Reduction of cardiac adipose tissue volume with short-term empagliflozin treatment in patients with type 2 diabetes: A substudy from the SIMPLE randomized clinical trial.

OBJECTIVE: Ectopic accumulation of cardiac adipose tissue volume (CAT) has been associated with cardiac remodelling and cardiac dysfunction in type 2 diabetes and may be a future therapeutic target. In this substudy from the SIMPLE-trial, we investigated short-term empagliflozin therapy's effects on CAT in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Between 4 April 2017 and 11 May 2020, we randomized 90 patients with type 2 diabetes and established or high risk of cardiovascular disease to 25 mg empagliflozin or placebo for 13 weeks. The substudy focused on change in CAT evaluated by images acquired during 82 Rubidium-positron emissions tomography/computed tomography. The analysis included 78 patients who had at least one scan. Furthermore, we report on the relation to the concurrent effects on left ventricular mass, end-diastolic volume and end-systolic volume, body composition and glucometabolic status. RESULTS: Mean ± SD baseline CAT was 258.5 ± 117.9 ml. Empagliflozin reduced CAT after 13 weeks by 12.41 ml [95% CI (-23.83 to -0.99), p = .034] as compared with placebo. Similarly, left ventricular mass [-5.16 g, 95% CI (-8.80 to -1.52), p = .006], end-diastolic volume and end-systolic volume decreased with empagliflozin. In addition, significant improvements were observed in body composition, with reduced total fat mass, and in measures of glucose and lipid metabolism. However, no correlation was observed between changes in CAT and changes in cardiac parameters and change in CAT appeared mediated primarily by concurrent change in weight. CONCLUSIONS: Empagliflozin provides an early reduction of CAT; however, no association was observed with concurrent changes in cardiac volumetrics.

The effects of empagliflozin on measured glomerular filtration rate and estimated extracellular and plasma volumes in patients with type 2 diabetes.

AIMS: To investigate the effects of empagliflozin on measured glomerular filtration rate (mGFR), estimated plasma volume (PV) and estimated extracellular volume (ECV) in a cohort of patients with type 2 diabetes (T2D) and high risk of cardiovascular events. MATERIALS AND METHODS: In this prespecified substudy of the randomized, placebo-controlled SIMPLE trial, patients with T2D at high risk of cardiovascular events were allocated to either empagliflozin 25 mg or placebo once daily for 13 weeks. The prespecified outcome was between-group change in mGFR, measured by the 51 Cr-EDTA method after 13 weeks; changes in estimated PV and estimated ECV were included. RESULTS: From April 4, 2017 to May 11, 2020, 91 participants were randomized. Of these, 45 patients from the empagliflozin group and 45 patients from the placebo group were included in the intention-to-treat analysis. Treatment with empagliflozin reduced mGFR by -7.9 mL/min (95% confidence interval [CI] -11.1 to -4.7; P < 0.001), estimated ECV by -192.5 mL (95% CI -318.0 to -66.9; P = 0.003) and estimated PV by -128.9 mL (95% CI -218.0 to 39.8; P = 0.005) at Week 13. CONCLUSIONS: Treatment with empagliflozin for 13 weeks reduced mGFR, estimated ECV and estimated PV in patients with T2D and high risk of cardiovascular events.

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).

Persistently Decreased Quality of Life and its Determinants in Previous Illicit Androgen Users.

BACKGROUND AND OBJECTIVES: Quality of life (QoL) has never been assessed in previous illicit users of androgens years following androgen cessation. Therefore, the objective of this study was to assess QoL in previous illicit androgen users compared with current illicit androgen users and controls who had never used androgens. METHODS: Cross-sectional study including men involved in recreational strength training grouped according to their history of androgen use. We used the RAND Short-Form-36 questionnaire to assess physical and mental health-related QoL. RESULTS: We included 77 previous and 118 current androgen users and 39 healthy nonusers. The mean (SD) age of all participants was 33 (8) years. The elapsed duration since androgen cessation, geometric mean (95% CI), was 2.0 (1.5-2.6) years in former users. Median (25th-75th percentiles) serum total testosterone was lower in former users than controls, 14 (11-17) vs 19 (16-21) nmol/L, P < .001. Previous users displayed lower mean (SD) across both mental and physical (PCS) component summary scores, 48 (10) vs 54 (4) (P = .004) and 48 (9) vs 53 (3) (P = .002) compared with controls.Using multivariate linear regressions, evaluating physical and mental component scores as dependent variables, lower serum total testosterone, longer duration since androgen cessation, study recruitment from an endocrine outpatient clinic, and established chronic diseases were all independently associated with reduced QoL in previous users, P < .05. CONCLUSIONS: Previous illicit androgen users exhibited reduced QoL 2 years after androgen discontinuation, which may be a persistent condition.

Higher Myonuclei Density in Muscle Fibers Persists Among Former Users of Anabolic Androgenic Steroids.

