"Combination Therapy in Patients with Diabetic Nephropathy". The New England Journal of Medicine. 2013.
Links to original sources: Wiki Journal Post Full Journal Article
In patients with diabetic nephropathy and proteinuria, does combination therapy with angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) compared to monotherapy with ARBs improve renal outcomes and reduce mortality?
Combination therapy with an ACE inhibitor and an ARB in patients with diabetic nephropathy was associated with an increased risk of adverse events, including hyperkalemia and acute kidney injury, without providing a significant benefit in slowing disease progression, decreasing mortality, or reducing cardiovascular events.
The use of ACE inhibitors or ARBs has been shown to slow the progression of proteinuric kidney disease. Combination therapy with both classes of medication further reduces proteinuria, but the effects on the progression of kidney disease and the safety profile of this approach were uncertain. The VA NEPHRON-D study assessed the safety and efficacy of combination therapy versus monotherapy in slowing the progression of proteinuric diabetic nephropathy. The trial was discontinued early due to safety concerns resulting from increased rates of serious adverse events such as hyperkalemia and acute kidney injury with combination therapy. No significant benefit was detected regarding the primary composite outcome linked to renal-disease progression or death.
Current guidelines do not recommend the combination of ACE inhibitors and ARBs for the treatment of diabetic nephropathy due to associated risks without clear benefits.
- Multicenter, double-blind, randomized, controlled trial - N=1448 participants - Losartan monotherapy (100 mg per day) group - Combination therapy (Losartan 100 mg per day + Lisinopril 10 to 40 mg per day) group - Median follow-up: 2.2 years - Interventions: After a losartan run-in period, participants were randomized to either lisinopril or placebo while continuing losartan. - Primary endpoint: First occurrence of a decline in the estimated GFR, end-stage renal disease (ESRD), or death.
- Inclusion criteria: Type 2 diabetes, urinary albumin-to-creatinine ratio of at least 300, estimated GFR of 30.0 to 89.9 ml per minute per 1.73 m2. - Exclusion criteria: Known nondiabetic kidney disease, serum potassium >5.5 mmol per liter, current treatment with sodium polystyrene sulfonate, inability to stop medications that increase the risk of hyperkalemia.
- Participants were initially provided with losartan and then randomized to receive lisinopril (titrated from 10 to 40 mg per day) or matching placebo.
- Primary Outcome: No significant difference in the risk of the primary endpoint between the two groups. - Secondary Outcomes: Trend suggesting a benefit from combination therapy for secondary renal endpoints, which decreased over time. - Mortality and Cardiovascular Events: No benefit with respect to mortality or cardiovascular events. - Safety Outcomes: Combination therapy increased the risk of hyperkalemia and acute kidney injury.
- The early termination of the trial could have led to an underestimation of the potential benefits of the combination therapy. - The trial does not definitively rule out any possible benefit due to fewer accrued events than planned.
The Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development funded the study. Merck provided the study drugs.
- Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892-1903.