The effects of SGLT2 inhibition on vascular health and physical function in Veterans with CKD

About This Grant

PROJECT SUMMARY/ABSTRACT Chronic kidney disease (CKD) is often a relentlessly progressive disease leading to multi-systemic disorders, with exponentially increased risks for cardiovascular (CV) diseases and death as kidney function declines. A principal pathogenic mechanism driving the multi-organ failure in CKD is endothelial dysfunction. The uremic milieu characterized by chronic inflammation and oxidative stress in CKD reduces bioavailability of nitric oxide (NO) and leads to impaired vascular function across multiple levels of the arterial tree, including (a) decreased endothelium-dependent vasodilation in both macrovascular (aorta and conduit arteries) and microvascular (resistance arteries and capillaries) circulations and (b) stiffening of macrovascular arteries. These vascular maladaptations, which are already evident in early stages of CKD and progress with CKD severity, collectively result in diminished perfusion at the tissue level, leading to hypoxia and failure of multiple target organs including kidney, heart, and skeletal muscle. Vascular dysfunction is thus not only an independent predictor of CKD progression, CV events, and death but also a major determinant of exercise intolerance in CKD. Indeed, poor functional capacity, also a powerful predictor of CV death in CKD, is one of the most consequential and costly symptoms of CKD. Yet, interventions specifically targeting vascular dysfunction and functional capacity are limited in CKD, with paucity of clinical trials addressing these important unmet needs. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), a novel class of hypoglycemic agents, have recently demonstrated unprecedented efficacy to slow CKD progression and prevent heart failure (HF) and CV death irrespective of diabetes status. In patients with HF, SGLT2is also significantly improve functional capacity. While the mechanisms underlying the benefits of SGLT2is have not been fully elucidated, one of the key hypothesized mechanisms focuses on the potent anti-inflammatory and anti-oxidant effects of SGLT2is to restore NO bioavailability, thereby improving endothelial function and arterial stiffness. The improved vascular health, in turn, is postulated to be a critical contributor to enhanced physical function. There are no available data evaluating the effects of SGLT2is on vascular or physical function in CKD, in which increased inflammation and oxidative stress and decreased NO availability are well established. Importantly, it also remains unclear if SGLT2is are as beneficial in CKD without heavy albuminuria (<300 mg/g), which is highly prevalent in Veterans and is the major cause for end-stage kidney disease. To address this knowledge gap, we propose a randomized, double-blind, placebo-controlled, phase-II study in 52 Veterans with non-diabetic CKD without heavy albuminuria (<300 mg/g) and eGFR 20-59 mL/min/1.73m2 to investigate if empagliflozin, a selective SGLT2i, can (1) improve vascular health, as determined by conduit artery endothelium-dependent vasodilation (flow-mediated dilation, FMD) and peripheral microvasculature reactivity (passive limb movement, PLM) and arterial stiffness (carotid-femoral pulse wave velocity, PWV), (2) enhance functional capacity using handgrip exercise and mobility tests (Timed Up and Go test, gait speeds, and 6-minute walk), and (3) reduce plasma biomarkers of systemic inflammation (C-reactive protein, interleukin-6, tumor necrosis factor-) and oxidative stress (free radical concentration assessed by electron paramagnetic resonance spectroscopy) and increase plasma NO, as reflected by plasma nitrite and nitrosyl hemoglobin levels. Veterans will be recruited from Salt Lake City VA and randomized to 10 mg of empagliflozin or placebo at 1:1 ratio and treated for 16 weeks. The duration and sample size of this trial would not permit the assessment of kidney or CV events. Our proposal is the first SGLT2i study to pair evaluation of vascular health with physical function in CKD. Positive results will provide mechanistic insight underlying the clinical benefits of SGLT2i and greater scientific rationale to expand the use of SGLT2is to CKD patients without heavy albuminuria.