What are the primary kidney protective agents in diabetes?

Kidney Protective Agents in Diabetes

For patients with diabetes and chronic kidney disease, SGLT2 inhibitors are now the primary kidney protective agents, recommended for all patients with eGFR ≥20 mL/min/1.73 m² and type 2 diabetes, as they slow CKD progression independent of glucose control. 1

Primary Kidney Protective Agents by Class

SGLT2 Inhibitors (First-Line for CKD Protection)

SGLT2 inhibitors are recommended as the cornerstone of kidney protection in type 2 diabetes with established CKD, providing benefits independent of glycemic control. 1

• Empagliflozin and canagliflozin reduced the risk of incident or worsening nephropathy by 39% and reduced the risk of doubling serum creatinine by 44% compared to placebo 1
• These agents can be initiated and continued with eGFR ≥20 mL/min/1.73 m², expanding their use to more advanced CKD stages 1
• SGLT2 inhibitors reduce oxidative stress in the kidney by >50%, decrease intraglomerular pressure, reduce albuminuria, and slow GFR loss through mechanisms independent of glycemia 1
• They also reduce NLRP3 inflammasome activity and blunt increases in angiotensinogen 1

ACE Inhibitors and ARBs (For Albuminuria and Hypertension)

ACE inhibitors or ARBs are recommended for patients with albuminuria ≥30 mg/24h and should be titrated to maximum tolerated doses. 1

When to Use:

• For albuminuria 30-299 mg/24h (with hypertension): Either ACE inhibitors or ARBs reduce progression to higher levels of albuminuria and slow CKD progression 1
• For albuminuria ≥300 mg/24h: ACE inhibitors or ARBs are first-line therapy and reduce progression to ESKD in both type 1 and type 2 diabetes 1
• For eGFR <60 mL/min/1.73 m² with UACR ≥300 mg/g: ACE inhibitors or ARBs are preferred first-line agents for blood pressure control due to proven CKD progression benefits 1

When NOT to Use:

• Do not use ACE inhibitors or ARBs in diabetic patients with normal blood pressure and albumin excretion <30 mg/24h, as they do not prevent diabetic kidney disease development 1
• In normotensive type 1 diabetes patients without albuminuria, ACE inhibitors or ARBs did not prevent diabetic glomerulopathy on kidney biopsy 1
• In type 2 diabetes with normal urine albumin, ARBs reduced albuminuria development but increased cardiovascular events 1

Critical Monitoring:

• Monitor serum creatinine and potassium within 2-4 weeks of initiation or dose changes 1
• Continue ACE inhibitors/ARBs even if creatinine increases up to 30% without associated hyperkalemia, as this reflects hemodynamic changes rather than kidney injury 1
• Titrate to maximum approved doses that are tolerated for optimal kidney protection 1

GLP-1 Receptor Agonists (For Cardiovascular Risk Reduction)

GLP-1 RAs are suggested when cardiovascular risk is the predominant concern, as they reduce CVD events and may slow CKD progression. 1

• GLP-1 RAs have direct effects on the kidney and improve renal outcomes compared with placebo, though definitive renoprotective effects are still being determined 1
• These agents are safe across all stages of renal impairment 2
• Clear cardiovascular risk reduction has been demonstrated in patients with type 2 diabetes and CKD 1

Mineralocorticoid Receptor Antagonists (Emerging Evidence)

Finerenone, a selective nonsteroidal MRA, reduces both CKD progression and cardiovascular events when added to RAS blockade. 1

• The FIDELIO trial demonstrated lower risks for CKD progression and cardiovascular events in patients with CKD and type 2 diabetes already on ACE inhibitors or ARBs 1
• MRAs are effective for resistant hypertension 1
• Close monitoring for hyperkalemia is essential when adding MRAs to existing RAS blockade 1

Critical Treatment Algorithm

Step 1: Assess Kidney Function and Albuminuria

• Measure eGFR and urine albumin-to-creatinine ratio annually in type 2 diabetes from diagnosis, and in type 1 diabetes after 5 years duration 1

Step 2: Initiate SGLT2 Inhibitor (Type 2 Diabetes)

• If eGFR ≥20 mL/min/1.73 m²: Start SGLT2 inhibitor regardless of albuminuria status for kidney and heart failure protection 1
• SGLT2 inhibitors are particularly beneficial for patients at high risk of CKD progression (those with albuminuria or documented eGFR loss) 1

Step 3: Add ACE Inhibitor or ARB Based on Albuminuria

• If UACR ≥30 mg/g: Add ACE inhibitor or ARB, titrate to maximum tolerated dose 1
• If UACR <30 mg/g and normotensive: Do not use ACE inhibitor or ARB for kidney protection; use alternative antihypertensives if needed for blood pressure control 1

Step 4: Optimize Blood Pressure Control

• Target blood pressure <130/80 mmHg for all patients with diabetes to reduce CVD mortality and slow CKD progression 1
• If ACE inhibitor/ARB alone is insufficient, add thiazide-like diuretics or dihydropyridine calcium channel blockers rather than combining ACE inhibitor with ARB 1

Step 5: Consider GLP-1 RA for High Cardiovascular Risk

• Add GLP-1 RA if cardiovascular disease is present or cardiovascular risk is predominant concern 1

Common Pitfalls to Avoid

Never Combine ACE Inhibitors with ARBs

Dual RAS blockade with ACE inhibitor plus ARB increases adverse events (hyperkalemia, acute kidney injury) without additional benefits on CVD or CKD outcomes. 1, 3

Do Not Withhold SGLT2 Inhibitors Due to Modest eGFR Decline

• SGLT2 inhibitors cause an initial modest decline in eGFR due to hemodynamic effects, which is not harmful and reflects reduced intraglomerular pressure 1
• Continue SGLT2 inhibitors as long as eGFR remains ≥20 mL/min/1.73 m² 1

Do Not Use ACE Inhibitors/ARBs for Primary Prevention Without Albuminuria

• In normotensive patients with normal albumin excretion, ACE inhibitors and ARBs do not prevent diabetic kidney disease and may increase cardiovascular events 1

Monitor for Hyperkalemia When Using RAS Blockade

• Check potassium within 2-4 weeks of starting or increasing ACE inhibitor/ARB doses 1
• Consider dietary potassium restriction, diuretics, or sodium bicarbonate (if metabolic acidosis present) before discontinuing beneficial RAS blockade 1

Additional Interventions That Lower Albuminuria

Beyond pharmacologic agents, several interventions reduce albuminuria and slow CKD progression: 1

• Intensive glucose control to achieve near-normoglycemia delays onset and progression of albuminuria 1
• Smoking cessation is strongly recommended 1
• Weight loss reduces albuminuria 1
• Dietary sodium restriction to <2,300 mg/day helps manage blood pressure and reduce cardiovascular risk 1
• Dietary protein restriction below usual intake is NOT recommended, as it does not alter glycemic measures, cardiovascular risk, or GFR decline 1