ABSTRACT
OBJECTIVE: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. RESEARCH AND DESIGN METHODS: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Global myocardial strain was assessed by feature tracking; cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); and cardiac tissue inflammation was assessed by T2 mapping. RESULTS: Between the baseline and 12-month time point, plasma IL-1B was reduced (- 1.8 pg/mL, P = 0.003) while ketones were increased (0.26 mM, P = 0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (- 158.9 pmole/min/106 cells, P = 0.0497 vs. - 5.2 pmole/min/106 cells, P = 0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. Global myocardial strain, ECV and T2 relaxation time did not change in both study groups. GOV REGISTRATION: NCT03782259.
Subject(s)
Benzhydryl Compounds , Biomarkers , Diabetes Mellitus, Type 2 , Glucosides , Inflammation Mediators , Sodium-Glucose Transporter 2 Inhibitors , Humans , Benzhydryl Compounds/therapeutic use , Benzhydryl Compounds/adverse effects , Glucosides/therapeutic use , Glucosides/adverse effects , Female , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Male , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Middle Aged , Aged , Treatment Outcome , Inflammation Mediators/blood , Biomarkers/blood , Time Factors , Anti-Inflammatory Agents/therapeutic use , Fibrosis , Inflammation/drug therapy , Inflammation/blood , Inflammation/diagnosis , Double-Blind Method , Myocardium/pathology , Myocardium/metabolism , Diabetic Cardiomyopathies/etiology , Diabetic Cardiomyopathies/prevention & control , Diabetic Cardiomyopathies/diagnostic imaging , Diabetic Cardiomyopathies/drug therapy , Diabetic Cardiomyopathies/bloodABSTRACT
The mitochondrial dysfunction characteristic of heart failure (HF) is associated with changes in intracellular nicotinamide adenine dinucleotide (NAD+) and NADH levels. Raising NAD+ levels with the NAD+ precursor, nicotinamide riboside (NR), may represent a novel HF treatment. In this 30-participant trial of patients with clinically stable HF with reduced ejection fraction, NR, at a dose of 1,000 mg twice daily, appeared to be safe and well tolerated, and approximately doubled whole blood NAD+ levels. Intraindividual NAD+ increases in response to NR correlated with increases in peripheral blood mononuclear cell basal (R 2 = 0.413, P = 0.003) and maximal (R 2 = 0.434, P = 0.002) respiration, and with decreased NLRP3 expression (R 2 = 0.330, P = 0.020). (Nicotinamide Riboside in Systolic Heart Failure; NCT03423342).
