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Microvascular Residual Risk Studies

11 February 2009
Residual risk of progression of diabetic nephropathy in patients treated with irbesartan
Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-60. s MICROVASCULAR RESIDUAL RISK Drug Therapy/Irbesartan 2001
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I
Objective and study population: To determine whether the use of an angiotensin-II-receptor blocker or a calcium-channel blocker would provide protection against the progression of nephropathy due to type 2 diabetes beyond that attributable to blood pressure lowering
Type of study: 3-arm randomized controlled study
Study population:

1,715 patients of both genders (mean age, 58 years) with type 2 diabetes, hypertension (BP >135/85 mmHg or antihypertensive treatment) and nephropathy defined as:

  • urinary protein excretion ≥900 mg per 24 hours
  • and serum creatinine concentration between
    - 1.0 and 3.0 mg/dL (88 and 265 μmol/L) in women
    - 1.2 and 3.0 mg/dL (106 and 265 μmol/L) in men
  • ACE inhibitors, angiotensin-receptor blockers, and calcium-channel blockers discontinued at least 10 days before the screening period
  • Blood pressure controlled with other agents during the screening period
  • Then, patients randomly assigned to receive either:
    • irbesartan 75 to 300 mg per day
    • amlodipine 2.5 to 10 mg per day
    • or placebo
  • Other antihypertensive agents used as needed; same target blood pressure for all 3 groups (≤135/85 mmHg or 10 mmHg lower than the value at screening)
Primary endpoint:

Composite endpoint of doubling of baseline serum creatinine concentration, development of end-stage renal disease, or death from any cause

Mean study duration: 2.6 years
Main results:
  • Blood pressure achieved during the study period:
    • irbesartan group: 140/77 mmHg (p<0.001 vs. placebo)
    • amlodipine group: 141/77 mmHg (p<0.001 vs. placebo)
    • placebo group: 144/80 mmHg
  • Effects of treatments on relative risks of outcomes: Tables 1 and 2

Table 1. Relative risks of outcomes: Primary composite endpoint


Relative risk reduction or increase

Relative risk


P value

Irbesartan vs. placebo

20% reduction




Irbesartan vs. amlodipine

23% reduction




Amlodipine vs. placebo

4% increase




Table 2. Relative risks of outcomes: Main secondary endpoints


Irbesartan vs. placebo

Irbesartan vs. amlodipine

Amlodipine vs. placebo

Doubling of serum creatinine

33% reduction (p=0.003)

27% reduction (p<0.001)

6% increase (p=0.60)

End-stage renal disease

23% reduction (p=0.007)

23% reduction (p=0.007)

No difference (p=0.99)

Death from any cause

8% reduction (p=0.57

4% increase (p=0.80)

12% reduction (p=0.40)


Author's conclusion : The angiotensin-II–receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure.


Glycemic control and blood pressure control are the cornerstones of prevention and treatment of diabetic nephropathy, the leading cause of end-stage renal disease in industrialized countries. Among antihypertensive agents that may be used in this setting, those acting on the renin-angiotensin-aldosterone system have received particular attention. Beyond the beneficial effects of blood pressure control, blockade of the intrarenal angiotensin II activity by either ACE inhibitors or angiotensin-II-receptor blockers has been shown to lower intraglomerular pressure,1 reduce proteinuria,2 and decreased collagen formation.(3)

The hypothesis tested in the Irbesartan Diabetic Nephropathy Trial (IDNT) was that, due to these complex activities, the angiotensin-II-receptor blocker irbesartan could slow the progression of diabetic retinopathy in patients with type 2 diabetes independently of its blood pressure-lowering effect.

A population of high-risk patients with advanced kidney disease

The entry criteria selected patients with advanced kidney disease: all had macroalbuminuria and elevated serum creatinine levels indicative of decreased kidney function (glomerular filtration rate was not estimated in this study), The IDNT participants had other characteristics of long-standing hyperglycemia and/or of advanced diabetes. More than two-thirds had retinopathy, while insulin therapy was used in about 60% of patients at study entry.

Progression of diabetic retinopathy significantly reduced, although a substantial residual risk persists

Lewis and the IDNT Collaborative Study Group reported a significant 20% reduction of the relative risk of progression (composite endpoint) in patients treated with irbesartan compared to those assigned to placebo. The reduction was 23% when the irbesartan group was compared to the amlodipine group. The authors stress that these reductions were independent of both the reduction of blood pressure and the nature of the nonstudy antihypertensive agents used. Patients from both the irbesartan and the amlodipine groups required 3 nonstudy drugs to control blood pressure (3.3 for those in the placebo group) and the distribution of classes of nonstudy drugs was similar in all groups. The significant differences reported were also independent of the glycated hemoglobin values which did not differ significantly between the 3 groups (mean value 8.1 to 8.2%).

These results are obviously positive, but looking at the other side of the coin, it becomes obvious that 80% and 77% of the progression of diabetic nephropathy that occurred in the placebo and amlodipine groups, respectively, were not prevented by irbesartan. Looking at the secondary endpoints, 77% of the progression to end-stage renal disease that occurred in both the placebo and amlodipine groups were not prevented by irbesartan.

In another study,(4) irbesartan 150 mg per day prescribed to type 2 diabetes patients with microalbuminuria reduced progression to macroalbuminuria by 39% (p<0.001), therefore leaving a residual risk of 61%. With irbesartan 300 mg per day, progression was reduced by 70%, but this decrease was not significant (p=0.08).

These and other studies led to recommend that hypertension in patients with type 2 diabetes should be treated with either an ACE inhibitor or an ARB(.5,)6 This is now incorporated into the updated standards of care for patients with type 2 diabetes.

All in all, IDNT is a fair example of a prospective randomized landmark trial demonstrating a significant and clinically meaningful progress in the prevention of microvascular risk (more precisely in slowing down the worsening of diabetic nephropathy) through control of a “classical” cardiovascular risk factor, while evidencing the persistence of a not-less-meaningful residual risk unaddressed by the intervention investigated.


1. Zatz R, et al. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 1986;77:1925-30.
2. Abbate M, et al. In progressive nephropathies, overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation. J Am Soc Nephrol 1998;9:1213-24.
3. Wolf G, Haberstroh U, Neilson EG. Angiotensin II stimulates the proliferation and biosynthesis of type I collagen in cultured murine mesangial cells. Am J Pathol 1992;140:95-107.
4. Parving HH, et al.; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870-8.
5. American Diabetes Association. Standards of medical care in diabetes--2011. Diabetes Care 2011;34(Suppl. 1):S11-S61.6. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. Eur Heart J 2007;28:88-136.

Key words Diabetic nephropathy – hypertension – irbesartan – amlodipine.