Nocturnal Hypertension and Prevention of Microalbuminuria in Type I Diabetics

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DESCRIPTION (provided by applicant): Only a fraction of persons with Type 1 diabetes, less than 40%, go on to develop nephropathy. In those individuals susceptible to nephropathy, the natural history is characterized by a fairly predictable pattern of events. When urinary albumin excretion is within the normal range, the prevalence of hypertension based on office blood pressure readings is similar to that in the general population. Many of these patients, however, develop nocturnal hypertension before the development of microalbuminuria. Yet, early pharmacological intervention with ACE inhibitors is currently recommended only after there is an indication of kidney damage, as reflected by the presence of microalbuminuria. Prior to microalbuminuria initiation of ACE therapy is currently not recommended because it would result in over-treatment of a majority of subjects who will never develop microalbuminuria or overt nephropathy. By the time that microalbuminuria develops, however, the renal lesions of diabetes are often present and many patients progress to overt clinical nephropathy. It would therefore be greatly beneficial if one could identify those patients susceptible to develop microalbuminuria, so that therapy could be instituted early for those individuals at high risk. The proposed study is aimed at demonstrating that it is possible to prevent the progression to microalbuminuria by the preemptive administration of an ACE inhibitor to "normotensive", normoalbuminuric subjects with type 1 diabetes targeted on the basis of nocturnal hypertension, i.e. those in whom the physiologic fall in sleep blood pressure is blunted ("non-dippers"). This approach would be of great preventative value at a very early stage in the course of diabetes, i.e. prior to the development of either microalbuminuria or hypertension. Thus, we propose a novel trial of primary prevention of microalbuminuria in "normotensive" type 1 diabetes targeted on the basis of nocturnal hypertension. The specific aims of this study are: 1) to demonstrate that in subjects with nocturnal hypertension ("non- dippers"), the administration of the ACE inhibitor, ramipril, will decrease the rate of development microalbuminuria. 2) To demonstrate that progression to microalbuminuria in subjects with nocturnal hypertension, "non-dippers", treated with placebo is higher than in "dippers" also treated with placebo. In addition, these studies will provide novel information as to whether endothelial dysfunction, assessed by brachial artery flow mediated vasodilation antedates microalbuminuria in subjects with Type 1 diabetes, particularly in those with nocturnal hypertension. Moreover, these studies will reveal the impact of long-term ACE inhibition on nocturnal hypertension and endothelial dysfunction in normotensive type 1 diabetics.