. SGLT-2 accounts for about 90percent of glucose reabsorption into the blood. Blocking SGLT-2 reduces blood glucose by blocking glucose reabsorption in the kidney and thereby excreting glucose (i.e., blood sugar) via the urine.[29] [30] [31] Of all the SGLT-2 Inhibitors currently available, empagliflozin has the highest degree of selectivity for SGLT-2 over SGLT-1, SGLT-4, SGLT-5 and SGLT-6.[32]

History

It was developed by Boehringer Ingelheim and is co-marketed by Eli Lilly and Company. It is also available as the fixed-dose combinations empagliflozin/linagliptin,[33] empagliflozin/metformin,[34] and empagliflozin/linagliptin/metformin.[35]

For cardiovascular death, the FDA based its decision on a postmarketing study it required when it approved empagliflozin in 2014, as an adjunct to diet and exercise to improve glycemic control in adults with type2 diabetes.[36] Empagliflozin was studied in a postmarket clinical trial of more than 7,000 participants with type2 diabetes and cardiovascular disease. In the trial, empagliflozin was shown to reduce the risk of cardiovascular death compared to a placebo when added to standard of care therapies for diabetes and atherosclerotic cardiovascular disease.

For heart failure, the safety and effectiveness of empagliflozin were evaluated by the FDA as an adjunct to standard of care therapy in a randomized, double-blind, international trial comparing 2,997 participants who received empagliflozin, 10 mg, once daily to 2,991 participants who received the placebo. The main efficacy measurement was the time to death from cardiovascular causes or need to be hospitalized for heart failure. Of the individuals who received empagliflozin for an average of about two years, 14% died from cardiovascular causes or were hospitalized for heart failure, compared to 17% of the participants who received the placebo. This benefit was mostly attributable to fewer participants being hospitalized for heart failure.

The FDA granted the application for empagliflozin priority review and granted the approval of Jardiance to Boehringer Ingelheim.

Legal status

As of May 2013, Boehringer and Lilly had submitted applications for marketing approval to the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).[37] Empagliflozin was approved in the European Union in May 2014,[38] and was approved in the United States in August 2014.[39] The FDA required four postmarketing studies: a cardiovascular outcomes trial, two studies in children, and a toxicity study in animals related to the pediatric trials.[39]

Research

A meta-analysis of short-term randomized controlled trials has shown similar efficacy on glycemic control between empagliflozin 10mg and 25mg in people with type2 diabetes. While there may be a higher reduction in HbA1c with higher doses, this difference is more clinically significant when the patients' baseline HbA1c is ≥ 8.5%.[40] [41]

Weight and blood pressure

Empagliflozin causes moderate reductions in blood pressure and body weight. These effects are likely due to the excretion of glucose in the urine and a slight increase in urinary sodium excretion.[42] [43]

In clinical trials, participants with type2 diabetes taking empagliflozin with other diabetic medications lost an average of 2% of their baseline body weight.[44] [45] A higher percentage of people taking empagliflozin achieved weight loss greater than 5% from their baseline, which has been associated with improved glucose control. The same extent of weight loss was also observed in a study with heart failure patients taking empagliflozin.[46]

Empagliflozin has been shown to reduce systolic blood pressure by 3 to 5millimeters of mercury (mmHg) without changes in pulse rate. A greater percentage of people with uncontrolled blood pressure at baseline, achieved controlled blood pressure (i.e. systolic blood pressure <130 mmHg and diastolic blood pressure <80 mmHg) after taking empagliflozin at 24 weeks. The effects on blood pressure and body weight are generally viewed as favorable, as many people with type2 diabetes have high blood pressure or are overweight or obese.[47] [48]

