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

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ClinicalTrials.gov Identifier: NCT03640221
Recruitment Status : Not yet recruiting
First Posted : August 21, 2018
Last Update Posted : August 24, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Ron Victor, Cedars-Sinai Medical Center

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. 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.


Condition or disease Intervention/treatment Phase
Hypertension Diabetes Mellitus, Type 2 Drug: Ertugliflozin 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 Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:

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)
Primary Purpose: Treatment
Official Title: A Double-blind, Randomized, Parallel 2- Arm Study to Compare the Efficacy of Ertugliflozin Versus Hydrochlorothiazide in Reducing Sympathetic Neural Overactivity in Patients With Hypertension and Recently-diagnosed Type 2 Diabetes Who Are Receiving Background Standard-of-care Cardio-metabolic Therapy With Metformin, an Angiotensin Converting Enzyme Inhibitor or Angiotensin Receptor Blocker, and a Statin.
Estimated Study Start Date : September 1, 2018
Estimated Primary Completion Date : May 31, 2020
Estimated Study Completion Date : August 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Experimental
will receive two bottles of Ertugliflozin 15mg tablets (active drug) and a placebo for hydrochlorothiazide.
Drug: Ertugliflozin
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.
Other Name: SGLT2 inhibitor

Device: Microneurography
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.

Other: SKNA recordings
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.

Other: Static Handgrip
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.

Other: Post-handgrip forearm vascular occlusion
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.

Other: Testing of the Arterial Baroreflex Function
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: Active Comparator
will receive two bottles of Placebo for ertugliflozin and hydrochlorthiazide 12.5mg capsules (active drug)
Drug: Hydrochlorothiazide 12.5mg
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.
Other Name: mild antihypertensive comparator

Device: Microneurography
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.

Other: SKNA recordings
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.

Other: Static Handgrip
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.

Other: Post-handgrip forearm vascular occlusion
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.

Other: Testing of the Arterial Baroreflex Function
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).




Primary Outcome Measures :
  1. Muscle sympathetic nerve activity (bursts/minute) [ Time Frame: 3 months ]
    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).


Secondary Outcome Measures :
  1. Outcome 2 is the increase in muscle sympathetic nerve activity in bursts/minute induced by static handgrip. [ Time Frame: 3 months ]
    Muscle sympathetic nerve activity will be measured at rest and after 2 minutes of static (isometric) handgrip at 33% maximum voluntary contraction. This exercised-induced response will be measured at baseline and after 3 months of Ertugliflozin or HCTZ.

  2. Increase in muscle sympathetic nerve activity induced by post-hand grip forearm vascular occlusion [ Time Frame: 3 months ]
    Muscle sympathetic nerve activity will be measured at rest and after 2 minutes of by post-handgrip forearm vascular occlusion. After 2 minutes of static handgrip at 33% maximum, a pneumatic cuff will be inflated on the upper exercised arm for 2 minutes. This response will be measured at baseline and after 3 months of Ertugliflozin or HCTZ.

  3. Change in chest wall skin sympathetic nerve activity in bursts per minute. [ Time Frame: 3 months ]
    Chest wall skin sympathetic nerve activity, a non-invasive measure of cardiac sympathetic nerve activity, will be measured from standard surface ECG leads using appropriate filtering and amplification.

  4. Arterial baroreflex gain. [ Time Frame: 3 months ]
    Baroreflex gain will be measured as the reflex increase in muscle sympathetic nerve activity in bursts/minutes per mm Hg peak decrease in mean arterial pressure induced by Valsalva strain (Phase III) and the reflex decrease in muscle sympathetic nerve activity per mm Hg during the peak overshoot in mean arterial pressure upon release of the Valsalva maneuver (Phase IV).



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Ages Eligible for Study:   35 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03640221


Locations
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United States, California
Cedars-Sinai Medical Center
Los Angeles, California, United States, 90048
Sponsors and Collaborators
Cedars-Sinai Medical Center
Merck Sharp & Dohme Corp.

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Responsible Party: Ron Victor, Burns and Allen Chair in Cardiology Research Director, Hypertension Center Associate Director, Smidt Heart Institute, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT03640221     History of Changes
Other Study ID Numbers: 51991
First Posted: August 21, 2018    Key Record Dates
Last Update Posted: August 24, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ron Victor, Cedars-Sinai Medical Center:
Hypertension
Diabetes
Additional relevant MeSH terms:
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Hypertension
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Vascular Diseases
Cardiovascular Diseases
5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-hydroxymethyl-6,8-dioxabicyclo(3.2.1)octane-2,3,4-triol
Sodium-Glucose Transporter 2 Inhibitors
Hydrochlorothiazide
Antihypertensive Agents
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents