› 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?
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%.3-6 In trials, the effect was similar regardless of study duration (18-104 weeks); generally, higher doses corresponded with larger HbA1c reductions.3-6
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.)