What are the sodium‑glucose cotransporter‑2 (SGLT2) inhibitors, their approved agents, typical starting doses, contraindications, and therapeutic role in type 2 diabetes?

SGLT2 Inhibitors: Definition and Clinical Overview

SGLT2 inhibitors are oral antidiabetic medications that block glucose reabsorption in the proximal renal tubules, increasing urinary glucose excretion through an insulin-independent mechanism. 1, 2

Mechanism of Action

SGLT2 inhibitors work by blocking the sodium-glucose cotransporter 2 proteins expressed predominantly in the S1 and S2 segments of the proximal convoluted tubule, where approximately 90% of filtered glucose is normally reabsorbed. 3, 2 This blockade:

• Reduces renal glucose reabsorption and promotes glucosuria when blood glucose exceeds approximately 180 mg/dL (the renal threshold for glucose). 3, 2
• Functions independently of insulin secretion or β-cell function, making them effective across all stages of diabetes. 3, 2
• Decreases oxygen consumption by proximal tubular cells, thereby reducing renal cortical hypoxia. 3
• Increases sodium delivery to the distal tubule, contributing to blood pressure reduction and diuretic effects. 4

FDA-Approved Agents and Dosing

Three SGLT2 inhibitors are FDA-approved for type 2 diabetes in the United States: 1, 2

Empagliflozin (Jardiance)

• Starting dose: 10 mg once daily 5
• May increase to 25 mg once daily 5
• Taken in the morning, with or without food 5

Canagliflozin

• Starting dose: 100 mg once daily 2
• May increase to 300 mg once daily 2

Dapagliflozin

• Starting dose: 10 mg once daily 2, 6

Ertugliflozin is also FDA-approved but less commonly discussed in major guidelines. 2

Clinical Benefits Beyond Glucose Control

Glycemic Efficacy

• Reduce HbA1c by 0.5% to 1.0% 2, 7
• Low intrinsic risk of hypoglycemia when used alone or with metformin 1, 2

Cardiovascular and Renal Protection

• Reduce major adverse cardiovascular events (MACE) and cardiovascular death 2, 7
• Decrease heart failure hospitalizations significantly 1, 2
• Slow progression of diabetic kidney disease and reduce risk of end-stage renal disease 2, 7
• These cardiorenal benefits persist even when glucose-lowering efficacy is lost at lower eGFR levels 3

Metabolic Benefits

• Promote weight loss of 1.5 to 3.5 kg 2, 7
• Lower systolic blood pressure by 3 to 5 mmHg 2, 7
• Improve lipid profiles and reduce hyperuricemia 7

Renal Function Considerations

The glucose-lowering efficacy of SGLT2 inhibitors progressively declines as kidney function deteriorates: 3

• eGFR ≥45 mL/min/1.73 m²: Full glucose-lowering efficacy expected 3
• eGFR 30-45 mL/min/1.73 m²: Substantially reduced glucose-lowering efficacy 3
• eGFR <30 mL/min/1.73 m²: Minimal to no glucose-lowering effect 3

However, cardiovascular and kidney benefits persist across all eGFR categories down to 20 mL/min/1.73 m², making continuation appropriate for cardiorenal protection even when glycemic efficacy is lost. 3

Initiation and Discontinuation Thresholds

• Do not initiate if eGFR is below 45 mL/min/1.73 m² 5
• Discontinue if eGFR falls persistently below 45 mL/min/1.73 m² (per FDA labeling for empagliflozin) 5
• For cardiorenal protection in established users, continuation down to eGFR 20 mL/min/1.73 m² is supported by guidelines 3

Contraindications

SGLT2 inhibitors are contraindicated in: 5

• Severe renal impairment, end-stage renal disease, or dialysis 5
• History of serious hypersensitivity reaction to the specific agent 5
• Type 1 diabetes (not FDA-approved for this indication) 1

Safety Profile and Adverse Effects

Common Adverse Effects (≥5% incidence)

• Urinary tract infections 5, 7
• Female genital mycotic infections 5, 7
• Increased urination due to osmotic diuresis 7

Serious but Rare Adverse Effects

Euglycemic diabetic ketoacidosis (DKA) is the most critical safety concern: 1, 5

• Can occur even with normal or near-normal blood glucose levels 1
• Symptoms include dyspnea, nausea, vomiting, and abdominal pain 1
• Immediately discontinue SGLT2 inhibitor and seek emergency care if DKA is suspected 1, 5
• Risk factors include reduced food intake, severe illness, surgery, alcohol abuse, and insulin dose reduction 5

Volume depletion and hypotension: 5

• Higher risk in elderly patients, those with renal impairment, low baseline blood pressure, or concurrent diuretic use 5
• Assess and correct volume status before initiating therapy in at-risk patients 5

Acute kidney injury: 5

• Consider temporarily discontinuing in settings of reduced oral intake or fluid losses 5
• Monitor renal function during therapy 5

Urosepsis and pyelonephritis: 5

• Evaluate and treat urinary tract infections promptly 5

Agent-specific concerns:

• Canagliflozin has been associated with increased risk of lower extremity amputations and bone fractures 2, 7

Therapeutic Role in Type 2 Diabetes

SGLT2 inhibitors are recommended as preferred second-line agents (after metformin) in patients with: 1

• Established cardiovascular disease 1
• Heart failure 1, 2
• Chronic kidney disease with albuminuria 2
• Need for weight loss 2

They may be used in combination with metformin, sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, or insulin. 6, 8 When combined with insulin or insulin secretagogues, consider dose reduction of these agents to minimize hypoglycemia risk. 5

Common Pitfalls to Avoid

• Do not discontinue SGLT2 inhibitors solely because glucose-lowering efficacy has declined with reduced eGFR—the cardiorenal benefits justify continuation. 3
• Do not mistake the initial reversible eGFR dip (hemodynamic effect) as acute kidney injury requiring discontinuation. 3
• Always educate patients about DKA symptoms and the need to stop the medication during acute illness, fasting, or surgery. 1, 5
• Monitor for volume depletion in elderly patients and those on diuretics. 5
• Screen for and treat genitourinary infections promptly. 5, 7