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.

项目概要 黑人的胰岛素抵抗患病率较高，并且更有可能患有胰岛素抵抗 心脏代谢疾病，与死亡风险增加有关。其原因 黑人胰岛素抵抗增加的情况尚不完全清楚。利钠肽激素 系统有助于调节葡萄糖利用和能量稳态，是主要的系统之一 心脏代谢健康的决定因素。我们已经证明黑人的死亡率要低 30-40% 与白人相比，钠尿肽水平较高，这一点在年轻时就很明显。黑人也有 对膳食的胰高血糖素样肽-1 (GLP-1) 反应受损。这两种代谢调节剂都是 由脑啡肽酶清除。我们已经证明黑人的脑啡肽酶表达较高，并且 黑人中脑啡肽酶介导的清除途径可能是其较高的生物学贡献者 心脏代谢疾病风险。沙库巴曲/缬沙坦是美国食品药品监督管理局批准的抑制剂 脑啡肽酶可增加利尿钠肽和 GLP-1 水平。增加 NP 和 GLP-1 浓度 这些荷尔蒙调节剂水平相对较低或活性受损的黑人 新陈代谢可能是改善心脏代谢健康的一个有吸引力的策略。我们假设 使用沙库巴曲/缬沙坦抑制脑啡肽酶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中心的生理学 在患有胰岛素抵抗的黑人中进行的试验，以测试沙库巴曲/缬沙坦会产生影响的假设 (1) 提高胰岛素敏感性，(2) 增加静息和运动能量消耗，(3) 改善 GLP-1 与中性脑啡肽酶药物（缬沙坦）相比，对进餐的反应。在我们的研究目标 1 中，我们 将招募 200 名自认患有胰岛素抵抗的黑人个体，并将他们按照 1:1、双 盲法给予沙库巴曲/缬沙坦（脑啡肽酶抑制剂）或单独使用缬沙坦（脑啡肽酶中性）12周。 我们将比较通过静脉注射葡萄糖测量的胰岛素敏感性变化的差异 在接受 sacubitril/valsartan 治疗的患者和仅接受 valsartan 治疗的患者之间进行 12 周的耐受性测试。 在研究的第二个目标中，我们将比较静息能量消耗变化的差异 两个治疗组之间使用 12 周的研究药物。我们还将评估差异 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 研究治疗 12 周后 GLP-1 对标准化混合膳食的反应发生变化 药物。这项研究的目标是一种潜在的重要且创新的方法来理解和改进 通过多种机制调节黑人个体的心脏代谢指数。这 这项研究的结果将提供一种治疗途径，可能有助于控制高 黑人的心脏代谢疾病负担。