“ROADMAP” Controversies

Microalbuminuria is a precursor to diabetic nephropathy and a predictor of cardiovascular (CV) disease. ¹ Physicians are urged to screen all diabetic patients for microalbuminuria and, once established, to treat patients early with agents that inhibit the renin‐angiotensin‐aldosterone system. Previously, angiotensin‐converting enzyme (ACE) inhibitors were shown to be beneficial in delaying the onset of microalbuminuria in patients with type II diabetes (DM) and normal renal function. ³ There is now evidence that these benefits are also present with the use of the angiotensin receptor blocker (ARB) olmesartan; however, this study has been shrouded in controversy.

The Randomized Olmesartan and Diabetes Microalbuminuria Prevention Trial (ROADMAP) was a double‐blind, multicenter randomized controlled trial with 4447 patients from 19 European countries with DM and normoalbuminuria. ⁴ No prior use of ACE inhibitors or ARBs was permitted for 6 months prior to enrollment. Patients were randomized to receive either 40 mg of olmesartan vs placebo. Blood pressure (BP) goal of <130/80 mm Hg was achieved using additional antihypertensive drugs aside from ACE inhibitors or ARBs. The primary outcome was time to first onset of microalbuminuria. Secondary end points included time to onset of renal and CV events. Median follow‐up period was 3.2 years. Target BP was achieved in nearly 80% of the olmesartan group vs 71% in the placebo group. BP was 3.1/1.9 mm Hg lower in the olmesartan group than in the placebo group. Microalbuminuria developed in 8.2% of the active treatment group vs 9.8% in the placebo group. Time to onset of microalbuminuria was increased by 23% in the olmesartan group. The serum creatinine doubled in 1% of the patients in each group. There were slightly fewer nonfatal CV events in the olmesartan group vs placebo (3.6% vs 4.1%; P=.37), but interestingly, there was a greater number of fatal CV events in the olmesartan group vs placebo (15 vs 3 patients (0.7% vs 0.1%; P=.01). There was a higher rate of preexisting coronary heart disease in the olmesartan group vs the placebo group (2.0% vs 0.2%; P=.02). The fatal CV event rate, although higher in the olmesartan group, was still extremely low. In further analysis of study patients with preexisting CV disease, there were more fatal events in patients with the lowest and highest quartiles of BP after treatment, indicating a possible “J‐curve” phenomenon.

In the Olmesartan Reducing Incidence of End‐Stage Renal Disease in Diabetic Nephropathy Trial (ORIENT) in patients with preexisting diabetic nephropathy, ⁵ the addition of olmesartan to preexisting treatment also resulted in a higher rate of death from CV causes (10 patients vs 3 patients). Due to the increased rate of fatal CV death (although admittedly low) both these studies are under investigation by the Food and Drug Administration (FDA). To date, the FDA has not yet announced any conclusions concerning the risk of death with olmesartan.

Like many good studies, ROADMAP poses as many questions as it provides answers. How much did the extra BP reduction in the olmesartan group contribute to the microalbuminuria benefit, and was it a two‐edged sword perhaps contributing, albeit modestly, to the greater CV death in that group through a J‐curve type of effect? An even more important issue, in our opinion, is the ultimate benefit of microalbuminuria prevention. There is little to support substantial CV protection based on the experience of Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) when factoring in effects on urine protein excretion. ⁶ , ⁷ In addition, although protein excretion is one of the most powerful predictors of future kidney function impairment, it remains challenging to sort out whether urine albumin excretion is more of a “reporter” on conditions that influence ultimate loss of kidney function or a critical component in the causal pathway of kidney function decline, and thus a therapeutic “target.”