Microvascular Residual Risk Studies

COMMENT

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.