Dual RAS Blockade No Better Than Monotherapy to Prevent Renal Disease Progression

For type 2 diabetes patients with established nephropathy, blocking the renin-angiotensin system (RAS) with two blood pressure drugs does not add any benefit over using just one of the drugs. A combination of the ACE inhibitor lisinopril with the angiotensin receptor blocker irbesartan had similar effects to monotherapy with either drug at doses that achieved the same level of blood pressure reduction.

José Luño, MD, head of the department of nephrology at the Hospital General Universitario Gregoria Marañón, presented results of this late breaking trial at the 49th European Renal Association–European Dialysis and Transplant Association Congress in Paris in May. He said that more severe proteinuria and lower estimated glomerular filtration rate (eGFR) at baseline, as well as vitamin D deficiency, were independent predictors of progression of type 2 diabetic nephropathy.

This multicenter, open-label, four-year follow-up clinical trial ran from 2005 to 2011. After a four-week drug wash out period, 133 participants were randomly assigned in a 1:1:2 fashion to lisinopril titrated from 10 to 40 mg/day (n = 35), to irbesartan titrated from 150 to 600 mg/day (n = 28), or to lisinopril 20 mg plus irbesartan 300 mg (n = 70) to achieve equivalent blood pressure lowering in each group. Medication doses were titrated up at the first and second monthly visits. Median follow-up was 32 months, over which time blood pressure, renal function, and proteinuria were measured.

Participants were at least 35 years old, had type 2 diabetes, hypertension, and clinical proteinuria with a urinary protein-to-creatinine ratio (UPCR) of at least 300 mg/g.

Luño Luño reported that blood pressure control was similar among the three arms of the study. Although eGFR declined in each group, there were no differences in the amount of decline among the lisinopril, irbesartan, and combination therapy groups at 6, 12, or 24 months, or at the end of the study. For each group the annual rate of decline in eGFR was about 3.4 mL/min/1.73 m2.

The composite primary endpoint of an increase of more than 50 percent in serum creatinine, progression to end stage renal disease (ESRD), or death was the same among the groups, with 29–30 in each group reaching it (hazard ratio 0.95). There was also no statistical difference among the groups in the proportion who achieved the individual components of the primary endpoint — 21–23 percent with a creatinine increase of at least 50 percent, 14–18 percent developing ESRD, and 4–7 percent dying.

“Those patients that achieved the renal endpoint — that progressed to renal disease —had at baseline higher proteinuria and lower renal function, [and] lower glomerular filtration rate,” Luño said. They also had lower blood hemoglobin values at baseline (p < .05 for all values, comparing patients who had progression of renal disease to those who did not).

Also, vitamin D levels were lower at baseline in the patients whose renal disease progressed (12.6 ng/mL) than in the ones who did not progress (16.9 ng/mL, p < 0.01).

In a multivariate regression analysis adjusting for age, sex, body mass index, treatment group, and vitamin D levels, the only significant independent predictors of the primary composite outcome were the baseline proteinuria (UPCR, hazard ratio = 1.32, p < 0.001) and the baseline eGFR (hazard ratio = 0.96, p = 0.03).

Only four patients dropped out of the study because of hyperpotassemia, an important adverse effect when the RAS is blocked. Nine patients died in the study.

Luño noted that the study was limited by the relatively small sample size, and the study was not done in a double-blind fashion. There may also have been confounding effects by the use of other drugs to control blood pressure and diabetes, which was permitted according to good clinical practice, and the investigators could not evaluate these possible effects.


[1] The trial was funded in part by Bristol-Myers Squibb of Spain.

[2] 49th European Renal Association - European Dialysis and Transplant Association Congress: No abstract (Late Breaker). Presented May 25, 2012.

July 2012 (Vol. 4, Number 7)