Achtergrond: Microalbuminurie voorspelt diabetische nefropathie en premature cardiovasculaire ziekten vroegtijdig.
In deze studie werd onderzocht of een ARB (Angiotensine-receptorblokker) het optreden van microalbuminurie zou kunnen  voorkomen bij patiënten met diabetes type II.
Methoden: 4447 patiënten met diabetes type II werden gerandomiseerd in een dubbelblinde trial naar placebo of olmesartan (1dd 40mg) voor een mediane periode van 3.2 jaar. Additionele antihypertensieve medicatie was toegestaan (behalve ACE remmers of ARBs) bij een bloeddruk boven de 130/80. Het primaire eindpunt was de tijd tot het optreden van microalbuminurie. De tijd tot het optreden van renale en cardiovasculaire events werden als secundaire eindpunten geregistreerd.
Resultaten: Bloeddrukreductie werd bereikt bij 80% van de olmesartangroep en in 71% van de placebogroep. In de olmesartangroep ontwikkelden 8,2% van de patiënten microalbuminurie en 9,8% van de patiënten in de placebogroep.
In de olmesartangroep werd een hogere frequentie gezien van cardiovasculaire events, met name in de groep patiënten met pre-existent hartlijden. Niet-fatale cardiovasculaire events traden daarentegen minder vaak op in de olmesartangroep.
Conclusies: Olmesartan was geassocieerd met een vertraagd optreden van microalbuminurie ten opzichte van placebo bij patiënten met diabetes type II ondanks het feit dat in beide groepen de bloeddrukreductie uitstekend was naar huidige standaarden. Echter, er bestaat een verhoogde incidentie van cardiovasculaire events bij patiënten met pre-existent cardiovasculair lijden die olmesartan gebruikten.

 
Lees onderstaand het volledige artikel.

ARB Averts Early Sign of Diabetic Nephropathy

Preemptive treatment with an angiotensin-receptor blocker (ARB) may delay onset of microalbuminuria in type 2 diabetes but with a concerning signal for cardiovascular death, a randomized trial showed. The ARB olmesartan added on top of good blood pressure control extended the time to development of microalbuminuria onset by 23% compared with placebo (median 576 days versus 722, P=0.01), according to Hermann Haller, MD, of the Hannover Medical School in Hannover, Germany, and colleagues. But this advantage came with a concerning rise in fatal cardiovascular events with olmesartan (15 cases [0.7%] versus three with placebo [0.1%], P=0.01), they reported in the March 10 issue of the New England Journal of Medicine.

The cardiovascular events were largely seen in patients with preexisting heart disease (2.0% versus 0.2%, P=0.02).

Those findings from the 4,447-patient Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) trial, along with the similar elevated cardiac death risk with olmesartan among diabetic nephropathy patients in the ORIENT trial, prompted an FDA review of the drug's safety last year that has yet to reach a verdict.

Despite its size, ROADMAP was markedly underpowered for cardiovascular endpoints, given the small number of events in the relatively healthy population studied, cautioned Julie R. Ingelfinger, MD, deputy editor of the NEJM, in an accompanying editorial. The opposite signal in nonfatal cardiovascular events (3.6% olmesartan versus 4.1% placebo, P=0.37) might argue that the cardiovascular deaths were a chance finding, she noted. A real effect is plausible, though, she suggested. The high dose of a drug promoted for its rapid blood pressure reduction may have dropped pressure too low in high-risk patients, Ingelfinger implied, pointing to the correlation of excess cardiovascular deaths with being in the lowest quartile of BP. If so, that would fit with the well-known but somewhat controversial "J-curve effect," Haller's group noted. "However, a direct effect of olmesartan cannot be ruled out," they wrote. The trial randomized patients with type 2 diabetes to 40 mg of olmesartan once daily or placebo for a median of 3.2 years of double-blind treatment with additional non-ARB, non-ACE antihypertensive drugs used as needed to keep blood pressure under 130/80 mm Hg. Nearly all the trial participants (97%) had at least two cardiovascular risk factors in addition to diabetes; more than two-thirds had at least four risk factors. Blood pressure reached the target more often with the addition of olmesartan (nearly 80% versus 71%) with a 3.1/1.9 mm Hg lower mean compared with placebo.

Aside from the interactions of cardiovascular death risk with lower blood pressure and preexisting coronary heart disease, being in the highest quartile for reduction in systolic pressure during double-blind treatment was also a predictor of risk.

Systolic blood pressure over 135 mm Hg was associated with the microalbuminuria benefit, among other factors.

The lower rate of microalbuminuria onset with olmesartan (8.2% versus 9.8%) wasn't mirrored by a difference in renal function (1% of patients in both groups had a doubling in serum creatinine level). Olmesartan was associated with a small but significant -- about 4 ml/minute/1.73 m2 -- reduction in estimated glomerular filtration rate, but the researchers suggested that averting microalbuminuria might be of greater importance in the long run. The researchers noted that their short-term prevention study could not determine how the microalbuminuria effect would impact the long-term rate of renal and cardiovascular events.

Serious adverse events were similar between groups, though drug-related adverse events were more common with olmesartan (11.4% versus 7.5%, P<0.001), in part due to more hypotension (58 versus six cases, P<0.001) and dizziness (103 versus 61, P=0.001). Until the FDA reaches its conclusion, opinions are likely to remain divided, with one group finding it encouraging that the small excess risk seen in the trial hasn't led to a black box warning during months of FDA review and another group that sees plenty of other ARB and ACE options not associated with a signal for cardiovascular death risk, Ingelfinger concluded.
 

1. Haller H, et al "Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes" N Engl J Med 2011; 364: 907-17.