Is an SGLT2 inhibitor right for your patient with type 2 diabetes?

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Applied Evidence

Is an SGLT2 inhibitor right for your patient with type 2 diabetes?

J Fam Pract. 2016 September;65(9):587-593

By

Katelin M. Lisenby, PharmD, BCPS

Allison Meyer, BCACP

Nicole A. Slater, PharmD, BCACP

Metformin isn’t quite doing the job or is contraindicated? Here’s a look at the patients who may benefit from these agents and the monitoring required.

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References

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4. Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010:33:2217-2224.

5. Roden M, Weng J, Eilbracht J, et al. Empagliﬂozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013;1:208-219.

6. Ferrannini E, Berk A, Hantel S, et al. Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: an active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes Care. 2013;36:4015-4021.

7. Wilding JPH, Charpentier G, Hollander P, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract. 2013;67:1267-1282.

8. Forst T, Guthrie R, Goldenberg R, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab. 2014;16:467-477.

9. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013;36:2508-2515.

10. Bristol-Myers Squibb [press release]. New phase III data showed dapagliflozin significantly reduced HbA1c compared to placebo at 24 weeks in patients with type 2 diabetes inadequately controlled with the combination of metformin plus sulfonylurea. Available at: http://news.bms.com/press-release/rd-news/new-phase-iii-data-showed-dapagliflozin-significantly-reduced-hba1c-compared-p&t=635156160653787526. Accessed September 17, 2015.

11. Jabbour SA, Hardy E, Sugg J, et al. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24- week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care. 2014;37:740-750.

12. DeFronzo RA, Lewin A, Patel S, et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015;38:384-393.

13. Kovacs CS, Seshiah V, Merker L, et al. Empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus. Clin Ther. 2015;37:1773-1788.

14. Haring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized double-blind, placebo-controlled trial. Diabetes Care. 2013;36:3396-3404.

15. Neal B, Percovik V, de Zeeuw D, et al. Efficacy and safety of canagliflozin, an inhibitor of sodium–glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care. 2015;38:403-411.

16. Wilding JPH, Woo V, Soler NG, et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med. 2012;156:405-415.

17. Rosenstock J, Jelaska A, Frappin G, et al. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliﬂozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care. 2014;37:1815-1823.

18. Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382:941-950.

19. Bailey CJ, Gross JL, Pieters A, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010:375:2223-2233.

20. Bailey CJ, Gross JL, Hennicken D, et al. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med. 2013;11:43.

21. Rosenstock J, Vico M, Wei L, et al. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 2012;35:1473-1478.

22. Merker L, Häring HU, Christiansen AV, et al. Empagliflozin as add-on to metformin in people with type 2 diabetes. Diabet Med. 2015;32:1555-1567.

23. Ridderstråle M, Anderson KR, Zeller C, et al. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2:691-700.

24. Kohan DE, Fioretto P, Tang W, et al. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85:962-971.

25. Invokana (canagliflozin) tablets [product information]. Titusville, NJ: Janssen Pharmaceuticals Inc. Available at: https://www.invokana.com. Accessed March 15, 2013.

26. Lavalle-González FJ, Januszewicz A, Davidson J, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56:2582-2592.

27. Strojek K, Yoon KH, Hruba V, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2011;13:928-938.

28. Leiter LA, Yoon KH, Arias P, et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care. 2015;38:355-364.

29. US Food and Drug Administration. FDA drug safety communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm. Accessed July 11, 2016.

30. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38:1638-1642.

31. US Food and Drug Administration. FDA drug safety communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm461449.htm. Acces-sed July 11, 2016.

32. Canagliflozin, dapagliflozin, empagliflozin. In: RED BOOK [AUHSOP intranet database]. Greenwood Village, CO: Truven Health Analytics; [updated daily]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/BB1644/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/FAF693/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/redbook.ShowProductSearchResults?SearchTerm=JARDIANCE&searchType=redbookProductName&searchTermId=42798&searchContent=%24searchContent&searchFilterAD=filterADActive&searchFilterRepackager=filterExcludeRepackager&searchPattern=%5Ejard. Accessed March 15, 2016.

33. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.

34. CANagliflozin cardioVascular Assessment Study (CANVAS). Available at: http://clinicaltrials.gov/show/NCT01032629. Accessed October 12, 2015.

35. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI 58). Available at: http://clinicaltrials.gov/show/NCT01730534. Accessed October 12, 2015.

36. FDA background document. BMS-512148 NDA 202293. In: Proceedings of the US Food and Drug Administration Endocrinologic & Metabolic Drug Advisory Committee Meeting, 2013. Available at: http://www.fda.gov/downloads/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm378079.pdf. Accessed October 12, 2015.

37. Lin HW, Tseng CH. A review of the relationship between SGLT2 inhibitors and cancer. Int J Endocrinol. 2014;2014:719578.

38. Center for Drug Evaluation and Research. Risk assessment and risk mitigation review(s). July 28, 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/ 204629Orig1s000RiskR.pdf. Accessed September 21, 2015.

39. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab. 2014;16:1016-1027.

40. Barnett AH, Mithal A, Manassie J, et al. Efﬁcacy and safety of empagliﬂozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2: 369-384.

