Effect on cardiac function among patients with type 2 diabetes following high-dose mineralocorticoid receptor antagonist using echocardiography; data from the MIRAD randomized clinical trial.

BACKGROUND: Early heart failure prevention is central in patients with type 2 diabetes, and mineralocorticoid receptor antagonists (MRAs) have shown to improve prognosis. We investigated the effect of high-dose MRA, eplerenone, on cardiac function and structure in patients with type 2 diabetes and established or increased risk of cardiovascular disease but without heart failure. METHODS: In the current randomized, placebo-controlled clinical trial, 140 patients with high-risk type 2 diabetes were randomized to high-dose eplerenone (100-200 mg daily) or placebo as add-on to standard care for 26 weeks. Left ventricular systolic and diastolic function, indexed left ventricular mass (LVMi), and global longitudinal strain (GLS) were assessed using echocardiography at baseline and after 26 weeks of treatment. RESULTS: Of the included patients, 138 (99%) had an echocardiography performed at least once. Baseline early diastolic in-flow velocity (E-wave) indexed by mitral annulus velocity (e') was mean (SD) 11.1 (0.5), with 31% of patients reaching above 12. No effect of treatment on diastolic function was observed measured by E/e' (0.0, 95%CI [-1.2 to 1.2], P = 0.992) or E/A (-0.1, 95%CI [-0.2 to 0.0], P = 0.191). Mean left ventricular ejection fraction (LVEF) at baseline was 59.0% (8.0). No improvement in systolic function was observed when comparing groups after 26 weeks (LVEF: 0.9, 95%CI [-1.1 to 2.8], P = 0.382; GLS: -0.4%, 95%CI [-1.5 to 0.6], P = 0.422), nor in LVMi (-3.8 g/m2 95%CI [-10.2 to 2.7], P = 0.246). CONCLUSION: In the present echo sub-study, no change in left ventricular function was observed following high-dose MRA therapy in patients with type 2 diabetes when evaluated by conventional echocardiography. TRIAL REGISTRATION: Date of registration 25/08/2015 (EudraCT number: 2015-002,519-14).

Mineralocorticoid Receptor Antagonist Improves Cardiac Structure in Type 2 Diabetes: Data From the MIRAD Trial.

OBJECTIVES: This study investigated the impact of the MR antagonist (MRA) eplerenone on LVM in type 2 diabetes patients at high risk for cardiovascular disease (CVD). BACKGROUND: MRA activation is associated with cardiac fibrosis and increased left ventricular mass (LVM), which is an independent predictor of adverse CVD, including heart failure in patients with type 2 diabetes. METHODS: A prespecified analysis of secondary endpoints in a randomized, double-blinded clinical trial of 140 patients with type 2 diabetes at high risk of or established CVD. Patients were randomized to receive high-dose eplerenone therapy (100 mg-200 mg) or placebo as an add-on to standard care for 26 weeks. Indexed LVM (LVMi) and T1 time were measured using cardiac magnetic resonance (CMR) imaging. Biomarkers included N-terminal pro-B-type natriuretic peptide (NT-proBNP), pro-collagen type I N-terminal propeptide (P1NP), and type III N-terminal propeptide (P3NP). RESULTS: Of 140 patients in the MIRAD trial, 104 patients were subject to CMR imaging (eplerenone: 54 patients; placebo: 50 patients). Mean LVMi at baseline was 74.2 ± 16 g/m2. The treatment effect (ie, between-group differences) was a decrease of 3.7 g/m2 following the eplerenone treatment (95% CI: -6.7 to -0.7; P = 0.017), with a corresponding decrease in absolute LVM. Plasma NT-proBNP concentrations decreased by 22% (P = 0.017) using eplerenone compared with placebo, and P1NP decreased 3.3 ng/mL (P = 0.019). No differences in T1 times or P3NP concentrations were observed between groups. CONCLUSIONS: The addition of high-dose eplerenone in high-risk type 2 diabetes was associated with a clear reduction in LVMi and in NT-proBNP and P1NP levels, which may suggest a clinical benefit in heart failure prevention. (EU Clinical trials: Mineralocorticoid Receptor Antagonists in Type 2 Diabetes [MIRAD]; 2015-002519-14).

Effect of high-dose mineralocorticoid receptor antagonist eplerenone on urinary albumin excretion in patients with type 2 diabetes and high cardiovascular risk: Data from the MIRAD trial.

AIM: As mineralocorticoid receptor antagonists (MRAs) may possess renoprotective effects in type 2 diabetes (T2D), it was decided to investigate the impact of high-dose MRA on prespecified secondary endpoints-namely, change in urinary albumin-creatinine ratio (UACR) and 24-h ambulatory blood pressure-in the MIRAD trial. METHODS: This was a double-blind clinical trial in which T2D patients at high risk of or with established cardiovascular disease (CVD) were randomized to either high-dose (100-200 mg) eplerenone or a dose-matched placebo as an add-on to background antihypertensive treatment for 26 weeks. Safety was evaluated by the incidence of hyperkalaemia and kidney-related adverse events. RESULTS: A total of 140 patients were enrolled (70 in each group). Baseline UACR was 17 mg/g (geometric mean; 95% CI: 13-22); this decreased by 34% in the eplerenone group compared with the placebo group at week 26 (95% CI: -51% to -12%; P = 0.005). There was no significant decrease in 24-h systolic blood pressure (SBP) due to treatment (-3 mmHg; 95% CI: -6 to 1; P = 0.150). However, the observed change in 24-h SBP correlated with the relative change in UACR in the eplerenone group (r = 0.568, P < 0.001). Mean baseline (± SD) estimated glomerular filtration rate (eGFR) was 85 (± 18.6) mL/min/1.73 m2, and 12 (± 9%) had an eGFR of 41-59 mL/min/1.73 m2. No significant differences in the incidence of mild hyperkalaemia (≥ 5.5 mmol/L; eplerenone vs placebo: 6 vs 2, respectively; P = 0.276) and no severe hyperkalaemia (≥ 6.0 mmol/L) were observed. CONCLUSION: The addition of high-dose eplerenone to T2D patients at high risk of CVD can markedly reduce UACR with an acceptable safety profile.

