1 D&b Comp 1994; 8:189-192

Strategies for the Prevention of Diabetic Kidney Disease: Early Antihypertensive Treatment or Improved Glycemic Control? D. J. Barnes G. C. Viberti

iabetic nephropathy affects about one-third

D of patients with insulin-dependent diabe- tes mellitus (IDDM)l,* and is associated with increased morbidity and mortality due

to cardiovascular disease.3-5 Once proteinuria is estab- lished, renal function inexorably declines such that 50% of patients will reach endstage renal failure within 7 years of onset of proteinuria.6 Most of these patients would be offered renal replacement therapy in the form of dialysis or transplantation. Microalbuminuria [defined as urinary albumin excretion rate (AER) of ZO- 200 @mm] is a powerful predictor of clinical diabetic nephropathy.‘-lo

Prevention of diabetic kidney disease in IDDM can be considered at the primary, secondary, and tertiary level. Tetriary prevention is the attempt to arrest the development of end stage renal failure in patients with established diabetic nephropathy (defined as the com- bination of persistent proteinuria with urinary AER > 200 @min, declining glomerular filtration rate, and elevated blood pressure). Secondary prevention relates to stopping the progression of incipient nephropathy (which is best predicted by persistent microalbuminu- ria) to overt nephropathy. Primary prevention, which is the ideal goal as it would lead to patients not pro- gressing to the phase of incipient nephropathy, is presently difficult to achieve as early markers to iden- tify at diagnosis the subset of IDDM subjects who are

Unit for Metabolic Medicine, United Medical and Dental Schools, Guy’s Hospital, London, England.

Address reprint requests to: Dr. D. J. Barnes, Unit for Metabolic Medicine, United Medical and Dental Schools, Floor 4 Hunt’s House, London SE1 9RT, England

0 1994 ]oumal of Diabetes and Its Complications

at greatest risk of developing this important complica- tion are not as yet available.

In patients with established nephropathy, only two treatment strategies have been shown to slow the rate of decline in glomerular filtration rate (GER) and reduce the rate of increase in albuminuria. These are anti- hypertensive therapy and low-protein diets. These beneficial effects on GFR and albuminuria have been demonstrated for most groups of commonly used anti- hypertensive drugs, 11-13 but it has been suggested that angiotensin-converting enzyme (ACE) inhibitors pre- serve renal function independent of their effects of systemic blood pressure. 14-16 Two studies using reli- able markers of glomerular function have also shown similar beneficial effects using a low-protein diet.“J8 Improvement in glycemic control in overt nephropa- thy has not been shown to slow down the progression of renal disease.19

Many studies have examined the effects of antihy- pertensive treatment in normotensive IDDM subjects with microalbuminuria.2 ACE inhibitors were the most commonly used drugs in the active treatment arm and, generally speaking, microalbuminuria was reduced over the follow-up periods compared with placebo while GFR remained stable. All such studies to date have been relatively short term (up to 4 years follow-up). The definition of nomtotension varied in these trials with the upper limits of arterial pressure defined as either 140/90, 160195, or a diastolic BP < 95 mm Hg. It has been suggested by Mogensen et al. that the threshold for progression of microalbuminuria in such patients is a mean arterial pressure of 95 mm Hg - a level that is lower than that used for entry criteria in these clinical studies.% Two recent papers have sug-

0156-8727/94/$7.00

190 BARNES AND VIBERTI J Diab Comp 1994; 8:189-192

gested that screening for and treatment of microal- buminuria would be worthwhile if antihypertensive therapy could reduce the annual increase in rate of albumin excretion by 8%-10% (from 20% to 18% a year) .29*30

Studies that have assessed the role of improved gly- cemic control in the secondary prevention of diabetic nephropathy have provided favorable results in terms of retardation as opposed to absolute prevention of progression to albuminuria. It has been shown that a relatively short period of improved diabetic control can lead to a correction of the exaggerated albuminuric response to exercise.31,32 Strict metabolic control using continuous subcutaneous insulin infusions has been effective in reducing the albumin excretion rate%” and in preventing the progressive increase in fractional clearance of albumin in the long term.% More recently, Reichard et al. showed that long-term intensified insu- lin therapy significantly reduced the incidence of ne- phropathy.39 Although the mean glomerular filtration rate in the intensified-treatment and standard- treatment groups were no different after 7.5 years fol- low-up, those patients who developed frank protein- uria in the standard-treatment group had a subnormal GFR compared with none in the intensified-treatment group. Most of the patients with microalbuminuria at baseline were treated with antihypertensive medica- tion during the study period, which may have had a confounding influence on these results.

