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Combination angiotensin inhibition increased hyperkalemia, acute kidney injury in diabetic neuropathy
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Combination therapy with an angiotensin-converting enzyme inhibitor and an angiotensin-receptor blocker was tied to an increased risk for hyperkalemia and acute kidney injury among patients with diabetic neuropathy, according to data from the VA NEPHRON-D study.
These findings suggest the use of combination therapy does not provide an overall clinical benefit, according to Linda F. Fried, MD, MPH, from the Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh School of Medicine, and colleagues.
“The rate of hyperkalemia in the combination therapy group was more than double the rate in the monotherapy group,” researchers wrote.
Patients with type 2 diabetes were administered losartan 100 mg per day (Cozaar, Merck) and randomly assigned to lisinopril 10 mg to 40 mg per day or placebo. Median follow-up was 2.2 years.
The primary endpoint was the first change in the estimated glomerular filtration rate (eGFR), end-stage renal disease or death. The secondary renal endpoint was the first decline in the eGFR or end-stage renal disease. Safety outcomes included all-cause mortality, hyperkalemia and acute kidney injury.
Combination therapy appeared to increase the risk for hyperkalemia (6.3 events per 100 person-years vs. 2.6 events per 100 person-years with monotherapy; P<.001) and acute kidney injury (12.2 events per 100 person-years vs. 6.7 events per 100 person-years; P<.001), researchers wrote.
Therefore, the study was halted in October 2012 due to safety concerns.
In an accompanying editorial, Dick de Zeeuw, MD, PhD, from the department of clinical pharmacology at the University of Groningen and University Medical Center Groningen in the Netherlands, wrote that the results of the VA NEPHRON-D study add to available data and clarify that dual renin-angiotensin-aldosterone system (RAAS) blockade for the treatment of patients with diabetes cannot currently be recommended.
“For now, dual RAAS blockade can be resuscitated only if we can show renal and cardiovascular protection in a defined group of patients in whom the desired decreases in blood pressure, albuminuria, or both are achieved without major increases in potassium levels or other side effects,” de Zeeuw wrote.
Of 1,448 patients, there were 152 primary endpoint events in the monotherapy group and 132 events in the combination therapy group (HR=0.88; 95% CI, 0.70-1.12), according to researchers.
Secondary endpoints signaled a trend toward a benefit in the combination therapy group (HR=0.78; 95% CI, 0.58-1.05), which decreased over time (P=.02), according to data. However, there was no mortality or CV benefit (HR=1.04; 95% CI, 0.73-1.49).
For more information:
De Zeeuw D. N Engl J Med. 2013;doi:10.1056/NEJMe1312286.
Fried LF. N Engl J Med. 2013;doi:10.1056/NEJMoa1303154.
Disclosure: Fried reports receiving support from Reata Pharmaceuticals as a site investigator for a study. See the study for a full list of disclosures. De Zeeuw reports personal fees from AbbVie, Astellas, AstraZeneca, Bristol-Myers Squibb, Chemocentryx, Johnson & Johnson, Novartis, Reata and Takeda.