CONTEXT: No information exists on the long-lasting effects of supraphysiological anabolic androgenic steroids (AASs) usage on the myocellular properties of human skeletal muscle in previous AAS users. OBJECTIVE: We hypothesized that former AAS users would demonstrate smaller myonuclei domains (ie, higher myonuclei density) than matched controls. METHODS: A community-based cross-sectional study in men aged 18-50 years engaged in recreational strength training. Muscle biopsies were obtained from the m. vastus lateralis. Immunofluorescence analyses were performed to quantify myonuclei density and myofiber size. RESULTS: Twenty-five males were included: 8 current and 7 previous AAS users and 10 controls. Median (25th-75th percentiles) accumulated duration of AAS use was 174 (101-206) and 140 (24-260) weeks in current and former AAS users, respectively (P = .482). Geometric mean (95% CI) elapsed duration since AAS cessation was 4.0 (1.2; 12.7) years among former AAS users. Type II muscle fibers in former AAS users displayed higher myonuclei density and DNA to cytoplasm ratio than controls, corresponding to smaller myonuclei domains (P = .013). Longer accumulated AAS use (weeks, log2) was associated with smaller myonuclei domains in previous AAS users: beta-coefficient (95% CI) -94 (-169; -18), P = .024. Type I fibers in current AAS users exhibited a higher amount of satellite cells per myofiber (P = .031) than controls. CONCLUSION: Muscle fibers in former AAS users demonstrated persistently higher myonuclei density and DNA to cytoplasm ratio 4 years after AAS cessation suggestive of enhanced retraining capacity.

Effect of empagliflozin on myocardial structure and function in patients with type 2 diabetes at high cardiovascular risk: the SIMPLE randomized clinical trial.

To investigate the effects of 13 weeks treatment with empagliflozin in patients with high-risk type-2 diabetes mellitus on echocardiographic measures of left ventricular (LV) structure and function compared to placebo. A total of 91 patients were randomized to treatment with empagliflozin (25 mg/day, n = 45) or matching placebo (n = 45) for 13 weeks. Left ventricular (LV) mass, volumes and geometry as well as measures of LV systolic and diastolic function were measured using echocardiography at baseline and follow up. Mean LV mass index (LVMi) was reduced by - 11.5 g/m2 (95% CI - 56.4; 33.4, p = 0.03) with empagliflozin compared to - 1.4 g/m2 (95% CI - 36.5; 33.8, p = 0.63) for placebo. The proportion of patients with LV hypertrophy was reduced by 16.3% (p = 0.04) in the empagliflozin group compared to 1.1% in the placebo group (p = 1.00). The proportion of patients with left atrial volume index > 34 mL/m2 was reduced by 20.0% (p = 0.02) with empagliflozin compared to 9.5% for placebo (p = 0.45) and the E/e' ratio decreased (∆-0.8 (1.9) vs. ∆0.5 (2.0), p < 0.01). 13 weeks empagliflozin treatment in patients with type-2 diabetes at high CV risk significantly reduced LV mass, improved LV geometry and improved diastolic function compared to placebo.

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.

Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus: The SIMPLE Trial.

Background Sodium-glucose cotransporter 2 inhibitors reduce hospitalizations for heart failure and cardiovascular death, although the underlying mechanisms have not been resolved. The SIMPLE trial (The Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus) investigated the effects of empagliflozin on myocardial flow reserve (MFR) reflecting microvascular perfusion, in patients with type 2 diabetes mellitus at high cardiovascular disease risk. Methods and Results We randomized 90 patients to either empagliflozin 25 mg once daily or placebo for 13 weeks, as add-on to standard therapy. The primary outcome was change in MFR at week 13, quantified by Rubidium-82 positron emission tomography/computed tomography. The secondary key outcomes were changes in resting rate-pressure product adjusted MFR, changes to myocardial flow during rest and stress, and reversible cardiac ischemia. Mean baseline MFR was 2.21 (95% CI, 2.08-2.35). There was no change from baseline in MFR at week 13 in either the empagliflozin: 0.01 (95% CI, -0.18 to 0.21) or placebo groups: 0.06 (95% CI, -0.15 to 0.27), with no treatment effect -0.05 (95% CI, -0.33 to 0.23). No effects on the secondary outcome parameters by Rubidium-82 positron emission tomography/computed tomography was observed. Treatment with empagliflozin reduced hemoglobin A1c by 0.76% (95% CI, 1.0-0.5; P<0.001) and increased hematocrit by 1.69% (95% CI, 0.7-2.6; P<0.001). Conclusions Empagliflozin did not improve MFR among patients with type 2 diabetes mellitus and high cardiovascular disease risk. The present study does not support that short-term improvement in MFR explains the reduction in cardiovascular events observed in the outcome trials. Registration URL: https://clinicaltrialsregister.eu/; Unique identifier: 2016-003743-10.

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).