Bichu et al type 2 diabetics after 6 months of intention to treat therapy.25 Importantly, the improvement in albuminuria was independent of blood pressure, as the amlodipine treatment arm achieved similar reductions in blood pressure, once again demonstrating non-hemodynamic effects of ARBs in modulating pathophysi- ology of DKD. The Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) compared the efﬁcacy of ACE inhibitor trandalopril versus non-dihydropyridine calcium channel blocker verapamil versus trandalopril alone versus verapamil alone versus placebo in delaying the incidence of microalbu- minuria in type 2 diabetics.26,27 The trandalopril containing arms demonstrated signiﬁcant delay in the development of microalbuminuria. Interestingly, ONTARGET evaluated the use of ACE inhibitor in prevention of early chronic kidney disease.28 RAAS control with ACE inhibitor has been shown to prevent the emergence of persistent microalbuminuria in patients with type 2 diabetes and apparently normal urinary albumin levels ( 20 μg/min). The Diabetics Exposed to Telmisartan and EnalaprIL (DETAIL) study was among the ﬁrst studies to compare the efﬁcacy of long-acting telmisartan with ACE inhibitor enalapril.29 Although there was an initial advantage in slow- ing down the decline in GFR with telmisartan, end of trial analyses could only demonstrate non-inferiority over enala- pril. Based on the ﬁndings of DETAIL, it may be argued that a more aggressive approach to renoprotection may be required in the long term.16 The recently published Telmisartan versus Ramipril in renal Endothelial DYsfunction (TRENDY) study provided the ﬁrst head-to-head comparison of an ARB and an ACE inhibitor on renal endothelial function.30 TRENDY was performed in 96 patients with type 2 diabetes who had mild-to-moderate hypertension (seated SBP/diastolic blood pressure [DBP] 140 to 180/90 to 110 mm Hg), normo- or microalbuminuria, and GFR 80 mL/minute/1.73 m2. Patients were randomized to either telmisartan 40 mg or ramipril 5 mg for 3 weeks, followed by telmisartan 80 mg or ramipril 10 mg for 6 weeks. Both telmisartan and ramipril improved nitric oxide activity (a measure of endothelial func- tion), with a trend toward superiority of telmisartan. There was also a signiﬁcant decrease in urinary albumin excretion from 9.0 to 7.3 mg/24 hours with telmisartan (p = 0.022), whereas the change from baseline with ramipril was not signiﬁcant. In the study to inVestIgate the efﬁcacy of telmIsartan versus VALsartan in hypertensive type 2 DIabetic patients with overt nephropathy (VIVALDI), both telmisartan and valsartan improved proteinuria by 33% at the end of 1 year.31 134 However, the beneﬁts from telmisartan were not signiﬁcantly greater than valsartan in this intention to treat analysis. The authors did note that patients in the valsartan treatment arm tended to receive additional antihypertensives in a greater proportion than the telmisartan group most probably due to the shorter half-life of the former drug.31 Moreover, pro- teinuria measurements were based on 24-hour urine protein collections. The INcipieNt to OVert: Angiotensin II recep- tor blocker, Telmisartan, Investigation On type 2 diabetic Nephropathy (INNOVATION) trial showed that telmisartan is able to prevent the transition to overt renal disease in Japanese patients after a mean follow-up of 1.3 years.32 The relative risk of transition to overt nephropathy was reduced by 66% and 55%, respectively, with telmisartan 80 mg and telmisartan 40 mg compared with placebo in the overall patient population. Thus, for every 3 patients treated, telmis- artan 80 mg prevented 1 transition to overt nephropathy over the course of approximately 1 year. The renoprotective beneﬁt of telmisartan was also apparent in patients who were normotensive at baseline, which suggests that there is a blood pressure-independent effect. In addition, INNOVATION showed treatment of patients with telmisartan could bring about regression of incipient disease, with 21.2% and 12.8% of patients in the telmisartan 80 mg and 40 mg arms respectively, becoming normoalbuminuric compared with 1.2% of patients receiving placebo (both doses p 0.001).32 Interestingly, both the DROP trial and the IRMA-2 substudy demonstrated a greater anti-proteinuric effect with ultra-high doses of ARBs while not signiﬁcantly achieving any further lowering in blood pressure.33,34,35 The recently published ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET trial) compared the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their com- bination in patients aged 55 years or older with established atherosclerotic vascular disease or diabetes with end-organ damage.28 The number of events for the composite primary outcome dialysis, doubling of serum creatinine, and death were similar for telmisartan and ramipril but was increased with combination therapy. The secondary renal outcome, dialysis or doubling of serum creatinine, was similar for telmisartan and ramipril and more frequent with combination therapy. The trial authors concluded that in people at high vascular risk, telmisartan’s effects on major renal outcomes are similar and non-inferior to those of ramipril. Although combination therapy reduced proteinuria to a greater extent than monotherapy, the net effect on renal outcomes was opposite. The take-home message was that, proteinuria by Vascular Health and Risk Management 2009:5