To the Editor:
We read with interest the study of Costa and colleagues1 regarding the effect of 25 mg/d to 50 mg/d spironolactone on blood pressure and serum metabolic parameters of obese individuals with the metabolic syndrome (MetS). More specifically, systolic and diastolic blood pressure, serum glucose and triglycerides significantly decreased, whereas high-density lipoprotein cholesterol (HDL-C) increased 8 weeks following spironolactone treatment.
In this regard, we have recently published preliminary results of a randomized clinical trial investigating the 8-week effect of 400 mg/d vitamin E (group 1) vs 25 mg/d spironolactone plus 400 mg/d vitamin E (group 2) [Correction after online publication 14-Jul-2011: units of vitamin e updated from IU/d to mg /d.] on serum metabolic parameters and insulin resistance (IR) in adults with histologically documented nonalcoholic fatty liver disease (NAFLD) (ClinicalTrials.gov NCT01147523).2 Because IR seems to play a key role in its pathogenesis, NAFLD is considered the hepatic component of MetS.3 Similarly to the findings of Costa and colleagues,1 systolic blood pressure was significantly decreased in group 2 compared with group 1 and baseline values of group 2 (163±7 mm Hg at baseline, 142±4 mm Hg at week 8; P=.034). Diastolic blood pressure was also relatively decreased, although it did not reach statistical significance (97±3 mm Hg and 91±2 mm Hg, respectively). Contrary to findings from Costa and colleagues,1 serum glucose, triglyceride, and HDL-C levels were unaffected after spironolactone plus vitamin E treatment in our study; however, serum insulin significantly decreased in group 2 (P=.013), resulting in a significant decrease in the homeostatic model of assessment of insulin resistance (HOMA-IR) (P=.047). Both insulin and HOMA-IR remained unaffected in group 1.2 In the study by Costa and colleagues,1 HOMA-IR also showed a nonsignificant trend toward decrease after spironolactone treatment.
It seems that spironolactone has further metabolic effects, apart from lowering blood pressure. Other animal and human studies reinforce this concept. Wada and colleagues4 investigated the 8-week effect of spironolactone on glucose and lipid metabolism in a mouse model with diet-induced diabetes and NAFLD. Spironolactone (16 mg/kg/d) decreased HOMA-IR and blood pressure, serum triglyceride, total cholesterol, glucose, insulin, free fatty acids, and leptin levels. Furthermore, spironolactone improved hepatic steatosis, presumably by ameliorating IR and hepatic inflammation.4
In humans, serum glucose remained unaffected in most studies with patients with hypertension,5–7 type 2 diabetes mellitus (T2DM) complicated with diabetic nephropathy8 or polycystic ovary syndrome (PCOS).9–11 The effect of spironolactone on IR has been mainly investigated in women with PCOS, considered to be the ovarian component of MetS, because of its antiandrogenic action. Spironolactone (100 mg/d) either alone (12 months)9 or in combination with ethinyl estradiol/cyproterone acetate (3 months)10 decreased both insulin and HOMA-IR. On the other hand, spironolactone (50 mg/d) did not affect serum insulin and HOMA-IR in patients with T2DM complicated with diabetic nephropathy8; however, diabetic nephropathy may interfere with serum glucose and insulin.
With respect to serum lipid levels, spironolactone administration decreased serum total cholesterol and LDL-C in two studies of women with PCOS.10,12 Nevertheless, spironolactone had no effect on serum lipids in other studies that recruited patients with hypertension,5–7,13 T2DM complicated with nephropathy,8 or PCOS,9,11 apart from a decrease in triglycerides in one of them.9 Differences in population, duration and/or drug coadministration (ie, estrogens, progestins, diuretics, angiotensin-converting enzyme inhibitors or angiotensin type 1 receptor blockers) might have accounted for these controversial results.
Spironolactone has also been reported to decrease albuminuria in hypertensive patients with14,15 or without5,16 T2DM, improve endothelial function,12 and decrease myocardial and vascular fibrosis, thereby reducing the mortality of patients with heart failure.17 Although spironolactone seems to have pleiotropic action, further studies are needed to clarify whether it could be a beneficial and inexpensive therapeutic approach for MetS-related morbidity.