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.
试验速览
- 阶段
- 4 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Muscle sympathetic nerve activity (bursts/minute)
研究概览
简要总结
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:
- abnormally high resting (ambient) levels of sympathetic nerve activity; and
- 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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
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)
入排标准
- 年龄范围
- 35 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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
排除标准
- •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
研究组 & 干预措施
Experimental
will receive two bottles of Ertugliflozin 15mg tablets (active drug) and a placebo for hydrochlorothiazide.
干预措施: Ertugliflozin (Drug)
Experimental
will receive two bottles of Ertugliflozin 15mg tablets (active drug) and a placebo for hydrochlorothiazide.
干预措施: Microneurography (Device)
Experimental
will receive two bottles of Ertugliflozin 15mg tablets (active drug) and a placebo for hydrochlorothiazide.
干预措施: SKNA recordings (Other)
Experimental
will receive two bottles of Ertugliflozin 15mg tablets (active drug) and a placebo for hydrochlorothiazide.
干预措施: Static Handgrip (Other)
Experimental
will receive two bottles of Ertugliflozin 15mg tablets (active drug) and a placebo for hydrochlorothiazide.
干预措施: Post-handgrip forearm vascular occlusion (Other)
Experimental
will receive two bottles of Ertugliflozin 15mg tablets (active drug) and a placebo for hydrochlorothiazide.
干预措施: Testing of the Arterial Baroreflex Function (Other)
Active Comparator
will receive two bottles of Placebo for ertugliflozin and hydrochlorthiazide 12.5mg capsules (active drug)
干预措施: Hydrochlorothiazide 12.5mg (Drug)
Active Comparator
will receive two bottles of Placebo for ertugliflozin and hydrochlorthiazide 12.5mg capsules (active drug)
干预措施: Microneurography (Device)
Active Comparator
will receive two bottles of Placebo for ertugliflozin and hydrochlorthiazide 12.5mg capsules (active drug)
干预措施: SKNA recordings (Other)
Active Comparator
will receive two bottles of Placebo for ertugliflozin and hydrochlorthiazide 12.5mg capsules (active drug)
干预措施: Static Handgrip (Other)
Active Comparator
will receive two bottles of Placebo for ertugliflozin and hydrochlorthiazide 12.5mg capsules (active drug)
干预措施: Post-handgrip forearm vascular occlusion (Other)
Active Comparator
will receive two bottles of Placebo for ertugliflozin and hydrochlorthiazide 12.5mg capsules (active drug)
干预措施: Testing of the Arterial Baroreflex Function (Other)
结局指标
主要结局
Muscle sympathetic nerve activity (bursts/minute)
时间窗: 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).
次要结局
- 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)