MON-114 Effect of Selective Mineralocorticoid Receptor Antagonist on liver Fat and Metabolism in Patients with Type 2 Diabetes: A Randomized Controlled Trail

OBJECTIVE Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes. A growing body of evidence points at a beneficial effect of MR antagonists (MRAs) on adipocyte function via the inhibition of adipocyte differentiation, downregulation of rho-kinase activity, pro-inflammatory proteins and increase of adiponectin expression in visceral fat. Therefore, intervention with MRAs may improve dysfunctional adipose tissue metabolism and reverse NAFLD. The primary hypothesis of the MIRAD trial was that treatment with high dose of the selective MRA eplerenone as an add-on to standard therapy, would improve liver fat content, lipid and glucose metabolism in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In this investigator-initiated, double-blinded clinical trial, 140 patients with type 2 diabetes and high cardiovascular disease risk were randomized 1:1 to eplerenone 100 - 200 mg or placebo for 26 weeks. The primary outcome was change in liver fat assessed by proton magnetic resonance spectroscopy. Secondary outcomes were changes in fat distribution assessed by DXA scan, measures of lipid and glucose metabolism by 4 point OGTT with measurements of glucose and insulin, and safety as evaluated by incident hyperkalaemia and increase in serum creatinine. RESULTS The mean ± SD age was 63.4 ± 9 years, BMI 30.7 ± 4.2 kg/m(2), HbA1c 7.6 ± 3.5% (59.6 ± 14.5 mmol/mol) and duration of diabetes was 11.7 ± 7.2 years. At baseline, more than 80% of the patients were on ACE-inhibitor or ARB. The prevalence of NAFLD, defined as liver fat content ≥5.6%, was 48%. Liver fat content did not change after 26 weeks of treatment with eplerenone (1.1% [0.68; 1.66], P = 0.776) or with a placebo (-0.8% [-1.4; 0.5], P = 0.500), while a minor difference between groups was observed (P=0.026). Furthermore, there was no beneficial impact on supporting secondary outcome measures of lipid and glucose metabolism as abdominal fat distribution, lipids, circulating free fatty acids, plasma adiponectin or IR. Despite a high dosage of eplerenone (164 vs 175 mg) in patients treated with placebo (P = 0.228), the incidence of hyperkalaemia during the 26 weeks was low (p-potassium ≥5.5 mmol/L; 10 vs 2) for eplerenone vs placebo (P = 0.038). Only four patients had an increase ≥ 30% in s-creatinine during titration, with no difference between groups. At baseline, no differences between groups in liver fibrosis score NFS was observed, while at week 26, the NFS score decreased in the eplerenone group compared to placebo (P = 0.021). CONCLUSIONS We report no metabolic beneficial effect from eplerenone on liver fat or parameters of glucose and lipid metabolism in patients with type 2 diabetes, although a potential beneficial effect on liver fibrosis was found.