What are the dosages for metformin (Metformin) plus SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors, such as canagliflozin (Canagliflozin), dapagliflozin (Dapagliflozin), or empagliflozin (Empagliflozin), single pill combination and solo therapies?

Metformin Plus SGLT2 Inhibitor Dosing: Single-Pill Combinations and Solo Therapies

Solo Therapy Dosages

Metformin Monotherapy

For patients with eGFR ≥45 mL/min/1.73 m², start metformin at 500-850 mg once daily and titrate upward by 500-850 mg every 7 days until reaching the target dose of 1,000 mg twice daily (2,000 mg total daily dose). 1, 2

• Maximum approved daily dose is 2,000-2,550 mg, though doses above 2,000 mg provide minimal additional glycemic benefit with worse gastrointestinal tolerability 1, 2
• For eGFR 30-44 mL/min/1.73 m², reduce maximum dose to 1,000 mg daily 1, 2
• For eGFR <30 mL/min/1.73 m², metformin is contraindicated 1, 2
• Monitor eGFR at least annually when ≥60 mL/min/1.73 m², and every 3-6 months when eGFR falls below 60 mL/min/1.73 m² 1, 2

SGLT2 Inhibitor Monotherapy

Canagliflozin: Start at 100 mg once daily; may increase to 300 mg once daily for additional glycemic control if eGFR ≥60 mL/min/1.73 m² 1, 3

• Maximum dose is 100 mg daily when eGFR 30-59 mL/min/1.73 m² 3
• Not recommended for initiation when eGFR <30 mL/min/1.73 m² for glycemic control, but may continue 100 mg daily if tolerated for cardiovascular/renal benefit until dialysis 3

Dapagliflozin: Start at 5 mg once daily for glycemic control; may increase to 10 mg once daily 1, 3

• For heart failure and chronic kidney disease indications, use 10 mg once daily regardless of glycemic needs 4, 3
• Not recommended for initiation when eGFR <25 mL/min/1.73 m², but may continue 10 mg daily if already established 4
• Not effective for glycemic control when eGFR <45 mL/min/1.73 m², though cardiovascular and renal benefits persist 4, 5

Empagliflozin: Start at 10 mg once daily; may increase to 25 mg once daily for additional glycemic control 1, 3, 2

• Not recommended for initiation when eGFR <45 mL/min/1.73 m² for glycemic control 3, 2
• May continue 10 mg daily when eGFR 20-44 mL/min/1.73 m² if already established for cardiovascular/renal protection 2

Combination Therapy Dosing

Initial Combination Strategy

For treatment-naive patients or those inadequately controlled on metformin alone, start metformin 1,000 mg twice daily plus an SGLT2 inhibitor at standard starting dose (empagliflozin 10 mg, dapagliflozin 5-10 mg, or canagliflozin 100 mg once daily). 1, 2

• This approach is particularly recommended when A1C is ≥1.5% above target, as initial combination therapy provides more rapid glycemic control than sequential addition 1
• Most patients in cardiovascular outcomes trials were on metformin at baseline, supporting this combination approach 1

Titration of Combination Therapy

• Increase metformin gradually to minimize gastrointestinal side effects, targeting 2,000 mg total daily dose 2
• SGLT2 inhibitors require no titration for cardiovascular/renal benefits, but may increase empagliflozin to 25 mg or canagliflozin to 300 mg (if eGFR ≥60 mL/min/1.73 m²) for additional glycemic control 3, 2
• Dapagliflozin may be increased from 5 mg to 10 mg once daily for improved glycemic control 3

Fixed-Dose Combination Products

FDA-approved fixed-dose combination tablets are available for all three SGLT2 inhibitors with metformin, which can reduce pill burden and potentially improve adherence. 6

• These combinations contain various strengths of each component to allow flexibility in dosing 6
• The fixed-dose combinations demonstrate synergistic effects with complementary mechanisms of action 7

