The Effects of Neprilysin Inhibition on Cardiometabolic Health in Black Individuals

项目摘要 黑人个体的胰岛素抵抗患病率较高， 心脏代谢疾病，这与死亡风险增加有关。的原因 对黑人胰岛素抵抗的增加还不完全了解。利钠肽激素 系统有助于调节葡萄糖利用和能量稳态，并且是葡萄糖代谢的主要途径之一。 心脏代谢健康的决定因素。我们已经表明，黑人个体比男性低30 - 40%， 利钠肽水平与白人相比，这在年轻时很明显。黑人也 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 被脑啡肽酶清除我们已经表明，黑人有较高的脑啡肽酶表达， 在黑人中脑啡肽酶介导的清除途径可能是其更高的生物学贡献者， 心脏代谢疾病风险。沙库巴曲/缬沙坦是一种食品和药物管理局批准的抑制剂， 脑啡肽酶增加利钠肽和GLP-1水平。增加NP和GLP-1浓度， 黑人个体的这些激素调节剂水平相对较低或活性受损， 代谢可能是一个有吸引力的策略，以改善他们的心脏代谢健康。我们假设 使用沙库巴曲/缬沙坦抑制脑啡肽酶将改善心脏代谢健康，如通过胰岛素测量的 能量消耗和能量消耗在黑人成年人。我们建议进行一次以病人为中心的生理检查， 在患有胰岛素抵抗的黑人个体中进行的试验，以检验沙库比曲/缬沙坦将（1） 改善胰岛素敏感性，（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名自认为患有胰岛素抵抗的黑人个体，并将他们随机分为1：1，双重- 以盲法给予沙库巴曲/缬沙坦（脑啡肽酶抑制剂）或单独缬沙坦（脑啡肽酶中性）12周。 我们将比较胰岛素敏感性变化的差异，如通过静脉葡萄糖测量的 耐受性测试，接受沙库比曲/缬沙坦和那些只接受缬沙坦12周。 在本研究的第二个目的中，我们将比较两组在运动后静息能量消耗变化的差异， 两个治疗组之间的研究药物给药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 研究治疗12周后GLP-1对标准化混合餐的反应变化 药物治疗这项研究的目标是一个潜在的重要和创新的方法，以了解和改善 通过多种机制调节黑人个体的心脏代谢指数。的 这项研究的结果将提供一种治疗途径，可能有助于控制高血压。 黑人的心脏代谢疾病负担。

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.