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Adding lisinopril to losartan increased hyperkalemia and acute kidney injury in type 2 diabetes and proteinuria

Question In veterans with type 2 diabetes and proteinuria, does adding an angiotensin-converting enzyme (ACE) inhibitor to an angiotensin IIreceptor blocker (ARB) reduce progression of proteinuric diabetic nephropathy more than ARB monotherapy? Methods Design Randomized controlled trial (RCT) (Veterans Affairs Nephropathy in Diabetes [VA NEPHRON-D] study). ClinicalTrials.gov NCT00555217. Allocation {Concealed}*. Blinding Blinded {patients, clinicians, data collectors, and outcome assessors}*. Follow-up period Median 2.2 years. Setting 32 Veterans Affairs medical centers in the USA. Patients 1448 veterans (mean age 65 y, 99% men) who had type 2 diabetes, estimated glomerular filtration rate (eGFR) 30.0 to 89.9 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 300 mg/g. Exclusion criteria included adverse events while taking the full losartan dose during a run-in phase with losartan only (50 mg/d increased to 100 mg/d for 30 d if potassium level remained <5.5 mmol/L and creatinine did not increase by >30%). Intervention Lisinopril (n =724) or placebo (n =724) added to losartan. Lisinopril began at a dose of 10 mg/d and increased to 20 mg/d and then to 40 mg/d at 2-week intervals. Outcomes A composite of decline in eGFR (reduction in eGFR 30 mL/min/1.73 m2 if initial eGFR was 60 mL/min/1.73 m2 or 50% if initial eGFR was <60 mL/min/1.73 m2), end-stage renal disease, or death. Secondary renal endpoints included a composite of decline in eGFR or end-stage renal disease. Safety outcomes included death, hyperkalemia, and acute kidney injury {50% increase in creatinine from baseline}*. With an estimated 45% event rate in the control group and a 10% attrition rate, 1850 patients were needed to detect an 18% relative reduction in the primary outcome (85% power, =0.05). Patient follow-up 90% (intention-to-treat analysis). Main results The trial was stopped early because of increased hyperkalemia and acute kidney injury in the combination-therapy group. Groups did not differ for the primary or secondary renal composite endpoints or death (Table). Losartan plus lisinopril increased risk for hyperkalemia and acute kidney injury compared with losartan only (Table). Conclusion In veterans with type 2 diabetes and proteinuria, adding lisinopril to losartan increased risk for hyperkalemia and acute kidney injury. Losartan plus lisinopril vs losartan plus placebo in veterans with type 2 diabetes and proteinuria Outcomes Losartan plus lisinopril Losartan plus placebo At a median 2.2 y RRR (95% CI) NNT (CI) Decline in eGFR, ESRD, or death 18% 21% 11% (10 to 28) Not significant Decline in eGFR or ESRD 11% 14% 21% (5 to 40) Not significant RRI (CI) NNH (CI) Death 8.7% 8.3% 4% (26 to 46) Not significant Hyperkalemia 9.9% 4.4% 169% (77 to 300) 14 (8 to 30) Acute kidney injury 18% 11% 63% (28 to 106) 15 (9 to 33) eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; other abbreviations defined in Glossary. RRR, RRI, NNH, and CI calculated from control event rates and hazard ratios in article. Commentary Previous RCTs in patients with overt proteinuria have shown that blockade of the reninangiotensin system (RAS) using a single agent prevents clinically important renal outcomes (1). Dual inhibition (ACE inhibitors plus ARBs) reduced proteinuria more than a single agent alone (2), 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 (3). Similarly, a meta-analysis of 33 RCTs with >68000 patients found no benefit with dual blockade and increased risk for renal failure, hyperkalemia, and adverse effects in patients with or without heart failure (4). 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 (3). 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 (5). New therapies are needed.