Empagliflozin

Empagliflozin, sold under the trade name Jardiance among others, is a medication used together with diet and exercise to treat type 2 diabetes.[1][2] It is less preferred than metformin and sulfonylureas.[3] It may be used together with other medications such as metformin or insulin.[1][2] It is not recommended for type 1 diabetes.[1] It is taken by mouth.[1]

Empagliflozin
Clinical data
Trade namesJardiance, others
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration    		By mouth
    Drug classSodium-glucose cotransporter-2 (SGLT2) inhibitor[1]
    ATC code
    Legal status
    Legal status
    • In general: ℞ (Prescription only)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    ChemSpider
    UNII
    KEGG
    ChEBI
    ECHA InfoCard100.122.058
    Chemical and physical data
    FormulaC23H27ClO7
    Molar mass450.91 g·mol−1
    3D model (JSmol)

    Common side effects include urinary tract infections, fungal infections of the groin, and joint pains.[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][4] Use in pregnancy and breastfeeding is not recommended.[3] Use is not recommended in those with significant kidney disease, though it may help slow the progression of mild kidney problems.[1][2] Empagliflozin is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2), and works by increasing sugar lost in the urine.[1]

    Empagliflozin was approved for medical use in the United States in 2014.[1] A month supply in the United Kingdom costs the NHS about £36.59 as of 2019.[3] In the United States the wholesale cost of this amount is about US$442.[5] In 2016 it was the 289th most prescribed medication in the United States with more than a million prescriptions.[6]

    Medical use

    Type 2 diabetes

    Empagliflozin is used in combination with proper diet and exercise to help people with type 2 diabetes lower their blood sugar levels.[7] It can be used alongside other medications for type 2 diabetes such as metformin, sulfonylureas, and insulin.[8] When compared against a placebo, empagliflozin led to a drop of 0.7% in hemoglobin A1c, a long-term marker of blood glucose levels.[9]

    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.[10][9] In clinical trials, patients taking empagliflozin lost an average of 2% of their baseline body weight.[11] A higher percentage of people taking empagliflozin achieved weight loss greater than 5% from their baseline.[9] The medication reduced systolic blood pressure by 3 to 5 millimeters of mercury (mmHg).[9] The effects on blood pressure and body weight are generally viewed as favorable, as many patients with type 2 diabetes have high blood pressure or are overweight or obese.[12][13]

    Heart kidney disease

    SGLT2 inhibitors, including empagliflozin, appear to reduce the likelihood of hospitalization for heart failure or progression of chronic kidney disease in persons with type 2 diabetes. Empagliflozin may reduce the likelihood of death due to cardiovascular causes in people with type 2 diabetes who have known cardiovascular disease.[14][15][16] One concern regarding the trial on which these claims are based is that the different arms received different amounts of other medications; thus, the reduced risk cannot necessarily be attributed to empaglifozin.[17] In some countries it has also been approved to reduce the risk of death from cardiovascular causes in people with type 2 diabetes and heart disease.[16]

    Treatment guidelines

    Guidelines by the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recommend SGLT-2 inhibitors like empagliflozin as second-line medications after metformin for type 2 diabetes in people with heart failure or chronic kidney disease.[2] For type 2 diabetes with established cardiovascular disease, the guidelines recommend either a SGLT-2 inhibitor or a GLP-1 agonist as second-line medications after metformin. In all other type 2 diabetes cases, SGLT-2 inhibitors like empagliflozin can be appropriate second-line options if blood glucose control or weight loss are treatment priorities. They are less appropriate if cost is a major factor.[2]

    In the United Kingdom empagliflozin is typically only recommended together with metformin if a sulfonylurea cannot be taken.[8]

    Type 1 diabetes

    Empagliflozin is not recommended for type 1 diabetes.[1] One trial has studied its use in addition to insulin in people with type 1 diabetes.[18] The medications delivered modest improvements in blood glucose control and body weight but were associated with an increased risk of diabetic ketoacidosis, a dangerous complication of diabetes.[18] At this time, empagliflozin is not approved by the US FDA for use in type 1 diabetes.[7]

    Contraindications

    Side effects

    Common
    • Empagliflozin increases the risk of genital fungal infections. The risk is highest in people with a prior history of genital fungal infections.[9]
    • Urinary tract infections (UTIs) may be more common with empagliflozin. Certain individual clinical trials have demonstrated an increase risk but cumulative data across multiple trials show no increase in UTI risk.[11][9][12]
    • Empagliflozin reduces systolic and diastolic blood pressure and can increase the risk of low blood pressure, which can cause fainting and/or falls.[9] The risk is higher in older people, people taking diuretics, and people with reduced kidney function.[9]
    • Slight increases in LDL cholesterol can be seen with empagliflozin, in the range of 2% to 4% from baseline.[9]

    Serious
    • Diabetic ketoacidosis (DKA), a rare but potentially life-threatening condition, may occur more commonly with empagliflozin and other SGLT-2 inhibitors.[19][20] While DKA is usually associated with elevated blood glucose levels, in people taking SGLT-2 inhibitors DKA may be seen with uncharacteristically normal blood glucose levels, a phenomenon called euglycemic ketoacidosis.[19] The absence of elevated blood glucose levels in people on an SGLT-2 inhibitor may make it more difficult to diagnose DKA. The risk of empagliflozin-associated DKA may be higher in the setting of illness, dehydration, surgery, and/or alcohol consumption.[19] It is also seen in type 1 diabetes who take empagliflozin, which notably is an unapproved or "off-label" use of the medication.[20]
    • Fournier's gangrene, a rare but serious infection of the groin, occurs more commonly in people taking empaglflozin and other SGLT-2 inhibitors.[4][1] Symptoms include feverishness, a general sense of malaise, and pain or swelling around the genitals or in the skin behind them. The infection progresses quickly and urgent medical attention is recommended.[4]
    • Empagliflozin can increase people' risk of low blood sugar when it is used together with a sulfonylurea or insulin.[21] When used by itself or in addition to metformin it does not appear to increase the risk of hypoglycemia.[12]

    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 90 percent 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.[22][23][24]

    History

    It was developed by Boehringer Ingelheim and Eli Lilly and Company. It is also available as the combination empagliflozin/linagliptin.

