In a diabetic patient with proteinuria who is already on a GLP‑1 receptor agonist, what medication should be added to improve proteinuria?

Add an SGLT2 Inhibitor to Improve Proteinuria

In a diabetic patient with proteinuria already on a GLP-1 receptor agonist, add an SGLT2 inhibitor (empagliflozin, canagliflozin, or dapagliflozin) as the next medication to improve proteinuria. 1

Primary Recommendation: SGLT2 Inhibitor

• SGLT2 inhibitors with proven kidney benefit are recommended for patients with type 2 diabetes, CKD, and eGFR ≥20 ml/min/1.73 m² to reduce proteinuria and prevent kidney disease progression. 1

• The CREDENCE trial demonstrated that canagliflozin reduced the composite renal endpoint (end-stage renal disease, doubling of serum creatinine, or renal/cardiovascular death) by 30% in patients with type 2 diabetes and albuminuria (albumin-to-creatinine ratio 33.9-565 mg/mmol). 1

• SGLT2 inhibitors provide nephroprotection independent of their glucose-lowering effects, with benefits observed even when eGFR falls below the threshold for glycemic efficacy. 1

• Once initiated, continue the SGLT2 inhibitor even if eGFR declines below 20 ml/min/1.73 m², unless kidney replacement therapy is required. 1

Optimize Renin-Angiotensin System Blockade

• Add or uptitrate an ACE inhibitor or ARB to the maximum tolerated dose if not already prescribed, as this is the cornerstone of antiproteinuric therapy in diabetic patients with hypertension and albuminuria. 1

• ACE inhibitors and ARBs reduce proteinuria by approximately 30% and significantly delay progression to end-stage renal disease in patients with chronic kidney disease. 1

• Titrate to the highest approved antihypertensive dose, as renoprotective benefits in clinical trials were achieved with maximum doses. 2

• Accept up to a 30% increase in serum creatinine after uptitration—this is an expected hemodynamic effect, not a reason to reduce the dose. 2

Consider Adding a Nonsteroidal Mineralocorticoid Receptor Antagonist

• If proteinuria persists despite maximum tolerated doses of an SGLT2 inhibitor and ACE inhibitor/ARB, add finerenone (a nonsteroidal MRA) for patients with eGFR ≥25 ml/min/1.73 m², normal serum potassium, and albumin-to-creatinine ratio ≥30 mg/g. 1, 2

• Finerenone provides additional kidney and cardiovascular protection when added to standard therapy in high-risk patients with type 2 diabetes and albuminuria. 1

• Critical caveat: Monitor serum potassium within 4 weeks of starting finerenone and regularly thereafter, as hyperkalemia is the primary safety concern. 2

• Manage hyperkalemia proactively with potassium-wasting diuretics, potassium binders, dietary potassium restriction, or sodium bicarbonate (if serum bicarbonate <22 mmol/L) rather than immediately discontinuing renoprotective medications. 2

Do NOT Combine ACE Inhibitor and ARB

• Dual ACE inhibitor/ARB therapy is explicitly contraindicated in patients with diabetes and CKD, as it increases serious adverse events without additional renoprotective benefit. 1

• The ONTARGET and ALTITUDE trials demonstrated that combination ACE inhibitor/ARB therapy increased hyperkalemia, acute kidney injury, and hypotension without improving renal outcomes in diabetic patients. 3, 4

Optimize Blood Pressure Control

• Target systolic blood pressure <130 mmHg (and <120 mmHg if tolerated) in diabetic patients with proteinuria, as lower blood pressure targets provide additional renoprotection. 1, 2

• Add a thiazide-like diuretic (chlorthalidone or indapamide preferred) or dihydropyridine calcium channel blocker if additional blood pressure lowering is needed. 2

Essential Lifestyle Modifications

• Restrict dietary sodium to <2.0 g/day (<90 mmol/day), as sodium restriction synergistically enhances the antiproteinuric effects of ACE inhibitors/ARBs and is as important as medication optimization. 2

• Achieve weight normalization through diet and exercise, as obesity independently worsens proteinuria. 2

• Counsel smoking cessation if applicable. 2

Monitoring Parameters

• Monitor urine albumin-to-creatinine ratio every 3-6 months, aiming for at least a 30-50% reduction from baseline. 2

• Check serum creatinine, eGFR, and potassium within 2-4 weeks after adding or uptitrating medications, then regularly thereafter. 1, 2

• Continue annual screening for CKD progression with spot urine albumin-to-creatinine ratio and eGFR. 1

Common Pitfalls to Avoid

• Do not discontinue ACE inhibitor/ARB prematurely due to modest creatinine elevation (<30% increase), as this removes critical renoprotection. 2

• Do not withhold SGLT2 inhibitors or finerenone solely due to fear of side effects in appropriate candidates—proactive monitoring allows continuation of renoprotective therapy. 2

• Do not use fixed low doses of renin-angiotensin system blockers; uptitrate to maximum tolerated doses for optimal antiproteinuric effect. 2