What is the best treatment approach for a patient with type 2 diabetes (T2D) and chronic kidney disease (CKD) with impaired renal function?

Diabetes Treatment in CKD: Evidence-Based Approach

For patients with type 2 diabetes and chronic kidney disease with impaired renal function, initiate an SGLT2 inhibitor immediately if eGFR ≥20 mL/min/1.73 m², combined with metformin if eGFR ≥30 mL/min/1.73 m², and add a long-acting GLP-1 receptor agonist if glycemic targets are not met—this triple therapy approach prioritizes kidney and cardiovascular protection over glycemic control alone. 1

First-Line Therapy: SGLT2 Inhibitors

SGLT2 inhibitors are the cornerstone of treatment and should be started regardless of baseline HbA1c or current glycemic control. 1

• Initiate SGLT2i when eGFR ≥20 mL/min/1.73 m² with a strong 1A recommendation from KDIGO 2024 guidelines 1
• Continue SGLT2i even if eGFR falls below 20 mL/min/1.73 m² after initiation, unless not tolerated or kidney replacement therapy begins 1
• The glucose-lowering effect diminishes with declining kidney function, but the kidney and cardiovascular protective benefits persist 2
• Expect and accept an acute, reversible drop in eGFR of up to 10% after initiation—this is not a reason to discontinue therapy 1

Practical SGLT2i Initiation

• Assess volume status before starting: patients on concurrent diuretics or with tenuous volume status require closer monitoring 1
• Withhold during sick days, prolonged fasting, surgery, or critical illness to reduce ketoacidosis risk 1
• For procedures requiring ≥1 day hospitalization or bowel preparation, withhold at least 2 days in advance 1
• Monitor for genital mycotic infections, particularly in immunocompromised patients 1

Second-Line Therapy: Metformin

Metformin remains first-line for glycemic control but must be dose-adjusted or discontinued based on kidney function. 1, 3

• Use metformin at full dose when eGFR ≥45 mL/min/1.73 m² 1
• Reduce dose by 50% when eGFR 30-44 mL/min/1.73 m² 1, 3
• Discontinue metformin when eGFR <30 mL/min/1.73 m² due to lactic acidosis risk 1, 3
• The FDA revised labeling confirms safety only down to eGFR ≥30 mL/min/1.73 m² 3

Third-Line Therapy: GLP-1 Receptor Agonists

When glycemic targets are not met with SGLT2i and metformin, add a long-acting GLP-1 receptor agonist. 1, 3

• Preferred agents: dulaglutide, liraglutide, or injectable semaglutide with proven cardiovascular benefits 1, 3
• These agents can be used safely down to eGFR 15 mL/min/1.73 m² without dose adjustment 3
• Dulaglutide 0.75-1.5 mg once weekly requires no dose adjustment with eGFR >15 mL/min/1.73 m² 3
• Liraglutide showed greater cardiovascular benefit in patients with eGFR <60 mL/min/1.73 m² 3

Fourth-Line Therapy: Nonsteroidal MRA

For patients with persistent albuminuria ≥30 mg/g despite maximum tolerated RAS inhibitor and SGLT2i, add a nonsteroidal mineralocorticoid receptor antagonist. 1

• Requires eGFR ≥25 mL/min/1.73 m² and normal serum potassium 1
• Most appropriate for high-risk patients with persistent albuminuria despite standard therapy 1
• Monitor serum potassium regularly after initiation to mitigate hyperkalemia risk 1
• Prioritize agents with documented kidney or cardiovascular benefits (e.g., finerenone) 1, 4

Essential Concomitant Therapy: RAS Inhibition

All patients with diabetes, CKD, and albuminuria (A2 or A3) should receive an ACE inhibitor or ARB at maximum tolerated dose. 1

• Strong 1B recommendation for moderately-to-severely increased albuminuria (A2 and A3) with diabetes 1
• Continue ACE inhibitor or ARB even when eGFR falls below 30 mL/min/1.73 m² 1
• Check BP, serum creatinine, and potassium within 2-4 weeks of initiation or dose increase 1
• Continue therapy unless creatinine rises >30% within 4 weeks or uncontrolled hyperkalemia develops 1
• Manage hyperkalemia with potassium-lowering measures rather than stopping RAS inhibitor 1

Alternative Agents When Standard Therapy Insufficient

DPP-4 Inhibitors

• Linagliptin requires no dose adjustment and can be added if GLP-1 receptor agonists are not tolerated 3, 5
• Other DPP-4 inhibitors require dose reduction: sitagliptin needs adjustment when eGFR <45 mL/min/1.73 m² 5
• Less preferred than GLP-1 receptor agonists due to lack of cardiovascular outcome benefits 3

Insulin

• Always an option at any level of kidney function 3
• Reduce insulin doses by ≥25% when eGFR <45 mL/min/1.73 m² due to decreased insulin clearance and increased hypoglycemia risk 3
• If patient is on insulin or sulfonylureas and meeting targets, reduce or withdraw these when adding SGLT2i to prevent hypoglycemia 3

Medications to AVOID

Critical contraindications in CKD: 3, 6

• Glyburide: NOT recommended due to high hypoglycemia risk in renal impairment 3
• Pioglitazone: causes fluid retention, contraindicated in heart failure; use only if no other options 3
• Metformin when eGFR <30 mL/min/1.73 m²: absolute contraindication 3

Glycemic Monitoring Considerations

HbA1c reliability decreases with advanced CKD (stages 4-5), particularly in dialysis patients. 1

• Monitor HbA1c twice yearly for stable patients, up to 4 times yearly if targets not met or after therapy changes 1
• Consider glucose management indicator (GMI) from continuous glucose monitoring when HbA1c is discordant with measured glucose or symptoms 1
• Continuous glucose monitoring may be beneficial when HbA1c becomes unreliable in advanced CKD 3

Cardiovascular Risk Reduction

Statin therapy is mandatory regardless of baseline lipid levels. 1, 3

• Moderate-intensity statin for primary prevention in all adults with diabetes and CKD 1
• High-intensity statin for secondary prevention in patients with known atherosclerotic cardiovascular disease 1
• Exception: patients on dialysis where primary prevention with statins has been generally ineffective 1

Monitoring Schedule

Patients with CKD stages 3-4 require intensive monitoring: 3

• Monitor eGFR at least every 3-6 months when eGFR 30-44 mL/min/1.73 m² 3
• Check blood pressure at every clinic visit (minimum every 3 months) with target <130/80 mmHg 7
• Monitor potassium regularly, especially after initiating RAS inhibitor or nonsteroidal MRA 1
• Monitor vitamin B12 if metformin was used long-term before discontinuation 3

Common Pitfalls to Avoid

• Do not withhold SGLT2i solely because eGFR is declining—the reversible eGFR decrease is expected and beneficial 1
• Do not withhold ACE inhibitors/ARBs based on reduced kidney function alone unless specific contraindications exist 1, 7
• Do not continue metformin when eGFR <30 mL/min/1.73 m²—this is an absolute contraindication 3
• Do not neglect frequent monitoring—these patients require at least quarterly visits 7
• Do not prioritize glycemic control over organ protection—SGLT2i and GLP-1 RA provide benefits beyond glucose lowering 1