PRACTICE RECOMMENDATIONS

› Consider sodium-glucose cotransporter 2 (SGLT2) inhibitors as second-line agents in patients with type 2 diabetes mellitus who need mild hemoglobin A1c reductions (≤1%) and who would benefit from mild to modest weight and blood pressure reductions. A
› Avoid using SGLT2 inhibitors in patients with a history of recurrent genital mycotic or urinary tract infections. B
› Use SGLT2 inhibitors with caution in patients at risk for volume-related adverse effects (dizziness and hypotension), such as the elderly, those with moderate renal dysfunction, and those taking concomitant diuretic therapy. C

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

CASE 1 › Joe S is a 41-year-old African-American man who comes to your clinic after his employee health screening revealed elevated triglycerides. The patient has a 3-year history of type 2 diabetes mellitus (T2DM); he also has a history of hypertension, gastroesophageal reflux disease, and obstructive sleep apnea. Mr. S tells you he takes metformin 1000 mg twice daily, but stopped taking his glipizide because he didn’t think it was helping his blood sugar. His last hemoglobin (Hb) A1c result was 8.8%, and he is very resistant to starting insulin therapy.

The patient’s other medications include enalapril 10 mg/d, atorvastatin 10 mg/d, and omeprazole 20 mg/d. Mr. S weighs 255.6 lbs (body mass index=34.7), his BP is 140/88 mm Hg, and his heart rate is 82 beats per minute. Laboratory values include: serum creatinine, 1.01 mg/dL; estimated glomerular filtration rate (eGFR) >100 mL/min/1.73 m²; potassium (K), 4.3 mmol/L; serum phosphorous (Phos), 2.8 mg/dL; magnesium (Mg), 1.9 mg/dL; total cholesterol, 167 mg/dL; low-density lipoprotein (LDL), 78 mg/dL; high-density lipoprotein (HDL), 38 mg/dL; and triglycerides, 256 mg/dL.

CASE 2 › Susan R, a 68-year-old Caucasian woman, returns to your clinic for a follow-up visit 3 months after you prescribed dapagliflozin 10 mg/d for her T2DM. Her glucose levels have improved, but she complains of vaginal pruritus and is worried that she has a yeast infection.

You diagnose vulvovaginal candidiasis in this patient and prescribe a single dose of fluconazole 150 mg. After reviewing her laboratory test results, you notice that since starting the dapagliflozin, her HbA1c level has improved slightly from 9.8% to 9.3%, but is still not where it needs to be. Her eGFR is 49 mL/min/1.73 m².

What would you recommend to improve control of these patients’ blood glucose levels?

SIDEBAR
When to consider an SGLT2 inhibitor

Consider therapy with SGLT2 inhibitors in adult patients with T2DM who:^{3-9,13-15,17-24}

have an HbA1c between 7% and 9%
would benefit from weight and/or blood pressure reductions
have metabolic syndrome
have adequate means to pay for the medication (ie, prescription coverage or the ability to afford it).

In addition, consider an SGLT2 inhibitor as initial monotherapy if metformin is contraindicated or not tolerated, or as add-on therapy to metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase IV inhibitors, or insulin.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of agents to enter the T2DM management arena. They act in the proximal renal tubules to decrease the reabsorption of glucose by targeting the SGLT2 transmembrane protein, which reabsorbs about 90% of the body’s glucose.^1,2 The class is currently made up of 3 agents—canagliflozin, dapagliflozin, and empagliflozin—all of which are approved by the US Food and Drug Administration (FDA) for the treatment of T2DM (TABLE 1).²

The American Diabetes Association and the European Association for the Study of Diabetes published updated guidelines for T2DM management in 2015.¹ In addition to lifestyle modifications, the guidelines recommend the use of metformin as first-line therapy unless it is contraindicated or patients are unable to tolerate it (eg, because of gastrointestinal adverse effects). They recommend other pharmacologic therapies as second-line options based on specific patient characteristics. Thus, SGLT2 inhibitors may be used as add-on therapy after metformin, or as a first-line option if metformin is contraindicated or not tolerated. Because the mechanism of action of SGLT2 inhibitors is independent of insulin secretion, these agents may be used at any stage of the diabetes continuum.

SGLT2 agents as monotherapy, or as add-on therapy

All SGLT2 agents have been studied as monotherapy accompanied by diet and exercise and shown to produce HbA1c reductions of 0.34% to 1.11%.^3-6In trials, the effect was similar regardless of study duration (18-104 weeks); generally, higher doses corresponded with larger HbA1c reductions.^3-6

Used as monotherapy, SGLT2 inhibitors produce HbA1c reductions of as much as 1.11%.

SGLT2 inhibitors have also been studied as add-on therapy to several oral agents including metformin, sulfonylureas, thiazolidinediones (TZDs), and the combination of metformin plus sulfonylureas or TZDs or dipeptidyl peptidase IV (DPP-IV) inhibitors.¹ When used in any of these combinations, each SGLT2 agent demonstrated a consistent HbA1c lowering effect of 0.62% to 1.19%.^7-14

Additionally, SGLT2 inhibitors have been studied in combination with insulin therapy (median or mean daily doses >60 units), which yielded further reductions in HbA1c of 0.58% to 1.02% without significant insulin adjustments or an increase in major hypoglycemia events.^15-17 Patients receiving insulin and an SGLT2 inhibitor had lower insulin doses and more weight loss compared to placebo groups.

SGLT2 inhibitors offer additional benefits

Secondary analyses of most studies of SGLT2 inhibitors include changes in BP and weight from baseline as well as minor changes (some positive, some not) in several lipid parameters.^{3-5,7-9,13-15,17-24} In general, these effects do not appear to be dose-dependent (with the exception of canagliflozin and its associated lipid effects²⁵) and are similar among the 3 medications.^{3-5,7-9,13-15,17-24} (For more on who would benefit from these agents, see “When to consider an SGLT2 inhibitor” above.)