Neurovascular Effects of Empagliflozin

Prehypertension is recognized clinically as a precursor to hypertension, an independent predictor of cardiovascular disease (CVD) risk. Vascular and sympathetic nervous system dysfunction are non-traditional risk factors contributing to increased CVD risk that are mediated, in part, by systemic inflammation and oxidative stress. Targeting vascular and sympathetic nervous system function represents a therapeutic strategy for mitigating CVD risk in prehypertension.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors (e.g., empagliflozin) have emerged as a transformative therapeutic class with robust anti-inflammatory and antioxidant properties. The efficacy of SGLT2 inhibitors to improve vascular and sympathetic nervous system function through reductions in pro-inflammatory and improved redox balance have yet to be investigated in prehypertension.

In this randomized, double-blind, placebo-controlled clinical trial, the investigators seek to utilize integrative methods for evaluating vascular and sympathetic nervous system function following 2-week treatment with empagliflozin. Understanding the mechanisms underpinning increased CVD risk in prehypertension will inform us about specific pharmacological prevention strategies in this ever-growing clinical population.

• Empagliflozin (EMPA) (Drug): Oral ingestion for 2 weeks
• Placebo (Other): Oral placebo for 2 weeks.

Primary outcomes

• Macrovascular endothelial function as assessed by brachial artery flow-mediated dilation (FMD) [At the end of each 2-week treatment period]: The brachial artery will be imaged using high-resolution Doppler ultrasound at baseline and following a period of forearm blood-flow occlusion induced by an inflatable blood pressure cuff. FMD will be calculated as the percentage (%) increase in brachial artery diameter from baseline following cuff release, reflecting the ability of the brachial artery to dilate in response to increased blood flow and shear stress. Higher FMD values indicate greater endothelium-dependent vasodilatory function.

Secondary outcomes

• Sympathetic nervous system function as assessed by muscle sympathetic nerve activity [At the end of each 2-week treatment period]: Muscle sympathetic nerve activity (MSNA) will be measured using microneurography, in which a recording electrode will be inserted into a nerve of the lower leg to directly record sympathetic nerve activity. Sympathetic bursts will quantified as burst frequency (bursts/min) and burst incidence (bursts/100 heartbeats). Higher values indicate greater MSNA sympathetic nerve activity.

Sex: All, ages: 45 Years to 75 Years, accepts healthy volunteers

Inclusion Criteria

* Midlife and older (>/= 45-75 yrs) males and females
* Body mass index 18-35 kg/m2
* Able to give informed consent

Blood Pressure Status:

Normotensive (control group)

* Systolic (<120 mmHg) and Diastolic (<80 mmHg) Prehypertension (experimental group)
* Systolic (120-129 mmHg) and Diastolic (<80 mmHg)

Exclusion Criteria

* Age <45 and/or >75 yrs
* BMI >35 kg/m2
* Blood pressure: Systolic (>130 mmHg) and Diastolic (>80 mmHg)
* Anti-hypertensive therapy
* Type 2 diabetes (blood glucose >126 mg/dL or HbA1c >6.2%)
* Currently prescribed SGLT2i medication
* Currently prescribed GLP-1 medication
* Currently prescribed Beta-Blocker medication
* Known or recently (last 6 months) diagnosed renal, pulmonary, and/or neurological diseases/disorders (chronic kidney disease, acute kidney injury, kidney stones, urinary tract infection, glomerulonephritis, chronic obstructive pulmonary disease, asthma, pulmonary embolism, epilepsy, multiple sclerosis, Parkinson's, peripheral neuropathy)
* Known or recently (last 6 months) diagnosed cardiovascular and cerebrovascular disorders (heart failure, coronary artery disease, stroke, transient ischemic attack, cerebral aneurysm, arteriovenous malformation, cerebral venous thrombosis, dementia, Alzheimer's, moyamoya disease)
* Secondary or resistant hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg despite treatment with at least 3 different classes of antihypertensive medications
* History of cancer
* Smoking or tobacco/cannabis use (current use or quit within the last 6 months)
* Pregnant, breastfeeding, planning to become pregnant, or unwilling to use adequate birth control
* Psychiatric or psychological disorders
* Hormone-based therapy
* History of myocardial infarction, heart failure, liver disease, or chronic kidney disease (estimated glomerular filtration rate < 60 ml/min/1.73m2)
* History of lactic acidosis
* History of alcohol abuse
* Severe infection within the last 30 days
* Immunosuppressive therapy within the past year
* Life expectancy < 1 year
* Study compliance: Unwilling to fast overnight
* Known allergy to Empagliflozin

• Kanokwan Bunsawat, PHD, Principal investigator, University of Iowa