Table 1 (Continued) Trial/year ONTARGET28 2008 Patient population 55 years or older with established atheroscle- rotic vascular disease or with diabetes with end-organ damage N 8542 Treatment arms Telmisartan/ramipril/ telmisartan + ramipril Primary endpoint Composite of dialysis, doubling of CR, and death Blockade of RAAS in diabetic kidney disease Final outcome Composite primary outcome was similar for telmisartan (1147 [13.4%]) and ramipril (1150 [13.5%]; HR 1.00, 95% CI 0.92−1.09), but was increased with combination therapy (1233 [14.5%]; HR 1.09, 1.01−1.18, p = 0.037). Abbreviations: BL, baseline; CI, conﬁdence interval; RR, relative risk; HR, hazard ratio; Cr, serum creatinine; CV, cardiovascular; HF, heart failure; CAD, coronary artery disease; MA, microalbuminuria; ESRD, end stage renal disease; RPF, renal plasma ﬂow; MI, myocardial infarction; N, number of patients enrolled; UAER, urine albumin excretion; wk, weeks; GFR, glomerular ﬁlteration rate; NIDDM, non-insulin-dependent diabetes mellitus; HOPE, Heart Outcomes Prevention Evaluation study; IRMA, IRbesartan in patients with type 2 diabetes with MicroAlbuminuria study; IDNT, Irbesartan Diabetic Nephropathy Trial; LIFE, Losartan Intervention For Endpoint reduction in hypertension Study; MARVAL, MicroAlbuminuria Reduction with VALsartan trial; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist; Losartan; BENEDICT, Bergamo Nephrologic Diabetes Complications Trial;TRENDY,Telmisartan versus Ramipril in renal Endothelial Dysfunction; INNOVATION, INcipieNt to OVert:Angiotensin II receptor blocker,Telmisartan, Investigation On type 2 diabetic Nephropathy;VIVALDI, inVestIgate the efﬁcacy of telmIsartan versus VALsartan in hypertensive type 2 DIabetic patients with overt nephropathy; ONTARGET, ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial. and overt nephropathy.17 Current management consensus statements from the National Kidney Foundation (NKF)/ Kidney Disease Outcomes Quality Initiative (KDOQI),10 American Diabetes Association (ADA),1 and Joint National Committee (JNC) VII18 advocate the use of ARBs for man- agement of patients with hypertension and DKD, even in those with advanced stages of nephropathy as well as in those with microalbuminuria. ARBs have been shown to exert their beneﬁcial effect by blood pressure reduction, improving endothelial dysfunction and reducing oxidative stress.17 Data from the Heart Outcomes Prevention Evaluation (HOPE) Study evaluated microalbuminuria as a progressive manifestation of overt type nephropathy in patients with type 2 diabetes as a secondary endpoint.19 Ramipril was shown to reduce the onset of overt nephropathy by 22%. Similar observations were reported in the Irbesartan type II Diabetic Nephropathy Trial (IDNT), irbesartan was superior to both placebo and amlodipine in improving time to the primary endpoint, which was the composite of doubling of baseline serum creatinine and development of ESRD.20 Interestingly, the beneﬁts of irbesartan were seen with similar reductions in blood pressure when compared to amlodipine, revealing non-hemodynamic effects of ARBs. However, this trial did not include ACE inhibition in its treatment arms. Another caveat that was borne out of post-hoc analyses was that initial changes in proteinuria were not independent predictors of long-term renal outcomes, but were dependent on speciﬁc treatment arms (in this case irbesartan). This effect was later tested in the AMADEO trial. Analysis of IDNT showed that over a follow up period of 2.6 years there was a 2.2 times increase in risk of doubling serum creatinine or ESRD in patients with systolic blood pressure (SBP) 149 mmHg Vascular Health and Risk Management 2009:5 compared with those with SBP 143 mmHg regardless of the intervention used for treatment of blood pressure. Among the patients achieving comparable reduction in SBP, the incidence of renal endpoints was lower in patients treated with irbesartan compared to amlodipine.21 The Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study (IRMA) further strengthened the results of IDNT by showing that irbesartan has a dose- dependent improvement in time to onset of DKD.22 After a follow up of 2 years, it was found that only 5.2% patients treated with irbesartan 300 mg progressed to overt nephropa- thy as opposed to 9.7% of those receiving irbesartan 150 mg and 14.9% of those receiving placebo. In fact, the IRMA study group hypothesized that the renoprotective effect of irbesartan was not fully evident in their original study due to dose limitations and they demonstrated even greater renal protection with 900 mg of irbesartan and minimal increase in side effects (IRMA-2). The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study (RENAAL) study was similar to the IDNT and IRMA studies and demonstrated delayed time to onset of renal dysfunction in the losartan treated group.23 Post hoc analyses of protein- uria as secondary endpoint showed that early response to losartan therapy is an important predictor of long term renal protection.24 Both baseline and residual (6 month) albu- minuria were linearly correlated with renal outcomes. The authors recommended reduction in albuminuria to the lowest achievable level as the optimum goal for therapy. MicroAlbuminuria Reduction With VALsartan (MARVAL) Study targeted urine microalbumin excretion (UAER) as the primary endpoint and demonstrated reduction in albuminuria to 56% of its baseline in both normotensive and hypertensive 133