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Fried LF, et al. "Combined angiotensin inhibition for the treatment of diabetic nephropathy". The New England Journal of Medicine. 2013. 369(20):1892-1903.
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Clinical Question

In patients with T2DM, CKD stage 2-3, and elevated urine albumin:creatinine, does the addition of an ACE inhibitor to ARB therapy prevent eGFR reduction, ESRD, or death?

Bottom Line

Among patients with T2DM, CKD stage 2-3, and elevated urine albumin:creatinine ratio, the addition of an ACE inhibitor to ARB therapy does not prevent eGFR reduction, ESRD, or death. Additionally, combination therapy is associated with increased rates of AKI and hyperkalemia.

Major Points

The 1993 CSG Captopril Trial demonstrated that the ACE inhibitor captopril prevented progression of DM nephropathy in patients with T1DM. The 2001 RENAAL trial demonstrated efficacy of the ARB losartan in patients with T2DM nephropathy. Whether adding an ACE inhibitor to ARB therapy would provide further benefit in T2DM with DM nephropathy and was unknown.

The 2013 Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial enrolled 1,448 patients with T2DM and DM nephropathy defined by urine albumin:creatinine ratio ≥300 and CKD stage 2-3. Participants were randomized to losartan 100 mg PO qday plus either lisinopril 10-40 mg PO qday or placebo. With a median follow-up of 2.2 years, the trial was stopped early when an interim safety analysis demonstrated increased rates of hyperkalemia (4.4% vs. 9.9%; NNH 18) and AKI (11.0% vs. 18.0%; NNH 14) with combination therapy. There was no benefit for the primary endpoint of reduction eGFR, ESRD, or death. Participants on combination therapy did experience a greater reduction in albuminuria, raising the question of adequacy of this test as a surrogate for diabetic nephropathy outcomes.[1]

VA-NEPHRON D joins multiple other studies demonstrating the lack of benefit and increased risk of complications with combination ACE inhibitor and ARB therapy for multiple conditions, most notably ONTARGET (2008, high risk CVD). Similarly, the 2012 ALTITUDE trial[2] showed no benefit but increased risk with the addition of the direct renin inhibitor aliskiren to either an ACE inhibitor or ARB in patients with T2DM.


2017 ACC AHA AAPA ABC ACPM AGS APhA ASH ASPC NMA PCNA Hypertension (2017, adapted)[3]

  • New definitions for BP ranges: Normal BP is <120/<80, elevated BP is 120-129/<80, stage 1 HTN is 130-139/80-89, and stage 2 HTN is ≥140/≥90 mm Hg
  • Use antihypertensive medications if prior clinical CVD or 10-year ASCVD risk score is ≥10% and BP is ≥130/≥80 mm Hg (COR I, LOE A for SBP and C-EO for DBP)
  • Use antihypertensive medications if no prior clinical CVD and 10-year ASCVD risk score is <10% and BP is ≥140/≥90 mm Hg (COR I, LOE C-LD)
  • First line agents include thiazide diuretics (chlorthalidone preferred), CCBs, and ACE-inhibitors or ARBs (COR I, LOE A)
  • If CKD, treat to BP goal <130/80 mm Hg (COR I, LOE B-R for SBP and C-EO for DBP)
    • If CKD stage ≥III or stage I or II with albuminuria ≥300 mg/day or ≥300 mg/g alb:creat, treating with ACE-inhibitor (COR IIa, LOE B-R) or ARB (COR IIb, LOE C-EO) is reasonable to slow kidney disease progression
    • If kidney transplantation, it's reasonable to target BP <130/80 mm Hg (COR IIa, LOE B-NR for SBP and C-EO for DBP), with calcium antagonist as choice to improve GFR and kidney survival (COR IIa, LOE B-R)


  • Multi-centered, randomized, double-blinded, placebo-controlled trial
  • N=1,448
    • Losartan (n=724)
    • Losartan+lisinopril (n=724)
  • Setting: 32 Veterans Affairs medical centers
  • Enrollment: 2008-2012 (stopped early)
  • Analysis: intention-to-treat
  • Median follow-up: 2.2 years
  • Primary efficacy outcome: First occurrence of decreased eGFR, ESRD, or death
  • Primary safety outcome: Hyperkalemia and acute kidney injury


Inclusion Criteria

  • Previously diagnosis of T2DM
  • CKD stage 2-3 (eGFR of 30-89.9ml/min per 1.73 m2 of body surface area as calculated by the MDRD formula)
  • Random urinary albumin:creatinine ≥300

Exclusion Criteria

  • Known non-diabetic kidney disease
  • Serum potassium >5.5 mmol/L
  • Current treatment with sodium polystyrene sulfonate
  • Inability to stop prescribed medications that increase risk of hyperkalemia

Baseline Characteristics

From the losartan group. Groups were similar.

