What are the doses, indications, and durations of thiazolidinediones (TZDs) and Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors for patients with type 2 diabetes?

Thiazolidinediones and SGLT2 Inhibitors: Doses, Indications, and Durations for Type 2 Diabetes

Both thiazolidinediones (TZDs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors are effective treatment options for type 2 diabetes, with SGLT2 inhibitors offering additional cardiovascular and renal benefits while pioglitazone remains the only widely used TZD due to safety concerns with other agents in this class. 1, 2

Thiazolidinediones (TZDs)

Pioglitazone

• Dosing: No dose adjustment required for renal impairment; standard dosing is 15-45 mg once daily 1
• Indications: Glucose lowering in type 2 diabetes 2
• Duration: Long-term therapy; no specific duration limitations 2
• Renal Considerations: Can be used across all stages of CKD without dose adjustment 1

Key Considerations for TZDs

• Pioglitazone is the only TZD still widely used clinically, as rosiglitazone has been severely restricted due to cardiovascular concerns and troglitazone was withdrawn due to liver toxicity 2
• Approximately 25-40% of patients currently treated with TZDs have evidence of heart failure and should not be candidates for this therapy 3
• Common side effects include fluid retention, weight gain, and increased risk of heart failure 3
• TZDs should be avoided in patients with heart failure or at high risk for heart failure 3

SGLT2 Inhibitors

Canagliflozin

• Dosing: 100 mg once daily before first meal, may titrate to 300 mg if needed 1
• Indications:
  • Glucose lowering in type 2 diabetes
  • Reduce risk of kidney failure, doubling of serum creatinine, CV death, and hospitalization for heart failure in adults with T2D and diabetic kidney disease with albuminuria >300 mg/day
  • Reduce risk of CV death, nonfatal MI, and stroke in adults with T2D and established CVD 1
• Renal Adjustments:
  • eGFR >60: No dose adjustment
  • eGFR 30-60: 100 mg/day
  • eGFR <30 with albuminuria >300 mg/day: 100 mg/day
  • eGFR <30 without albuminuria: Initiation not recommended 1

Dapagliflozin

• Dosing: 5-10 mg once daily 1
• Indications:
  • Glucose lowering in type 2 diabetes
  • Risk reduction of sustained eGFR decline, kidney failure, CV death, and hospitalization for heart failure in adults with CKD
  • Risk reduction of CV death and hospitalization for heart failure in adults with HFrEF
  • Risk reduction of hospitalization for heart failure in adults with T2D and established CVD or multiple CV risk factors 1
• Renal Adjustments:
  • Not recommended for glucose lowering in T2D patients with eGFR <45
  • For HF or CKD indications with eGFR 25 to <45: 10 mg
  • If eGFR <25, initiation not recommended; may continue 10 mg in patients with HF and CKD
  • Contraindicated in dialysis 1

Empagliflozin

• Dosing: 10 mg once daily, may titrate to 25 mg if needed 1
• Indications:
  • Glucose lowering in type 2 diabetes
  • Reduce risk of CV death in patients with T2D and CVD
  • Reduce risk of CV death plus hospitalization for HF in adults with HFrEF 1
• Renal Adjustments:
  • Not recommended for glucose lowering in T2D patients with eGFR <30
  • Use not recommended with eGFR <45 ml/min/1.73 m² for glycemic control
  • Initiation not recommended with eGFR <30 ml/min/1.73 m² for glycemic control or <20 ml/min/1.73 m² for HF 1

Ertugliflozin

• Dosing: Start at 3 mg once daily, may increase to 7 mg and then 14 mg daily 1
• Indications: Glucose lowering in type 2 diabetes 1
• Renal Adjustments: Use not recommended with eGFR <45 ml/min/1.73 m² 1

Monitoring and Safety Considerations

For SGLT2 Inhibitors

• Monitor for genital mycotic infections; counsel on genital hygiene 1
• Watch for volume depletion; consider reducing diuretic doses in high-risk patients 1
• Risk of diabetic ketoacidosis; educate patients about signs/symptoms 1
• Adjust background glucose-lowering agents (insulin or sulfonylureas) to prevent hypoglycemia 1
• Institute sick day protocols; advise holding medication during acute illness 1

For Thiazolidinediones

• Monitor for fluid retention and weight gain 2, 3
• Avoid use in patients with heart failure or at high risk for heart failure 3
• No dose adjustment required in renal impairment 1

Treatment Duration

• Both medication classes are typically prescribed for long-term use without specific duration limitations 1, 2
• SGLT2 inhibitors can be continued even if eGFR falls below initiation thresholds, unless not tolerated or kidney replacement therapy is initiated 1

Common Pitfalls

• Failing to recognize heart failure contraindications with TZDs 3
• Not adjusting doses of SGLT2 inhibitors based on renal function 1
• Not educating patients about diabetic ketoacidosis risk with SGLT2 inhibitors 1
• Not considering the cardiovascular and renal benefits of SGLT2 inhibitors when selecting therapy 1