Ertugliflozin

Ertugliflozin
Names
Trade namesSteglatro
Other namesPF-04971729, ertugliflozin l-pyroglutamic acid
IUPAC name
  • (1S,2S,3S,4R,5S)-5-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol
Clinical data
Drug classSGLT2 inhibitor[1]
Main usesType 2 diabetes[1][2]
Side effectsFungal infections of the vagina, diabetic ketoacidosis (DKA), limb amputation, Fournier's gangrene[2][1]
Pregnancy
category
    Routes of
    use    		By mouth
    Typical dose5 to 15 mg OD[4]
    External links
    AHFS/Drugs.comMonograph
    US NLMErtugliflozin
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability~100%
    Protein binding93.6%
    MetabolismUGT1A9, UGT2B7
    MetabolitesGlucuronides
    Elimination half-life~17 hours
    Excretion41% faeces, 50% urine
    Chemical and physical data
    FormulaC22H25ClO7
    Molar mass436.89 g·mol−1
    3D model (JSmol)
    SMILES
    • CCOc1ccc(cc1)Cc2cc(ccc2Cl)[C@@]34[C@@H]([C@H]([C@@H]([C@@](O3)(CO4)CO)O)O)O
    InChI
    • InChI=1S/C22H25ClO7/c1-2-28-16-6-3-13(4-7-16)9-14-10-15(5-8-17(14)23)22-20(27)18(25)19(26)21(11-24,30-22)12-29-22/h3-8,10,18-20,24-27H,2,9,11-12H2,1H3/t18-,19-,20+,21-,22-/m0/s1
    • Key:MCIACXAZCBVDEE-CUUWFGFTSA-N

    Ertugliflozin, sold under the brand name Steglatro, is a medication used to treat type 2 diabetes.[1][2] It is used together with diet and exercise.[1] It is taken by mouth.[1] It should not be used in people with type 1 diabetes.[1]

    Common side effects include fungal infections of the vagina and other infections of the female reproductive system.[2] Other side effects may include diabetic ketoacidosis (DKA), limb amputation, and Fournier's gangrene.[2][1] Use in pregnancy is not recommended.[2] It is a sodium glucose cotransporter 2 (SGLT2) inhibitor which increases the amount of glucose lost in the urine.[1][2]

    Ertugliflozin was approved for medical use in the United States in 2017 and Europe in 2018.[5][2] In the United Kingdom 4 weeks of medication costs the NHS about £30 as of 2021.[4] This amount in the United States is 280 USD.[6]

    Medical uses

    Steglatro is indicated for the treatment of adults with insufficiently controlled type 2 diabetes as an adjunct to diet and exercise as monotherapy when metformin is considered inappropriate due to intolerance or contraindications or in addition to other medicinal products for the treatment of diabetes.[2]

    In September 2020, The New England Journal of Medicine reported that ertugliflozin was shown to be essentially non-inferior to placebo.[7]

    Dosage

    It is started at a dose of 5 mg per day which may be increased to 15 mg per day.[1]

    Combinations

    A combination with metformin is marketed as Segluromet and a combination with sitagliptin is marketed as Steglujan.[3][8][9][10][11]

    Contraindications

    Ertugliflozin is contraindicated for patients with severe kidney failure, end-stage renal disease, and dialysis.[1] The European Union approval does not list any contraindications apart from hypersensitivity to the drug, which is standard for all drug approvals.[12]

    Side effects

    Side effects in studies that were significantly more common under ertugliflozin than under placebo included mycosis of the genitals in both men and women, vaginal itch, increased urination, thirst, hypoglycaemia (low blood sugar), and weight loss under the higher dosing scheme. A rare but life-threatening side effect of gliflozins is ketoacidosis; it occurred in three patients (0.1%) in ertugliflozin studies.[1]

    To lessen the risk of developing ketoacidosis (a serious condition in which the body produces high levels of blood acids called ketones) after surgery, the FDA has approved changes to the prescribing information for SGLT2 inhibitor diabetes medicines to recommend they be stopped temporarily before scheduled surgery. Ertugliflozin should be stopped at least four days before scheduled surgery.[13]

    Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing.[13]

    Overdose

    Up to sixfold clinical doses over two weeks, or 20-fold single doses, are tolerated by people without any toxic effects.[12]

    Interactions

    As with many diabetes drugs, combining ertugliflozin with insulin or insulin secretagogues (such as sulfonylureas) may result in an increased risk for low blood sugar. Combination with diuretics may result in a higher risk for dehydration and low blood pressure. No clinically relevant pharmacokinetic interactions have been found in studies.[1][12]

    Pharmacology

    Mechanism of action

    Further information: Gliflozin § Mechanism of action

    Pharmacokinetics

    After oral intake, ertugliflozin is practically completely absorbed from the gut and undergoes no relevant first-pass effect. Highest blood plasma concentrations are reached after one hour. When in circulation, 93.6% of the substance are bound to plasma proteins. Ertugliflocin is metabolised mainly to glucuronides by the enzymes UGT1A9 and UGT2B7. Cytochrome P450 enzymes play only a minor role in its metabolism.[1][12]

    The elimination half-life is estimated to be 17 hours. 40.9% are eliminated via the feces (33.8% in unchanged form and 7.1% as metabolites) and 50.2% via the urine (1.5% unchanged and 48.7% as metabolites). The high proportion of unchanged substance in the feces is probably due to hydrolysis of the metabolites back to the parent substance.[1][12]

    Society and culture

    Ertugliflozin, ertugliflozin/metformin, and ertugliflozin/sitagliptin were approved for medical use in the United States in December 2019, and in the European Union in March 2018.[1][8][10][2][9][11]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 "Steglatro- ertugliflozin tablet, film coated". DailyMed. 30 January 2020. Archived from the original on 4 August 2020. Retrieved 24 September 2020.
    2. 1 2 3 4 5 6 7 8 9 10 11 "Steglatro EPAR". European Medicines Agency (EMA). Archived from the original on 8 October 2020. Retrieved 24 September 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
    3. 1 2 Australian Public Assessment Report for Ertugliflozin, Ertugliflozin / Sitagliptin, Ertugliflozin / Metformin (PDF) (Report). Archived (PDF) from the original on 30 September 2021. Retrieved 30 September 2021.
    4. 1 2 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 749. ISBN 978-0857114105.
    5. ↑ "Ertugliflozin Monograph for Professionals". Drugs.com. Archived from the original on 28 January 2021. Retrieved 16 December 2021.
    6. ↑ "Steglatro Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 16 December 2021.
    7. ↑ Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, et al. (October 2020). "Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes". The New England Journal of Medicine. 383 (15): 1425–1435. doi:10.1056/NEJMoa2004967. PMID 32966714.
    8. 1 2 "Segluromet- ertugliflozin and metformin hydrochloride tablet, film coated". DailyMed. 11 August 2020. Archived from the original on 8 October 2020. Retrieved 24 September 2020.
    9. 1 2 "Segluromet EPAR". European Medicines Agency (EMA). Archived from the original on 13 August 2020. Retrieved 24 September 2020.
    10. 1 2 "Steglujan- ertugliflozin and sitagliptin tablet, film coated". DailyMed. 31 January 2020. Archived from the original on 24 September 2020. Retrieved 24 September 2020.
    11. 1 2 "Steglujan EPAR". European Medicines Agency (EMA). Archived from the original on 7 October 2020. Retrieved 24 September 2020.
    12. 1 2 3 4 5 "Steglatro: EPAR – Product Information" (PDF). European Medicines Agency. 4 June 2018. Archived (PDF) from the original on 18 June 2018. Retrieved 30 September 2021.
    13. 1 2 "FDA revises labels of SGLT2 inhibitors for diabetes to include warning". U.S. Food and Drug Administration. 19 March 2020. Archived from the original on 7 June 2020. Retrieved 6 June 2020. Public Domain This article incorporates text from this source, which is in the public domain.
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