What is the role of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors in managing type 2 diabetes, particularly in patients with established cardiovascular disease or at high risk of cardiovascular events?

Role of SGLT2 Inhibitors in Type 2 Diabetes Management

SGLT2 inhibitors should be prescribed for patients with type 2 diabetes who have established cardiovascular disease, multiple cardiovascular risk factors, heart failure, or chronic kidney disease, regardless of baseline HbA1c levels, to reduce mortality and improve cardiovascular and renal outcomes. 1

Cardiovascular Benefits of SGLT2 Inhibitors

SGLT2 inhibitors have demonstrated significant cardiovascular benefits in patients with type 2 diabetes:

• For patients with established atherosclerotic cardiovascular disease (ASCVD): SGLT2 inhibitors reduce major adverse cardiovascular events (MACE), heart failure hospitalization, and cardiovascular death 1

• For patients with heart failure: SGLT2 inhibitors are particularly beneficial in heart failure with reduced ejection fraction (HFrEF), reducing hospitalization for heart failure and cardiovascular mortality 1

• For patients with chronic kidney disease (CKD): SGLT2 inhibitors prevent progression of CKD, reduce heart failure hospitalization, MACE, and cardiovascular death 1

Patient Selection Algorithm for SGLT2 Inhibitors

1. First priority: Patients with type 2 diabetes and:

   • Heart failure (particularly HFrEF with EF <45%) 1
   • CKD (eGFR 30 to ≤60 mL/min/1.73m² or UACR >30 mg/g, particularly >300 mg/g) 1

2. Second priority: Patients with type 2 diabetes and established ASCVD:

   • Prior myocardial infarction
   • Ischemic stroke
   • Unstable angina with ECG changes
   • Myocardial ischemia on imaging or stress test
   • Revascularization of coronary, carotid, or peripheral arteries 1

3. Third priority: Patients with type 2 diabetes and multiple risk factors for ASCVD:

   • Age ≥55 years with coronary, carotid, or lower extremity artery stenosis >50%
   • Left ventricular hypertrophy
   • eGFR <60 mL/min/1.73m²
   • Albuminuria 1

Important Clinical Considerations

• Baseline HbA1c: The decision to use SGLT2 inhibitors for cardiovascular and renal protection should be made independently of baseline HbA1c or individualized HbA1c targets 1

• Renal function: SGLT2 inhibitors should not be initiated if eGFR is below 45 mL/min/1.73m² and should be discontinued if eGFR falls persistently below this threshold 2

• Combination therapy: In patients with established ASCVD or multiple risk factors, combined therapy with an SGLT2 inhibitor and a GLP-1 receptor agonist (both with demonstrated cardiovascular benefits) may be considered for additive reduction of cardiovascular and renal events 1

Safety Considerations and Precautions

• Foot ulcers: Patients with foot ulcers or at high risk for amputation should only be treated with SGLT2 inhibitors after careful shared decision-making, with comprehensive education on foot care and amputation prevention 1

• Volume depletion: Assess and correct volume status before initiating SGLT2 inhibitors, particularly in patients with renal impairment, the elderly, those with low systolic blood pressure, and patients on diuretics 2

• Diabetic ketoacidosis (DKA): Monitor for signs and symptoms of ketoacidosis, regardless of blood glucose level. Consider risk factors for DKA before initiating therapy 2

• Genitourinary infections: Monitor for urinary tract infections and genital mycotic infections 2

Comparison with GLP-1 Receptor Agonists

• For patients where atherosclerotic MACE is the primary concern, GLP-1 receptor agonists have the strongest evidence for benefit 1

• For patients with heart failure or CKD, SGLT2 inhibitors have the strongest evidence for benefit 1

• Both drug classes reduce risk of atherosclerotic MACE to a comparable degree in patients with established ASCVD 1

SGLT2 inhibitors represent a significant advancement in type 2 diabetes management, offering benefits beyond glycemic control by reducing cardiovascular and renal morbidity and mortality. Their use should be prioritized in patients with established cardiovascular disease, heart failure, or chronic kidney disease, regardless of baseline glycemic control.