Olmesartan reduced the risk of microalbuminuria by 23% in normoalbuminuric patients with Type 2 diabetes and at least one additional cardiovascular disease risk factor, results from a large European trial showed.
The angiotensin receptor blocker also yielded unprecedented blood pressure control for this population of patients.
Those are the first key findings from the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study, which were unveiled during a press briefing at the annual meeting of the American Society of Nephrology.
Dr. Hermann G. Haller of the department of nephrology at Hannover (Germany) Medical School, who chaired the study, stated that, “Despite all of our efforts, we still have problems effectively treating diabetic nephropathy…. The problem for prevention is that we have to diagnose and treat it early. Microalbuminuria is the first sign of the pathogenesis of diabetic nephropathy. It is also an important marker of early development of cardiovascular disease and can indicate microvascular disease.”
The primary end point of the study was occurrence of microalbuminuria based on two or more positive morning spot urine measurements. Secondary end points were cardiovascular events, renal function, and microvascular morbidity.
With support from Daiichi Sankyo, which markets olmesartan, researchers in 19 countries enrolled 4,449 patients, aged 18-75 years, with well-controlled Type 2 diabetes. All patients were normoalbuminuric (defined as a level of 25 mg/g or less for men and 35 mg/g or less for women) and had at lease one additional cardiovascular risk factor, such as high triglyceride levels or hypertension. None of the participants had received an ACE inhibitor or an angiotensin receptor blocker within 6 months of participation.
The patients were randomized to receive either 40 mg olmesartan per day or placebo (conventional antihypertensive treatment without blockade of the renin-angiotensin system). The urine albumin creatinine ratio was determined every 6 months. Patients were followed for an average of 3.2 years.
At their discretion, study investigators could add calcium channel blockers, diuretics, or beta-blockers to the regimen to help patients achieve the target blood pressure goal of 130/80 mm Hg.
“It’s not that easy to put this [patient] population together,” Dr. Haller commented. “On the one hand we wanted to have very early disease with no signs of heart or organ damage. On the other hand, we wanted to have as many risk factors as possible in order to see the effect of the treatment strategy.”
The patients’ mean age was 58 years, mean duration of diabetes was 6 years, mean hemoglobin A1c level was 7.6%, and mean body mass index was 31 kg/m2. The mean baseline blood pressure was 141/84 mm Hg.
Dr. Haller reported that nearly 80% of patients in the olmesartan group reached the target BP of 130/80 mm Hg at 42 months, compared with about 75% of patients in the placebo group. “The percentage of patients reaching the blood pressure goal was very high,” he said. “ROADMAP will need further analysis to find out what this high percentage of control actually means.”
Over the study period, microalbuminuria occurred in about 8% of the patients in the olmesartan group and 10% of the patients in the placebo group, a statistically significant difference (hazard ratio 0.77). This translated into a risk reduction of 23% for the olmesartan group, compared with the placebo group.
After 1 year, the first incidence of microalbuminuria occurred in about 3% of patients in both groups. For the remainder of the study, fewer patients in the olmesartan group experienced microalbuminuria, compared with patients in the placebo group. “The divergence after 1 year indicates that the specific effects of olmesartan are not due to early hemodynamic changes that would have happened in the first couple of months,” Dr. Haller said in an interview. “We think that olmesartan has a specific, perhaps structural effect on the kidney, either in the glomeruli or in the basal membrane, in the microcirculation.”
Part of the reduced incidence in the olmesartan group can be attributed to blood pressure control, he added, “but the majority of the effect is explained directly by olmesartan. What we are actually affecting in the kidney and in the microvasculature I can only speculate on, whether it’s endothelium or protocytes, we don’t know at the moment.”
When the researchers assessed the blood pressure effect in the olmesartan group corrected for diastolic and systolic blood pressure, the risk reductions did not reach statistical significance (18% vs. 17%, respectively).
No adverse events from olmesartan were observed on renal outcomes, and the incidence of cardiovascular morbidity and mortality was low overall, affecting fewer than 1% of the entire study population. “Most likely the event rate is very low because of the excellent blood pressure control,” he said.
Some cardiovascular events were seen, such as a higher incidence of nonfatal stroke and sudden cardiac death in the olmesartan group, compared with the placebo group, but due to the small number of cases “we have to analyze this further,” Dr. Haller emphasized. “The steering committee thinks it is too early to draw conclusions from this data. We have to carry out follow-up.”
Trial results released at the American Society of Nephrology (ASN) Renal Week 2009.[Presentation title: Prevention of Albuminuria and Cardiovascular Morbidity With Olmesartan — The ROADMAP Trial. Abstract 7026]