Week 5 – IDNT

“Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes”

aka the Irbesartan Diabetic Nephropathy Trial (IDNT)

N Engl J Med. 2001 Sep 20;345(12):851-60. [free full text]
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Diabetes mellitus is the most common cause of ESRD in the US. In 1993, a landmark study in NEJM demonstrated that captopril (vs. placebo) slowed the deterioration in renal function in patients with T1DM. However, prior to this 2002 study, no study had addressed definitively whether a similar improvement in renal outcomes could be achieved with RAAS blockade in patients with T2DM. Irbesartan (Avapro) is an angiotensin II receptor blocker that was first approved in 1997 for the treatment of hypertension. Its marketer, Bristol-Meyers Squibb, sponsored this trial in hopes of broadening the market for its relatively new drug.

This trial randomized patients with T2DM, hypertension, and nephropathy (per proteinuria and elevated Cr) to treatment with either irbesartan, amlodipine, or placebo. The drug in each arm was titrated to achieve a target SBP ≤ 135, and all patients were allowed non-ACEi/non-ARB/non-CCB drugs as needed. The primary outcome was a composite of the doubling of serum Cr, onset of ESRD, or all-cause mortality. Secondary outcomes included individual components of the primary outcome and a composite cardiovascular outcome.

1715 patients were randomized. The mean blood pressure after the baseline visit was 140/77 in the irbesartan group, 141/77 in the amlodipine group, and 144/80 in the placebo group (p = 0.001 for pairwise comparisons of MAP between irbesartan or amlodipine and placebo). Regarding the primary composite renal endpoint, the unadjusted relative risk was 0.80 (95% CI 0.66-0.97, p = 0.02) for irbesartan vs. placebo, 1.04 (95% CI 0.86-1.25, p = 0.69) for amlodipine vs. placebo, and 0.77 (0.63-0.93, p = 0.006) for irbesartan vs. amlodipine. The groups also differed with respect to individual components of the primary outcome. The unadjusted relative risk of creatinine doubling was 33% lower among irbesartan patients than among placebo patients (p = 0.003) and was 37% lower than among amlodipine patients (p < 0.001). The relative risks of ESRD and all-cause mortality did not differ significantly among the groups. There were no significant group differences with respect to the composite cardiovascular outcome. Importantly, a sensitivity analysis was performed which demonstrated that the conclusions of the primary analysis were not impacted significantly by adjustment for mean arterial pressure achieved during follow-up.

In summary, irbesartan treatment in T2DM resulted in superior renal outcomes when compared to both placebo and amlodipine. This beneficial effect was independent of blood pressure lowering. This was a well-designed, double-blind, randomized, controlled trial. However, it was industry-sponsored, and in retrospect, its choice of study drug seems quaint. The direct conclusion of this trial is that irbesartan is renoprotective in T2DM. In the discussion of IDNT, the authors hypothesize that “the mechanism of renoprotection by agents that block the action of angiotensin II may be complex, involving hemodynamic factors that lower the intraglomerular pressure, the beneficial effects of diminished proteinuria, and decreased collagen formation that may be related to decreased stimulation of transforming growth factor beta by angiotensin II.” In September 2002, on the basis of this trial, the FDA broadened the official indication of irbesartan to include the treatment of type 2 diabetic nephropathy. This trial was published concurrently in NEJM with the RENAAL trial. RENAAL was a similar trial of losartan vs. placebo in T2DM and demonstrated a similar reduction in the doubling of serum creatinine as well as a 28% reduction in progression to ESRD. In conjunction with the original 1993 ACEi in T1DM study, these two 2002 ARB in T2DM studies led to the overall notion of a renoprotective class effect of ACEis/ARBs in diabetes. Enalapril and lisinopril’s patents expired in 2000 and 2002, respectively. Shortly afterward, generic, once-daily ACE inhibitors entered the US market. Ultimately, such drugs ended up commandeering much of the diabetic-nephropathy-in-T2DM market share for which irbesartan’s owners had hoped.

Further Reading/References:
1. “The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.” NEJM 1993.
2. CSG Captopril Trial @ Wiki Journal Club
3. IDNT @ Wiki Journal Club
4. IDNT @ 2 Minute Medicine
5. US Food and Drug Administration, New Drug Application #020757
6. RENAAL @ Wiki Journal Club
7. RENAAL @ 2 Minute Medicine

Summary by Duncan F. Moore, MD