NAD Augmentation to Treat Diabetic Kidney Disease: A Randomized Controlled Trial

烟酰胺腺嘌呤二核苷酸（NAD）依赖性脱乙酰酶的sirtuin家族充当代谢能量传感器，介导热量限制对寿命的一些有益影响，并且是衰老过程的重要调节剂。通过给予NAD前体（如烟酰胺单甘肽（NMN））来增加NAD，预防或逆转许多与衰老相关的病症，包括糖尿病和糖尿病性肾病，并改善有氧运动能力。肾脏中NAD水平的降低与小鼠以及人类中糖尿病肾病（DKD）的致病机制密切相关，并且NMN补充可预防DKD的发展并降低DKD小鼠模型中的死亡率。这些数据支持NMN给药增加NAD将降低尿白蛋白与肌酐比值（UACR）的假设，UACR是DKD的标志，可预测肾脏和心血管结局。尽管存在许多有效的DKD治疗方法，但发展终末期肾病的大量剩余风险仍然存在;因此，需要通过靶向不同机制提供额外风险降低的新方法。sirtuin-NAD激活剂之所以有吸引力，是因为：1）它们的作用机制与目前批准的药物不同; 2）它们靶向衰老机制，并有可能改善身体功能和其他与年龄相关的疾病。我们计划在60岁或以上的2型糖尿病患者中进行一项2a期、随机、安慰剂对照、双盲、平行组试验，患者UACR > 100 mg/g肌酐，估计肾小球滤过率（eGFR）> 30 mL/min/ /1.73m2。受试者将随机接受1.0 g NMN或安慰剂，每日两次，持续6个月，按性别和年龄（60-75岁，>75岁）分层。主要结局是6个月期间UACR的变化。次要结局包括6个月内以下指标较基线的变化：UACR降低30%或以上的受试者比例;血清肌酐和eGFR的变化;血糖控制（血红蛋白A1 c，空腹血糖）;血压;衰老和肾损伤的生物标志物;自我报告（晚年功能和残疾指数-计算机自适应技术版）和基于表现的身体功能测量（有氧能力测量为VO 2峰值; 6分钟步行距离）;和NMN及其代谢物的循环水平，以及NAD水平。我们还将确定PBMC中NAD水平的增加和UACR的改善是否在治疗完成后持续3个月（遗留效应）。本试验的严谨性和创新性通过使用高质量的NMN晶体制剂;通过仔细进行的药代动力学研究提供的剂量方案;严格的样品收集程序以确保分析前稳定性;以及基于NAD消耗在DKD中的重要作用的令人信服的临床前和人体研究的强有力的科学前提来强调。

The sirtuin family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases act as metabolic energy sensors, mediate some of the beneficial effects of caloric restriction on lifespan, and are important regulators of the aging process. NAD augmentation by administration of NAD precursors, such as nicotinamide mononucleotide (NMN), prevents or reverses a number of aging-related conditions, including diabetes and diabetic nephropathy, and improves aerobic performance. Reduced NAD levels in the kidney are closely linked to the pathogenic mechanisms of diabetic kidney disease (DKD) in mice as well as in humans, and NMN supplementation prevents the development of DKD and reduces mortality in a mouse model of DKD. These data support the hypothesis that NAD augmentation by NMN administration will reduce urinary albumin to creatinine ratio (UACR), a hallmark of DKD that is predictive of renal and cardiovascular outcomes. Despite the availability of a number of effective therapies for DKD, substantial residual risk to develop end-stage kidney disease still remains; thus, there is a need for new approaches that provide additional risk reduction by targeting different mechanisms. The sirtuin-NAD activators are attractive because: 1) they act by a mechanism distinct from that of currently approved drugs; and 2) they target aging mechanisms and have the potential to improve physical function and other age-related conditions. We propose to conduct a Phase 2a, randomized, placebo-controlled, double-blind, parallel group trial in older adults, 60 years or older, with type 2 diabetes mellitus, UACR > 100 mg/g creatinine, and estimated glomerular filtration rate (eGFR) > 30 mL/min/ /1.73m2. Participants will be randomized to receive either 1.0 g NMN or placebo twice daily for 6 months, stratified by sex and age (60-75, >75 years). The primary outcome is the change in UACR over the 6-month period. Secondary outcomes include change from baseline over 6-months in the following: the proportion of participants with 30% or greater reduction in UACR; change in serum creatinine and eGFR; glycemic control (hemoglobin A1c, fasting glucose); blood pressure; biomarkers of aging and kidney injury; self-reported (Late Life Function and Disability Index - Computer Adaptive Technology Version) and performance-based measures of physical function (aerobic capacity measured as VO2peak; 6-minute walking distance); and circulating levels of NMN and its metabolites, and NAD levels. We will also determine whether the increases in NAD levels in the PBMCs and improvements in UACR persist 3 months after treatment completion (legacy effect). The rigor and innovation in this trial is underscored by the use of a high-quality crystalline formulation of NMN; a dose-regimen informed by carefully performed pharmacokinetic studies; rigorous sample collection procedures to ensure preanalytical stability; and strong scientific premise founded on compelling preclinical and human studies of the important role of NAD depletion in DKD.