Sodium-Glucose Cotransporter 2 Inhibitors: An Overview

Essie Samuel, PharmD, BCPS; Jiehyun Lee, PharmD, BCACP, CACP


US Pharmacist. 2017;42(10):42-47. 

In This Article

Safety Concerns

The most common adverse reactions associated with SGLT2 inhibitors are polyuria and genitourinary infections. A high concentration of glucose in filtered urine causes osmotic diuresis, which leads to polyuria and contributes to volume depletion. It is important to recognize that uncontrolled T2DM patients may present with polyuria.[4,19,20]

Postmarketing data include reports of serious urinary tract infections (UTIs) with SGLT2 inhibitors, including urosepsis and pyelonephritis requiring hospitalization. Consequently, the FDA revised SGLT2 inhibitor labeling to warn about the risk of serious UTIs. In addition, patients taking SGLT2 inhibitors, especially females and uncircumcised males, are at increased risk for genital mycotic infections, likely because of the high glucose concentration in excreted urine. Signs and symptoms of UTIs and genital infections should be evaluated and treated promptly.[3,4,19,20]

SGLT2 inhibitors cause intravascular volume depletion. As a result, symptomatic hypotension can occur, especially in patients with reduced renal function (Table 2), elderly patients, patients taking diuretics or medications that interfere with the renin-angiotensin-aldosterone system (RAAS), and patients with low SBP. Volume status should be assessed prior to and during SGLT2 inhibitor therapy.[4,19,20]

Volume depletion also may lead to renal impairment. Acute kidney injury (AKI) requiring hospitalization and dialysis has been reported in patients taking SGLT2 inhibitors. Based on these reports, the FDA has strengthened the existing warning about the risk of AKI with SGLT2 inhibitor use. In addition, concomitant use of medications that interfere with potassium excretion or the RAAS can put patients at risk for developing hyperkalemia, especially in the case of concurrent renal impairment. Patients with hypovolemia, chronic renal insufficiency or congestive heart failure or who are taking concomitant nephrotoxic medications should not be started on SGLT2 inhibitors. Renal function should be evaluated before SGLT2 inhibitors are initiated and periodically during use.[4,15,19,20]

Reports of ketoacidosis, including fatal cases, have surfaced in postmarketing surveillance of SGLT2 inhibitors. Unlike typical diabetic ketoacidosis, SGLT2 inhibitor–associated ketoacidosis presents with euglycemia or only modestly elevated BG concentrations (often <250 mg/dL), which causes delayed detection and treatment of ketoacidosis. Clinicians should keep this in mind and discontinue SGLT2 inhibitors immediately if ketoacidosis is suspected. It may be necessary to temporarily withhold SGLT2 inhibitors in clinical situations—such as prolonged fasting due to acute illness or surgery—that are known to predispose patients to ketoacidosis.[4,19,20]

SGLT2 inhibitors increase the risk of hypoglycemia when they are used concurrently with insulin and insulin secretagogues. To minimize the risk of hypoglycemia, the doses of insulin and insulin secretagogue should be reduced upon initiation of SGLT2 inhibitors.[4,19,20]

Postmarketing reports on canagliflozin prompted the FDA to strengthen the warning for increased risk of bone fractures.[21] However, a new meta-analysis including all three SGLT2 inhibitors found that the increased risk of bone fractures associated with SGLT2 inhibitors was not significant. Long-term RCTs and real-world data are warranted for more definitive conclusions.[22]

The FDA recently issued a new warning that canagliflozin increases the risk of leg and foot amputations. Patients should be instructed to notify their providers of any new pain or tenderness, sores or ulcers, or infections in the legs or feet. Healthcare professionals should evaluate predisposing factors such as history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.[23]