The Effects of Neprilysin Inhibition on Cardiometabolic Health in Black Individuals

项目总结 黑人有更高的胰岛素抵抗患病率，而且更有可能患有 心脏代谢性疾病，这与死亡风险增加有关。出现这种情况的原因 黑人胰岛素抵抗增加的原因还不完全清楚。利钠肽激素 系统有助于调节葡萄糖利用和能量动态平衡，是主要的 心脏代谢健康的决定因素。我们已经表明，黑人个体的死亡率降低了30%-40% 利钠肽水平与白人相比，这在很小的年龄就很明显。黑人个人也 对进餐的高血糖素样多肽-1(GLP-1)反应受损。这两种代谢调节剂都是 被neprilysin酶清除。我们已经证明，黑人有更高的neprilysin表达，并且 Neprilysin介导的黑人体内清除途径可能是其高致死率的生物学贡献因素 心脏代谢性疾病风险。萨舒比利/valsartan是美国食品和药物管理局批准的一种 能增加利钠肽和GLP-1水平的奈普利辛。血浆中NP和GLP-1浓度升高 这些激素调节因子水平相对较低或活性受损的黑人个体 代谢可能是改善他们心脏代谢健康的一个有吸引力的策略。我们假设 根据胰岛素测量，使用萨库比利/valsartan抑制奈普利辛将改善心脏代谢健康 黑人成年人的敏感性和能量消耗。我们建议进行一次以病人为中心的生理检查 对患有胰岛素抵抗的黑人进行试验，以检验萨舒比利/valsartan将会的假说(1) 改善胰岛素敏感性，(2)增加休息和运动能量消耗，(3)改善GLP-1 与奈普利辛中性药物(Valsartan)相比，对进餐的反应。在我们研究的目标1中，我们 将招募200名自认为有胰岛素抵抗的黑人个体，并以1：1、双倍- 采用盲法给药12周，分别给予舒必利/伐沙坦(奈普利辛抑制剂)或单用伐沙坦(奈普利辛中性)。 我们将通过静脉注射葡萄糖来比较胰岛素敏感性变化的差异。 耐受性试验，在服用萨舒比利/valsartan的患者和仅接受valsartan的患者之间进行12周。 在研究的第二个目标中，我们将比较治疗后静息能量消耗变化的差异 在两个治疗臂之间进行12周的药物研究。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 GLP-1对标准化混合膳食治疗12周后反应的变化 药物。这项研究的目标是以一种潜在的重要和创新的方法来理解和改进 黑人个体心脏代谢指标的多种调节机制。这个 这项研究的发现将提供一种治疗途径，可能有助于控制兴奋 黑人个体的心脏代谢性疾病负担。

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.