itself cannot be taken as a deﬁnitive marker of improved renal function, and that the beneﬁts of any treatment, including combination blockade of the RAS on major renal outcomes, remain to be elucidated. Rationale for AMADEO trial Substantial evidence has accumulated over the last decade in favor of using RAAS inhibitors for slowing down the progression and onset of DKD. Use of ARB and ACE inhibition is clearly superior to the use of non-RAAS blood pressure control medications in ameliorating renal damage at similar levels of blood pressure control.20 This may be due to the non-hemodynamic and metabolic improvements in the cardiovascular system including better endothelial func- tion, reduced oxidative stress, decrease in inﬂammation and ﬁbrosis. Evidence has emerged demonstrating that a 30% reduction in proteinuria at 6 months to 1 year following ini- tiation of treatment was associated with slower progression of DKD and a reduction in the incidence of cardiovascular events, independent of reductions in blood pressures. The ARBs have been shown to be non-inferior to ACE inhibi- tors in achieving blood pressure control and reductions in proteinuria, often leading to interchangeable regimens based on these drugs depending on the tolerability by patients. Telmisartan, an ARB with high lipophilicity, a high level of angiotensin II type-1 (AT1) receptor (AT1R) binding and a long half-life is currently FDA approved for the treatment of hypertension but is not indicated yet for the treatment of proteinuria in patients with diabetes. Instead, losartan is currently approved as a ﬁrst-line treatment for DKD. Telmisartan has been reported to achieve smoother blood pressure control with fewer side effects when compared to other ARBs. In addition, animal experiments have demon- strated other potential mechanisms for its beneﬁcial effects including PPAR-γ agonist properties.36 All of these properties together may make telmisartan an ideal drug to achieve the target of 30% reduction in proteinuria ultimately resulting in a slower progression to kidney failure. Table 2 Pharmacokinetics of ARBs37,38,39 Drug Bioavailability (%) Half-life (hours) Losartan 33 2 (6–9) Valsartan 25 9 Irbesartan 70 11–15 Telmisartan 43 24 Eprosartan 15 5–7 aThe logarithm of the ratio of the concentrations of the un-ionized solute in the solvents is called log P (partition coefﬁcient). Vascular Health and Risk Management 2009:5 135 Blockade of RAAS in diabetic kidney disease Pharmacology of telmisartan Telmisartan is a potent, long-lasting, non-peptide antagonist of the AT1R. It selectively and insurmountably inhibits stimulation of the AT1 receptor by angiotensin II without affecting other receptor systems involved in cardiovascular regulation. Very high lipophilicity, a unique feature of telmis- artan, coupled with a high volume of distribution; indicate that the compound offers a clinically important advantage of good tissue penetration (Table 2). Due to its physicochemical properties, telmisartan shows excellent oral absorption and tissue penetration.38 Afﬁnity for AT1 receptor Studies have demonstrated that telmisartan has the stron- gest binding afﬁnity to AT1 receptor among various ARBs (Table 2). The rank order of afﬁnity is in the following order; telmisartan olmesartan candesartan EXP3174 valsartan losartan.39 The ﬁndings of AMADEO suggest that telmisartan may have long-lasting blood pressure-low- ering effects and superior cardioprotective properties in patients with hypertension due to its strong AT1 receptor antagonistic ability. Pharmacokinetics Telmisartan is not a pro-drug and has a longer terminal elimination half-life than other commercially available sartans (∼24 hours), making it suitable for once-daily dosing. The compound is not metabolized by cytochrome P450 isoenzymes and has a low risk for P450-based drug interactions.37,38 A relevant fact to be noted is that unlike other ARBs, where up to 50% of the dose is excreted by the kidney, only 1% of a telmisartan dose in excreted by the kidney. Therefore renal impairment is unlikely to affect the pharmacokinetics of telmisartan.37 Telmisartan has a pharmacokinetic proﬁle that allows differentiating it from other angiotensin receptor blockers; long duration of action (mean terminal half-life of 24 hours, the longest in its class) and high tissue penetration (illustrated by the Lipophilicity (log P)a −2.45 −0.95 +1.48 +1.48 – Protein binding (%) 98.7 95 90 99 98 AT1 receptor afﬁnity 20 nmol/L 1.3 nmol/L 2.7 nmol/L 3.7 nmol/L 1.4–3.9 nmol/L