What oral diabetes medications can be given to patients with Chronic Kidney Disease (CKD)?

Oral Diabetes Medications in Chronic Kidney Disease

SGLT2 inhibitors and metformin are the preferred first-line oral agents for patients with type 2 diabetes and CKD, with SGLT2 inhibitors prioritized for their proven cardiovascular and renal protection benefits. 1

First-Line Therapy Algorithm

Metformin

• Use when eGFR ≥30 mL/min/1.73 m² with dose adjustments based on kidney function 2
• No dose adjustment needed when eGFR ≥45 mL/min/1.73 m² 1
• Reduce dose by 50% when eGFR 30-44 mL/min/1.73 m² 3
• Discontinue when eGFR <30 mL/min/1.73 m² 2, 3

SGLT2 Inhibitors (Preferred Add-On or Alternative to Metformin)

These agents provide cardiovascular and renal benefits independent of glucose-lowering effects and should be prioritized in patients with CKD 1

Empagliflozin

• Use when eGFR ≥45 mL/min/1.73 m² for initiation 1
• Doses: 10 mg or 25 mg daily 1
• Do not initiate if eGFR <45 mL/min/1.73 m², but continue if already established even when eGFR falls below 30 mL/min/1.73 m² unless not tolerated 1

Canagliflozin

• Use when eGFR ≥60 mL/min/1.73 m² for full dosing (100-300 mg daily) 1
• Limit to 100 mg daily when eGFR 45-59 mL/min/1.73 m² 1
• Demonstrated 30% reduction in renal disease progression in the CREDENCE trial 1

Key SGLT2 Inhibitor Considerations

• Cardiovascular benefits persist down to eGFR 30 mL/min/1.73 m² 1
• A reversible eGFR decrease upon initiation is expected and not a reason to discontinue 1
• Withhold during prolonged fasting, surgery, or critical illness due to ketosis risk 1
• Consider reducing diuretic doses before initiation to prevent hypovolemia 1

Second-Line Oral Agents

DPP-4 Inhibitors

Linagliptin (Preferred DPP-4 Inhibitor in CKD)

Linagliptin is the only DPP-4 inhibitor requiring no dose adjustment at any level of renal function, making it ideal for CKD patients 3, 4

• Dose: 5 mg once daily regardless of eGFR 3, 4
• Primarily hepatobiliary elimination (only 5% renal) 4
• Can be used throughout all stages of CKD including severe impairment 5, 6
• Monitor kidney function closely when combining with ACE inhibitors due to rare AKI risk from volume contraction 7

Saxagliptin

• Requires dose reduction to 2.5 mg daily when eGFR <45 mL/min/1.73 m² 8
• Less preferred than linagliptin in CKD due to dose adjustment requirements 8

Sitagliptin

• Requires dose adjustment: 50 mg daily when eGFR 30-45 mL/min/1.73 m², 25 mg daily when eGFR <30 mL/min/1.73 m² (based on general medical knowledge)

GLP-1 Receptor Agonists (Injectable, but Oral Semaglutide Available)

GLP-1 RAs are recommended when glycemic targets are not met with metformin and SGLT2 inhibitors, or when those agents cannot be used 1

Oral Semaglutide

• Doses: 3 mg, 7 mg, or 14 mg daily 1
• No dose adjustment required, but limited data in severe CKD 1
• Prioritize agents with documented cardiovascular benefits 1, 2

Injectable GLP-1 RAs (for completeness)

• Dulaglutide: Use with eGFR >15 mL/min/1.73 m², no dose adjustment 1
• Liraglutide: No dose adjustment, limited data in severe CKD 1
• Semaglutide (injection): No dose adjustment, limited data in severe CKD 1
• Exenatide: Use only with CrCl >30 mL/min 1

Do not combine GLP-1 RAs with DPP-4 inhibitors 1

Agents to Avoid or Use with Extreme Caution

Sulfonylureas

• High risk of severe and prolonged hypoglycemia in CKD due to impaired drug clearance and reduced renal gluconeogenesis 9
• If absolutely necessary, glipizide is preferred as it lacks active metabolites that accumulate in kidney dysfunction 9
• Completely avoid chlorpropamide, tolazamide, and tolbutamide in any degree of kidney impairment 9
• Gliclazide and glimepiride require significant dose reduction and close monitoring 9
• When used with GLP-1 RAs or insulin, sulfonylurea doses must be reduced to prevent hypoglycemia 1

Thiazolidinediones (TZDs)

• Avoid in patients with heart failure due to fluid retention risk 2
• Can be used in CKD without dose adjustment but monitor for edema (based on general medical knowledge)

Clinical Monitoring Recommendations

• Monitor eGFR every 3-6 months when eGFR <60 mL/min/1.73 m² 3
• Check vitamin B12 levels annually in long-term metformin users 2
• Do not rely solely on HbA1c in CKD patients as it may underestimate glycemic burden due to anemia and altered red blood cell turnover 3
• Increase blood glucose monitoring frequency, particularly 2-hour postprandial readings, when adding new medications 3

Common Pitfalls to Avoid

• Do not discontinue SGLT2 inhibitors solely due to initial eGFR decline - this is hemodynamic and reversible 1
• Do not intensify sulfonylurea therapy in CKD - this dramatically increases hypoglycemia risk 9
• Do not forget to adjust metformin dose when eGFR falls below 45 mL/min/1.73 m² 2, 3
• Do not use DPP-4 inhibitors and GLP-1 RAs together - no additional benefit and increased cost 1