The Effects of Neprilysin Inhibition on Cardiometabolic Health in Black Individuals

脑啡肽酶抑制对黑人心脏代谢健康的影响

• 批准号: 10627738
• 负责人: Pankaj Arora
• 金额: $ 72.56万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627738
• 关键词: Adult; Affect; Aftercare; Age; Biological; Biological Markers; Black Populations; Black race; Blood Vessels; Body mass index; Brown Fat; Cardiac; Cardiometabolic Disease; Data; Development; Diabetes Mellitus; Double-Blind Method; Endocrine system; Endocrinology; Energy Metabolism; Enrollment; Enzymes; Epidemiology; Exercise; FDA approved; Glucose; Glycosylated Hemoglobin; Health; High Prevalence; Homeostasis; Hormonal; Human; Impairment; Individual; Insulin Resistance; Intervention; LDL Cholesterol Lipoproteins; Lipolysis; Measures; Mediating; Metabolic; Metabolism; Modeling; Natriuresis; Natriuretic Peptides; Neprilysin; Obesity; Participant; Pathway interactions; Pharmaceutical Preparations; Physiological; Population Study; Protocols documentation; Randomized; Randomized, Controlled Trials; Regulation; Rest; Role; Skeletal Muscle; Standardization; Testing; Therapeutic; United States Food and Drug Administration; arm; blood glucose regulation; burden of illness; cardiometabolism; cohort; disorder risk; experimental study; glucagon-like peptide 1; health disparity; improved; indexing; inhibitor; innovation; insulin regulation; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; lipoprotein cholesterol; mortality risk; novel strategies; novel therapeutic intervention; novel therapeutics; patient oriented; pharmacologic; primary outcome; response; treatment arm; valsartan

PROJECT SUMMARY Black individuals have a higher prevalence of insulin resistance and are more likely to have cardiometabolic diseases, which is associated with an increased risk of mortality. The reasons for the increased insulin resistance in Blacks are incompletely understood. The natriuretic peptide hormonal system contributes to the regulation of glucose utilization and energy homeostasis, and is one of the major determinants of cardiometabolic health. We have shown that Black individuals have 30-40% lower natriuretic peptide levels compared with Whites, and this is evident at a young age. Black individuals also have an impaired glucagon-like peptide-1 (GLP-1) response to meals. Both these metabolic regulators are cleared by the neprilysin enzyme. We have shown that Blacks have a higher expression of neprilysin, and the neprilysin mediated clearance pathway in Blacks may be a biological contributor to their higher cardiometabolic disease risk. Sacubitril/valsartan is a Food & Drugs Administration approved inhibitor of neprilysin that augments natriuretic peptide and GLP-1 levels. Increasing NP and GLP-1 concentrations in Black individuals who have relatively low levels or impaired activity of these hormonal regulators of metabolism may be an attractive strategy to improve their cardiometabolic health. We hypothesize that neprilysin inhibition using sacubitril/valsartan will improve cardiometabolic health as measured by insulin sensitivity and energy expenditure in Black adults. We propose to conduct a patient-oriented physiological trial in Black individuals with insulin resistance to test the hypotheses that sacubitril/valsartan will (1) improve insulin sensitivity, (2) increase resting and exercise energy expenditure, (3) improve GLP-1 response to meal as compared with neprilysin neutral medication (valsartan). In our aim 1 of the study, we will enroll 200 self-identified Black individuals with insulin resistance and randomize them in a 1:1, double- blind manner to sacubitril/valsartan (neprilysin inhibitor) or valsartan alone (neprilysin neutral) for 12 weeks. We will compare the difference in the change in insulin sensitivity, as measured by the intravenous glucose tolerance test, between those receiving sacubitril/valsartan and those receiving valsartan only for 12 weeks. In the second aim of the study, we will compare the difference in change in resting energy expenditure after 12 weeks of the study drug between the two treatment arms. We will also assess the difference in the change in exercise energy expenditure after 12 weeks. In our aim 3, we will assess the difference in the change in the GLP-1 response to standardized mixed meals after 12-weeks of treatment with study medications. This study targets a potentially important and innovative approach to understand and improve the regulation of cardiometabolic indices among Black individuals through multiple mechanisms. The findings from this study will provide a therapeutic pathway that may help in controlling the high cardiometabolic disease burden in Black individuals.

项目摘要 黑人患有胰岛素抵抗的患病率更高，并且更有可能 心脏代谢性疾病与死亡率的增加有关。原因 黑人胰岛素抵抗的增加尚不完全理解。亚钠肽激素 系统有助于调节葡萄糖利用和能量稳态，是主要的 心脏代谢健康的决定因素。我们已经证明黑人个体降低了30-40％ 与白人相比，亚钠肽水平与白人相比，这在年轻时就显而易见。黑人也是如此 对饮食的胰高血糖素样肽-1（GLP-1）反应受损。这两个代谢调节剂都是 由Neprilysin酶清除。我们已经表明，黑人对Neprilysin的表达更高，并且 黑人中的Neprilysin介导的清除途径可能是其更高的生物学贡献 心脏代谢疾病风险。 Sacubitril/Valsartan是食品药品管理局批准的抑制剂 Neprilysin增强了纳地酸肽和GLP-1水平。增加NP和GLP-1浓度 这些激素调节剂的水平相对较低或活动受损的黑人 代谢可能是改善其心脏代谢健康的有吸引力的策略。我们假设这一点 使用sacubitril/valsartan抑制Neprilysin将改善胰岛素测量的心脏代谢健康 黑人成年人的敏感性和能量消耗。我们建议进行以患者为导向的生理 胰岛素抵抗性的黑人审判，以检验sacubitril/valsartan的假设（1） 提高胰岛素敏感性，（2）增加静止和行使能量消耗，（3）改善GLP-1 与Neprilysin中性药物（Valsartan）相比，对餐的反应。在我们研究的目标1中，我们 将招募200个具有胰岛素抵抗性的自我识别的黑人，并在1：1中随机将其随机化 单独使用Sacubitril/valsartan（Neprilysin抑制剂）或瓦尔萨坦（Neprilysin Neutral）的盲人方式12周。 我们将比较胰岛素敏感性变化的差异，如静脉葡萄糖测量 公差测试，在接收Sacubitril/Valsartan的人与仅接受Valsartan的人之间进行12周。 在研究的第二个目标中，我们将比较静息能量消耗的变化差异 两个治疗臂之间的研究药物的12周。我们还将评估 12周后，运动能量消耗的变化。在我们的目标3中，我们将评估 在研究12周的治疗后，GLP-1对标准化混合餐的反应变化 药物。这项研究针对一种潜在的重要和创新的方法来理解和改进 通过多种机制调节黑人个体中心脏代谢指数。这 这项研究的发现将提供一种治疗途径，可能有助于控制高 黑人个体的心脏代谢疾病负担。