ACE inhibitor/ARB combo risky in patients with diabetic nephropathy

Using ACE inhibitors along with ARBs increased the risk of adverse events in patients with diabetic nephropathy in a study published online Nov. 9 in the New England Journal of Medicine. Investigators stopped the study early due to safety concerns.

“Combination therapy with angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain,” wrote the authors, led by Linda Fried, MD, MPH, of the Veterans Affairs (VA) Pittsburgh Healthcare System.

The VA NEPHRON-D study (Veterans Affairs Nephropathy in Diabetes) randomized 1,448 veterans from 32 VA facilities to receive either the ARB losartan (Cozaar, Merck) with the ACE inhibitor lisinopril (Prinivil, Merck) or the ARB alone. All participants had type 2 diabetes, an estimated glomerular filtration rate (GFR) of 30 to 89.9 mL per minute per 1.73 meters-squared of body-surface area and a urinary albumin-to-creatinine ratio of 300.

The primary endpoint was the first time there was a change in the estimated GFR (defined as either a decrease of 30 ml or more per minute per 1.73 meters-squared if the initial GFR was 60 ml or greater or a decrease of 50 percent or more if the initial GFR was less than 60 ml per minute per 1.73 meters-squared), end-stage renal disease (ESRD) or death. To assess safety, the investigators looked at mortality, hyperkalemia and acute kidney injury (AKI).

The study was stopped in October 2012 due to concerns over safety after an average follow-up time of 2.2 years. Among the participants in the combination therapy group, 152 experienced a primary endpoint event. There were 132 such events in the ARB-only group (hazard ratio [HR] 0.88).

There was some nonsignificant benefit from combination therapy in the secondary endpoint, but the trend decreased over time. But participants in the combination therapy group also did not benefit in terms of mortality risk (HR 1.04) or cardiovascular events. Their risk for hyperkalemia was also higher (6.3 events per 100 person-years vs. 2.6 events per 100 person-years in the monotherapy group) as was their risk for AKI (12.2 events per 100 person-years vs. 6.7 events per 100 person-years).

There were more serious adverse events in the combination-therapy group (98 per 100 person-years vs. 82 per 100 person years in the monotherapy group). AKI was the main reason for the difference between the groups. There were 190 AKI cases in the combination therapy group compared with 80 cases in the ARB-only group. 

“The patients in our trial represent a high-risk population with residual proteinuria, despite the use of a full dose of an ARB,” the authors wrote. “We had hypothesized that the benefit in slowing the progression of kidney disease would outweigh the risks of hyperkalemia and acute kidney injury associated with more intensive blockade of the renin-angiotensin system. However, the significant increase in risk overshadowed a nonsignificant trend toward a benefit with respect to the primary and secondary endpoints.”