partial PPAR-γ agonist and may have SPPARγMs properties as well.43 Schupp et al used diet-induced obese mouse models and analysis of PPAR-γ protein conformation using protease protection to show that telmisartan directly interacts with the receptor, producing distinct conformational change compared with a TZD.43 Telmisartan signiﬁcantly reduced fasting plasma insulin and glucose levels and improved glucose tolerance and insulin sensitivity and caused signiﬁcantly less weight gain compared with mice treated with pioglitazone. In vivo studies therefore suggest that Telmisartan has the beneﬁcial properties of PPAR-γ agonists sans the side effects including sodium retention, peripheral edema and weight gain exhibited by some of the other full PPAR-γ agonists. The safety proﬁle may imply an important use for drugs like telmisartan in the treatment of metabolic syndrome.45 AMADEO trial2 In the AMADEO trial, diabetic patients fulﬁlling the inclu- sion criteria were prospectively randomized (double-blind, double-dummy, forced titration) to receive telmisartan (n = 419) or losartan (n = 441), following a 2-month drug-free wash- out period. Patients were treated for 52 weeks in a forced- titration dosing, reaching maximum doses of 100 mg/day losartan and 80 mg/day telmisartan. Add on therapy with other antihypertensive medications were provided in case SBP remained 130 mmHg and DBP 80 mmHg after forced titration of the study drugs. The two study arms did not have signiﬁcant differences in the use of adjunctive therapy. A drug-free follow up group included 346 patients for 2 months after the trial was concluded. After a 4-week run-in period, 860 hypertensive patients (BP 130/80 mmHg) with type 2 diabetes and overt nephropathy (UPC 700 mg/g) were randomized to one of two treatment arms: telmisartan 40 mg or losartan 50 mg. After 2 weeks, the doses were increased to 80 mg Table 3A Primary endpoint of AMADEO trial2 Primary endpoint Telmisartan Losartan Urine protein: creatinine 0.71 0.80 P value 0.0284 Table 3B Secondary endpoint of AMADEO trial2 Secondary endpoint Telmisartan 80 mg Serum creatinine 15% (12% to 18%) eGFR −6.49 (–7.56 to 5.42) Serum aldosterone −23 (–29% to 18%) CRP −6 (–15% to 4%) Abbreviations: CRP, C-reative protein; eGFR, estimated glomerular ﬁltration rate. Vascular Health and Risk Management 2009:5 Blockade of RAAS in diabetic kidney disease and 100 mg, respectively. If blood-pressure control was not at goal, 25 mg of hydrochlorothiazide (HCTZ) was added, and if blood pressure was still resistant, clinicians were free to add a calcium-channel blocker. Baseline characteristics between the two treatment arms were not statistically differ- ent. After one year of therapy with the two ARBs, telmisartan provided greater reductions in the amount of protein in the urine (Table 3A), a ﬁnding not attributed to blood-pressure control, as reductions in SBP and DPB were similar in both treatment arms. As per study protocol, after a 2-month period at study completion in which both drugs were stopped, inves- tigators reported a sustained and persistent antiproteinuric effect with the novel ARB, telmisartan. The persistent effect of telmisartan was surprising and the authors suggest that this beneﬁcial effect could be explained by differences in receptor bindings, duration of action, or lipophilicity between the two drugs used in the trial. The difference in secondary end points of serum creatinine, eGFR, serum aldosterone and CRP failed to reach signiﬁcance (Table 3B). Serum aldosterone tended to decrease to a greater extent in the telmisartan group, however statistical signiﬁcance could not be attained (p = 0.07). Does AMADEO trial unequivocally prove superiority of telmisartan? Based on the AMADEO trial, a telmisartan-based regi- men provides for robust anti-proteinuric effect in type 2 diabetic patients with hypertension and overt nephropathy. This anti-proteinuric effect is greater than a losartan-based regimen at levels of blood pressure that were not signiﬁcantly different between groups and is attributed to greater lipophilic- ity and longer duration of action of this drug. Based on avail- able trial data, this difference in anti-proteinuric effect may translate into better cardiovascular and renal outcomes. The contribution of confounding factors to telmisartan’s superiority over losartan remain unclear, especially telmis- artan’s partial PPAR-γ agonist effect. As discussed above, PPAR-γ agonists limit high glucose-induced inﬂammation in proximal tubular cells, exert anti-ﬁbrotic effects in the same cells by attenuating the increase in AP-1, TGF-β1 Losartan 100 mg 15% (12% to 18%) −6.50 (−7.56% to −5.43) −17% (–23% to −11%) 1% (−9% to 13%) P value 0.895 0.9913 0.0746 0.277 137