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

点击翻译按钮获取中文摘要

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.