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

Activation of the mineralocorticoid receptor (MR) may promote dysfunctional adipose tissue in patients with type 2 diabetes, where increased pericellular fibrosis has emerged as a major contributor. The knowledge of the association among the MR, fibrosis, and the effects of an MR antagonist (MRA) in human adipocytes remains very limited. The present substudy, including 30 participants, was prespecified as part of the Mineralocorticoid Receptor Antagonist in Type 2 Diabetes (MIRAD) trial, which randomized patients to either high-dose eplerenone or placebo for 26 weeks. In adipose tissue biopsies, changes in fibrosis were evaluated by immunohistological examination and by the expression of mRNA and protein markers of fibrosis. Treatment with an MRA reduced pericellular fibrosis, synthesis of the major subunits of collagen types I and VI, and the profibrotic factor α-smooth muscle actin compared with placebo in subcutaneous adipose tissue. Furthermore, we found decreased expression of the MR and downstream molecules neutrophil gelatinase-associated lipocalin, galectin-3, and lipocalin-like prostaglandin D2 synthase with an MRA. In conclusion, we present original data demonstrating reduced fibrosis in adipose tissue with inhibition of the MR, which could be a potential therapeutic approach to prevent the extracellular matrix remodeling of adipose tissue in type 2 diabetes.

Fibroblast growth factor 21 in patients with cardiac cachexia: a possible role of chronic inflammation.

AIMS: Cardiac cachexia is a wasting syndrome characterized by chronic inflammation and high mortality. Fibroblast growth factor 21 (FGF-21) and monocyte chemoattractant protein 1 (MCP-1) are associated with cardiovascular disease and systemic inflammation. We investigated FGF-21 and MCP-1 in relations to cardiac function, inflammation, and wasting in patients with heart failure with reduced ejection fraction (HFrEF) and cardiac cachexia. METHODS AND RESULTS: Plasma FGF-21 and MCP-1 were measured in a cross-sectional study among the three study groups: 19 patients with HFrEF with cardiac cachexia, 19 patients with HFrEF without cachexia, and 19 patients with ischaemic heart disease and preserved ejection fraction. Patients with HFrEF and cardiac cachexia displayed higher FGF-21 levels median (inter quantile range) 381 (232-577) pg/mL than patients with HFrEF without cachexia 224 (179-309) pg/mL and ischaemic heart disease patients 221 (156-308) pg/mL (P = 0.0496). No difference in MCP-1 levels were found among the groups (P = 0.345). In a multivariable regression analysis, FGF-21 (logarithm 2) was independently associated with interleukin 6 (logarithm 2) (P = 0.015) and lower muscle mass (P = 0.043), while no relation with N-terminal pro-hormone brain natriuretic peptide was observed. CONCLUSIONS: Fibroblast growth factor 21 (FGF-21) levels were elevated in patients with HFrEF and cardiac cachexia, which could be mediated by increased inflammation and muscle wasting rather than impaired cardiac function.

Insulin sensitivity in relation to fat distribution and plasma adipocytokines among abusers of anabolic androgenic steroids.

OBJECTIVE: Abuse of anabolic androgenic steroids (AAS) is prevalent among young men, but information regarding effects on insulin sensitivity and fat distribution is limited. The objective was to investigate insulin sensitivity in relation to fat distribution and adipocytokines among current and former AAS abusers compared with controls. DESIGN: Cross-sectional study among men involved in recreational strength training. Current and former AAS abusers (n=37 and n=33) and controls (n=30) volunteered from the community. METHODS: We assessed insulin sensitivity by Matsuda index (oral glucose tolerance test). Using overnight fasting blood samples, adiponectin and leptin were measured. Body composition and fat distribution, including visceral adipose tissue (VAT), were assessed by dual energy X-ray absorptiometry. RESULTS: Current and former AAS abusers displayed lower Matsuda index than controls (%-difference (95%CI) from controls, -26% (-45; -1) and -39% (-55; -18)). Testosterone was markedly higher among current AAS abusers and subnormal among former AAS abusers compared with controls. Current AAS abusers displayed higher mean VAT than controls (388 (17) vs 293 (12) cm3 , P<.001) whereas body fat %, adiponectin and leptin concentrations were lower. In contrast, former AAS abusers showed highest leptin concentrations and body fat %. Multivariate linear regressions identified VAT as independent predictor of lower Matsuda index among current AAS abusers compared with controls; while body fat % independently predicted lower Matsuda index among former AAS abusers. CONCLUSIONS: Both current and former AAS abusers displayed lower insulin sensitivity which could be mediated by higher VAT and total body fat %, respectively.