Oral Sodium Nitrite Improves Insulin Sensitivity, Blood Pressure, and Arterial Thickening in Adults with Uncontrolled Hypertension and Metabolic Syndrome

Abstract

Introduction: Although nitrate and nitrite have traditionally been considered to be inert and potentially toxic metabolites of nitric oxide (NO) oxidation, it is now appreciated that both can be recycled to bioactive NO. Recent evidence suggests that the human nitrate-nitrite-NO pathway mediates signaling through NO to reduce blood pressure and endothelial function. The effects of oral nitrite on insulin sensitivity, however, are not known. Therefore, we developed the investigational drug, oral inorganic sodium nitrite, to assess its therapeutic effects. Methods: Our goal was to examine the effect of 12 weeks of open-label oral sodium nitrite 40 mg three times daily in this pilot study. We employed hyperinsulinemic-euglycemic clamps to assess insulin sensitivity, flow mediated dilation (FMD) to measure endothelial function, and pulse wave velocity (PWV) and carotid intima media thickness (IMT) to measure arterial stiffening and thickening, respectively, in obese adults with metabolic syndrome and uncontrolled hypertension. Results: Eighteen subjects were recruited with mean age 53 years, BMI 41 kg/m2 and BP 147/88 mmHg and 72% were female. Following 12 weeks of nitrite treatment, systolic (-10 mmHg), diastolic (-13 mmHg) and mean arterial pressures were reduced (-12 mmHg; all p<0.001). Insulin stimulated glucose disposal tended to improve (14%; 7.4±0.7 at baseline to 8.4±0.8 mg/kg/min post, p=0.08) after oral nitrite treatment compared to baseline. Carotid IMT decreased from 0.762±0.02 at baseline to 0.727±0.03 mm post (p<0.01), and FMD and PWV trended towards improvement with oral sodium nitrite treatment. There were no changes in body weight, BMI, fasting glucose, HbA1c or lipids. Conclusion: Oral sodium nitrite treatment is a promising therapeutic to improve insulin sensitivity, blood pressure and arterial thickening in at-risk obese adults with metabolic syndrome and uncontrolled hypertension. Disclosure K.S. Hughan: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. N.L. Helbling: None. S.J. Anthony: None. J. DeLany: None. B.H. Goodpaster: None. M. Gladwin: Other Relationship; Self; National Institutes of Health, Globin Solutions, Bayer AG.