General Information on Diabetic Nephropathy
and the "Improving Outcomes in Diabetic Nephropathy" Trial
Chronic kidney disease is a major health problem, with recent data from NHANES III suggesting that as many as 19.2 million U.S. adults are afflicted. Many of these patients progress to end-stage renal disease, with current projections of 520,000 dialysis patients in the U.S. by 2010. Of these patients, diabetic nephropathy remains the number one cause of end-stage renal disease in the United States and around the world.
Important progress has been made in understanding the epidemiology and pathogenesis of this disease over the past 20 years; however, prevention and treatment lag behind. There is no cure for diabetic nephropathy, and the morbidity and mortality associated with this disease are excessive. Moreover, diabetic nephropathy disproportionately afflicts minority populations, including Hispanics and African-Americans.
Recent advances in the treatment of established diabetic nephropathy have included long-term administration of angiotensin converting enzyme inhibitors (ACEi) in type 1 diabetics and angiotensin II receptor blockers (ARBs) in type 2 diabetics diagnosed with nephropathy based on clinical and laboratory parameters. Unfortunately, these drug classes have not been shown to stop the progression of nephropathy. Consequently the rate of progression of kidney disease in most patients is still 4-5 times the normal rate of decline in filtration function of the kidney that accompanies the aging process. Therefore additional therapies are needed to further improve outcome in this patient population.
Recently, the COOPERATE trial showed the combination of the (ACEi) trandolapril + the (ARB) losartan was more renoprotective than either agent alone in non-diabetics with nephropathy, despite similar blood pressure control. However, there are no comparable studies in diabetics with nephropathy, a population that is known to benefit from either ACEi or ARB treatment. Moreover, there is a major safety concern with this approach in diabetics with nephropathy because of their greater likelihood of developing serious hyperkalemia.
The use of mineralcorticoid receptor antagonists (MRA) such as spirnolactone and eplerenone have been shown to offer significant benefit in patients with congestive heart failure and post myocardial infarction. However, hypertensive animal model studies have also demonstrated a significant benefit with use of MRA in slowing the progression of renal disease. While a recent study in diabetics has shown a superior reduction in albuminuria with the use of combination ACEi + MRA, no studies exist with patients with overt nephropathy and more advanced chronic kidney disease. Furthermore, no studies have directly compared the efficacy ACEi + ARB to ACEi + MRA.
Currently there is limited data on either the safety or efficacy of combination therapy with ARB or MRA in diabetic nephropathy. It is not clear that combination therapies consisting of an ACEi + ARB or an ACEi + MRA in diabetics with nephropathy would be superior to a high dose of an ACEi alone. The purpose of the "Improving Outcomes in Diabetic Nephropathy" trial is help establish the role of combination ACEi + ARB or ACEi + MRA in diabetic nephropathy by comparing reduction in proteinuria between the two groups and compared to ACEi + placebo.
