What are the typical doses of second-line oral hypoglycemic agents (OHAs), including sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists?

Second-Line Oral Hypoglycemic Agent Doses

For patients with type 2 diabetes not achieving glycemic control on metformin alone, sulfonylureas remain the WHO-recommended second-line agent in resource-limited settings, while SGLT2 inhibitors and GLP-1 receptor agonists are preferred in patients with cardiovascular disease, heart failure, or chronic kidney disease. 1

Sulfonylureas (Second-Generation)

Glimepiride:

• Starting dose: 1-2 mg once daily with breakfast or first main meal 2
• Patients at high risk for hypoglycemia (elderly, renal impairment): start at 1 mg daily 2
• Titration: increase by 1-2 mg every 1-2 weeks based on glycemic response 2
• Maximum dose: 8 mg once daily 2

Glipizide:

• Starting dose: 2.5 mg once daily, titrate slowly to avoid hypoglycemia 1
• Lower hypoglycemia risk compared to glyburide 1

Glyburide:

• Not recommended in patients with renal impairment 1

DPP-4 Inhibitors

Sitagliptin:

• eGFR ≥45 mL/min/1.73 m²: standard dosing 1
• eGFR 30-44: maximum 50 mg daily 1
• eGFR 15-29: maximum 25 mg daily 1

Linagliptin:

• No dose adjustment required for any level of renal function 1

Saxagliptin:

• eGFR <45 mL/min/1.73 m²: maximum 2.5 mg daily 1

Alogliptin:

• eGFR 30-44: maximum 12.5 mg daily 1
• eGFR 15-29: maximum 6.25 mg daily 1

SGLT2 Inhibitors

Empagliflozin:

• Standard dose: 10 mg once daily 1
• May increase to 25 mg daily if needed 1
• eGFR ≥45: no dose adjustment required 1
• eGFR <45: do not initiate; discontinue if eGFR persistently below 45 1
• Note: FDA labeling differs from guideline recommendations; KDIGO recommends continuation at eGFR ≥20 for cardiovascular and kidney benefits 1

Canagliflozin:

• Standard dose: 100 mg once daily 1
• May increase to 300 mg daily if eGFR ≥60 mL/min/1.73 m² 1
• eGFR 45-59: do not exceed 100 mg daily 1
• eGFR 30-44: maximum 100 mg daily; initiation not recommended but may continue for cardiovascular/kidney benefit 1

Dapagliflozin:

• Standard dose: 10 mg once daily 1
• eGFR 25-44: 10 mg daily (FDA-approved) 1
• eGFR <25: initiation not recommended; may continue if tolerated for cardiovascular/kidney benefit until dialysis 1

Ertugliflozin:

• Not recommended with eGFR <45 mL/min/1.73 m² 1

GLP-1 Receptor Agonists

Dulaglutide:

• No dose adjustment required for renal impairment 1
• Has demonstrated cardiovascular benefit in outcomes trials 1

Liraglutide:

• No dose adjustment required for renal impairment 1
• Has demonstrated cardiovascular benefit in outcomes trials 1

Semaglutide (injectable):

• No dose adjustment required for renal impairment 1
• Has demonstrated cardiovascular benefit in outcomes trials 1

Exenatide:

• Use caution when initiating or increasing dose with eGFR 30-44 1
• Avoid once-weekly formulation with eGFR 30-44 1
• Not recommended with eGFR <30 1

Lixisenatide:

• No dose adjustment required for eGFR 30-44 1
• Not recommended with eGFR <30 1

Key Clinical Considerations

Patient Selection by Comorbidity:

• Established ASCVD or high cardiovascular risk: prioritize SGLT2 inhibitor or GLP-1 receptor agonist with proven cardiovascular benefit 1
• Heart failure: prioritize SGLT2 inhibitor 1
• CKD with eGFR ≥30: SGLT2 inhibitor recommended as first-line with metformin 1
• CKD with eGFR <30: GLP-1 receptor agonist preferred; insulin if needed 1

Hypoglycemia Risk:

• DPP-4 inhibitors and SGLT2 inhibitors have significantly lower hypoglycemia risk than sulfonylureas (OR 0.14 and 0.09 respectively) 1
• Sulfonylureas carry moderate hypoglycemia risk, especially in elderly and those with renal impairment 1, 2

Weight Effects:

• SGLT2 inhibitors and GLP-1 receptor agonists promote weight loss 1
• DPP-4 inhibitors are weight neutral 1
• Sulfonylureas cause modest weight gain 1

Cost Considerations:

• In resource-limited settings, sulfonylureas remain the WHO-recommended second-line choice due to significantly lower cost compared to newer agents 1
• DPP-4 inhibitors and SGLT2 inhibitors cost several times more than human insulin in most markets 1