Initial Diabetic Medication for CKD Stage 3
For patients with type 2 diabetes and CKD stage 3 (eGFR 30-59 mL/min/1.73 m²), start with combination therapy of metformin plus an SGLT2 inhibitor as first-line treatment. 1, 2
First-Line Dual Therapy Approach
Metformin Dosing by eGFR
- eGFR 45-59 mL/min/1.73 m²: Start at half the standard dose (500 mg once daily), titrate upward to maximum 1000 mg daily 1
- eGFR 30-44 mL/min/1.73 m²: Start at 500 mg once daily, maximum dose 1000 mg daily 1
- Monitor eGFR every 3-6 months when eGFR <60 mL/min/1.73 m² 1
- Continue metformin throughout disease progression unless contraindicated 3
SGLT2 Inhibitor Selection
- Canagliflozin 100 mg once daily is FDA-approved for CKD stage 3 with proven renal and cardiovascular benefits 4
- SGLT2 inhibitors reduce CKD progression by 40%, cardiovascular events, and provide benefits independent of glucose lowering 2, 3
- Do not increase canagliflozin to 300 mg if eGFR <60 mL/min/1.73 m²—the 100 mg dose provides renal protection without additional glycemic benefit at lower eGFR 4
- Continue SGLT2 inhibitor even if eGFR falls below 30 mL/min/1.73 m² unless dialysis is initiated 1
Critical Safety Measures When Starting Therapy
Volume Status Assessment
- Assess for volume depletion before initiating SGLT2 inhibitor 1, 4
- Consider reducing loop or thiazide diuretic doses before starting SGLT2 inhibitor 1
- Expect a reversible 3-5 mL/min/1.73 m² eGFR dip in first 2-4 weeks—this is hemodynamic and not a reason to stop therapy 1
Hypoglycemia Prevention
- If patient is on insulin or sulfonylureas, reduce insulin dose by 20% and consider stopping sulfonylureas when adding SGLT2 inhibitor 1, 5
- Metformin and SGLT2 inhibitors together have minimal hypoglycemia risk when used without insulin or sulfonylureas 2
Ketoacidosis Risk Mitigation
- Withhold SGLT2 inhibitor at least 3 days before surgery or prolonged fasting 4
- Educate patients to stop SGLT2 inhibitor during acute illness with poor oral intake 1
When Additional Glucose-Lowering Is Needed
Third-Line Agent Selection
If A1C remains above target after 12 weeks on metformin plus SGLT2 inhibitor:
- GLP-1 receptor agonist is the preferred third agent due to cardiovascular benefits, weight loss, and low hypoglycemia risk 1, 2
- Choose long-acting GLP-1 RA with proven cardiovascular outcomes: semaglutide, dulaglutide, or liraglutide 1
- Start at lowest dose and titrate slowly over 8-12 weeks to minimize gastrointestinal side effects 1
- No dose adjustment needed for GLP-1 RA in CKD stage 3 1
Alternative Third-Line Options
- DPP-4 inhibitors (linagliptin preferred—no dose adjustment needed; sitagliptin 50 mg daily if eGFR 30-50) for patients who refuse injections 1, 2
- Avoid sulfonylureas due to high hypoglycemia risk in CKD 1, 6
- Never combine GLP-1 RA with DPP-4 inhibitors—they work through the same pathway 1
Common Pitfalls to Avoid
- Do not delay SGLT2 inhibitor initiation waiting for metformin titration—start both simultaneously for maximum renal protection 1, 2
- Do not stop metformin when eGFR is 30-44 mL/min/1.73 m²—reduce dose to 1000 mg daily instead 1
- Do not discontinue SGLT2 inhibitor for initial eGFR dip—this represents beneficial hemodynamic changes 1
- Do not use glyburide at any level of kidney function—it is contraindicated in CKD 1
- Monitor vitamin B12 annually in long-term metformin users 2
Special Considerations for CKD Stage 3
If Patient Has Heart Failure
- Prioritize SGLT2 inhibitor as it reduces heart failure hospitalization by 30-40% 2
- Avoid thiazolidinediones due to fluid retention risk 1
If Patient Has Established Cardiovascular Disease
- Both SGLT2 inhibitor and GLP-1 RA provide cardiovascular mortality reduction—consider starting all three agents (metformin + SGLT2i + GLP-1 RA) if A1C ≥9% at diagnosis 2, 3