Ertugliflozin Versus Hydrochlorothiazide in Reducing Sympathetic Neural Overactivity in Patients With Hypertension and Recently-diagnosed Type 2 Diabetes.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors are an exciting new class of antidiabetic drugs that cause a modest reduction in high blood pressure and large reductions in the risk of cardiovascular disease (CVD) outcomes and renal outcomes in patients with advanced type 2 diabetes and very high CVD risk. However, the mechanistic underpinning of these CVD benefits is not well understood. Mechanistic studies are needed to define specific biologic targets and thus optimize therapeutic benefits.

Type 2 diabetes mellitus is firmly established as a state of sympathetic neural overactivity, which may contribute to coexistent hypertension, heart failure, sudden cardiac death, macro- and micro-vascular complications of diabetes, and diabetic nephropathy. In patients recently diagnosed with Type 2 diabetes, microelectrode recordings of sympathetic nerve activity (SNA) targeted to the skeletal muscle circulation have shown both:

1. abnormally high resting (ambient) levels of sympathetic nerve activity; and
2. greatly exaggerated increases in sympathetic nerve activity during isometric (static) handgrip exercise.

The purpose of the proposed study is to determine if Ertugliflozin, a SGLT2 inhibitor, constitutes an effective countermeasure against sympathetic overactivity in patients with diagnosed hypertension and recently diagnosed type 2 diabetes by normalizing the high resting level of muscle sympathetic nerve activity (SNA) as measured by intraneural microelectrodes in the peroneal nerve.

Thus, an effective countermeasure is an urgent unmet medical need. The SGLT2 inhibitors hold exciting promise to address this need.

Static handgrip provides unique mechanistic insights into putative therapeutic targets (in this case the SGLT2 inhibitors) within the human autonomic nervous system include examining the reflexes within the nervous system and its response as a result. Static handgrip will require that patients lay down and with the use of a dyanometer (handgrip device which measures the force output generated from the handgrip exercise) and they will squeeze to the maximum of their ability for 30 seconds, then have a relaxation period, and grip again.

Typically responses to the nervous system travel via unmyelinated skeletal muscle nerve fibers (afferent signals) and the brain responds via the central motor command (or voluntary motor effort) which is its communication to the body to indicate the perception of effort needed in order to complete the task at hand. This volitional component of exercise- is the main mechanism driving heart rate during static handgrip.

When activated by exercise-induced skeletal muscle acidosis (as with static handgrip), muscle afferents signal the brain of a mismatch between muscle perfusion and metabolic demand and trigger a reflex increase in sympathetic nerve activity to non-exercising skeletal muscles. This raises blood pressure and shunts blood to the metabolically active muscle groups. Also, with voluntary exercise, the activation of brain pathways leading to the engagement of parallel central inhibition of the vagus nerve. The result is an increase in cardiac sympathetic nerve activity but it has an an insignificant effect on muscle sympathetic nerve activity, which is driven almost entirely by direct input from the afferent signals.

Thus, the investigators hypothesize that, in type 2 diabetes, impaired skeletal muscle energetics requires patients to use excessive voluntary motor effort to perform routine static handgrip, resulting in a parallel augmentation in cardiac sympathetic nerve activity. If Ertugliflozin improves skeletal muscle energetics, the same isometric exercise will require less motor effort which should result in smaller increases in cardiac sympathetic nerve activity and heart rate as well as a lower rating of perceived exertion on the Borg scale (an established index of central command).

The proposed work stands to advance several innovative concepts that could change the clinical approach to the early management of type 2 diabetes:

1. The sympathetic nervous system as a novel therapeutic target in the mechanistic underpinning of how SGLT2 inhibitors protect against major CVD.
2. Hyperfunction of unmyelinated autonomic (skeletal muscle) sensory nerves as a putative abnormal indicator of diabetic autonomic cardiovascular neuropathy.
3. Early SGLT2-mediated correction of sympathetic overactivity in patients with type 2 diabetes could favorably alter the natural history of diabetic autonomic neuropathy.

The proposed methodology incorporates several scientific rigors:

1. Direct measurement of sympathetic nerve action potentials in human patients using intraneural microelectrodes. This is the gold standard for studying the regulation of the sympathetic nervous system in patients.
2. This microneurographic technique is highly quantitative and remarkably reproducible when a given subject is studied repeatedly without intervention. The spatial resolution is a major advantage by permitting recording of postganglionic fibers innervating the skeletal muscle circulation without "interfering noise" from surrounding postganglionic fibers innervating the skin and from muscle spindles. The temporal resolution permits calculation of the primary endpoint which relates sympathetic discharge rate to the cardiac cycle, providing the best indicator that sympathetic regulation is altered by an SGLT2 inhibitor.
3. Skin sympathetic nerve activity recorded using standard ECG chest leads. The rationale is that the stellate ganglion gives off parallel sympathetic fibers to the heart and to the skin of the chest wall. Conscious dog studies in Dr. Peng-Shen Chen's lab at Indiana University show \> 70% concordance of bursts in simultaneous recordings from the stellate ganglion, the cardiac sympathetics, and the chest wall skin sympathetics; similar data are obtained from standard non-invasive ECG chest leads using appropriate bandpass filtering and amplification. Collaborative translational data on healthy human subjects in my lab at Cedars-Sinai show that Skin sympathetic nerve activity displays characteristic discharge properties of Skin sympathetic nerve activity recorded with our intraneural microelectrodes: large non-pulse synchronous bursts of activity that increase immediately with the onset of static handgrip preceded by clear anticipatory bursts. Thus, Skin sympathetic nerve activity provides in conscious human patients a novel quantitative measurement of the centrally-influenced/baroreceptor-insensitive component of cardiac sympathetic nerve activity. Dr. Chen has shown large bursts of Skin sympathetic nerve activity trigger episodes of ventricular tachycardia (VT) in some VT patients with implanted automatic defibrillators. So, if SGLT2 inhibitors buffer excessive increases in Skin sympathetic nerve activity at rest or during static handgrip in patients with type 2 diabetes, this could potentially protect against one form of catecholamine-induced sudden cardiac death.
4. CleverCaps Pill Dispensing System- this unique electronic pill bottle system incorporates wireless technology and state-of-the-art methodology for quantifying and optimizing medication compliance. The system sends reminders for each scheduled dose of each pill type and tracks opening and closing of the bottles in real time as well as the weight of the remaining pills.
5. Welch Allyn Spot Vital Signs Monitor-- provides vital signs in seconds with hospital-grade technology and received an AA rating for continuous inflation mode which takes 6 readings per inflation sequence. This will allow for close titration of medications to induce a 10mmHg bidirectional changes in the mean arterial pressure.
6. the investigators will conduct careful pharmacologic quantitative testing of the baroreceptor reflex.

Eligibility Criteria:
Inclusion Criteria:

1. Diagnosis of diabetes mellitus established \< 24 months before enrollment
2. Ages 30-65 years
3. Men and women, inclusive or race/ethnic groups
4. Background standard-of-care cardiometabolic therapy including a stable dose regimen for 6 weeks of: a) metformin and b) an ACEI or an ARB and c) any statin.
5. HBA1C of 6.5 to 8.0
6. Urine albumin/creatinine \< 300
7. eGFR \> 60
8. Systolic BP 130 to 150 mmHg on the first screening visit and a Systolic BP of 130 to 145 mmHg on the second screening visit
9. BMI 25 to 35 inclusive
10. Normal sinus rhythm by 12-lead ECG with no major conduction abnormalities
11. Left ventricular ejection fraction \> 50% by transthoracic echocardiogram
12. Willing and able to cooperate with all aspects of the protocol;
13. Willing and able to give written informed consent for study participation and provide consent for access to medical data according to appropriate local data protection legislation, allowing authorization to access medical records and describe events captured in the endpoints

Exclusion Criteria:

1. Known history of previous cardiovascular disease (CVD)
2. Currently on other diabetes medications such as: insulin analogs, GLP-1 analogs, DPPIV inhibitors, thiazolidinediones, sulfonylureas, meglitinides, alpha glucosidase inhibitors, amylin analogies.
3. Any concomitant medications or supplements, with the exception of: aspirin, ACE-I or ARB, and statin therapy
4. Diagnosed diabetic peripheral sensory neuropathy or retinopathy
5. Orthostatic hypotension defined as standing BP \< 100/60 or postural fall of SBP \> 20 or DBP \> 10
6. Female patients who are pregnant, intend to become pregnant during the study, or are nursing
7. Known hypersensitivity to SGLT-2 inhibitors
8. Presence of hepatic disease
9. History of diabetic ketoacidosis
10. Type 1 diabetes
11. Pancreas or beta-cell transplantation
12. Pancreatitis or pancreatic surgery
13. Unable to communicate or cooperate with the investigator due to language, poor mental development or impaired cerebral function.
14. History of illicit drug use
15. Any other condition(s) deemed by the physician-investigators to be unsafe to participate