A Prospective, Randomized, Probe Trial to Evaluate Whether,at Comparable Blood Pressure Control,Combined Therapy With ACEI BEN and ARB VAL Reduces Progression to ESRD More Effectively Than BEN or VAL Alone in High Risk Patients With Type 2 Diabetes and Overt Nephropathy

Introduction Nephropathy of type 2 diabetes is the leading cause of end stage renal disease (ESRD). Currently, more than 50% of patients on renal replacement therapy in the US are diabetics. The yearly incidence of diabetics progressing to ESRD and the proportion of ESRD patients with diabetes is progressively increasing due to the progressively increasing prevalence of type 2 diabetes worldwide.

Two large, multinational trials in overt nephropathy of type 2 diabetes found that interruption of the renin angiotensin system (RAS) with angiotensin II receptor blockers (ARBs) reduces the incidence of ESRD by about 30%, but has no appreciable effects on cardiovascular mortality. On the basis of these findings, ARB therapy has become standard treatment of patients with type 2 diabetes and nephropathy. However, despite ARB treatment, about 7% of patients continue to progress to ESRD and 7% continue to die every year.

Large-scale randomized trials evaluating the nephro- and cardio-protective effects of RAS inhibition with angiotensin-converting enzyme (ACE) inhibitors in overt nephropathy of type 2 diabetes are missing. However, studies in patients with type 1 diabetic nephropathy showed that ACE inhibitor therapy may decrease progression to ESRD by 40% and cardiovascular mortality by about 50%. Similar studies in non diabetic chronic nephropathies. consistently found a 40-50% reduction in the risk of progression to ESRD with ACE inhibitors as compared to non-RAS inhibitor therapy. Moreover, a meta-analysis of studies including type 2 diabetic patients with different degree of renal involvement showed that ACE inhibitors and ARBs sheared a similar renoprotective effect, but only ACE inhibitors significantly decreased the cardiovascular mortality.

A recent trial in non diabetic nephropathies found that combined RAS inhibition with ARBs and ACE inhibitors decreases progression to ESRD by 50% as compared to ARB or ACE inhibition alone. Evidence that combined therapy more effectively than ACE inhibitor or ARB therapy alone reduces albuminuria or proteinuria in patients with type 2 diabetes, suggests that a similar renoprotective effect could be achieved also in overt nephropathy of type 2 diabetes. Indeed, short-term proteinuria reduction is a strong predictor of slower progression of renal disease and reduced cardiovascular mortality in the long term.

A randomized trial powered to detect a reduced incidence of ESRD or cardiovascular mortality with combined ARB and ACE inhibition as compared to ACE inhibition or ARB alone would require several thousands of patients. However, identifying high risk patients who may benefit the most of nephro- and cardio-protective therapy would allow to design an adequately powered trial with remarkably less patients. By using a Bayesian decision-tree analysis we identified, among patients included in the RENAAL study, a subgroup of high risk patients with a baseline serum creatinine of 1.8 mg/dl or more and spot morning urine albumin to creatinine ratio >1000mg/g or more. Of note, over 3.5 year follow-up, 70% of these high-risk patients progressed to ESRD despite ARB therapy. Thus, the incidence of ESRD was three-fold higher in high-risk patients (20%) than in the whole study group (6.8%). High risk patients with these clinical characteristics are therefore the ideal target for randomized clinical trials aimed to evaluate the effect of novel nephro- and, possibly, cardio-protective treatments in overt nephropathy of type 2 diabetes.