What are the recommended doses of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors and GLP-1 (Glucagon-Like Peptide-1) agonists for a patient with type 2 diabetes?

SGLT2 Inhibitors and GLP-1 Agonists: Practical Dosing Guide

SGLT2 Inhibitors in Clinical Practice

The three SGLT2 inhibitors with proven cardiovascular and renal benefits are empagliflozin, canagliflozin, and dapagliflozin, each with specific dosing based on indication and renal function. 1

Empagliflozin (Jardiance)

• Starting dose: 10 mg orally once daily 1, 2
• Maximum dose: 25 mg orally once daily 1, 2
• Renal dosing:
  • eGFR ≥45 mL/min/1.73 m²: No dose adjustment required 1
  • eGFR <45 mL/min/1.73 m²: Do not initiate; discontinue if eGFR persistently falls below 45 mL/min/1.73 m² 1, 2
• Key point: Both 10 mg and 25 mg doses showed similar cardiovascular benefits in EMPA-REG OUTCOME trial 1

Canagliflozin (Invokana)

• Starting dose: 100 mg orally once daily, taken before first meal 1, 3
• Maximum dose: 300 mg orally once daily (only if eGFR ≥60 mL/min/1.73 m²) 1, 3
• Renal dosing:
  • eGFR ≥60 mL/min/1.73 m²: No dose adjustment; may increase to 300 mg daily if additional glycemic control needed 1
  • eGFR 45-59 mL/min/1.73 m²: Maximum 100 mg daily 1
  • eGFR <45 mL/min/1.73 m²: Not recommended for glycemic control 3
  • eGFR <30 mL/min/1.73 m²: Not recommended 1
• Special consideration: Canagliflozin 300 mg ranked highest for HbA1c and weight reduction in meta-analysis 4

Dapagliflozin (Farxiga)

• Standard dose: 10 mg orally once daily for all indications (heart failure, CKD, diabetes) 1, 5
• Glycemic control: May start at 5 mg daily, increase to 10 mg if needed 5
• Renal dosing:
  • eGFR ≥45 mL/min/1.73 m²: No adjustment for glycemic control 5
  • eGFR 25-44 mL/min/1.73 m²: 10 mg daily for cardiovascular/renal protection (not for glycemic control) 1, 5
  • eGFR <25 mL/min/1.73 m²: Do not initiate; may continue 10 mg if already on therapy 5
  • eGFR ≥20 mL/min/1.73 m²: Can be initiated per 2022 KDIGO guidelines for CKD protection 1

Critical SGLT2 Inhibitor Considerations

• Cardiovascular and renal benefits persist even when glycemic efficacy is lost at lower eGFR levels 1, 5
• Withhold at least 3 days before major surgery or prolonged fasting to prevent postoperative ketoacidosis 1, 5
• Hold during acute illness (fever, vomiting, diarrhea, reduced oral intake) to prevent euglycemic DKA and volume depletion 5
• Monitor for genital mycotic infections (6% incidence vs 1% placebo) and urinary tract infections 1, 5

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GLP-1 Receptor Agonists in Clinical Practice

GLP-1 receptor agonists with proven cardiovascular benefits include liraglutide, semaglutide (subcutaneous and oral), dulaglutide, and exenatide extended-release, with dosing varying by agent and formulation. 1

Liraglutide (Victoza)

• Starting dose: 0.6 mg subcutaneously once daily 1
• Titration: Increase to 1.2 mg after 1 week 1
• Maximum dose: 1.8 mg once daily (or maximum tolerated dose) 1
• Renal dosing: No adjustment required; can be used with eGFR >30 mL/min/1.73 m² 1
• Cardiovascular benefit: Reduced CV death by 22% in LEADER trial 1

Semaglutide Subcutaneous (Ozempic)

• Starting dose: 0.25 mg subcutaneously once weekly (not therapeutic, for tolerability) 1
• Titration: Increase to 0.5 mg weekly after 4 weeks 1
• Maximum dose: 1 mg once weekly (may increase to 2 mg if additional control needed) 1
• Renal dosing: No adjustment required 1
• Cardiovascular benefit: Reduced 3-point MACE by 26% in SUSTAIN-6 trial 1

Semaglutide Oral (Rybelsus)

• Starting dose: 3 mg orally once daily for 30 days 1
• Titration: Increase to 7 mg daily, then may increase to 14 mg daily 1
• Maximum dose: 14 mg once daily (or maximum tolerated dose) 1
• Administration: Take on empty stomach with ≤4 oz water, wait 30 minutes before eating 1
• Renal dosing: No adjustment required 1

Dulaglutide (Trulicity)

• Starting dose: 0.75 mg subcutaneously once weekly 1
• Standard dose: 1.5 mg once weekly 1
• Maximum dose: May increase to 3 mg or 4.5 mg weekly if additional glycemic control needed 1
• Renal dosing: No adjustment required 1
• Cardiovascular benefit: Reduced 3-point MACE by 12% in REWIND trial, including 68.5% without established CVD 1

Exenatide (Byetta - twice daily)

• Starting dose: 5 mcg subcutaneously twice daily within 60 minutes before morning and evening meals 1
• Maximum dose: 10 mcg twice daily after 1 month 1
• Renal dosing: Use with caution if eGFR 30-50 mL/min/1.73 m²; not recommended if eGFR <30 mL/min/1.73 m² 1

Exenatide Extended-Release (Bydureon)

• Dose: 2 mg subcutaneously once weekly 1
• Renal dosing: Similar to twice-daily formulation 1
• Cardiovascular outcome: Neutral effect in EXSCEL trial 1

Lixisenatide (Adlyxin)

• Starting dose: 10 mcg subcutaneously once daily within 60 minutes before first meal 1
• Maximum dose: 20 mcg once daily (increase on day 15) 1
• Cardiovascular outcome: Neutral effect in ELIXA trial 1

Critical GLP-1 Receptor Agonist Considerations

• Preferred for patients with established ASCVD where MACE reduction is the primary goal 1
• Can be used interchangeably with SGLT2 inhibitors in patients with CKD who are SGLT2i-intolerant 1
• No renal dose adjustment required for most agents (except exenatide) 1
• Reduce sulfonylurea or insulin doses by ~20% when initiating to prevent hypoglycemia 1
• Monitor for pancreatitis in patients with known history; contraindicated in medullary thyroid cancer history 6

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Clinical Decision Algorithm

For Type 2 Diabetes with Established ASCVD

Prioritize GLP-1 receptor agonist (liraglutide, semaglutide, or dulaglutide) for maximum MACE reduction 1

For Type 2 Diabetes with Heart Failure (EF <45%)

Prioritize SGLT2 inhibitor (empagliflozin, canagliflozin, or dapagliflozin) for heart failure hospitalization reduction 1

For Type 2 Diabetes with CKD (eGFR 25-60 or albuminuria ≥200 mg/g)

Prioritize SGLT2 inhibitor as first-line for kidney disease progression prevention 1

• If SGLT2i contraindicated or not tolerated, use GLP-1 receptor agonist 1

For Type 2 Diabetes with Multiple Risk Factors

Consider combination therapy with both SGLT2 inhibitor and GLP-1 receptor agonist for complementary mechanisms and enhanced efficacy 7, 8

Independent of HbA1c Target

Both drug classes should be considered independently of baseline HbA1c or individualized glycemic targets in high-risk patients 1