What are the indications for Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors?

SGLT2 Inhibitor Indications

SGLT2 inhibitors are indicated for glycemic control in type 2 diabetes, cardiovascular risk reduction in patients with established cardiovascular disease, heart failure management (particularly HFrEF), and chronic kidney disease progression prevention, with specific indications varying by agent. 1

FDA-Approved Indications by Agent

Canagliflozin

• Glycemic control: Adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus 2
• Cardiovascular protection: Reduce the risk of major adverse cardiovascular events (MI, stroke, or CV death) in adults with type 2 diabetes and established cardiovascular disease 1, 2
• Renal protection: Reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes and diabetic nephropathy with albuminuria 1, 2

Dapagliflozin

• Chronic kidney disease: Reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression 3
• Heart failure: Reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure (with or without reduced ejection fraction) 1, 3
• Cardiovascular protection in diabetes: Reduce the risk of hospitalization for heart failure in adults with type 2 diabetes and either established cardiovascular disease or multiple cardiovascular risk factors 1, 3
• Glycemic control: Adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus 3

Empagliflozin

• Glycemic control: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus 1, 4
• Cardiovascular protection: Reduce the risk of cardiovascular death in adult patients with type 2 diabetes and established cardiovascular disease 1, 4

Guideline-Based Clinical Indications

Type 2 Diabetes with Established Atherosclerotic Cardiovascular Disease

• SGLT2 inhibitors are strongly recommended for patients with type 2 diabetes and established ASCVD (prior MI, ischemic stroke, unstable angina with ECG changes, myocardial ischemia on imaging, or revascularization of coronary, carotid, or peripheral arteries) to reduce MACE, hospitalization for heart failure, and cardiovascular death. 1
• The decision to treat should be made independently of baseline HbA1c or individualized HbA1c target 1

Type 2 Diabetes with Heart Failure

• SGLT2 inhibitors are recommended in patients with type 2 diabetes and heart failure, particularly those with HFrEF (EF <45%), to reduce hospitalization for heart failure, MACE, and cardiovascular death. 1
• Dapagliflozin demonstrated a 26% reduction in worsening heart failure or cardiovascular death in the DAPA-HF trial 1

Type 2 Diabetes with Chronic Kidney Disease

• SGLT2 inhibitors are recommended to prevent the progression of CKD, hospitalization for heart failure, MACE, and cardiovascular death in patients with type 2 diabetes and CKD (eGFR 30 to ≤60 mL/min/1.73 m² or UACR >30 mg/g, particularly UACR >300 mg/g). 1
• The level of evidence for benefit is greatest for SGLT2 inhibitors in patients with HFrEF or CKD, with or without established atherosclerotic CVD 1

High-Risk Type 2 Diabetes Without Established CVD

• SGLT2 inhibitors can be considered in patients aged 55 years or older with coronary, carotid, or lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR <60 mL/min/1.73 m², or albuminuria 1
• Patients at very high or high cardiovascular risk should be treated with an SGLT2 inhibitor or GLP-1 RA (Class IA recommendation per ESC guidelines) 1

Heart Failure Without Diabetes

• Dapagliflozin is indicated to reduce cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure, regardless of diabetes status 3

Chronic Kidney Disease Without Diabetes

• Dapagliflozin is indicated to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression, regardless of diabetes status 3

Important Limitations of Use

Contraindications for Glycemic Control

• Not recommended for glycemic control in type 1 diabetes mellitus 2, 4, 3
• Not recommended for glycemic control in type 2 diabetes with eGFR <45 mL/min/1.73 m² (dapagliflozin, empagliflozin) or eGFR <30 mL/min/1.73 m² (canagliflozin), as they are likely ineffective based on mechanism of action 1, 3

Special Populations Requiring Caution

• Patients with foot ulcers or at high risk for amputation should only be treated with SGLT2 inhibitors after careful shared decision-making around risks and benefits with comprehensive education on foot care and amputation prevention 1
• Use with caution in patients with prior amputation, severe peripheral neuropathy, severe peripheral vascular disease, or active diabetic foot ulcers or soft tissue infections 1

Conditions Where SGLT2 Inhibitors Are Not Expected to Be Effective

• Not recommended for chronic kidney disease in patients with polycystic kidney disease or patients requiring or with recent history of immunosuppressive therapy for kidney disease 3

Mechanism-Based Benefits Beyond Glycemic Control

• SGLT2 inhibitors provide cardiovascular and renal benefits that are out of proportion to their glucose-lowering effects and persist even when glycemic efficacy is lost at lower eGFR levels 5, 6
• Benefits include osmotic diuresis, natriuresis, reduced sodium reabsorption, and hemodynamic effects that contribute to cardiorenal protection 7
• Weight loss of 2-3 kg and blood pressure reduction of 3-5 mmHg are consistently observed 7, 8, 9