Neurovascular Effects of Empagliflozin

Neurovascular Effects of Empagliflozin in Mid-Life and Older Adults With Prehypertension

The goal of this clinical trial is to examine whether empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, improves vascular and autonomic function in adults with prehypertension. The main questions this clinical trial aims to answer are:

1. Does empagliflozin improve endothelial function?
2. Does empagliflozin improve sympathetic nervous system function?

This clinical trial employs a double-blind, placebo-controlled crossover study lasting up to 6 weeks for participants with prehypertension and up to 2 weeks for normotensive participants. Participants with prehypertension will take empagliflozin or placebo for 2 weeks, separated by a 2-week washout. Normotensive participants will complete baseline, pre-treatment visits only and will serve as a control group.

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.

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