Early blockade of the renin–angiotensin system with
two antihypertensive medications — enalapril and losartan — delayed
progression of retinopathy in more than 65% of patients with type 1 diabetes in
the Renin–Angiotensin System Study.
In the multicenter, randomized, controlled trial,
researchers randomly assigned 253 normotensive patients with type 1 diabetes
and normoalbuminuria to daily losartan 100 mg (Cozaar, Merck) enalapril 20 mg
(Vasotec, Merck) or placebo for five years.
The researchers measured blood pressure, albumin
excretion rate, HbA1c levels and pill counts quarterly; glomerular filtration
rate was assessed annually. Ninety-percent of the study population had a renal
biopsy at baseline and at five years.
At baseline, 9% of patients had moderate-to-severe
nonproliferative diabetic retinopathy, 18% had early nonproliferative
retinopathy, 34% had no diabetic retinopathy and 40% had minimal
nonproliferative retinopathy.
Administration of enalapril or losartan did not protect
the participants’ kidneys from damage or from losing function.
During five years, the primary endpoint — changes
in mesangial fractional volume per glomerulus — did not differ
significantly between the placebo (0.016 units), enalapril (P=0.38) or
losartan groups (P=0.26).
Five-year cumulative incidence of microalbuminuria was
17% in the losartan group (P=.01), 6% in the placebo group and 4% in the
enalapril group (P=.96).
The odds for retinopathy progression by two steps or
more was decreased by 65% in the enalapril group when compared with placebo
(OR=0.35) and by 70% in the losartan group (OR=0.30).
“Given the current status of our ability to predict
the risk for nephropathy, blockade of the renin–angiotensin system for the
primary prevention of diabetic nephropathy in patients with type 1 diabetes is
not supported by the present evidence,” the researchers wrote. “In
contrast, we found beneficial effects of the angiotensin-converting–enzyme
inhibitor enalapril and the angiotensin-receptor blocker losartan in reducing
the risk for progression of diabetic retinopathy.”
Chronic cough occurred in 12 patients assigned to
enalapril, six assigned to losartan and four patients assigned to placebo.
Three biopsy-related serious adverse events occurred during the study period,
but were completely resolved.
Mauer M. N Engl J Med. 2009;361: 40–51.
