CLINICAL PHARMACOLOGY UPDATE Overview of Ertugliflozin Vivianne K. Nguyen and John R. White, Jr. Introduction combinations with the DPP-4 sita- espite the availability of 12 gliptin (brand name Stegujan) or with different classes of medica- metformin (brand name Segluromet). Dtions, many people with type Ertugliflozin is not approved for the 2 diabetes struggle to maintain gly- treatment of type 1 diabetes, renal im- cemic control (1). Among the many pairment, or ketoacidosis. new antidiabetic medications to have Mechanism of Action emerged in recent years, sodium– As other SGLT2 inhibitors, ertug- glucose cotransporter 2 (SGLT2) liflozin works by blocking glucose inhibitors have proved to be a par- transport from the glomerular filtrate ticularly effective oral treatment for across the apical membrane of the these patients (2). Since the approval proximal epithelial cells, resulting in of the first drug in this class, canagli- increased urinary glucose excretion flozin, by the U.S. Food and Drug and reduced filtered glucose renal re- Administration (FDA) in March absorption. Ertugliflozin is predom- 2013, a total of four SGLT2 agents inantly metabolized by the enzymes have become available (both as single UGT1A9 and UGT2B, with minor and fixed-dose combination formu- contributions by CYP3A4, and even las) (1). In 2017, an estimated 1.7 less by CYP3A5 and CYP2C8 (4). million patients received a dispensed Ertugliflozin does not inhibit CYP450 prescription for an SGLT2 inhibitor isoenzymes (CYPs) 1A2, 2C9, 2C19, from U.S. outpatient retail pharmacies 2C8, 2B6, 2D6, or 3A4 and does not (2). Ertugliflozin is the newest agent induce CYPs 1A2, 2B6, or 3A4 (4). among these, having received FDA This might be beneficial in patients approval in December 2017 (3). with type 2 diabetes who have com- Indications plications and are on multiple med- Ertugliflozin is indicated as an adjunct ications because taking ertugliflozin to diet and exercise for control of hy- would reduce the chance of having perglycemia in adults (≥18 years of major interactions with drugs that age) with type 2 diabetes (4). It can are metabolized by these common College of Pharmacy and Pharmaceutical enzymes (2). Sciences, Washington State University, be used as monotherapy in patients Spokane, WA for whom metformin is contraindi- Potential Advantages Corresponding author: John R. White, Jr., cated or not well tolerated. It can also Ertugliflozin has been shown to lower [email protected] be used in combination with other A1C in adults with type 2 diabetes. It https://doi.org/10.2337/cd18-0097 antidiabetic agents (most commonly has been studied extensively in multi- metformin or a dipeptidyl peptidase ple clinical trial settings and has been ©2018 by the American Diabetes Association. Readers may use this article as long as the work 4 [DPP-4] inhibitor) to help reduce found to be effective in all of them is properly cited, the use is educational and not A1C. Currently, ertugliflozin is avail- (5). Three multicenter, randomized, for profit, and the work is not altered. See http:// creativecommons.org/licenses/by-nc-nd/3.0 able as an oral tablet sold under the double-blind, placebo- and active for details. brand name Steglatro or in oral tablet comparator–controlled clinical studies 176 CLINICAL.DIABETESJOURNALS.ORG NGUYEN AND WHITE evaluating ertugliflozin have demon- in patients taking an SGLT2 inhibi- not achieved their glycemic goals. strated its efficacy in further lower- tor. Twelve cases have been identified Patients’ medical history, costs, and ing A1C when used in combination since 2013 in both male and female risk/benefit factors are key issues that with sitagliptin in 1,985 people with patients who were being treated with should be thoroughly considered be- type 2 diabetes from different ethnic an SGLT2 inhibitor (1). Ertugliflozin fore starting patients on ertugliflozin groups (6). Another phase 3 trial in has included this information in its therapy. 4,800 people with type 2 diabetes and package insert, and patients being moderate renal failure compared the treated with this medication will be Duality of Interest use of ertugliflozin as monotherapy monitored closely in its post-market- J.R.W. serves on an advisory board for and in combination with metformin ing surveillance. Sanofi. No other potential conflicts of inter- est relevant to this article were reported. or sitagliptin, as well as insulin and Cost a sulfonylurea. Results confirmed sig- The out-of-pocket price of ertuglifloz- nificantly lower A1C in those who Author Contributions in monotherapy tablets is $321.99 per took ertugliflozin alone or in combi- Both authors contributed to and were 30-tablet bottle for 1 month of use involved in the research, writing, and editing nation with sitagliptin (6). based on recommended dosing (6). of this article. J.R.W. is the guarantor of this Ertugliflozin therapy may also be work and, as such, had full access to all of Currently, Merck has a copayment beneficial for patients who are over- the references cited and takes