Spironolactone impairs endothelial function and heart rate variability in patients with Type 2 diabetes

Abstract

Aims/hypothesis. Aldosterone blockade has followed in the footsteps of ACE inhibition in reducing mortality in patients with heart failure. This is associated with its beneficial effects on endothelial function and heart rate variability. Diabetes is another area, where angiotensin II withdrawal has proven to be of particular value. We postulated that aldosterone blockade with spironolactone might also have beneficial effects on the prognostic markers of endothelial function and heart rate variability in diabetic patients. Methods. We assessed endothelial function by forearm venous occlusion plethysmography in 42 patients with Type 2 diabetes mellitus after 1 month of treatment with spironolactone or placebo allocated in a randomised double-blind trial. Of the 42 patients, 20 were on ACE inhibitor therapy. We also assessed heart rate variability, HbA 1 c and plasma angiotensin II levels at the end of each treatment period. Results. Compared to placebo, spironolactone decreased forearm blood flow response to acetylcholine by 44.56±14.56% (p=0.003) in the group as a whole and by 57.61±15.56% (p<0.001) in the 20 patients on ACE inhibition. Spironolactone also worsened heart rate variability parameters, with root mean squared standard deviation decreased by 1.99±0.93 ms (p=0.03), low-frequency normalised power increased by 2.00±0.91 normalised units (nu) (p=0.03), high-frequency normalised power decreased by 1.98±0.94 nu (p=0.04) and the low frequency : high frequency ratio increased by 0.40±0.19 (p=0.04). HbA 1 c and angiotensin II increased during treatment with spironolactone by 0.26±0.07% (p=0.001) and 8.12±1.94 pg/ml (p=0.001) respectively. Conclusions/interpretation. Spironolactone worsened endothelial function and heart rate variability in patients with Type 2 diabetes. These findings are possibly due to the worsening of glycaemic control and increase in plasma angiotensin II that were seen with spironolactone treatment. Thus the prescription of spironolactone to diabetic patients without heart failure does not seem to be justified.

Spironolactone for poorly controlled hypertension in type 2 diabetes: conflicting effects on blood pressure, endothelial function, glycaemic control and hormonal profiles

“…On the other hand, spironolactone did not actually worsen endothelial function, as it did in our previous study in normotensive patients with type 2 diabetes [10].…”

“…Intriguingly, a worsening of glycaemic control with spironolactone in type 2 diabetes has been previously reported in two other studies [10,36]. Furthermore, in the EPHESUS study, aldosterone blockade significantly reduced hypoglycaemia by 43%, which again could be consistent with a worsening of glycaemic control and the attendant negative impact on endothelial function [37][38][39].…”

“…However, when patients on ARBs were analysed separately in our study, there was again no significant difference in endothelial function between spironolactone and placebo groups, although number of patients ARBs in our study was too small [n=9] to make any firm conclusions in this subgroup. Third, spironolactone significantly increased plasma cortisol, which has been reported before [10]. Several possible mechanisms may mediate the adverse effects of cortisol on endothelial function.…”

“…We were therefore somewhat surprised by our previous study, which showed that in a normotensive population of patients with type 2 diabetes, spironolactone actually worsened the key prognostic marker of endothelial function [10]. We therefore selected a more hypertensive group of type 2 diabetes patients in the present study, as the additional risk of being hypertensive may well tip the scales in favour of spironolactone improving endothelial function.…”

“…As a backdrop to this question, we previously found that, to our surprise, spironolactone actually worsened the key prognostic marker of endothelial function in a normotensive population of patients with type 2 diabetes, while also worsening glycaemic control [10]. The situation could, however, be very different in patients with diabetes and poorly controlled hypertension.…”