The Use Of Antihypertensive Agents In Normotensive Dm With Microalbuminuria

The possibility that early therapy will postpone or retard progression of renal injury in diabetes has led to the use of antihypertensive agents in normotensive subjects. UAE has been shown to be reduced in a group of normotensive DM2 patients with microalbuminuria treated with captopril over a period of 6 months, whereas the untreated group had no change in albuminuria [50]. In the Melbourne study [43] there was no change in albuminuria after 12 months treatment with either nifedipine or perindopril in normotensive microalbuminuric patients, despite a small but significant reduction in blood pressure (4 mmHg). Nonetheless, on stopping therapy at 12 months a dramatic increase in albuminuria was detected in the DM2 but not in the DM1 subjects, which was independent of mode of treatment [51]. The inability of either agent to reduce albuminuria in the normotensive cohort coupled with the rapid rise after stopping therapy needs to be considered in the setting of the natural history of microalbuminuria. Albuminuria would be anticipated to rise by an average of 20 to 50 per cent if left untreated for 12 months in microalbuminuric DM2 subjects. This phenomenon of a rapid rise in albuminuria was not apparent in the DM1 patients and may indicate a difference in the underlying etiology and pathogenesis of albuminuria in DM2 as compared to DM1 It is possible that there are differences in the sensitivity to structural damage incurred from blood pressure between DM1 and DM2.

The first long-term (5 years) placebo controlled double blind randomized study to evaluate the effect of an antihypertensive agent in normotensive microalbuminuric DM2 with normal renal function (as assessed by a serum creatinine < 123 ^mol/l) was reported by Ravid et al [52]. These investigators reported an initial decrease of 15% in UAE during the first year of treatment in the enalapril treated group and a slow return to baseline levels at 5 years. Conversely, in the placebo treated patients there was an increase of 144% over the five years. Renal function, as assessed by the reciprocal of serum creatinine, decreased less in patients receiving enalapril than placebo. A follow up report after 7 years of treatment confirmed a renoprotective effect of ACE inhibition in this cohort [53]. Sano et al have observed in a 4 year study that enalapril treatment reduced albuminuria whereas placebo treatment was associated with no change in albuminuria in a group of normotensive, microalbuminuric DM2 patients [32]. Similar effects on albuminuria have been observed in a 6 month study by an Italian multi-centre group using the ACEI, ramipril [33]. Ahmad et al have reported similar effects on albuminuria after 5 years of ACEI therapy in a group of Indian normotensive DM2 subjects with microalbuminuria [54]. Enalapril treatment was associated with a reduction in albuminuria whereas in the placebo group there was a progressive rise in urinary albumin excretion. Of particular interest was the finding that these effects were observed in the absence of a discernible difference in blood pressure between the two groups. Muirhead et al, as described in the previous section, showed that both valsartan and captopril slow the progressive rise in albuminuria in DM2 normotensive and treated hypertensive patients with microalbuminuria [35].

The exciting results obtained with antihypertensive drugs including ACEI in hypertensive and macroalbuminuric diabetic subjects stimulated investigators to explore the possible role of these agents in the prevention of diabetic nephropathy. Ravid et al reported that treatment with enalapril for 6 years in a group of normotensive, normoalbuminuric DM2 subjects was associated with a retardation in the increase in AER and in the decrease in renal function [55]. Schrier et compared the effects of moderate control of blood pressure (diastolic blood pressure goal 80 - 90 mmHg, 243 patients) to intensive control (diastolic blood pressure less than 10 mmHg below the diastolic blood pressure at randomization, 237 patients) in normotensive DM2 patients, with only approximately 30% having microalbuminuria or overt albuminuria [56]. The patients in the intensive care group were randomized to receive either nisoldipine or enalapril, whereas those in the moderate group, received placebo and were only randomized to one of the two treatment drugs, if an increase in blood pressure was observed during the time-course of the study. The mean follow-up was over 5 years. In the patients with either normoalbuminuria or microalbuminuria at randomization, there was an initial fall in renal function

(creatinine clearance), but this stabilized within the first year. Subsequently there was no difference between the moderate and intensive groups nor any difference between those receiving nisoldipine and enalapril. These findings contrast with those observed in the patients with macroalbuminuria at randomization, who showed a steady fall in renal function throughout the follow-up period, which was independent of intensity of treatment or therapeutic regimen.

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