Can Jardiance (empagliflozin) replace Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) for kidney protection in a patient with diabetes?

Can Jardiance Replace ACE Inhibitors or ARBs for Kidney Protection in Diabetes?

No, Jardiance (empagliflozin) cannot replace ACE inhibitors or ARBs—these medications work through complementary mechanisms and should be used together, not as substitutes. 1

Evidence-Based Treatment Framework

First-Line Therapy: SGLT2 Inhibitors AND RAAS Blockade

The American Diabetes Association recommends SGLT2 inhibitors as first-line therapy for all patients with diabetic kidney disease, but this is in addition to, not instead of, ACE inhibitors or ARBs. 1 The evidence demonstrates that:

• SGLT2 inhibitors reduce kidney failure, dialysis, or renal death by 30-40% even when added to maximum ACE inhibitor/ARB therapy, meaning they provide additional benefit beyond RAAS blockade alone. 1

• ACE inhibitors or ARBs remain essential as they delay progression of nephropathy in both hypertensive and normotensive diabetic patients through distinct mechanisms—reducing intraglomerular pressure and proteinuria independent of blood pressure effects. 2

Complementary Mechanisms of Action

These drug classes protect kidneys through different pathways:

• ACE inhibitors/ARBs reduce intraglomerular pressure by blocking angiotensin II-mediated efferent arteriolar vasoconstriction, decreasing proteinuria and slowing GFR decline. 2

• Empagliflozin reduces proximal tubular glucose reabsorption, which restores tubuloglomerular feedback, lowers intraglomerular pressure through a different mechanism, and provides metabolic benefits. 3, 4

• When combined, empagliflozin added to ACE inhibitor/ARB therapy in the EMPA-REG OUTCOME trial showed a 44% reduction in doubling of serum creatinine and 55% reduction in need for renal replacement therapy. 3

Clinical Algorithm for Diabetic Kidney Disease

Step 1: Initiate Both Drug Classes

• Start ACE inhibitor or ARB in all patients with diabetes and albuminuria (UACR ≥30 mg/g), regardless of blood pressure status. 2, 1

• Start SGLT2 inhibitor (empagliflozin) simultaneously in all patients with diabetic kidney disease, regardless of baseline glucose control. 1

Step 2: Titration Strategy

• Titrate ACE inhibitor or ARB to maximum tolerated dose approved for hypertension treatment. 2

• Monitor serum creatinine and potassium within 2-4 weeks of initiation or dose changes. 2

• Continue ACE inhibitor/ARB unless creatinine increases >30% from baseline, uncontrolled hyperkalemia develops despite interventions, or symptomatic hypotension occurs. 2

Step 3: Add Third Agent if Needed

• If albuminuria persists despite SGLT2 inhibitor and ACE inhibitor/ARB, add finerenone (a nonsteroidal mineralocorticoid receptor antagonist) for additional 18% reduction in composite kidney outcomes. 1

Critical Evidence from EMPA-REG OUTCOME

The landmark trial that established empagliflozin's renal benefits specifically enrolled patients already on ACE inhibitors or ARBs (>80% of participants), demonstrating that empagliflozin's benefits are additive to, not replacements for, RAAS blockade. 3

• Incident or worsening nephropathy occurred in 12.7% with empagliflozin versus 18.8% with placebo (hazard ratio 0.61), despite most patients receiving background ACE inhibitor/ARB therapy. 3

• The renoprotective effects were consistent across all baseline eGFR subgroups, including those with stage 2 and 3 CKD. 5, 3

Essential Monitoring Parameters

• Annual UACR testing to guide therapy intensity and track treatment response. 1

• Serum creatinine at least annually to estimate GFR and stage CKD progression. 1

• Potassium monitoring within 2-4 weeks of ACE inhibitor/ARB initiation or dose changes, as both ACE inhibitors/ARBs and potential future addition of finerenone increase hyperkalemia risk. 2, 1

Critical Pitfalls to Avoid

• Never discontinue ACE inhibitor/ARB when starting empagliflozin—this eliminates proven renoprotective benefits that are mechanistically distinct from SGLT2 inhibition. 1, 6

• Never combine ACE inhibitor with ARB—dual RAAS blockade increases adverse events (hyperkalemia, acute kidney injury, hypotension) without additional cardiovascular or kidney benefits. 2, 1

• Do not withhold empagliflozin in patients with eGFR 30-60 mL/min/1.73 m²—while glycemic efficacy decreases with declining kidney function, renoprotective benefits persist even in moderate CKD. 5, 3

Blood Pressure and Glycemic Targets

• Target blood pressure <130/80 mmHg for patients with diabetic kidney disease and albuminuria ≥30 mg/24 hours. 1

• Target HbA1c as close to 7% as safely possible without causing hypoglycemia to reduce risk and slow progression of diabetic kidney disease. 1

Strength of Evidence

The recommendation to use both drug classes together (not as substitutes) is supported by:

• Multiple large randomized controlled trials with hard clinical endpoints (ESRD, dialysis, death) published in high-impact journals. 3, 4

• Incorporation into major society guidelines including the American Diabetes Association, KDOQI, and American College of Cardiology. 2, 1, 6

• Consistent mechanistic data showing complementary pathways of kidney protection. 3, 4, 7