Sodium-glucose co-transporter 2 inhibitors for the treatment of type 2 diabetes mellitus
- Anthony DeSantis, MD
Anthony DeSantis, MD
- Clinical Professor of Medicine
- University of Washington Medical School
Current treatments for type 2 diabetes have centered on increasing insulin availability (either through direct insulin administration or through agents that promote insulin secretion), improving sensitivity to insulin, delaying the delivery and absorption of carbohydrate from the gastrointestinal tract, or increasing urinary glucose excretion. Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce blood glucose by increasing urinary glucose excretion.
This topic will review the mechanism of action and therapeutic utility of SGLT2 inhibitors for the treatment of type 2 diabetes mellitus. A general discussion of the initial management of blood glucose and the management of persistent hyperglycemia in adults with type 2 diabetes is presented separately. (See "Initial management of blood glucose in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus".)
MECHANISM OF ACTION
The SGLT2 is expressed in the proximal tubule and mediates reabsorption of approximately 90 percent of the filtered glucose load. SGLT2 inhibitors promote the renal excretion of glucose and thereby modestly lower elevated blood glucose levels in patients with type 2 diabetes. The ability to lower blood glucose and glycated hemoglobin (A1C) levels is limited by the filtered load of glucose and the osmotic diuresis that is caused by this therapy. Moreover, although the currently developed SGLT2 inhibitors almost completely block proximal tubular glucose reabsorption, the measured inhibition is less than 50 percent based on urine glucose excretion.
The glucose-lowering effect is independent of insulin (beta cell function and insulin sensitivity). Thus, they do not usually cause hypoglycemia in the absence of therapies that otherwise cause hypoglycemia. SGLT2 inhibitors decrease blood pressure and weight .
SGLT2 inhibitors are relatively weak glucose-lowering agents, with mean reductions in A1C compared with placebo ranging between 0.4 to 1.1 percent depending on baseline level of hyperglycemia. They have been studied as monotherapy and in combination with metformin, sulfonylureas, pioglitazone, sitagliptin, and insulin [1-5]. Dapagliflozin, canagliflozin, and empagliflozin are available in Europe and the United States [6-8], and other SGLT2 inhibitors are in development.
- Clar C, Gill JA, Court R, Waugh N. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open 2012; 2.
- Musso G, Gambino R, Cassader M, Pagano G. A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann Med 2012; 44:375.
- Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013; 15:372.
- 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.
- Ridderstråle M, Andersen 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.
- US Food and Drug Administration. FDA News Release: FDA approves Invokana to treat type 2 diabetes, March 2013. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm (Accessed on April 10, 2013).
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm380829.htm (Accessed on January 09, 2014).
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm407637.htm (Accessed on August 06, 2014).
- Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013; 159:262.
- Sun YN, Zhou Y, Chen X, et al. The efficacy of dapagliflozin combined with hypoglycaemic drugs in treating type 2 diabetes mellitus: meta-analysis of randomised controlled trials. BMJ Open 2014; 4:e004619.
- Liu XY, Zhang N, Chen R, et al. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: a meta-analysis of randomized controlled trials for 1 to 2years. J Diabetes Complications 2015; 29:1295.
- Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011; 34:2015.
- Wilding JP, 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.
- 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.
- 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.
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117.
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377:644.
- Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016; 375:323.
- Foote C, Perkovic V, Neal B. Effects of SGLT2 inhibitors on cardiovascular outcomes. Diab Vasc Dis Res 2012; 9:117.
- Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis. JAMA 2016; 316:313.
- Zaccardi F, Webb DR, Htike ZZ, et al. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab 2016; 18:783.
- Shyangdan DS, Uthman OA, Waugh N. SGLT-2 receptor inhibitors for treating patients with type 2 diabetes mellitus: a systematic review and network meta-analysis. BMJ Open 2016; 6:e009417.
- National Institutes of Health - DailyMed: Invokana http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3#section-8.6 (Accessed on May 22, 2013).
- Canaglifozin (Invokana) for type 2 diabetes. Med Lett Drugs Ther 2013; 55:37.
- http://www.invokanahcp.com/prescribing-information.pdf (Accessed on May 22, 2013).
- http://ec.europa.eu/health/documents/community-register/2012/20121112124487/anx_124487_en.pdf (Accessed on May 22, 2013).
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204629s000lbl.pdf (Accessed on September 18, 2015).
- Nyirjesy P, Zhao Y, Ways K, Usiskin K. Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor. Curr Med Res Opin 2012; 28:1173.
- 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.
- http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm475553.htm (Accessed on December 10, 2015).
- Rosenwasser RF, Sultan S, Sutton D, et al. SGLT-2 inhibitors and their potential in the treatment of diabetes. Diabetes Metab Syndr Obes 2013; 6:453.
- Weir MR, Januszewicz A, Gilbert RE, et al. Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus. J Clin Hypertens (Greenwich) 2014; 16:875.
- https://www.invokanahcp.com/prescribing-information.pdf (Accessed on September 16, 2015).
- Invokana (canagliflozin). US FDA approved product information; Titusville, NJ: Janssen Pharmaceuticals, Inc; May 2016. (Available online at www.accessdata.fda.gov/drugsatfda_docs/label/2016/204042s015s019lbl.pdf (accessed May 31, 2016)).
- http://www.fda.gov/Drugs/DrugSafety/ucm505860.htm (Accessed on June 17, 2016).
- http://www.fda.gov/Drugs/DrugSafety/ucm461449.htm (Accessed on September 14, 2015).
- Watts NB, Bilezikian JP, Usiskin K, et al. Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus. J Clin Endocrinol Metab 2016; 101:157.
- Alba M, Xie J, Fung A, Desai M. The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on mineral metabolism and bone in patients with type 2 diabetes mellitus. Curr Med Res Opin 2016; 32:1375.
- Bilezikian JP, Watts NB, Usiskin K, et al. Evaluation of Bone Mineral Density and Bone Biomarkers in Patients With Type 2 Diabetes Treated With Canagliflozin. J Clin Endocrinol Metab 2016; 101:44.
- Tang HL, Li DD, Zhang JJ, et al. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab 2016; 18:1199.
- Peters AL, Buschur EO, Buse JB, et al. Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care 2015; 38:1687.
- Palmer BF, Clegg DJ, Taylor SI, Weir MR. Diabetic ketoacidosis, sodium glucose transporter-2 inhibitors and the kidney. J Diabetes Complications 2016; 30:1162.
- Fralick M, Schneeweiss S, Patorno E. Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor. N Engl J Med 2017; 376:2300.
- http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm (Accessed on June 18, 2015).
- Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. J Clin Endocrinol Metab 2015; 100:2849.
- Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial. Am Heart J 2013; 166:217.
- Neal B, Perkovic V, Matthews DR, et al. Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): A randomized, placebo-controlled trial. Diabetes Obes Metab 2017; 19:387.
- https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm (Accessed on May 17, 2017).
- https://www.fda.gov/downloads/Drugs/DrugSafety/UCM558427.pdf (Accessed on May 17, 2017).
- MECHANISM OF ACTION
- GLYCEMIC EFFICACY
- CARDIOVASCULAR EFFECTS
- MICROVASCULAR OUTCOMES
- WEIGHT LOSS
- PRACTICAL MANAGEMENT ISSUES
- Contraindications and precautions
- Choice of therapy
- Pretreatment evaluation
- ADVERSE EFFECTS
- Genitourinary tract
- Acute kidney injury
- Bone fracture
- Diabetic ketoacidosis
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS