Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design

Background. Patients with type 2 diabetes are at increased risk of macro- and microvascular disease, and the presence of albuminuria and/or reduced kidney function further enhances macrovascular risk. Angiotensin-converting-enzyme inhibitors reduce both macro- and microvascular events, yet the residual renal and cardiovascular risk still remains high. Aliskiren a novel oral direct renin inhibitor that unlike ACEi and ARBs, lowers plasma renin activity, angiotensin I and angiotensin II levels, may thereby provide greater benefit compared to ACEi or ARB alone. Methods. The primary objective of the ALTITUDE trial is to determine whether aliskiren 300 mg once daily, reduces cardiovascular and renal morbidity and mortality compared with placebo when added to conventional treatment (including ACEi or ARB). ALTITUDE is an international, randomized, double-blind, placebo-controlled, parallel-group study, which will include three categories of high-risk patients with type 2 diabetes (aged >= 35 years): those with either urinary albumin/creatinine ratio (UACR) >= 200 mg/g; microalbuminuria (UACR) >= 20 < 200 mg/g and eGFR >= 30 < 60 mL/min/1.73 m(2); and thirdly, those with a history of cardiovascular disease and eGFR >= 30 < 60 mL/min/1.73 m(2) with or without microalbuminuria. ALTITUDE is an event driven trial that aims to randomize 8600 patients with a planned follow-up time of 48 months. The primary outcome measure is time to first event for the composite endpoint of cardiovascular death, resuscitated death, myocardial infarction, stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease or doubling of baseline serum creatinine concentration. Secondary endpoints include a composite CV endpoint and a composite renal endpoint. Conclusion. ALTITUDE will determine whether dual RAAS blockade with the direct renin inhibitor aliskiren in combination with an ACEi or ARB will reduce major morbidity and mortality in a broad range of high-risk patients with type 2 diabetes.