Correspondence

Renal and Retinal Effects of Enalapril and Losartan in Type 1 Diabetes

N Engl J Med 2009; 361:1410-1411October 1, 2009

Article

To the Editor:

Mauer et al. (July 2 issue)1 used structural hallmarks of diabetic renal disease to show that early blockade of the renin–angiotensin system did not slow progression of type 1 diabetic nephropathy. The study excluded patients whose blood pressure was greater than 135/85 mm Hg. This may have had a major effect on study outcome. First, not all patients with type 1 diabetes are at risk for the development of nephropathy. In contrast to retinopathy, diabetic nephropathy develops in less than 50% of patients with type 1 diabetes.2,3 Arterial hypertension clearly contributes to the predisposition for diabetic nephropathy.3 Mauer et al. demonstrated that marked mesangial expansion develops in particular in patients with hypertension. Therefore, the exclusion of patients with hypertension may have resulted not only in the selection of patients lacking a predisposition for nephropathy but also in a selection of patients less prone to progression of mesangial fractional volume, the primary end point of the study. Selection of a relatively healthy subgroup of patients seems to be in line with the observed lower-than-expected progression of mesangial expansion.

Jouke T. Tamsma, M.D., Ph.D.
Leiden University Medical Center, Leiden, the Netherlands
jttamsma@lumc.nl

3 References

1. 1

   Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 2009;361:40-51
   Full Text | Web of Science | Medline

2. 2

   Seaquist ER, Goetz FC, Rick S, Barbosa J. Familial clustering of diabetic kidney disease: evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 1989;320:1161-1165
   Full Text | Web of Science | Medline

3. 3

   Krolewski AS, Canessa M, Warram JH, et al. Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N Engl J Med 1988;318:140-145
   Full Text | Web of Science | Medline

To the Editor:

The article by Mauer et al. demonstrated that early blockade of the renin–angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy. These findings may stimulate the widespread use of blockers of the renin–angiotensin system in normotensive patients with type 1 diabetes and normoalbuminuria. However, a higher incidence of microalbuminuria in the losartan group, which had the best retinopathy outcome, raises concern about possible adverse renal effects of blockade of the renin–angiotensin system in these patients. Do we have to trade nephropathy for retinopathy? Further studies are warranted, but a closer look into the data in the study by Mauer et al. might help clarify this question. For instance, the renal outcomes of patients without retinopathy progression in each group should be compared. Until more data are available, we would think that blockade of the renin–angiotensin system in normotensive patients with type 1 diabetes and normoalbuminuria, even with angiotensin-converting–enzyme inhibitors, should not be generally recommended.

Pisut Katavetin, M.D.
Chulalongkorn University, Bangkok, Thailand
pkatavetin@yahoo.com

Paravee Katavetin, M.D.
Thonburi Hospital, Bangkok, Thailand

Author/Editor Response

Although genetic predisposition to hypertension is associated with an increased risk of diabetic nephropathy in patients with type 1 diabetes, as Tamsma correctly points out, this does not mean that systemic hypertension is an important precondition for early mesangial expansion. In fact, earlier studies strongly suggested that hypertension in patients with type 1 diabetes is more likely the consequence than the cause of mesangial expansion.1 Nevertheless, the results of the Renin–Angiotensin System Study (RASS) should not be extrapolated to the relatively uncommon circumstance of patients with diabetes, normoalbuminuria, normal or increased glomerular filtration rate, and systemic hypertension. The fact remains that the large majority of patients with diabetes and normoalbuminuria are normotensive, and renal benefits from blockade of the renin–angiotensin system could not be demonstrated in such patients. If precise early predictors of diabetic nephropathy become available, new studies including only patients at high risk would be warranted. In regard to the suggestion by Katavetin and Katavetin about patients without retinopathy progression, the RASS does not have sufficient power for this kind of subanalysis. We agree that further studies are warranted.

Michael Mauer, M.D.
University of Minnesota, Minneapolis, MN
mauer002@umn.edu

Bernard Zinman, M.D.
University of Toronto, Toronto, ON, Canada

Ronald Klein, M.D., M.P.H.
University of Wisconsin, Madison, WI

1 References

1. 1

   Osterby R, Parving HH, Nyberg G, Hommel E, Mauer SM, Steffes MW. Morphology of diabetic glomerulopathy and relationship to hypertension. Diabetes Metab 1989;15:278-283
   Web of Science