Novel ARB Provides Greater Reductions in Proteinuria in Diabetics With Overt Nephropathy

May 22, 2007

May 22, 2007 (Chicago, IL) – One year of treatment with the novel angiotensin receptor blocker (ARB) telmisartan provided greater reductions in proteinuria when compared with losartan, a drug approved for the treatment of diabetic nephropathy to prevent renal-disease progression [1]. The greater protection was not attributed to differences in blood pressure, as investigators say the drug likely altered biology independent of hemodynamic changes, because the antiproteinuric effects were sustained with telmisartan two months after therapy was stopped.

These are the results of a new study, which included hypertensive patients with diabetes mellitus and overt nephropathy, presented here this week at the American Society of Hypertension 2007 Scientific Sessions. Dr George Bakris (University of Chicago, IL), lead investigator of the AMADEO trial and an editorial board member of Medscape Nephrology, said the increasing rates of end-stage renal disease (ESRD) are caused by the increased rates of diabetes mellitus and that the costs associated with ESRD are enormous.

"The metabolic burden and its consequences on organs are really incredible," said Bakris. "This is all being driven by increased obesity rates around the world."

Longer acting and greater binding to the receptor

Presenting the results of the study, Bakris explained that proteinuria, while being associated with kidney disease and progression to dialysis, is also linearly associated with cardiovascular risk. Blockers of the renin angiotensin system, such as ARBs, are essential to reducing renal-disease progression in diabetes, he said, with a >30% reduction in proteinuria at six to 12 months associated with slowed progression of diabetic nephropathy and reduced cardiovascular events, all independent of blood-pressure changes.

The hypothesis of the AMADEO trial, then, was to examine differences between telmisartan and losartan, two different pharmacological agents, and whether these differences translate into greater and more persistent reduction in urinary proteins over time. Telmisartan, explained Bakris, is the longest-acting ARB, and there are clear differences in binding to the AT1 receptor, with approximately 25% greater binding of telmisartan compared with losartan.

After a four-week run-in period, 860 hypertensive patients (>130/80 mm Hg) with type 2 diabetes and overt nephropathy were randomized to one of two treatment arms: telmisartan 40 mg or losartan 50 mg. After two weeks, the doses were increased to 80 mg and 100 mg, respectively. If blood-pressure control was not achieved, 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 different.

Mean change in urinary protein:creatinine after one year of treatment

End point Telmisartan (n=407) Losartan (n=420) p (between groups)
Mean final:baseline urine protein:creatinine ratio 0.71 0.80 0.0284

After one year of therapy with the two ARBs, telmisartan provided greater reductions in the amount of protein in the urine, a finding not attributed to blood-pressure control, as reductions in systolic and diastolic blood pressure were similar in both treatment arms. As per study protocol, after a two-month period in which both drugs were stopped, investigators report a sustained and persistent antiproteinuric effect with the novel ARB.

"At one year, one of the things that is really on the mind of theFDA, as well as on the mind of clinicians, in terms of whether you're actually altering the natural history of disease, is the persistent effect," said Bakris. "So we stopped the drugs at one year and followed the patients for two months to see what would happen with changes in proteinuria. We wanted to know whether everything would come back to where it was a year earlier or would everything stay down."

The persistent effect of telmisartan was surprising, said Bakris, but could be explained by differences in receptor bindings, duration of action, or lipophilicity between the two agents. With similar levels of blood-pressure control, the longer-acting, higher-binding telmisartan may confer relatively greater protection of ESRD, but that hypothesis needs to be tested in clinical trials, he said.

  1. Bakris G, Burgess E, Weir M et al. Comparative long-term effects of two AT1 receptor blockers on proteinuria in patients with type 2 diabetes and overt nephropathy and hypertension: results of the AMADEO study. American Society of Hypertension 2007 Scientific Sessions; May 21, 2007; Chicago, IL.

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