Effect of empagliflozin on coronary microvascular function in patients with type 2 diabetes mellitus-A randomized, placebo-controlled cross-over study

PURPOSE: Results from large scale cardiovascular outcome trials in patients with type 2 diabetes mellitus (DM2) have found that sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular death and hospitalization for heart failure, but the mechanisms behind the beneficial cardiovascular effects are not fully understood. We tested the hypothesis that the SGLT2i, empagliflozin, improves non-endothelial dependent coronary microvascular function, thereby leading to better cardiac function. METHODS: Patients with DM2 followed at the endocrinology outpatient clinic at Bispebjerg University Hospital were included in a double blinded, placebo-controlled cross-over study. Participants were allocated equally to each treatment sequence using simple randomization and treated with empagliflozin 25 mg and placebo for 12 weeks, interrupted by 2 weeks wash-out period. The primary outcome was coronary microvascular function, assessed as coronary flow velocity reserve (CFVR) and measured with transthoracic doppler echocardiography. Echocardiographic parameters of cardiac function were measured, and blood samples were analyzed for a broad panel of cardiovascular biomarkers. RESULTS: Thirteen patients were randomized to each sequence and 10 and 9 completed the study according to protocol, respectively, and were included in the analysis of outcome parameters. We found no improvement in CFVR (change in the empagliflozin period was -0.16 (SD 0.58)). There were no effects on cardiac systolic function or indicators of cardiac filling pressure. Well-known effects of empagliflozin were obtained, such as weight loss and reduction in Hba1c level. Creatinine level increased but remained within normal range. We observed a clear trend of reduction in cardiovascular biomarkers after empagliflozin treatment and increased levels after the placebo period. No serious adverse reactions were reported. CONCLUSIONS: Despite effect on weight-loss, Hba1c and biomarkers, treatment with empagliflozin for 12 weeks did not improve CFVR in patients with DM2

Comprehensive treatment of microvascular angina in overweight women - a randomized controlled pilot trial.

AimsCoronary microvascular dysfunction (CMD) carries a poor cardiovascular prognosis and may explain angina in women without obstructive coronary artery disease (CAD). Currently, no evidence-based treatment for CMD exists. We investigated whether reducing cardiovascular risk factors improves symptoms and microvascular function in women with non-endothelial dependent CMD and no obstructive CAD.MethodsWe randomized 62 women aged 40-75, with body mass index (BMI) >25 kg/m2, angina ≥monthly, and coronary flow velocity reserve (CFVR) ≤2.5 to a 24-week intervention comprising low energy diet, exercise training, and optimized treatment of hypertension, dyslipidemia and diabetes or to control. Patients were assessed before randomization and after 24 weeks. Primary outcomes were CFVR assessed by transthoracic Doppler stress-echocardiography and angina burden by Seattle Angina Questionnaire (SAQ). Secondary outcomes were exercise capacity, body composition, glycemic control, myocardial function, and anxiety and depression symptoms.ResultsFifty-six participants (90%) completed the study. Median (IQR) age was 65.2 (57.1;70.7) years, BMI was 30.1 (28.4;32.7) kg/m2. The intervention resulted in relevant improvement in angina symptoms (9-21-point increase on SAQ-scales (all pConclusionA major weight loss and intensified risk factor control resulted in significantly improved angina burden but no improvement of coronary microvascular function among women with microvascular angina

Biomarkers and Coronary Microvascular Dysfunction in Women With Angina and No Obstructive Coronary Artery Disease

Background Coronary microvascular dysfunction (CMD) is a major cause of ischemia with no obstructed coronary arteries. Objectives The authors sought to assess protein biomarker signature for CMD. Methods We quantified 184 unique cardiovascular proteins with proximity extension assay in 1,471 women with angina and no obstructive coronary artery disease characterized for CMD by coronary flow velocity reserve (CFVR) by transthoracic echo Doppler. We performed Pearson's correlations of CFVR and each of the 184 biomarkers, and principal component analyses and weighted correlation network analysis to identify clusters linked to CMD. For prediction of CMD (CFVR &lt; 2.25), we applied logistic regression and machine learning algorithms (least absolute shrinkage and selection operator, random forest, extreme gradient boosting, and adaptive boosting) in discovery and validation cohorts. Results Sixty-one biomarkers were correlated with CFVR with strongest correlations for renin (REN), growth differentiation factor 15, brain natriuretic protein (BNP), N-terminal-proBNP (NT-proBNP), and adrenomedullin (ADM) (all P &lt; 1e-06). Two principal components with highest loading on BNP/NTproBNP and interleukin 6, respectively, were strongly associated with low CFVR. Weighted correlation network analysis identified 2 clusters associated with low CFVR reflecting involvement of hypertension/vascular function and immune modulation. The best prediction model for CFVR &lt;2.25 using clinical data had area under the receiver operating characteristic curve (ROC-AUC) of 0.61 (95% CI: 0.56-0.66). ROC-AUC was 0.66 (95% CI: 0.62-0.71) with addition of biomarkers (P for model improvement = 0.01). Stringent two-layer cross-validated machine learning models had ROC-AUC ranging from 0.58 to 0.66; the most predictive biomarkers were REN, BNP, NT-proBNP, growth differentiation factor 15, and ADM. Conclusions CMD was associated with pathways particularly involving inflammation (interleukin 6), blood pressure (REN, ADM), and ventricular remodeling (BNP/NT-proBNP) independently of clinical risk factors. Model prediction improved with biomarkers, but prediction remained moderate.</p