What is the role of SGLT2 (sodium-glucose cotransporter 2) inhibitors in treating type 2 diabetes?

Role of SGLT2 Inhibitors in Type 2 Diabetes Management

SGLT2 inhibitors should be considered first-line therapy for type 2 diabetes patients with established cardiovascular disease, heart failure, or chronic kidney disease, regardless of baseline HbA1c levels, due to their proven benefits in reducing cardiovascular events, heart failure hospitalizations, and CKD progression.

Mechanism of Action

SGLT2 inhibitors work through a unique mechanism:

• Block renal glucose reabsorption in the proximal tubule of the kidneys
• Increase urinary glucose excretion (glucosuria)
• Lower blood glucose levels independent of insulin action
• Provide additional cardiorenal benefits beyond glycemic control

Glycemic Efficacy

• Reduce HbA1c by approximately 0.6-0.8% (6-8 mmol/mol) 1
• Effective as monotherapy or in combination with other diabetes medications
• Low risk of hypoglycemia when used alone (increases when combined with insulin or sulfonylureas)
• Glycemic benefits are reduced when eGFR <45 mL/min/1.73 m² 2

Cardiovascular Benefits

SGLT2 inhibitors have demonstrated significant cardiovascular benefits in multiple large trials:

• Established ASCVD: Reduce major adverse cardiovascular events (MACE) and cardiovascular death 2
• Heart Failure: Particularly beneficial in patients with heart failure with reduced ejection fraction (HFrEF) 2
• Recommendation: For patients with type 2 diabetes and heart failure (with either reduced or preserved ejection fraction), an SGLT2 inhibitor is recommended for glycemic management and prevention of heart failure hospitalizations 2

Renal Benefits

SGLT2 inhibitors provide significant renal protection:

• Reduce progression of chronic kidney disease 2
• Decrease risk of end-stage kidney disease 3
• Lower risk of doubling of serum creatinine 2
• Reduce albuminuria 2
• Strong recommendation: For adults at high or very high risk of CKD progression and complications, SGLT2 inhibitors are strongly recommended regardless of diabetes status 2

Patient Selection Algorithm

First-line use of SGLT2 inhibitors is recommended for:

1. Patients with established cardiovascular disease

   • Prior myocardial infarction
   • Ischemic stroke
   • Unstable angina with ECG changes
   • Myocardial ischemia on imaging/stress test
   • Coronary, carotid, or peripheral revascularization

2. Patients with heart failure (especially HFrEF with EF <45%)

   • To reduce heart failure hospitalizations
   • To reduce cardiovascular death

3. Patients with CKD

   • eGFR 20-60 mL/min/1.73 m²
   • Albuminuria (especially UACR >300 mg/g)
   • To prevent CKD progression

4. High-risk patients without established CVD who are:

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

Dosing and Monitoring

• Renal function assessment:

  • Do not initiate if eGFR <45 mL/min/1.73 m² 2
  • Discontinue if eGFR falls persistently below 45 mL/min/1.73 m² 4
  • Monitor renal function regularly during therapy

• Medication-taking behavior: Reevaluate every 3-6 months and adjust as needed 2

Adverse Effects and Precautions

• Genitourinary tract infections: Monitor and treat as appropriate
• Volume depletion/hypotension: Assess volume status before initiating, especially in elderly patients or those on diuretics
• Diabetic ketoacidosis (DKA): Rare but serious; can occur with normal blood glucose levels
• Foot ulcers/amputation risk: Careful shared decision-making and comprehensive foot care education for high-risk patients 2

Combination Therapy Considerations

• Consider early combination therapy to achieve glycemic targets faster 2
• Can be combined with metformin, GLP-1 receptor agonists, DPP-4 inhibitors, or insulin
• When combining with insulin or sulfonylureas, consider dose reduction of these agents to minimize hypoglycemia risk 2

Clinical Pearl

The decision to treat with an SGLT2 inhibitor to reduce cardiovascular events, heart failure hospitalizations, or CKD progression should be considered independently of baseline HbA1c or individualized HbA1c target in appropriate high-risk patients 2. This represents a paradigm shift in diabetes management, focusing on cardiorenal outcomes rather than solely on glycemic control.