responsibility assistance program that will help cover for the accuracy of the content. weight or hypertensive. Due to its some of patients’ out-of-pocket cost if mechanism of action, ertugliflozin private insurance is used to fill a pre- References induces more excretion of sodium scription for ertugliflozin or its com- 1. U.S. Food and Drug Administration. through osmotic diuresis, which then Drug safety and availability: FDA warns bination formulations with sitagliptin leads to a mild reduction in blood about rare occurrences of a serious infection or metformin. of the genital area with SGLT2 inhibitors pressure. Excretion of glucose in the for diabetes. Available from www.fda. urine also helps with weight loss due Commentary gov/Drugs/DrugSafety/ucm617360.htm. to loss of calories (7). Another study Given its risk/benefit profile, ertugli- Accessed 5 October 2018 of ertugliflozin has shown it to be flozin is considered a favorable drug 2. U.S. Food and Drug Administration. Steglatro (ertugliflozin), Steglujan associated with a mean reduction in of choice within the SGLT2 inhibi- (ertugliflozin and sitagliptin), Segluromet body weight of 6.6 lb with the 5-mg tor class of medications. It does not (ertugliflozin and metformin hydro- dose compared to 2.2 lb with placebo contain a black box warning, as does chloride) tablets. Available from www. accessdata.fda.gov/drugsatfda_docs/ (7). More data are being collected to canagliflozin for its risk of lower-limb nda/2017/209803,209805,209806 compare these benefits to those of amputation in people with type 2 di- Orig1s000TOC.cfm. Accessed 5 other SGLT2 inhibitors. abetes and established cardiovascular October 2018 Potential Disadvantages disease (CVD) (8). However, pre- 3. Pfizer. FDA approves SGLT2 inhibi- scribers must still consider carefully tor STEGLATRO™ (ertugliflozin) and Clinical trials have demonstrated that fixed-dose combination STEGLUJAN™ before starting this therapy in elderly the safety profile of ertugliflozin is (ertugliflozin and sitagliptin) for adults with patients with renal impairment and type 2 diabetes. Available from www.pfizer. similar to other compounds in its class CVD, those with recurrent infections com/news/press-release/press-release-detail/ (i.e., association with genital mycot- fda_approves_sglt2_inhibitor_steglatro_ and high risk of limb amputation, and ic infection, lower-limb amputation, ertugliflozin_and_fixed_dose_combination_ female patients with recurrent urinary steglujan_ertugliflozin_and_sitagliptin_for_ urinary tract infection, acute kidney tract infections. adults_with_type_2_diabetes. Accessed 5 injury hypotension, and ketoacidosis) October 2018 Patient education is key before (5). Because this drug has been ap- starting this therapy. The FDA 4. U.S. Food and Drug Administration. proved recently, data used to evaluate Medication guide: Steglujan (STEG-loo-jan) released a safety announcement in its associated risks with regard to these (ertugliflozin and sitagliptin) tablets, for oral August 2018 to advise patients treated use. Available from www.accessdata.fda.gov/ adverse effects are still being collected with SGLT2 inhibitors to seek med- drugsatfda_docs/label/2018/209805s001lbl. and will be updated in the near future pdf#page=32. Accessed 5 April 2018 ical attention immediately if they (5). However, one could expect to see 5. Merck, Sharp & Dohme. Steglatro experience symptoms of redness, a range of adverse effects with ertugli- (ertugliflozin) official website. Available swelling, or tenderness of the genital from www.steglatro.com. Accessed 5 flozin similar to those of other SGLT2 areas accompanied by a fever (8). October 2018 inhibitors. 6. U.S. Food and Drug Administration. A recent safety announcement Bottom Line Englund E. Center for Drug Evaluation from the FDA (1) has raised con- Ertugliflozin seems to be a reasonable and Research application number 209803. Available from www.accessdata.fda.gov/ cern regarding the risk of Fournier’s second- or third-line therapeutic op- drugsatfda_docs/nda/2017/209803,209805, gangrene, a rare but life-threatening tion adjuvant to diet and exercise for 209806Orig1s000SumR.pdf. Accessed 25 bacterial infection of the genial areas, people with type 2 diabetes who have April 2018 VOLUME 37, NUMBER 2, SPRING 2019 177 CLINICAL PHARMACOLOGY UPDATE 7. Clements JM. New SGLT-2 inhibitor: 8. Micromedex Canagliflozin (Invokana). evidencexpert/ND_T/evidencexpert/ ertugliflozin (Steglatro) [blog post]. Available from www.micromedexsolutions. PFActionId/evidencexpert.GoToDashboard? Available from www.diabeteseducator.org/ com/micromedex2/librarian/CS/0ECE1D/ docId=930464&contentSetId=100&title= news/aade-blog/aade-blog-details/jennifer- ND_PR/evidencexpert/ND_P/evidence Canagliflozin&servicesTitle=Canagliflozin n.-clements-pharmd-bcps-cde-bcacp/2018/ xpert/DUPLICATIONSHIELDSYNC/ &brandName=Invokana#. Accessed 5 05/01/new-sglt-2-inhibitor-ertugliflozin. F4ADC7/ND_PG/evidencexpert/ October 2018 Accessed 5 October 2018 ND_B/evidencexpert/ND_AppProduct/ 178 CLINICAL.DIABETESJOURNALS.ORG.