Effect of empagliflozin on the sympathetic nervous system in people with type 2 diabetes.

INTERVENTION: Empagliflozin. Dose = 25 mg once a day, Duration = 12 weeks. Mode of administration = oral tablet. Adherence will be monitored at study visits by empty drug packet return and pill counting of any returned study drug. CONDITION: Cardiovascular disease Type 2 diabetes mellitus PRIMARY OUTCOME: Whole body norepinephrine spillover rate ; This is assessed by assay of blood collected at catheterisation and determination of noradrenaline concentration by HPLC and liquid scintillation spectroscopy. SECONDARY OUTCOME: 24 hour urine albumin 24 hour urine electrolytes 24 hour urine glucose Ankle brachial pressure index ; This is measured with a vascular profiler which has limb cuffs, phonocardiogram, ECG and electronic pressure transducers Cardiac norepinephrine spillover rate ; This is assessed by assay of blood collected at catheterisation and determination of noradrenaline concentration by HPLC and liquid scintillation spectroscopy. Coronary arterial‐venous neurotransmitter, neuromodulator and metabolite gradients measured by serum assay. Epigenetics –DNA methylation , transcriptome and microRNA ; These will be assessed using epigenomic profiling of PBMCs using Illumina sequencing technology; RNA‐seq to perform unbiased measurement of all expressed genes in the specimens; microRNA sequencing to detect all expressed small RNAs; whole genome DNA methylation analysis using MBD‐seq and bisulfite sequencing; polymerase chain reaction experiments to validate methylation and gene expression signatures. ; These analyses will review patterns. One of the pathways to be examined will be the MTOR pathway. ; Fasting plasma glucose ; This is measured on blood collected in fluoride oxalate tube. Hba1c ; This is measured by assay on venous whole blood.. Left atrial pressure (pulmonary artery wedge pressure) ; This is measured using a Swan‐Ganz catheter with a pressure transducer. Left ventricular ejection fraction ; This is measured by echocardiogram. Left ventricular global longitudinal strain ; This is measured by echocardiogram with speckle tracing. Left ventricular volumes ; This is measured by echocardiogram. Pulse wave velocity ; This is measured with a vascular profiler which has limb cuffs, phonocardiogram, ECG and electronic pressure transducers. Questionnaire scores for anxiety: Spielberger’s State & Trait Anxiety Inventory (STAI Form Y‐1 and STAI Form X‐2) Questionnaire scores for depression: Beck Depression Inventory–II. Questionnaire scores for quality of life, SF‐36, Renal arterial‐venous neurotransmitter, neuromodulator and metabolite gradients measured by serum assay. Renal norepinephrine spillover rate ; This is assessed by assay of blood collected at catheterisation and determination of noradrenaline concentration by HPLC and liquid scintillation spectroscopy. Resting muscle sympathetic nerve activity ; This is assessed by microneurography in a muscle fascicle of the peroneal nerve at the fibular ; head. Splanchnic arterial‐venous neurotransmitter, neuromodulator and metabolite gradients measured by serum assay. Systolic and diastolic blood pressure ; This is measured by sphygmomanometry. VO2max ; This is measured by cycle ergometer maximum exercise capacity test. INCLUSION CRITERIA: Type 2 diabetes. HbA1c between 7.0% (53 mmol/mol) and 10.0% (86 mmol/mol) inclusive, at Visit 1. Antidiabetic therapy has to be unchanged for 12 weeks before Visit 1. eGFR greater than or equal to 45 mL/min/1.73 m2 BMI 20‐40 kg/m2 High cardiovascular risk, defined as at least one of the following: a) Confirmed history of myocardial infarction (>2 months prior to Visit 1). b) Evidence of multivessel coronary artery disease, in 2 or more major coronary arteries, irrespective of the revascularisation status, i.e. i) Either the presence of a significant stenosis (imaging evidence of at least 50% narrowing of the luminal diameter measured during a coronary angiography or a multi‐sliced computed tomography angiography), in 2 or more major coronary arteries, or ii) a previous revascularisation (percutaneous transluminal coronary angioplasty with or without stent, or coronary artery bypass grafting) at least 2 months ago, in 2 or