Angiotensin-receptor blockers in diabetic nephropathy [Classics Series]

Classics Series, Landmark Trials in Medicine

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1. Irbesartan was associated with a significantly lower risk of doubling of serum creatinine concentration, developing end-stage renal disease, or death from all causes.

2. Serum creatinine concentration increased at a slower rate in patients receiving irbesartan compared to amlodipine and placebo groups.

Original Date of Publication: September 20, 2001

Study Rundown: The Irbesartan Diabetic Nephropathy Trial assessed the ability of an angiotensin-II-receptor blocker (ARB), irbesartan and a calcium-channel blocker (CCB), amlodipine to protect against renal deterioration in patients with nephropathy due to type 2 diabetes mellitus (T2DM). At the time of this study’s publication, inhibitors of the renin-angiotensin-aldosterone system were known to be effective in patients with nephropathy due to type 1 diabetes but no major trial had investigated these agents in patients with nephropathy due to T2DM. While no significant differences were observed between the amlodipine and placebo treatment groups, irbesartan was associated with a significantly lower relative risk of a composite end point that included doubling of serum creatinine concentration, onset of end-stage renal disease, and death from any cause (P=0.02 for placebo, P=0.006 for amlodipine). Irbesartan was also associated with a slower rate of increase in serum creatinine concentration. These protective effects were found to be independent of the drug’s benefit in lowering blood pressure.

In summary, the ARB, irbesartan has renoprotective effects in addition to lowering blood pressure in patients with nephropathy due to T2DM.

Please click to read study in NEJM

In-Depth [randomized, controlled study]: Originally published in 2001 in NEJM, this trial randomly assigned 1,715 patients with a documented diagnosis of T2DM and hypertension to one of three treatment arms: 1) the ARB, irbesartan, 2) the CCB, amlodipine, or 3) placebo. The target blood pressure for all patients was the same (135/85 mmHg or less) and blood pressure was managed as needed with antihypertensive agents other than ACE-inhibitors, ARBs, and CCBs. The primary end point was a composite of doubling of baseline serum creatinine concentration, development of end-stage renal disease, or death from any cause. A composite cardiovascular end point was measured as a secondary outcome.

The relative risk of the primary end point was not significantly different between the placebo and amlodipine groups. Patients receiving irbesartan had a 20% lower relative risk of the primary end point than patients in the placebo group (P=0.02) and a 23% lower risk that those in the amlodipine group (P=0.006). There was no significant difference in the occurrence of the composite cardiovascular outcome among the three groups. Serum creatinine concentration increased at significantly slower rates in the irbesartan group than in the placebo and amlodipine groups. Hyperkalemia requiring discontinuation of trial medication occurred more frequently in the irbesartan group than in the placebo and amlodipine groups.

By Adrienne Cheung and Andrew Cheung, M.D.

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