Week 42 – 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]

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 definitively addressed 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.

Population: patients age 30-70 with T2DM, HTN, proteinuria (≥ 900mg/24hrs), and Cr 1.0-3.0 in women and 1.2-3.0 in men

Intervention: irbesartan, titrated from 75mg to 300mg per day

Comparison #1: amlodipine, titrated from 2.5mg to 10mg per day
Comparison #2: placebo

(All patients had a target SBP goal ≤ 135, and all patients were allowed non-ACEi/non-ARB/non-CCB drugs as needed.)

Outcomes:
Primary – time to doubling of serum Cr, onset of ESRD, or all-cause mortality

Secondary

  • individual components of the primary outcome
  • composite cardiovascular outcome – death from CV causes, nonfatal MI, hospitalization for CHF, CVA with permanent neurologic deficit, or lower limb amputation above ankle

Results:
1715 patients were randomized. Baseline characteristics were similar among the groups, except for a slightly lower proportion of women in the placebo group. The mean blood pressure after the baseline visit was 144/77 in the irbesartan group, 141/77 in the amlodipine group, and 144/80 in the placebo group (p = 0.001 for pairwise comparisons 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 secondary, cardiovascular outcome (see Table 3).

Sensitivity analyses were performed. Inclusion of baseline covariates in a Cox regression of the primary outcome did not alter the conclusions. Similarly, the conclusions of the primary analysis were not impacted significantly by adjustment for mean arterial pressure achieved during follow-up.

Hyperkalemia occurred in 1.9% of the irbesartan patients, but only 0.5% of the amlodipine patients and 0.4% of the placebo patients (p = 0.01 for both pairwise comparisons with irbesartan).


Implication/Discussion
:
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

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