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Ertugliflozin

Clinical data
Trade names	Steglatro
Other names	PF-04971729, ertugliflozin l-pyroglutamic acid
AHFS/Drugs.com	Monograph
License data	US DailyMed: Ertugliflozin
Pregnancy category	AU: D
Routes of administration	By mouth
Drug class	Antidiabetic agent
ATC code	A10BK04 (WHO)
Legal status
Legal status	CA: ℞-only UK: POM (Prescription only) US: ℞-only EU: Rx-only
Pharmacokinetic data
Bioavailability	~100%
Protein binding	93.6%
Metabolism	UGT1A9, UGT2B7
Metabolites	Glucuronides
Elimination half-life	~17 hours
Excretion	41% faeces, 50% urine
Identifiers
IUPAC name (1S,2S,3S,4R,5S)-5--1-(hydroxymethyl)-6,8-dioxabicyclooctane-2,3,4-triol
CAS Number	1210344-57-2
PubChem CID	44814423
DrugBank	DB11827
ChemSpider	26340533
UNII	6C282481IP
KEGG	D10313 as salt: D11043
CompTox Dashboard (EPA)	DTXSID40153120
ECHA InfoCard	100.237.989
Chemical and physical data
Formula	C22H25ClO7
Molar mass	436.89 g·mol
3D model (JSmol)	Interactive image
SMILES CCOc1ccc(cc1)Cc2cc(ccc2Cl)34((((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 for the treatment of type 2 diabetes.

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

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

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. In the European Union, it was approved in March 2018, for use as a monotherapy or combination therapy. A study published in September 2020, found that ertugliflozin to be essentially non-inferior to placebo with respect to cardiovascular events.

A combination with metformin is sold under the brand name Segluromet and a combination with sitagliptin is sold under the brand name Steglujan.

Medical uses

Ertugliflozin 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.

A systematic review and meta-analysis of ertugliflozin, published in 2024, found it to have a good glycemic efficacy and a reassuring safety profile in managing type 2 diabetes.

Contraindications

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

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

Overdose

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

Interactions

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.

Pharmacology

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.

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.

Society and culture

Legal status

Ertugliflozin, ertugliflozin combined with metformin, and ertugliflozin combined with sitagliptin were approved for medical use in the United States in December 2019, and in the European Union in March 2018.

References

1. ^ Australian Public Assessment Report for Ertugliflozin, Ertugliflozin / Sitagliptin, Ertugliflozin / Metformin (PDF) (Report).
2. "Drug and medical device highlights 2018: Helping you maintain and improve your health". Health Canada. 14 October 2020. Retrieved 17 April 2024.
3. ^ "Steglatro- ertugliflozin tablet, film coated". DailyMed. 30 January 2020. Retrieved 24 September 2020.
4. ^ "Steglatro EPAR". European Medicines Agency (EMA). 5 April 2018. Retrieved 24 September 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
5. 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 (BBA) - Molecular Basis of Disease. 1866 (6): 165729. doi:10.1016/j.bbadis.2020.165729. PMID 32068116. S2CID 211159566.
6. "FDA Approves SGLT2 Inhibitor Ertugliflozin for Type 2 Diabetes". MedScape.
7. ^ "Steglatro: EPAR – Product Information" (PDF). European Medicines Agency. 4 June 2018. Archived from the original (PDF) on 18 June 2018. Retrieved 18 June 2018.
8. 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.
9. ^ "Segluromet- ertugliflozin and metformin hydrochloride tablet, film coated". DailyMed. 11 August 2020. Retrieved 24 September 2020.
10. ^ "Segluromet EPAR". European Medicines Agency (EMA). 5 April 2018. Retrieved 24 September 2020.
11. ^ "Steglujan- ertugliflozin and sitagliptin tablet, film coated". DailyMed. U.S. National Library of Medicine. 31 January 2020. Retrieved 24 September 2020.
12. ^ "Steglujan EPAR". European Medicines Agency (EMA). 5 April 2018. Retrieved 24 September 2020.
13. Kamrul-Hasan AB, Alam MS, Talukder SK, Hannan MA, Dutta D, Nagendra L, et al. (September 2024). "Efficacy and Safety of Ertugliflozin Compared to Placebo in Patients With Type 2 Diabetes: An Updated Systematic Review and Meta-Analysis". Journal of Diabetes Research. 2024: 5553327. doi:10.1155/2024/5553327. PMC 11444800. PMID 39354951.
14. ^ "FDA revises labels of SGLT2 inhibitors for diabetes to include warning". U.S. Food and Drug Administration. 19 March 2020. Retrieved 6 June 2020. This article incorporates text from this source, which is in the public domain.

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