In the largest trial of its type to date, the Diabetes Control and Complications Trial (DCCT) provided evi- dence for reduction in the risk of development and progression of retinopathy, nephropathy, and neu- ropathy in those treated with intensified insulin ther- apy.40 It has to be remembered, however, that the pri- mary end point of this study was retinopathy. The 1441 patients with IDDM who participated in this trial were divided into two cohorts: a “primary prevention” and “secondary intervention” group. The latter group had evidence of mild-to-moderate nonproliferative retinopathy, and a 24-h urinary albumin excretion of less than 200 mg (AER 139 pglrnin). Patients were ran- domly assigned to either intensified insulin therapy (using three or more insulin injections a day or a con- tinuous subcutaneous insulin infusion), and guided by at least four home blood glucose assessments a day, or conventional treatment with twice-daily insulin in- jections. There was a very low dropout rate from this study (l%), and the mean follow-up period was 6.5 years. A difference in glycosylated hemoglobin con- centration between the two groups was maintained between 1.5% and 2.0% throughout the study period from 3 months onward. As far as nephropathy was concerned, it is important to realize that the DCCT results should be interpreted as a primary prevention study. The mean 24-h urinary albumin excretion at

baseline in the “secondary intervention“ group was around 20 mg (i.e., an AER of 14 uglmin), which is in the normoalbuminuric range. None of the patients in the “primary prevention” group had evidence of increased urinary albumin excretion. Excluding those patients with microalbuminuria at baseline (with the lower limit defined as 40 mg in 24 h or an AER of 28 nglrnin), intensified insulin therapy was found to reduce the risk of proteinuria (AER > 208 pglmin) by 54% and microalbuminuria by 39%. The effect of inten- sified treatment in reducing this risk was maintained even after adjustment for factors such as age, sex, du- ration of diabetes, mean arterial pressure, and dietary protein intake. Because DCCT provides evidence for the primary prevention of diabetic kidney disease, a comparison of cost effectiveness with antihyperten- sive treatment cannot be made, as no data is available on the use of such agents in normoalbuminuric IDDM subjects.

There are some problems in translating these im- pressive results from the DCCT into a cost-benefit analysis with respect to diabetic kidney disease. First, the primary end point of the study was progression to retinopathy, and not nephropathy. Second, the amount of resources put in to ensure good compliance in the intensively treated group was enormous in terms of consultations with medical and nursing staff, dietitians, and behavioral specialists, with close con- tact even in between the monthly hospital visits. Extra costs were also incurred with frequent home blood- glucose monitoring, monthly glycosylated hemoglo- bin estimations, multiple insulin injections daily, and the capital and maintenance costs of insulin-infusion pumps. Third, the motivation of the patients involved in the trial was remarkable, and it would be difficult to believe that such a high level of compliance would be achieved outside the realms of a research study. Indeed, the motivation of the hospital staff was also very high, and this too may be of importance in ex- plaining the beneficial results of the DCCT. The cost of educating health professionals to deliver this stan- dard of care would need to be considered. Fourth, for any reduction in the glycosylated hemoglobin, there was a decrease in the progression of retinopathy: it is not known whether a similar situation exists with regard to nephropathy, and whether this risk reduc- tion would be comparable in magnitude. Fifth, intensi- fied insulin therapy was associated with a two-to- threefold increase in episodes of severe hypoglycemia. With increasing duration of diabetes, the risk of severe hypoglycemia rises, principally because of blunted (or even absent) counterregulatory responses. The unpre- dictable consequences of severe hypoglycemia make it impossible to assess the cost of this adverse effect. It may be, however, that any improvement in glycemic control by whatever means would have a beneficial

] Diab Comp 1994; 8:189-192

effect on the primary prevention of diabetic kidney disease. Indeed, the benefit of tighter glycemic control goes beyond the prevention of diabetic kidney disease, as other microvascular complications will also be pre- vented.

The results to the DCCT do not directly apply to IDDM subjects with duration of disease greater than 15 years, age less than 12 or greater than 39 years, or those with severe retinopathy, a significant proportion of whom would have elevated albumin excretion rates (these groups were all excluded from entry into the trial).

None of the studies mentioned in this review relates to kidney disease in non-insulin-dependent diabetes (NIDDM). Microalbuminuria in Caucasians with NIDDM is a powerful predictor of morbidity and mor- tality, mainly from cardiovascular causes.41-43 It may be, therefore, that such patients die before they de- velop renal failure from diabetic nephropathy. The sit- uation is more complicated in NIDDM because pro- teinuria may be of nondiabetic origin in up to 30% of cases.@ If intensified insulin therapy were to be ap- plied to patients with MDDM, the potential adverse effect of severe hypoglycemia may precipitate attacks of angina, myocardial infarction, or stroke. Ethnic ori- gin is also an important risk factor for the development of endstage renal failure, being higher in blacks and Asians .&,&

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