Ertugliflozin

Ertugliflozin, sold under the brand name Steglatro, is a medication for the treatment of type 2 diabetes.[2][3]

Ertugliflozin
Clinical data
Trade namesSteglatro
Other namesPF-04971729, ertugliflozin l-pyroglutamic acid
AHFS/Drugs.comMonograph
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classAntidiabetic agent
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability~100%
Protein binding93.6%
MetabolismUGT1A9, UGT2B7
MetabolitesGlucuronides
Elimination half-life~17 hours
Excretion41% faeces, 50% urine
Identifiers
  • (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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.237.989
Chemical and physical data
FormulaC22H25ClO7
Molar mass436.89 g·mol−1
3D model (JSmol)
  • CCOc1ccc(cc1)Cc2cc(ccc2Cl)[C@@]34[C@@H]([C@H]([C@@H]([C@@](O3)(CO4)CO)O)O)O
  • 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

The most common side effects include fungal infections of the vagina and other infections of the female reproductive system.[3]

Ertugliflozin is a sodium/glucose cotransporter 2 (SGLT2) inhibitor[2][3] and is in the class of drugs known as gliflozins.[4]

In the United States, it was approved by the Food and Drug Administration for use as a monotherapy and as a fixed dose combination with either sitagliptin or with metformin.[5] In the European Union, it was approved in March 2018, for use as a monotherapy or combination therapy.[6] In September 2020, The New England Journal of Medicine reported that ertugliflozin was shown to be essentially non-inferior to placebo with respect to cardiovascular events.[7]

A combination with metformin is marketed as Segluromet and a combination with sitagliptin is marketed as Steglujan.[1][8][9][10][11]

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.[3]

Contraindications

Under the US approval, ertugliflozin is contraindicated for patients with severe kidney failure, end-stage renal disease, and dialysis.[2] The European Union approval does not list any contraindications apart from hypersensitivity to the drug, which is standard for all drug approvals.[6]

Adverse effects

Adverse 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.[2]

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.[12]

Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing.[12]

Overdose

Up to sixfold clinical doses over two weeks, or 20-fold single doses, are tolerated by patients without any toxic effects.[6]

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.[2][6]

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.[2][6]

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.[2][6]

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.[2][8][10][3][9][11]

References
  1. Australian Public Assessment Report for Ertugliflozin, Ertugliflozin / Sitagliptin, Ertugliflozin / Metformin (PDF) (Report).
  2. "Steglatro- ertugliflozin tablet, film coated". DailyMed. 30 January 2020. Retrieved 24 September 2020.
  3. "Steglatro EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 24 September 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. Trum M, Wagner S, Maier LS, Mustroph J (June 2020). "CaMKII and GLUT1 in heart failure and the role of gliflozins". Biochimica et Biophysica Acta. Molecular Basis of Disease. 1866 (6): 165729. doi:10.1016/j.bbadis.2020.165729. PMID 32068116. S2CID 211159566.
  5. "FDA Approves SGLT2 Inhibitor Ertugliflozin for Type 2 Diabetes". MedScape.
  6. "Steglatro: EPAR – Product Information" (PDF). European Medicines Agency. 4 June 2018.
  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. "Segluromet- ertugliflozin and metformin hydrochloride tablet, film coated". DailyMed. 11 August 2020. Retrieved 24 September 2020.
  9. "Segluromet EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 24 September 2020.
  10. "Steglujan- ertugliflozin and sitagliptin tablet, film coated". DailyMed. U.S. National Library of Medicine. 31 January 2020. Retrieved 24 September 2020.
  11. "Steglujan EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 24 September 2020.
  12. "FDA revises labels of SGLT2 inhibitors for diabetes to include warning". U.S. Food and Drug Administration. 19 March 2020. Retrieved 6 June 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  • "Ertugliflozin". Drug Information Portal. U.S. National Library of Medicine.
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