Renal Function-Based Dosing Algorithm

eGFR ≥60 mL/min/1.73 m²

• Metformin: Up to 2,000 mg daily (no adjustment needed) 1, 2
• Any SGLT2 inhibitor at full doses: canagliflozin up to 300 mg, dapagliflozin up to 10 mg, empagliflozin up to 25 mg 3, 2

eGFR 45-59 mL/min/1.73 m²

• Metformin: Consider initiating at half the standard dose and titrating to half of maximum (1,000 mg daily), though full doses may be continued if already established 1
• Canagliflozin: Maximum 100 mg daily 3
• Dapagliflozin: 10 mg daily (but not effective for glycemic control) 4
• Empagliflozin: Do not initiate for glycemic control; may continue 10 mg if established 2

eGFR 30-44 mL/min/1.73 m²

• Metformin: Maximum 1,000 mg daily; initiate at half dose 1, 2
• Canagliflozin: Maximum 100 mg daily (not for glycemic control, but for cardiovascular/renal benefit) 3
• Dapagliflozin: May continue 10 mg if established (not for glycemic control) 4
• Empagliflozin: May continue 10 mg if established (not for glycemic control) 2

eGFR 25-29 mL/min/1.73 m²

• Metformin: Contraindicated 1, 2
• Dapagliflozin: May continue 10 mg if established for cardiovascular/renal protection 4
• Canagliflozin and empagliflozin: May continue for cardiovascular/renal benefit 3, 2

eGFR <25 mL/min/1.73 m²

• Metformin: Contraindicated 1, 2
• SGLT2 inhibitors: Do not initiate; may continue if tolerated until dialysis for cardiovascular/renal benefits 4, 3, 2

Critical Safety Considerations

Withholding Therapy

Discontinue both metformin and SGLT2 inhibitors at least 3 days before major surgery or procedures requiring prolonged fasting to prevent postoperative ketoacidosis and lactic acidosis. 4, 2

• Withhold metformin during severe illness, vomiting, dehydration, or acute kidney injury 2
• Consider pausing SGLT2 inhibitors during acute illness or metabolic stressors 3

Metabolic Acidosis Risk

The combination of metformin and SGLT2 inhibitors carries a rare but serious risk of high anion gap metabolic acidosis, including metformin-associated lactic acidosis and SGLT2 inhibitor-associated euglycemic diabetic ketoacidosis. 6

• Educate patients about symptoms of ketoacidosis (nausea, vomiting, abdominal pain, fatigue) even with normal glucose levels 2
• Consider blood or urine ketone monitoring for early detection 3

Common Adverse Effects

• Metformin: Gastrointestinal intolerance (bloating, diarrhea, abdominal discomfort); vitamin B12 deficiency with long-term use 1, 2
• SGLT2 inhibitors: Genital mycotic infections (6% vs 1% placebo, higher in women), urinary tract infections, volume depletion, orthostatic hypotension 4, 3
• Monitor vitamin B12 levels periodically in patients on metformin, particularly those with anemia or neuropathy 2

Volume Status Management

Assess volume status before initiating SGLT2 inhibitors and correct any volume depletion; use caution with concurrent diuretics, ACE inhibitors, or ARBs. 4, 2

• An initial eGFR dip of 3-5 mL/min/1.73 m² typically occurs within 1-4 weeks of SGLT2 inhibitor initiation, which is transient and reversible 4
• Check eGFR within 1-2 weeks after initiation 4

Cardiovascular and Renal Protection Indications

For patients with type 2 diabetes and established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease with eGFR ≥25-30 mL/min/1.73 m², add an SGLT2 inhibitor with proven cardiovascular benefit (empagliflozin, canagliflozin, or dapagliflozin) independent of A1C level and independent of metformin use. 1

• These agents reduce major adverse cardiovascular events, hospitalization for heart failure, and progression of kidney disease 1, 3
• Cardiovascular and renal benefits persist even when glucose-lowering efficacy is minimal at lower eGFR levels 4, 3, 2