Data presented at Renal Week 2009 demonstrate that an angiotensin receptor blocker—olmesartan—appears to provide vascular protection in patients with type 2 diabetes by controlling blood pressure and delaying the occurrence of microalbuminuria.
According to the World Health Organization, about 170 million people in the world had diabetes in 2000, and that figure is expected to double within the next 20 years. The most prevalent form—type 2 diabetes—is usually associated with central (visceral) obesity, hyperinsulinemia, and insulin resistance as well as hypertension and dyslipidemia. This constellation of findings, often termed “the metabolic syndrome” (Figure 1), leads to premature cardiovascular, cerebrovascular, and renal disease.
Role of Microalbuminuria
Treatment and prevention of the metabolic syndrome, especially hypertension, are paramount to improving outcomes in patients with diabetes. “Unfortunately, treatment often comes too late because the metabolic syndrome has already translated into organ damage when interventions are implemented,” says Hermann G. Haller, MD. “Ideally, clinicians should strive to prevent this organ damage using markers for diagnostics as well as treatment. One of the integral markers is microalbuminuria.”
Microalbuminuria occurs when there is excess leakage of albumin from glomerular capillaries into urine. Microalbuminuria is a marker of generalized vascular disease as well as incipient diabetic nephropathy. While microalbuminuria is not indicative of overt cardiovascular disease (CVD) or kidney failure, it is an early marker and indicates the first pathological changes in the organs.
ROADMAP Study
The ROADMAP (Randomized Olmesartan and Diabetes Microalbuminuria Prevention) study was initiated to determine whether olmesartan, an angiotensin-receptor blocker (ARB), could prevent the development of microalbuminuria in subjects with type 2 diabetes (plus one additional cardiovascular risk factor) who had no microalbuminuria at baseline. The main results of the study were first presented at the American Society of Nephrology meeting in November 2009 (Figure 2). Overall, 4,449 participants who were not previously on an ACE inhibitor or an ARB entered the study and were followed on average for 3.2 years. Half were randomized to receive olmesartan 40 mg daily and half to placebo; other antihypertensive drugs (but no ACE inhibitors or ARBs) were also used to achieve a target blood pressure below 130/80 mm Hg in each participant.
The primary endpoint of ROADMAP was the time to the onset of confirmed microalbuminuria as documented by morning spot urine microalbumin-to-creatinine ratio. CVD events, morbidity and mortality, end-stage renal disease, and microvascular morbidity were secondary endpoints. Urine albumin-to-creatinine ratio levels were determined every 6 months. “In ROADMAP, we tried to treat patients with diabetes and hypertension early, even before they developed microalbuminuria,” says Dr. Haller, who was the lead investigator. “The goals were to lower blood pressure and prevent the occurrence of microalbuminuria.”
Important Findings
Blood pressure was exceptionally well controlled in ROADMAP, with 80% of subjects in the olmesartan group and 77% of subjects in the placebo group achieving the goal blood pressure of less than 130/80 mm Hg at 42 months, but there was a modest statistically significant difference (about 3/1 mm Hg) favoring the olmesartan group. Olmesartan was found to delay the onset of microalbuminuria by 23% (P=0.014).
With regard to other secondary endpoints, the ROADMAP investigators noted little difference in renal morbidity events between the olmesartan and placebo groups; cardiovascular events were also similar, but the study was not powered to detect a difference in cardiovascular or renal disease outcomes. Olmesartan was well tolerated, with an adverse-event profile similar to a placebo. The mortality rate and CVD event rates were among the lowest ever reported in a clinical trial, but there was a small difference in CVD-specific mortality in favor of placebo. Because this trend differs from other outcome trials in populations with higher CVD risk profiles, the investigators cautioned that it is too early to draw conclusions on mortality from ROADMAP.
More Research Coming
In addition to effective blood pressure lowering, the ROADMAP study demonstrated that olmesartan offers the potential benefit of preventing early vascular or renal disease in patients with type 2 diabetes and hypertension, but more research is necessary. An observational follow-up study is planned to help clinicians understand the long-term benefits of microalbuminuria prevention. The key is to determine if the positive effects seen with olmesartan use in ROADMAP will continue several years into the future. Dr. Haller says he and his team look forward to finding out if patients receiving an ARB can further benefit in the domains of risk reduction in heart failure, myocardial infarction, coronary artery disease, and stroke.
