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(AACE) Addition of Spironolactone to Ace Inhibitors Reduces Albuminuria in Type

May 2, 2006

By adding a small dose (25mg) of spironolactone to the treatment of patients with type 2 diabetes and albuminuria, a 26% drop was seen for those with microalbumuria and a 20.8% drop for those with macroalbuminuria. Adding a low dose of spironolactone to a standard angiotensin-converting enzyme (ACE) inhibitor reduces albuminuria in patients with type 2 diabetes, according to preliminary findings of a pilot study. The effect was seen in patients with both microalbuminuria and macroalbuminuria, and the addition caused no adverse effects, including no significant hyperkalemia.

Albuminuria in patients with type 2 diabetes mellitus (DM2) confers a high risk of significant morbidity and mortality, including end-stage renal disease. Randomized controlled trials have demonstrated the benefits of inhibiting the renin-angiotensin-aldosterone (RAA) axis in reducing albuminuria and slowing the progression of renal disease. In those studies, the inhibition of the RAA was achieved using angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB). While inhibition of aldosterone has been demonstrated to decrease mortality in patients with heart failure, there is only limited evidence of its effect on albuminuria. This study is intended to investigate whether the addition of spironolactone (a potent aldosterone inhibitor) to ACE inhibitors will provide further benefit in decreasing albuminuria.

This open-label pilot intervention trial has an enrollment goal of 40 subjects, with 18 studied to date. The trial requires that subjects visit the clinic 4 times during 12 weeks, with laboratory and clinical assessment at each visit. By design, 20 subjects will have macroalbuminuria (random albumin/creatinine ratio [ACR], 300 mg/g), and 20 will have microalbuminuria (ACR, 100-300 mg/g). Four weeks after consent, the patient starts spironolactone therapy, and 4 weeks later, stops it. Four weeks after stopping, the patient returns for a follow-up visit. At each visit the patient’s blood pressure, metabolic panel, 24-hour urine albumin, and 24-hour urine creatinine levels are recorded. Thus far 11 subjects with macroalbuminuria and 7 subjects with microalbuminuria have completed the trial. What we report here is a preliminary result of those 18 subjects. Subjects were followed for a total of 12 weeks. Serum chemistries, 24 hour urine albumin excretion (UAE), and 24 hour urine creatinine were obtained at 4 visits, each 4 weeks apart. Visit 1 was a screening visit. At visit 2 spironolactone 25 mg daily was initiated. At visit 3 the spironolactone was stopped. Visit 4 was a follow-up visit. Results were analyzed by paired t-tests and Wilcoxon Signed Rank Tests as indicated.

"We saw a statistically significant drop in proteinuria after initiating spironolactone," Dr. Davidson told Diabetes in Control.. "If you look at the percentage drop in the overall 18 patients, [there was a] 26% reduction in the albuminuria after the addition of spironolactone. In the micro group it was 34%, in the macro group, 21%. And those were all statistically significant."

Dr. Davidson added, "There was a concomitant drop in systolic blood pressure when we added spironolactone. However, when we looked at the correlation between albumin excretion, decline in albumin excretion, and decline in systolic blood pressure, they did not correlate. The correlation coefficient was 0.08. So it seems that the drop in systolic blood pressure was not driving the drop in albumin excretion, which I think is a very important finding." .Spironolactone 25 mg daily was well tolerated in all subjects with no withdrawals due to hyperkalemia.

From the results it was concluded that low dose spironolactone is effective in further decreasing albuminuria in patients with DM2, already treated with ACE inhibitors.

Asked whether this study should change clinical practice, Dr. Davidson was cautious. "I think at this point you can’t make the recommendation that every patient with proteinuria be put on spironolactone. Certainly you have to look at patient’s renal function. With worsening renal function, you have the potential for developing hyperkalemia when you add those agents such as ACE inhibitors and spironolactone. I think what this does is open the door for larger randomized, prospective trials," he said.

Presented at the AACE Annual meeting April 27th in Chicago. Michael B. Davidson, D.O.,
Department of Endocrinology, Diabetes, and Metabolism, The Cleveland Clinic Foundation