Combined angiotensin inhibition increased risks of adverse events in diabetic nephropathy

Combination therapy with an angiotensin-converting enzyme (ACE) inhibitor and angiotensin-receptor blocker (ARB) in patients with diabetic nephropathy was associated with an increased risk of adverse events, including hyperkalemia and acute kidney injury, a study found.

Researchers recruited patients from 32 Department of Veterans Affairs medical centers from July 2008 through September 2012. All patients had type 2 diabetes, a urinary albumin-to-creatinine ratio of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 mL/min/1.73 m².

Researchers administered losartan, starting with 50 mg/d and increasing to 100 mg/d if the potassium level remained below 5.5 mmol/L and the creatinine level did not rise by more than 30%. After at least 30 days, patients were randomized to receive lisinopril, 10 to 40 mg/d, or placebo.

The primary end point was the first occurrence of a change in the estimated GFR of ≥30 mL/min/1.73 m² if the initial estimated GFR was ≥60 mL/min/1.73 m² or a decline of 50% or more if the initial estimated GFR was <60 mL/min/1.73 m², end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia and acute kidney injury. Results were published Nov. 14 by the New England Journal of Medicine.

Among 1,448 patients with a median follow-up of 2.2 years, there were 152 primary end point events in the monotherapy group and 132 in the combination therapy group (21% vs. 18.2%; hazard ratio [HR], 0.88; 95% CI, 0.70 to 1.12; P=0.30). In October 2012, the data and safety monitoring committee recommended the study treatment be stopped, primarily due to rates of acute kidney injury. There were 190 acute kidney injury events in the combination therapy group (12.2 events per 100 person-years) compared to 105 acute kidney injury events in the monotherapy group (6.7 events per 100 person-years; HR, 1.7; 95% CI, 1.3 to 2.2; P<0.001). Researchers noted that the higher risk of acute kidney injury with combination therapy was evident from the start of treatment through 42 months of follow-up. Also, combination therapy was associated with more hyperkalemia (6.3 events per 100 person-years vs. 2.6 events with monotherapy; P<0.001).

While combination therapy did not provide a significant benefit for renal disease progression, mortality or cardiovascular disease, a benefit could not be ruled out since the trial was stopped early, the researchers wrote. However, conditional power calculations suggested that the observed effects on the primary end point would not have been significant even if the study had been completed.