  • Demographics: Age 65 years, male 99.6%
    • Race: White 73%, Black 24%, other 3%
    • Hispanic: 10%
  • Baseline health data: BMI 34 kg/m2, BP 137/72 mmHg
  • PMH: CAD 23%, HF 15%, retinopathy 43%
  • Baseline medications:
    • BP-medications: Diuretic 70%, CCB 57%, beta-blocker 69%, alpha-blocker 22%, other 20%
    • Either study medication classes at baseline: ACE-inhibitor 70%, ARB 16%, both 5%, neither 8%
  • Baseline labs: Tchol 159 mg/dL, LDL 84 mg/dL, HDL 39 mg/dL, TG 162 mg/dL, hgb a1c 7.8%, potassium 4.3 mmol/L
    • Renal specific:
      • Creatinine 1.5 mg/dL
      • GFR 54 mL/min/1.73 m2
        • 30-44.9 mL/min/1.73 m2: 30%
        • 45-59.9 mL/min/1.73 m2: 33%
        • ≥60 mL/min/1.73 m2: 38%
    • Urine albumin:creatinine: 862
    • Urine protein:creatinine: 1.6


  • All participants had their ACE inhibitors or ARBs discontinued and were started on losartan 50 mg/day, increased to 100 mg/day if potassium <5.5 mmol/L and creatinine did not increase by >30%
  • After 30 days on the full dose of the medication, patients without adverse events were randomized to a group with stratification by site, GFR, proteinuria, and ACE inhibitor/ARB dual therapy at enrollment:
    • Losartan plus placebo
    • Losartan plus lisinopril
      • Lisinopril or its placebo dosing was increased every two weeks from 10 mg/day to 20 mg/day to 40 mg/day as long as no side effects and as long as creatinine remained <5.5 mmol/L and creatinine did not increase by >30% from baseline
  • BP medications were modified to target SBP 110-130 mmHg and DBP <80 mmHg
  • Potassium 5-6 mmol/L managed by dietary modifications, diuretics, and other medications


Comparisons are losartan vs. losartan+lisinopril.

Primary Outcome

First occurrence of change in eGFR, ESRD, and death
Change in eGFR defined as decrease ≥30 mL/min/1.73 m2 if eGFR ≥60 mL/min/1.73 m2 or relative decrease ≥50% confirmed >4 weeks after treatment of potentially reversible factors.
21.0% vs. 18.2% (HR 0.88; 0.70-1.12; P=0.30)

Secondary Outcome

First occurrence of change in eGFR and ESRD
14.0% vs. 10.6% (HR 0.78; 0.58-1.05; P=0.10)

Additional Outcomes

Safety outcomes
All-cause mortality: 8.3% vs. 8.7% (HR 1.04; 95% CI 0.73-1.49; P=0.75)
Serious adverse events[4]: 52.5% vs. 57.5% (P=0.06)
Attributed to study medications, % of all: 0.9% vs. 1.8% (P is significant though not given)
Hyperkalemia: 4.4% vs. 9.9% (HR 2.8; 95% CI 1.8-4.3; P<0.001; NNH 18)
Potassium >6mmol/L or requiring ED visit, hospitalization, or HD.
AKI: 11.0% vs. 18.0% (HR 1.7; 95% CI 1.3-2.2; P<0.001; NNH 14)
Requiring hospitalization or occurring during a hospitalization.
MI, HF, or stroke
18.8% vs. 18.5% (HR 0.97; 95% CI 0.76-1.23; P=0.79)
Individual components of composite outcomes
ESRD: 5.9% vs. 3.7% (HR 0.66; 95% CI 0.41-1.07; P=0.07)
HF: 14.6% vs. 12.3% (HR 0.82; 95% CI 0.62-.109; P=0.17)
Stroke: 2.5% vs. 2.5% (HR 0.98; 95% CI 0.52-1.85; P=0.95)
eGFR over time
-2.9 vs. -2.7 ml/min/1.73 m2/year (P=0.17)
Decline in albumin
creatinine from randomization to 1 year
Greater reduction with losartan+lisinopril
829 to 701 vs. 786 to 517 (P<0.001)

Adverse Events

Serious adverse events
Atrial arrhythmias: 2.3% vs. 2.9%
Hypertension: 1.7% vs. 1.7%
Hypotension: 1.9% vs. 1.7%
Fall: 2.8% vs. 2.3%
Syncope: 1.2% vs. 1.4%
Hyperglycemia: 2.3% vs. 1.7%
Hypoglycemia: 3.0% vs. 2.8%
GIB: 1.4% vs. 3.3%
Anemia: 1.9% vs. 2.5%
COPD: 3.3% vs. 2.3%
Dyspnea: 1.4% vs. 0.3%
Respiratory failure: 1.5% vs. 1.2%
Taking lisinopril at ≥10 mg or its placebo daily at end of the dose-adjustment period
83.9% vs. 79.3%

Subgroup Analysis

There was no difference for the primary outcome for predefined subgroups including eGFR ≥ or <60 mL/min/1.73 m2, albuminuria ≥ or <1 g/gram creatinine, history of prior dual ACE inhibitor/ARB therapy, age ≥ or <65 years, and race.


  • Stopped early so underpowered for primary outcome analysis
  • Essentially zero female participants precludes generalizability[5]
  • Poor outcomes may be related to the high dose of the medications rather than the fact that multiple classes are used[5]
  • Given that ACE inhibitors are mostly excreted by the kidney and ARBs are mostly excreted through the biliary system, starting with ACE inhibitors first with an ARB add-on may have delineated patients who were unlikely to tolerate dual therapy without an uncontrollable reduction in renal function[5]
  • Unclear definition of AKI[5]
  • Unclear clinical significance of a potassium level of 6 to 6.5 mmol/L[5]
  • The predefined subgroups did not include many groups of clinical importance including uncontrolled HTN, HF, and severe proteinuria[5]
  • The target SBPs of 110-130 mmHg have not been shown to be associated with better outcomes in diabetics[5]


Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development

Further Reading