Adding lisinopril to losartan increased hyperkalemia and acute kidney injury in type 2 diabetes and proteinuria
In a trial of more than 1,000 diabetic patients with proteinuria, adding an ACE inhibitor to an ARB didn't improve estimated glomerular filtration rate and increased risk for hyperkalemia and acute kidney injury, so the trial was halted early.
In a randomized, controlled trial (RCT) of more than 1,000 diabetic patients with proteinuria, adding an angiotensin-converting enzyme (ACE) inhibitor to an angiotensin II receptor blocker (ARB) didn't improve estimated glomerular filtration rate (eGFR) and increased risk for hyperkalemia and acute kidney injury, so the trial was halted early.
The study was published in the New England Journal of Medicine on Nov. 14, 2013. A summary of the study was published in the December 2013 ACP DiabetesMonthly. The following commentary by Catherine M. Clase, MB, BChir, and Johannes F.E. Mann, MD, was published in the ACP Journal Club section of the March 18 Annals of Internal Medicine.
Previous RCTs in patients with overt proteinuria have shown that blockade of the renin–angiotensin system (RAS) using a single agent prevents clinically important renal outcomes. Dual inhibition (ACE inhibitors plus ARBs) reduced proteinuria more than a single agent alone, making this an attractive strategy. The VA NEPHRON-D study assessed whether dual blockade of the RAS improves clinically important outcomes compared with losartan alone in patients with diabetes, low eGFR, and proteinuria. The methodologically rigorous trial was stopped early because of increased harm without evidence of benefit. Recent randomized trials have shown similar results. Similarly, a meta-analysis of 33 RCTs with >68,000 patients found no benefit with dual blockade and increased risk for renal failure, hyperkalemia, and adverse effects in patients with or without heart failure. Dual RAS blockade is consistently harmful. There are no data to support the idea that the results of VA NEPHRON-D do not generalize to nondiabetic kidney disease.
What is the next step for improving outcomes in patients with diabetic nephropathy? It is unlikely that the harmful and potentially beneficial effects of more intense RAS inhibition could be dissociated given that both result from the same renal physiologic events. Such novel agents as bardoxolone have also been disappointing. New therapies are needed.