Notes and References

  1. Web site: Empagliflozin Monograph for Professionals . live . https://web.archive.org/web/20190406062958/https://www.drugs.com/monograph/empagliflozin.html . 6 April 2019 . 21 December 2018 . Drugs.com . AHFS.
  2. Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB . December 2018 . Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) . Diabetologia . 61 . 12 . 2461–2498 . 10.1007/s00125-018-4729-5 . 30288571 . free . doi.
  3. Web site: 9 February 2019 . FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes . live . https://web.archive.org/web/20191213201737/https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrences-serious-infection-genital-area-sglt2-inhibitors-diabetes . 13 December 2019 . 18 March 2019 . U.S. Food and Drug Administration (FDA).
  4. Book: British national formulary: BNF 76 . 2018 . Pharmaceutical Press . 9780857113382 . 76 . 691.
  5. Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, Preiss D, Judge P, Mayne KJ, Ng SY, Sammons E, Zhu D, Hill M, Stevens W, Wallendszus K, Brenner S, Cheung AK, Liu ZH, Li J, Hooi LS, Liu W, Kadowaki T, Nangaku M, Levin A, Cherney D, Maggioni AP, Pontremoli R, Deo R, Goto S, Rossello X, Tuttle KR, Steubl D, Petrini M, Massey D, Eilbracht J, Brueckmann M, Landray MJ, Baigent C, Haynes R . January 2023 . Empagliflozin in Patients with Chronic Kidney Disease . The New England Journal of Medicine . 388 . 2 . 117–127 . 10.1056/NEJMoa2204233 . 7614055 . 36331190.
  6. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE . November 2015 . Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes . The New England Journal of Medicine . 373 . 22 . 2117–2128 . 10.1056/NEJMoa1504720 . 26378978.
  7. Zannad F, Butler J, Filippatos GS, Pocock S, Jamal W, Schnee J, Zeller C, Brueckmann M, Anker SD, Packer M . May 2021 . Cardiovascular and Kidney Outcomes with Empagliflozin in Heart Failure . Präzisionsmedizin – Eine Reise in die Zukunft der Diabetologie www.diabeteskongress.de . Georg Thieme Verlag KG . 16 . 10.1055/s-0041-1727471.
  8. Herrington WG, Preiss D, Haynes R, von Eynatten M, Staplin N, Hauske SJ, George JT, Green JB, Landray MJ, Baigent C, Wanner C . August 2020 . Erratum: The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study . Clinical Kidney Journal . 13 . 4 . 722 . 10.1056/NEJMoa2204233 . 7467589 . 32905262 . free . 20.500.13003/18576.
  9. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B . July 2016 . Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes . The New England Journal of Medicine . 375 . 4 . 323–334 . 10.1056/nejmoa1515920 . 27299675.
  10. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B . July 2016 . Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes . The New England Journal of Medicine . 375 . 4 . 323–334 . 10.1056/NEJMoa1515920 . 27299675.
  11. Web site: 8 September 2014 . Drug Approval Package: Jardiance (empagliflozin) Tablets NDA #204629 . live . https://web.archive.org/web/20200211052628/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204629Orig1s000TOC.cfm . 11 February 2020 . 10 February 2020 . U.S. Food and Drug Administration (FDA).
  12. Book: World Health Organization . The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) . ((World Health Organization)) . World Health Organization . 2023 . Geneva . 10665/371090 . WHO/MHP/HPS/EML/2023.02 . free.
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  18. Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, Brueckmann M, Ofstad AP, Pfarr E, Jamal W, Packer M . September 2020 . SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials . Lancet . 396 . 10254 . 819–829 . 10.1016/s0140-6736(20)31824-9 . 32877652.
  19. Web site: 22 January 2020 . Jardiance- empagliflozin tablet, film coated . live . https://web.archive.org/web/20200211052721/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=faf3dd6a-9cd0-39c2-0d2e-232cb3f67565 . 11 February 2020 . 10 February 2020 . DailyMed.
  20. FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes . 6 December 2016 . U.S. Food and Drug Administration (FDA) . 12 December 2016 . live . https://web.archive.org/web/20200211052508/https://www.fda.gov/news-events/press-announcements/fda-approves-jardiance-reduce-cardiovascular-death-adults-type-2-diabetes . 11 February 2020.
  21. FDA Approves Treatment for Wider Range of Patients with Heart Failure . 24 February 2022 . U.S. Food and Drug Administration (FDA) . 27 February 2022 . live . https://web.archive.org/web/20220227044501/https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-wider-range-patients-heart-failure . 27 February 2022.
  22. FDA Approves New Class of Medicines to Treat Pediatric Type 2 Diabetes . 20 June 2023 . 20 June 2023 . live . https://web.archive.org/web/20230621014455/https://www.fda.gov/news-events/press-announcements/fda-approves-new-class-medicines-treat-pediatric-type-2-diabetes . 21 June 2023 . U.S. Food and Drug Administration (FDA).
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