Best ACE Inhibitor or ARB for Proteinuria
Either an ACE inhibitor or an ARB is equally effective for treating proteinuria—there is no clinically meaningful difference between these drug classes in terms of kidney protection, proteinuria reduction, or mortality outcomes. 1, 2
Evidence Supporting Equivalence
The most authoritative guidance comes from major kidney disease guidelines:
KDIGO 2022 guidelines recommend initiating either an ACE inhibitor OR an ARB in patients with diabetes, hypertension, and albuminuria, with titration to the highest approved tolerated dose. 1 The guideline explicitly states these agents are interchangeable as first-line therapy.
KDOQI 2007 guidelines concluded that "no claims of superiority between ACE inhibitors and ARBs can be made" in type 1 diabetes, and a head-to-head comparison in type 2 diabetes suggested clinical equivalency. 1
A 2019 comparative effectiveness study of 1,120 CKD patients found no significant difference between ACEI and ARB groups in progression to end-stage renal disease (HR 1.31,95% CI 0.37-4.66, p=NS). 2 Both drug classes were superior to no treatment, but equivalent to each other.
Practical Selection Strategy
Since efficacy is equivalent, choose based on these practical considerations:
Select an ARB (such as losartan) if the patient has a history of ACE inhibitor-induced cough or angioedema, as ARBs cause significantly fewer side effects while providing identical renoprotection. 3
Select an ACE inhibitor if cost is a primary concern, as generic ACE inhibitors are typically less expensive than ARBs. 3
For diabetic nephropathy specifically, losartan has FDA approval for this indication (reducing progression of nephropathy in type 2 diabetes with elevated creatinine and proteinuria ≥300 mg/g). 4
Critical Dosing Principle
The dose matters far more than the specific agent chosen:
Titrate to the maximum tolerated dose, not just to blood pressure control. 1, 5 The goal is proteinuria reduction to <1 g/day. 5
Only 29.8% of patients with proteinuria receive maximal ACE inhibitor/ARB dosing in real-world practice, representing a major treatment gap. 6 This underdosing is the most common error in proteinuria management.
Accept up to 30% increase in serum creatinine after initiation—this is hemodynamic and expected, not a reason to stop therapy. 1, 5 Continue treatment unless creatinine rises >30% or refractory hyperkalemia develops.
What NOT to Do
Do not combine an ACE inhibitor with an ARB. 4 The VA NEPHRON-D trial definitively showed that dual therapy with losartan plus lisinopril provided no additional benefit for the combined endpoint of GFR decline, ESRD, or death, but significantly increased hyperkalemia and acute kidney injury compared to monotherapy. 4
- While older meta-analyses suggested combination therapy reduces proteinuria by an additional 440 mg/day 7, this short-term surrogate benefit does not translate to improved clinical outcomes and comes with increased harm. 4
Essential Supportive Measures
Dietary sodium restriction to <2.0 g/day is mandatory, as it enhances the antiproteinuric effect of both ACE inhibitors and ARBs synergistically. 5, 8, 9
Monitor serum creatinine and potassium within 2-4 weeks after starting or increasing the dose. 1 Hyperkalemia can often be managed with dietary potassium restriction, diuretics, or potassium binders rather than stopping the ACE inhibitor/ARB. 1
Counsel patients to hold ACE inhibitor/ARB therapy during intercurrent illnesses with volume depletion risk (vomiting, diarrhea, fever) to prevent acute kidney injury. 8, 9
Blood Pressure Targets
Target systolic blood pressure <120 mmHg using standardized office measurement in most patients with proteinuria, as lower targets provide additional renoprotection beyond proteinuria reduction alone. 5, 8