    Regulatory status

    As of May 2013, Boehringer and Lilly had submitted applications for marketing approval to the European Medicines Agency and the U.S. Food and Drug Administration (FDA).[25] The drug was approved in Europe in May 2014 and was approved by the FDA in August 2014.[26] 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.[26]

    References
    1. "Empagliflozin Monograph for Professionals". Drugs.com. AHFS. Retrieved 21 December 2018.
    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. doi:10.1007/s00125-018-4729-5. PMID 30288571.
    3. British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 691. ISBN 9780857113382.
    4. "Drug Safety and Availability - FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes". www.fda.gov. Center for Drug Evaluation and Research. Retrieved 18 March 2019.
    5. "NADAC". Centers for Medicare and Medicaid Services. 27 February 2019. Retrieved 3 March 2019.
    6. "The Top 300 of 2019". clincalc.com. Retrieved 22 December 2018.
    7. "Empagliflozin: FDA Prescribing Information" (PDF). December 2016.
    8. "Empagliflozin in combination therapy for treating type 2 diabetes". NICE. Guidance and guidelines. 25 March 2015. Retrieved 21 December 2018.
    9. "Empagliflozin (Jardiance) National Drug Monograph" (PDF). VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives.
    10. Verma S, McMurray JJ (October 2018). "SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review". Diabetologia. 61 (10): 2108–2117. doi:10.1007/s00125-018-4670-7. PMID 30132036.
    11. Zimmermann J (December 2016). "Empagliflozin (Jardiance) for type 2 diabetes mellitus". American Family Physician. 94 (12): 1014–1015. PMID 28075091.
    12. Anderson JE, Wright EE, Shaefer CF (February 2017). "Empagliflozin: Role in treatment options for patients with type 2 diabetes mellitus". Diabetes Therapy. 8 (1): 33–53. doi:10.1007/s13300-016-0211-x. PMC 5306110. PMID 27837465.
    13. "Obesity and overweight fact sheet" (PDF). World Health Organization.
    14. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RH, Bhatt DL, Leiter LA, McGuire DK, Wilding JP, Sabatine MS (January 2019). "SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials". Lancet. 393 (10166): 31–39. doi:10.1016/S0140-6736(18)32590-X. PMID 30424892.
    15. Usman MS, Siddiqi TJ, Memon MM, Khan MS, Rawasia WF, Talha Ayub M, Sreenivasan J, Golzar Y (March 2018). "Sodium-glucose co-transporter 2 inhibitors and cardiovascular outcomes: A systematic review and meta-analysis". European Journal of Preventive Cardiology. 25 (5): 495–502. doi:10.1177/2047487318755531. PMID 29372664.
    16. "FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes". Office of the Commissioner. Press Announcement. United States Food and Drug Administration. Retrieved 12 December 2016.
    17. "EMPA-REG Outcome trial: What does it mean?" (PDF). Therapeutics Initiative. July–August 2017. Retrieved 21 December 2018.
    18. Riddle MC, Cefalu WT (December 2018). "SGLT Inhibitors for Type 1 Diabetes: An obvious choice, or too good to be true?". Diabetes Care. 41 (12): 2444–2447. doi:10.2337/dci18-0041. PMID 30459245.
    19. Rosenstock J, Ferrannini E (September 2015). "Euglycemic diabetic ketoacidosis: A predictable, detectable, and preventable safety concern with SGLT2 inhibitors". Diabetes Care. 38 (9): 1638–1642. doi:10.2337/dc15-1380. PMID 26294774.
    20. Handelsman Y, Henry RR, Bloomgarden ZT, Dagogo-Jack S, DeFronzo RA, Einhorn D, Ferrannini E, Fonseca VA, Garber AJ, Grunberger G, LeRoith D, Umpierrez GE, Weir MR (June 2016). "American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the Association of Sglt-2 Inhibitors and Diabetic Ketoacidosis". Endocrine Practice. 22 (6): 753–762. doi:10.4158/EP161292.PS. PMID 27082665.
    21. "Empagliflozin in combination therapy for treating type 2 diabetes". NICE. 25 March 2015. Retrieved 21 December 2018.
    22. Abdul-Ghani MA, DeFronzo RA (September 2008). "Inhibition of renal glucose reabsorption: A novel strategy for achieving glucose control in type 2 diabetes mellitus". Endocrine Practice. 14 (6): 782–790. doi:10.4158/ep.14.6.782. PMID 18996802.
    23. Nair S, Wilding JP (January 2010). "Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus". The Journal of Clinical Endocrinology and Metabolism. 95 (1): 34–42. doi:10.1210/jc.2009-0473. PMID 19892839.
    24. Bays H (March 2009). "From victim to ally: The kidney as an emerging target for the treatment of diabetes mellitus". Current Medical Research and Opinion. 25 (3): 671–681. doi:10.1185/03007990802710422. PMID 19232040.
    25. Tucker, Miriam E. (May 7, 2013). "First details of empagliflozin trials follow US and EU filings". Medscape Medical News.
    26. Mechatie E (August 1, 2014). "FDA approves empagliflozin for adults with type 2 diabetes". Clinical Endocrinology News Digital Network.
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