Oral Nitrite Trial for Hypertension and Metabolic Syndrome

Study Overview
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Brief Summary
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The objective of the study is to investigate effects of inorganic sodium nitrite on the cardiometabolic and hormonal disturbances observed in a targeted population of overweight/obese adults with metabolic syndrome and hypertension, at risk for insulin resistance and endothelial dysfunction.

Detailed Description
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Cardiovascular disease remains the leading cause of death in the United States and worldwide. Several studies have demonstrated that fruit and vegetable rich diets significantly reduced blood pressure and reduced the risk of ischemic stroke and cardiovascular disease in general, the exact mechanisms remain poorly understood. Preclinical and clinical research over the last decade has revealed the important vasoprotective effects of nitrates and nitrites with regards to reduction in blood pressure, vascular inflammation and endothelial dysfunction. More recent findings suggest that inorganic nitrate and nitrite therapy may be involved in the regulation of glucose-insulin homeostasis. For this reason, development of an oral formulation of nitrite salt represents a rational avenue of exploration for the treatment of cardiovascular diseases, whereby nitrite would ensure rapid acting effects upon absorption. Nitrite could then be oxidized to nitrate via the enterosalivary circulation pathway. In this pathway, about 25% of circulating nitrate is concentrated in the saliva and reduced to nitrite by commensal mouth bacteria with nitrate reductase enzymes. The proposal will investigate the inorganic nitrite effects (in any form) on insulin sensitivity in a targeted population of overweight/obese adults with metabolic syndrome and hypertension, at risk for insulin resistance and endothelial dysfunction. This will be the third human trial using orally delivered nitrite (previously as aqueous solution).

Official Title
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Nitrite Modulation of Hypertension, Platelet Activation, and Endothelial and Mitochondrial Function

Conditions
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Metabolic Syndrome, Hypertension

Intervention / Treatment
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* Drug: 14 Nitrogen (N) Sodium Nitrite
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-60 years Body mass index (BMI) ≥ 30 kg/m2 Hypertension: defined as systolic blood pressure ≥130 and/or diastolic blood pressure ≥85 mm Hg Waist circumference: >102 cm in men, >88 cm in women Exclusion Criteria: Positive urine pregnancy test or breastfeeding Concurrent use of medications affecting glucose metabolism (oral hypoglycemics, insulin, atypical antipsychotics) Recent addition or change in dosing of hormonal contraceptive medications (Oral Contraceptive Pill (OCP), Intra Uterine Device (IUD), DepoProvera shot) Current use of ≥3 anti-hypertensive agents regardless of blood pressure control or normotensive on a single or double agent Current use of phosphodiesterase-5 (PD) inhibitors or organic nitrates. We will not exclude for dietary sources of nitrate/nitrite. Not stable on treatments for the prior three months or not planning to remain on current dose of medications for blood pressure, contraception, etc. Known chronic psychiatric or medical conditions including diabetes, liver or kidney disease or obesity syndromes Thyroid Stimulating Hormone (TSH) >8 milli-International unit/mL Smoker Anemia (central lab hemoglobin < 11g/dL) Active periodontal disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active drug<br>14 Nitrogen (N) Sodium Nitrite 40mg three times daily (TID) | Drug: 14 Nitrogen (N) Sodium Nitrite<br>* oral formulation of sodium nitrite 40 mg three times daily for 12 weeks<br>* Other names: sodium nitrite;|
| Placebo Comparator: Placebo<br>placebo capsules three time daily (TID) | Drug: Placebo<br>* oral formulation of matching placebo three times daily for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in insulin sensitivity (i.e. insulin stimulated glucose disposal) | obtained by hyperinsulinemic euglycemic clamp | baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in systolic blood pressure | ambulatory blood pressure | baseline and 12 weeks | 
| Change in mean arterial pressure | ambulatory blood pressure | baseline and then biweekly throughout the 12 week treatment | 
| Change in diastolic blood pressure | ambulatory blood pressure | baseline and 12 weeks | 
| Change in methemoglobin level | by co-oximetry | baseline and then biweekly throughout the 12 week treatment |