What is the best initial treatment to add, Angiotensin-Converting Enzyme (ACE) inhibitor or Sodium-Glucose Cotransporter 2 (SGLT2) inhibitor, for a patient with diabetic renal disease?

SGLT2 Inhibitor Should Be Added First for Diabetic Renal Disease

For patients with diabetic kidney disease, add an SGLT2 inhibitor first, regardless of whether they are already on an ACE inhibitor or ARB. Both agents should ultimately be used together, but SGLT2 inhibitors now carry the strongest evidence (Level 1A) for reducing CKD progression, cardiovascular events, and mortality in diabetic kidney disease 1.

Why SGLT2 Inhibitors Take Priority

The 2022 KDIGO guidelines provide the highest level recommendation (1A) for SGLT2 inhibitors in patients with type 2 diabetes, CKD, and eGFR ≥20 mL/min/1.73 m² 1. This represents a paradigm shift from traditional approaches that prioritized RAS blockade alone.

Evidence Hierarchy

• SGLT2 inhibitors reduce kidney failure, cardiovascular death, and all-cause mortality in dedicated renal outcome trials like CREDENCE, which specifically enrolled patients with diabetic nephropathy (eGFR 30-90, albuminuria >300 mg/g) already on maximum-tolerated ACE/ARB therapy 2, 3.

• The CREDENCE trial demonstrated a 30% reduction in the primary composite outcome (ESRD, doubling of creatinine, or renal/cardiovascular death), a 34% reduction in renal-specific outcomes, and a 32% reduction in end-stage kidney disease 2.

• ACE inhibitors/ARBs carry a lower evidence grade (1B) and are recommended specifically for patients with diabetes, hypertension, AND albuminuria 1. Their recommendation is more conditional and focused on blood pressure control in the setting of albuminuria.

Practical Implementation Algorithm

Step 1: Initiate SGLT2 Inhibitor if eGFR ≥20 mL/min/1.73 m²

• Start immediately if eGFR ≥20 mL/min/1.73 m², regardless of albuminuria level or current glycemic control 1.

• Agent selection by eGFR 4:

  • eGFR ≥45: Empagliflozin 10 mg, canagliflozin 100 mg, or dapagliflozin 10 mg daily
  • eGFR 30-44: Canagliflozin 100 mg or dapagliflozin 10 mg daily (empagliflozin not recommended for initiation)
  • eGFR 20-29: Canagliflozin 100 mg or dapagliflozin 10 mg daily

Step 2: Pre-Initiation Safety Checks

Before starting SGLT2 inhibitors 1, 4:

• Assess volume status: Reduce loop or thiazide diuretics if patient has concurrent diuretic use, tenuous volume status, or history of AKI
• Check serum potassium: Ensure normal levels, especially if combining with ACE/ARB
• Educate on volume depletion symptoms: Dizziness, lightheadedness, orthostatic hypotension

Step 3: Add or Optimize ACE Inhibitor/ARB

After SGLT2 inhibitor initiation, add ACE inhibitor or ARB if the patient has hypertension AND albuminuria 1:

• Titrate to maximum tolerated dose
• Monitor creatinine and potassium within 2-4 weeks
• Continue ACE/ARB unless creatinine rises >30% within 4 weeks 1

Step 4: Monitor and Continue Therapy

• Expect and accept an acute eGFR decline of up to 30% within 4 weeks of SGLT2 inhibitor initiation—this represents beneficial hemodynamic changes (reduced glomerular hyperfiltration), not kidney injury 1, 4.

• Continue SGLT2 inhibitor even if eGFR subsequently falls below 20 mL/min/1.73 m², unless dialysis is initiated or the drug is not tolerated 1.

Critical Nuances and Pitfalls

Common Mistake: Stopping SGLT2 Inhibitors Due to eGFR Decline

Do not discontinue SGLT2 inhibitors for reversible eGFR decreases 1. The initial dip reflects afferent arteriole vasoconstriction through tubuloglomerular feedback—a protective mechanism that reduces hyperfiltration 5.

When to Temporarily Withhold SGLT2 Inhibitors

Hold during prolonged fasting, surgery, or critical illness due to increased ketoacidosis risk 1:

• Withhold the day of day-stay procedures
• Withhold ≥2 days before procedures requiring hospitalization or bowel preparation
• Restart only when eating and drinking normally

Combination Therapy is Additive, Not Redundant

SGLT2 inhibitors and ACE/ARB work through different mechanisms and should be used together 1:

• ACE/ARB: Reduces intraglomerular pressure via efferent arteriole dilation
• SGLT2i: Reduces hyperfiltration via afferent arteriole vasoconstriction through tubuloglomerular feedback 5
• Never combine ACE inhibitor + ARB (potentially harmful) 1

Special Consideration: Nonsteroidal MRA as Third Agent

For patients with persistent albuminuria ≥30 mg/g despite maximum-tolerated ACE/ARB and SGLT2 inhibitor, consider adding finerenone (nonsteroidal MRA) if eGFR ≥25 mL/min/1.73 m² and potassium is consistently normal 1. This provides additional 18% reduction in cardiovascular outcomes and 14% reduction in renal outcomes 1.

Why This Approach Prioritizes Outcomes

SGLT2 inhibitors are the only drug class proven to reduce all three critical outcomes—CKD progression, cardiovascular events, AND all-cause mortality—in patients with established diabetic kidney disease 6, 2. The CREDENCE trial enrolled the exact population in question (diabetic nephropathy with eGFR 30-90 and albuminuria >300 mg/g) and demonstrated benefit when added to existing ACE/ARB therapy 2, 3. This makes SGLT2 inhibitors the priority addition, with ACE/ARB optimization following if not already maximized.