麻豆传媒

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ATLANTA -- In yet another trial, dual blockade of the renin-angiotensin system (RAAS) didn't slow progression of kidney disease in diabetic patients and carried a higher risk of serious adverse events compared with monotherapy, researchers reported here.

The was stopped early in October 2012 because of increased rates of hyperkalemia and acute kidney injury among patients taking both an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) compared with monotherapy, according to , of the VA Pittsburgh Healthcare System, and colleagues.

They reported their findings simultaneously here at and online in the .

"Our study doesn't support the use of a combination of an ACE inhibitor and an ARB in patients with diabetic and proteinuric kidney disease," the authors stated.

Some previous research has shown that combination therapy with an ACE inhibitor and an ARB can diminish proteinuria, which ideally can prevent progression of diabetic kidney disease, but it's not clear whether that's the case.

Fried and colleagues enrolled 1,448 patients with type 2 diabetes who had a urinary albumin-to-creatinine ratio of at least 300, and an estimated glomerular filtration rate (eGFR) of 30 to 89.9 mL/min/1.73m².

All patients were put on losartan (100 mg/day), with an add-on of either lisinopril (10 to 40 mg/day) or placebo.

The primary endpoint was a composite of the first occurrence of a change in eGFR, end-stage renal disease (ESRD), or death.

Although the trial was stopped early, the median follow-up was 2.2 years, and the researchers found a similar proportion of primary endpoint events in both groups (152 with monotherapy or 21%; 132 with combination therapy or 18.2%).

Fried noted that it's impossible to definitively rule out a potential benefit of combination therapy because the trial was halted early, although she said that it "looked like the treatment was not safe and if you continued the study, the chance you'd see a benefit to outweigh that increased risk was small."

There was a trend toward a benefit from combination therapy on a secondary endpoint looking at change in eGFR or ESRD (without mortality). However, it wasn't significant (14% with monotherapy and 10.6% with combination therapy), and there were no benefits with regard to mortality or cardiovascular events, the researchers reported, although the treatments did reduce proteinuria.

There were more serious adverse events among those on combination therapy, particularly an increased risk of hyperkalemia (6.3 versus 2.6 events per 100 person-years, hazard ratio 2.8, 95% CI 1.8-4.3, P<0.001) and acute kidney injury (12.2 versus 6.7 events per 100 person-years, HR 1.7, 95% CI 1.3-2.2, P<0.001).

Fried and colleagues said the results are consistent with those of the ONTARGET and ALTITUDE trials, which showed increased harms and no cardiovascular or renal benefit with combination therapies that block the renin-angiotensin system.

In an accompanying editorial, , of University Medical Center Groningen in the Netherlands, wrote that taken together, these three trials "not only show that dual therapy does not decrease cardiovascular and renal morbidity, but also suggest that dual therapy carries an increased risk."

"Indeed, two of the three trials -- ALTITUDE and the VA NEPHRON-D trial -- were stopped early for safety reasons," he added.

"The effect of these 'failed' trials goes beyond the decision about whether we should use dual RAAS blockade in order to better protect our patients with diabetes," he continued. "The results suggest that improvement in surrogate markers -- lower blood pressure or less albuminuria -- does not translate into risk reduction."

He concluded that the literature now makes it "clear that dual RAAS blockade for the treatment of patients with diabetes cannot currently be recommended."