VA-NEPHRON D
Trial question
What is the role of combined therapy with ACEIs and angiotensin-receptor blockers in patients with T2DM who have diabetic nephropathy?
Study design
Multi-center
Double blinded
RCT
Population
Characteristics of study participants
1.0% female
99.0% male
N = 1448
1448 patients (12 female, 1436 male).
Inclusion criteria: patients with T2DM, a urinary albumin-to-creatinine ratio of at least 300, and an eGFR of 30.0 to 89.9 mL/min/1.73 m² of body-surface area.
Key exclusion criteria: known nondiabetic kidney disease, a serum potassium level > 5.5 mmol/L, treatment with sodium polystyrene sulfonate, or an inability to stop prescribed medications that increase the risk of hyperkalemia.
Interventions
N=724 combined angiotensin inhibition (losartan at a dose of 100 mg/day plus lisinopril at a dose of 10 to 40 mg/day).
N=724 monotherapy (losartan at a dose of 100 mg/day plus placebo).
Primary outcome
Decline in eGFR (by ≥ 30 mL/min if eGFR 60-90 at baseline, or by ≥ 50% eGFR 30-60 at baseline), ESRD, or death
18.2%
21%
21.0 %
15.8 %
10.5 %
5.3 %
0.0 %
Combined angiotensin
inhibition
Monotherapy
No significant
difference ↔
No significant difference in decline in eGFR (by ≥ 30 mL/min if eGFR 60-90 at baseline, or by ≥ 50% eGFR 30-60 at baseline), ESRD, or death (18.2% vs. 21%; HR 0.88, 95% CI 0.7 to 1.12).
Secondary outcomes
No significant difference in decline in eGFR or ESRD (10.6% vs. 14%; HR 0.78, 95% CI 0.58 to 1.05).
No significant difference in death (8.7% vs. 8.3%; HR 1.04, 95% CI 0.73 to 1.49).
No significant difference in CV events (18.5% vs. 18.8%; HR 0.97, 95% CI 0.76 to 1.23).
Safety outcomes
Significant differences in serious adverse events (57.5% vs. 52.5%, p = 0.06), including hyperkalemia (9.9% vs. 4.4%, p < 0.001) and AKI (18.0% vs. 11.0%, p < 0.001).
Conclusion
In patients with T2DM, a urinary albumin-to-creatinine ratio of at least 300, and an eGFR of 30.0 to 89.9 mL/min/1.73 m² of body-surface area, combined angiotensin inhibition was not superior to monotherapy with respect to decline in eGFR (by ≥ 30 mL/min if eGFR 60-90 at baseline, or by ≥ 50% eGFR 30-60 at baseline), ESRD, or death.
Reference
Fried LF, Emanuele N, Zhang JH et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013 Nov 14;369(20):1892-903.
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