Beneficial Effects of Adding Spironolactone to Recommended Antihypertensive Treatment in Diabetic Nephropathy

Abstract

OBJECTIVE -The objective of this study was to evaluate the safety and short-term effect of adding spironolactone to conventional antihypertensive treatment including diuretics and maximally recommended doses of an ACE inhibitor or an angiotensin II receptor blocker (ARB) on albuminuria and blood pressure in type 2 diabetic patients with nephropathy.RESEARCH DESIGN AND METHODS -Twenty-one type 2 diabetic patients with nephropathy were enrolled in a randomized, double-masked, cross-over study. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for 8 weeks, respectively, in addition to ongoing antihypertensive treatment including diuretics and maximally recommended doses of an ACE inhibitor and/or an ARB. At the end of each treatment period, albuminuria, 24-h ambulatory blood pressure (ABP), and glomerular filtration rate (GFR) were determined.RESULTS -During the addition of placebo, values were as follows: albuminuria (geometric mean [range]) 1,566 762] mg/24 h, ABP (mean Ϯ SE) 138 Ϯ 3/71 Ϯ 1 mmHg, and GFR (mean Ϯ SE) 74 Ϯ 6 ml/min per 1.73 m 2 . During the addition of spironolactone, albuminuria was reduced by 33% (95% CI 25-41) (P Ͻ 0.001), fractional clearance of albumin by 40% (24 -53) (P Ͻ 0.001), and 24-h ABP by 6 mmHg (2-10) for systolic and 4 mmHg (2-6) for diastolic (P Ͻ 0.001 for both). The change in albuminuria did not correlate with the change in systolic 24-h ABP (r ϭ 0.19, P ϭ 0.42) or diastolic 24-h ABP (r ϭ 0.01, P ϭ 0.96). Spironolactone treatment induced an insignificant reversible reduction in GFR of 3 ml/min per 1.73 m 2 (Ϫ0.3 to 6) (P ϭ 0.08). One patient was excluded from the study due to hyperkalemia. Otherwise treatment was well tolerated.CONCLUSIONS -Our study suggests that spironolactone safely adds to the reno-and cardiovascular protective benefits of treatment with maximally recommended doses of ACE inhibitor and ARB by reducing albuminuria and blood pressure in type 2 diabetic patients with nephropathy. Diabetes Care 28:2106 -2112, 2005A ldosterone, the end product of the renin-angiotensin-aldosterone system (RAAS), has attracted renewed attention as an important mediator of both cardiovascular and renal disease (1,2). Accumulating experimental evidence suggests that circulating aldosterone per se contributes directly to renal and cardiovascular disease by inducing inflammation, fibrosis, and necrosis in end-organ tissues such as the heart, brain, and kidney (3). Moreover, aldosterone blockade has been shown to greatly improve survival in patients with chronic heart failure (4,5).Angiotensin II has long been considered the main mediator of the pathophysiological effects of the RAAS, and in diabetic nephropathy the renoprotective effects of treatment with an ACE inhibitor or an angiotensin receptor blocker (ARB) are well established (6 -9). Both ACE inhibitor and ARB treatments initially suppress plasma aldosterone. Eventually, however, plasma aldosterone may return to pretreatment levels, i.e., the aldosterone escape phenomenon. Aldosterone e...

Evidence for renoprotection by blockade of the renin–angiotensin–aldosterone system in hypertension and diabetes

“…34,40,[46][47][48][56][57][58][59] Clinical trials, grouped by the degree of albuminuria, demonstrating the beneficial effects of RAAS inhibition on renal end points in patients with diabetes mellitus are summarized in Table 2. 34,40,42,48,49,[57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] Normoalbuminuria The Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) is the only primary prevention study to date to demonstrate that the development of microalbuminuria can be prevented by the use of an ACE inhibitor alone or in combination with a CCB in hypertensive normoalbuminuric patients with type II diabetes. 59 …”

“…In patients already receiving an ACE inhibitor or ARB, recent evidence suggests that additional renoprotection may be provided by agents that block aldosterone. 70,71 Studies of diuretics (alone or in combination with an ACE inhibitor) suggest possible renoprotective benefits. 64,68 A low-dose combination of perindopril plus indapamide induced a greater decrease in UAER (À42%) than once-daily monotherapy with enalapril (À27%) in diabetic patients with hypertension and albuminuria.…”

Use of Mineralocorticoid Receptor Antagonists in Patients With Heart Failure and Comorbid Diabetes Mellitus or Chronic Kidney Disease

“…Although the role of MRAs in patients with ejection fraction greater than 35% is unclear,2, 3 they may benefit patients with comorbid hypertension, diabetes mellitus, or renal insufficiency. MRAs can be used for blood pressure management regardless of heart failure status, and addition of an MRA to angiotensin‐converting enzyme inhibitor or angiotensin II receptor blocker therapy reduces proteinuria in patients with chronic kidney disease and diabetic nephropathy and can delay progression of renal dysfunction 3, 4, 5, 6, 7, 8, 9, 10…”

Therapeutic Modalities in Diabetic Nephropathy: Standard and Emerging Approaches

“…The mineralocorticoid receptor antagonists' spironolactone and eplerenone reduce proteinuria when administered alone with additional antiproteinuric benefits when given with ACEi or ARBs in patients with DMT1 and DMT2. [82][83][84][85][86][87][88][89][90][91][92][93] This additive antiproteinuric benefit is independent of further BP reduction. 86,87,93 The lack of sexual side-effects of eplerenone makes it a good alternative to spironolactone, particularly in men.…”