Effect of the mineralocorticoid receptor antagonist eplerenone on liver fat and metabolism in patients with type 2 diabetes: A randomized, double‐blind, placebo‐controlled trial (MIRAD trial)

Abstract

Aim To investigate whether the mineralocorticoid receptor antagonist eplerenone has beneficial effects on liver fat and metabolism in patients with type 2 diabetes (T2D), the mineralocorticoid receptor antagonist in type 2 diabetes (MIRAD) trial. Material and methods In this 26‐week, double‐blind, randomized, placebo‐controlled trial, we enrolled 140 patients with T2D and high risk of cardiovascular disease. Patients were randomized 1:1 to either eplerenone with a target dose of 200 mg/day for patients with estimated glomerular filtration rate (eGFR) of 60 mL/min per 1.73 m2 or more and 100 mg/day for patients with eGFR between 41 and 59 mL/min per 1.73 m2 or placebo. The primary outcome measure was change in liver fat by proton magnetic resonance spectroscopy at week 26 from baseline; secondary outcomes were changes in metabolism, and safety by incident hyperkalaemia. Results No changes in liver fat in the eplerenone group 0.91% (95% CI −0.57 to 2.39) or the placebo group −1.01% (−2.23 to 0.21) were found. The estimated absolute treatment difference was 1.92% (−3.81 to 0.01; P = 0.049). There was no beneficial impact on supporting secondary outcome variables of metabolism as fat mass distribution, lipid metabolism or insulin resistance. Despite a high dosage of eplerenone 164 versus 175 mg in patients treated with placebo (P = 0.228), the number of patients with incident hyperkalaemia (≥5.5 mmol/L) was low, with six in the eplerenone versus two in the placebo group (P = 0.276). Conclusion The addition of high doses of eplerenone to background antidiabetic and antihypertensive therapy does not show beneficial effects on liver fat and metabolism in patients with T2D.

The Mineralocorticoid Receptor Antagonist Eplerenone Suppresses Interstitial Fibrosis in Subcutaneous Adipose Tissue in Patients With Type 2 Diabetes

“…The beneficial impact of the MRA-induced reduction in Col-6 expression in the current study is supported by an experimental study that reported that elimination of Col-6 is linked with normalized adipose tissue structure and improved metabolism (1). The clinical implications of the reduced fibrosis in ScAT in patients with type 2 diabetes are yet to be determined since we did not demonstrate an effect of eplerenone on liver fat in the MIRAD trial (13). A human study reported an impact of increased pericellular fibrosis in ScAT on weight loss after bariatric surgery, thus suggesting a link with obesity (2).…”

“…The study population consisted of patients with type 2 diabetes enrolled in the MIRAD study, which was a 26-week, randomized, double-blind, placebo-controlled trial that investigated the effects of high-dose eplerenone on liver fat content in patients with type 2 diabetes (13). All patients were proposed to participate, with an aim of including 30 in this prespecified substudy.…”

Adipocyte-Mineralocorticoid Receptor Alters Mitochondrial Quality Control Leading to Mitochondrial Dysfunction and Senescence of Visceral Adipose Tissue

“…This might be due to the ability of lipoproteins and of adipocyte-derived factors, such as leptin, to induce the adrenal synthesis of aldosterone [42][43][44][45]. In patients with primary aldosteronism, treatment through pharmacological MR antagonists (MRA) (eplerenone or spironolactone) or adrenalectomy reduces visceral fat mass [46] and improves systemic and organ insulin sensitivity [47], but other studies have shown only limited effects of MRA in obese diabetic patients [48][49][50]. The reason for these diverging results could be that MRA are often used as a preventive treatment in mice, while human studies are done in patients that are already suffering from the MetS.…”

The mineralocorticoid receptor—an emerging player in metabolic syndrome?

“…Interventional studies investigating the effect of MRAs on liver fat have yielded inconsistent findings. Polyzos et al reported a significant improvement in liver fat score over 1 year in 31 subjects with biopsy-proven non-alcoholic fatty liver disease randomised to spironolactone (25 mg daily) plus vitamin E compared to vit E alone [68], while in a recent randomised controlled trial by Johansen et al involving 140 patients with longstanding type 2 DM (80% of whom were already on angiotensin receptor blocker or angiotensin converting enzyme inhibitor treatment), there was no change in liver fat after 26 weeks of treatment with eplerenone (50-200 mg daily) [69].…”