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

• Status: Withdrawn
• Trial end date: 2020-08-31
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Cedars-Sinai Medical Center
• Collaborator: Merck Sharp & Dohme Corp.
• Treatments: 5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-hydroxymethyl-6,8-dioxabicyclo(3.2.1)octane-2,3,4-triol; Antihypertensive Agents; Ertugliflozin; Hydrochlorothiazide; Sodium-Glucose Transporter 2 Inhibitors

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