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

NCT03640221 | Withdrawn Phase 4 FDA Drug

• 1 other identifier: 51991
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Hypertension; Diabetes Mellitus, Type 2

Keywords

Hypertension; Diabetes

Outcome Measures

Primary Outcomes (1)

• Muscle sympathetic nerve activity (bursts/minute)

  The primary outcome is the change from baseline in muscle sympathetic nerve activity after 3 months of daily treatment with either Ertugliflozin or hydrochlorothiazide. Muscle sympathetic nerve activity will be measured with microelectrodes inserted into the peroneal nerve (microneurography).

  3 months

Secondary Outcomes (4)

• Outcome 2 is the increase in muscle sympathetic nerve activity in bursts/minute induced by static handgrip.

  3 months

• Increase in muscle sympathetic nerve activity induced by post-hand grip forearm vascular occlusion

  3 months

• Change in chest wall skin sympathetic nerve activity in bursts per minute.

  3 months

• Arterial baroreflex gain.

  3 months

Study Arms (2)

Experimental

EXPERIMENTAL

will receive two bottles of Ertugliflozin 15mg tablets (active drug) and a placebo for hydrochlorothiazide.

Drug: Ertugliflozin; Device: Microneurography; Other: SKNA recordings; Other: Static Handgrip; Other: Post-handgrip forearm vascular occlusion; Other: Testing of the Arterial Baroreflex Function

Active Comparator

ACTIVE COMPARATOR

will receive two bottles of Placebo for ertugliflozin and hydrochlorthiazide 12.5mg capsules (active drug)

Drug: Hydrochlorothiazide 12.5mg; Device: Microneurography; Other: SKNA recordings; Other: Static Handgrip; Other: Post-handgrip forearm vascular occlusion; Other: Testing of the Arterial Baroreflex Function

Interventions

Ertugliflozin DRUG

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. this arm will allow us to test our hypothesis.

Also known as: SGLT2 inhibitor

Experimental

Hydrochlorothiazide 12.5mg DRUG

comparator arm allow us to mimic the mild anti hypertensive effect seen with the SGLT-2 inhibitors in order to enable us to differentiate whether the cardiovascular protection seen with the SGLT-2 inhibitors is secondary to its antihypertensive effects vs the potential decrease in sympathetics.

Also known as: mild antihypertensive comparator

Active Comparator

Microneurography DEVICE

Multiunit recordings of postganglionic sympathetic nerve activity will be obtained with unipolar tungsten microelectrodes inserted selectively into skeletal muscle nerve fascicles of the peroneal nerve. The nerve signals are amplified, filtered (bandwidth 700-2000 Hz), rectified and integrated to obtain a mean voltage display of sympathetic nerve activity. Sympathetic bursts are counted by inspection of the neurograms. A deflection on the mean voltage display is counted as a "burst" if it has a minimal signal to noise ratio of 2:1. The interobserver and intraobserver variations in identifying bursts are \<10% and \< 5%, respectively.

Active Comparator; Experimental

SKNA recordings OTHER

SKNA recordings will be captured by placing ECG electrodes on the chest wall. Recordings will be obtained simultaneously with microneurographic recording. The two techniques will undergo identical filtering and processing of the neurophysiologic inputs which are then displayed simultaneously using identical output functions.

Active Comparator; Experimental

Static Handgrip OTHER

Subjects will perform static handgrip at 33% MVC for 2 minutes, using a Stoelting recording handgrip dynamometer. Force output will be recorded continuously and displayed on the computer screen in real time to provide the subject with visual feedback. MVC will be determined for each subject at the beginning of each experiment. Subjects will be instructed to avoid straining maneuvers, changes in breathing, and contraction of non-exercising muscles during the experimental protocols. Ratings of perceived exertion (RPE) will be obtained at the end of each exercise by using a 6- to 20-unit Borg scale. Static handgrip at 33% MVC is accompanied by reflex increases in muscle sympathetic nerve activity caused by activation of the acid-sensing unmyelinated muscle afferents.

Active Comparator; Experimental

Post-handgrip forearm vascular occlusion OTHER

This will be performed by inflating a pneumatic cuff on the upper exercising arm to suprasystolic pressure (220 mmHg) beginning 10 seconds before the subject stops gripping and ending 2 minutes into the post-exercise period. The vascular occlusion maintains intramuscular acidosis and thus the stimulation of acid-sensing unmyelinated skeletal muscle afferents and their reflex increase in muscle sympathetic nerve activity and BP, while the muscular relaxation eliminates central command and the attendant increase in heart rate (which returns to the baseline level). As soon as the cuff is release and the forearm circulation is restored, muscle sympathetic nerve activity quickly returns to the baseline level and BP soon follows.

Active Comparator; Experimental

Testing of the Arterial Baroreflex Function OTHER

We will compare effects of Ertugliflozin vs. low-dose HCTZ on sinoaortic baroreflex function in hypertensive diabetic subjects during both spontaneous fluctuations in arterial pressure and during decreases and increases in arterial pressure induced by the Valsalva maneuver. The aim of this protocol is to determine if the sympathetic nerve, as well as the heart rate, component of the sinoaortic baroreflex can be augmented by the SGLT2 inhibitor. After obtaining stable baseline recordings, arterial pressure, heart rate, and muscle sympathetic nerve activity will recorded during spontaneous fluctuations in BP over 5 minutes and during both decreases in BP during phase III of the Valsavla maneuver and during the phase IV overshoot in BP upon its release. Frequent accurate measurement of arterial pressure will be obtained with a highly-rated oscillometric arm monitor that records 6 BP readings per minute (Welch Allyn Vital Signs Monitor).

Active Comparator; Experimental

Eligibility Criteria

• Age: 35 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of diabetes mellitus established \< 24 months before enrollment
• Ages 30-65 years
• Men and women, inclusive or race/ethnic groups
• 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.
• HBA1C of 6.5 to 8.0
• Urine albumin/creatinine \< 300
• eGFR \> 60
• 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
• BMI 25 to 35 inclusive
• Normal sinus rhythm by 12-lead ECG with no major conduction abnormalities
• Left ventricular ejection fraction \> 50% by transthoracic echocardiogram
• Willing and able to cooperate with all aspects of the protocol;
• 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

You may not qualify if:

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

Sponsors & Collaborators

• Cedars-Sinai Medical Center: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

MeSH Terms

Conditions

Hypertension; Diabetes Mellitus, Type 2; Diabetes Mellitus

Interventions

ertugliflozin; Sodium-Glucose Transporter 2 Inhibitors; Hydrochlorothiazide

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Hypoglycemic Agents; Physiological Effects of Drugs; Chlorothiazide; Benzothiadiazines; Sulfonamides; Sulfones; Sulfur Compounds; Organic Chemicals; Thiazides; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Cedars-Sinai Medical Center pharmacy will be responsible for filling individual patient containers, labeling the containers and performing the blinding of the supplies. subjects will receive two bottles of either: * Ertugliflozin 15mg tablets (active drug) and a placebo for hydrochlorothiazide; or * Placebo for ertugliflozin and hydrochlorthiazide 12.5mg capsules (active drug)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A double-blind, randomized, parallel 2- arm study, therapy will be randomly allocated 2:1 to Ertugliflozin oral tablet daily (n=20) or hydrochlorothiazide 12.5mg oral tablet (n=10) and followed for three months.

Study Record Dates

• First Submitted: August 1, 2018
• First Posted: August 21, 2018
• Study Start: September 1, 2018
• Primary Completion: May 31, 2020
• Study Completion: August 31, 2020
• Last Updated: January 14, 2020

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)