Diabetes mellitus currently affects 18.2 million Americans, roughly 6.3% of the total population . Diabetic nephropathy (DN) affects 10–21% of people with diabetes mellitus, and is the leading cause of end-stage renal disease in the USA, accounting for approximately 43% of new cases of end-stage renal disease . DN is characterized by the development of microalbuminuria, which, if left untreated, can lead to overt proteinuria, a progressive decline in renal function, and eventually renal failure .
Randomized trials have consistently demonstrated the benefit of ACE inhibitors (ACEIs) [4–8] and angiotensin receptor blockers (ARBs) [9–11] in slowing the progression of DN in patients with both Type 1 and Type 2 diabetes mellitus. The results of these trials are reflected in numerous guidelines. For instance, the American Diabetes Association position statement recommends an ACEI or an ARB for all patients with microalbuminuria or advanced stages of nephropathy . The National Kidney Foundation guidelines on hypertension and anti-hypertensive agents in chronic kidney disease recommend that patients with diabetic kidney disease, with or without hypertension, should be treated with either an ACEI or an ARB .
Although this body of literature clearly supports the use of either an ACEI or an ARB, there is a growing interest in dual blockade of the renin–angiotensin–aldosterone system (RAAS) for the treatment of DN. The RESOLVD Pilot Study demonstrated that combining enalapril with candesartan provided superior suppression of left-ventricular remodelling and RAAS neurohormones than either therapy alone . This trial demonstrates that single-drug therapy directed against the RAAS results in incomplete blockade of this system, a phenomenon commonly referred to as ‘ACE escape’. While the notion of ACE escape provides a rationale for the combination of an ACEI and an ARB in treating diseases associated with the RAAS such as DN, the RESOLVD pilot study did not examine this end point.
Several studies have examined the role of combined ACEI/ARB therapy for DN [15–27]. Although these studies support the benefit of combination therapy, all but one were small, involving only 24 patients or less. Therefore, less is known about the role of dual RAAS blockade in patients with DN. The purpose of this meta-analysis is to pool the results of these small studies in order to better understand the role of dual angiotensin II antagonism for the treatment of DN.