NAUTICAL: Effect of Natriuretic Peptide Augmentation on Cardiometabolic Health in Black Individuals

The Effects of Natriuretic Peptide Augmentation on Cardiometabolic Health in Black Individuals (NAUTICAL)

Black individuals are more likely to have decreased insulin sensitivity which results in a high risk for the development of cardiometabolic disease. The reasons for this are incompletely understood. Natriuretic peptides (NPs) are hormones produced by the heart that play a role in regulating the metabolic health of an individual. Low circulating level of NPs is an important contributor to increased risk for diabetes. The NP levels are relatively lower among Black individuals thus affecting their metabolic health and putting them at a higher risk for diabetes. This study aims to test the hypothesis that by augmenting NP levels using sacubitril/valsartan, among Black Individuals one can improve their metabolic health (as measured by insulin sensitivity & energy expenditure) and help establish the role of NPs in the underlying mechanism behind increased risk for cardiometabolic disease in these population.

Study Overview

• Status: Recruiting
• Conditions: Cardiovascular Diseases; Diabetes Mellitus; Insulin Sensitivity/Resistance; Metabolic Disease; Energy Expenditure; Metabolism; Natriuretic Peptides
• Intervention / Treatment: Drug: Sacubitril, Valsartan 97-103 mg Oral Tablet; Other: Intravenous Glucose Tolerance Test; Dietary supplement: Standardized Meals; Other: Exercise capacity VO2 maximum determination; Drug: Valsartan 160 mg

Detailed Description

Black individuals are more likely to have a reduced insulin sensitivity which results in a greater risk for diabetes. However, the reasons for their decreased insulin sensitivity are not clearly understood. Natriuretic peptides (NPs) are hormones produced by the heart that is known to have a wide range of favorable metabolic effects. Studies indicate that lower NP levels are associated with a decreased insulin sensitivity and this may be causally related to the development of diabetes.

Evidence suggests that Black individuals have low levels of NPs. Increased clearance of NPs by neprilysin, an NP degrading enzyme, contributes to the low levels of NP among Black individuals. Since NPs play an important role in the regulation of insulin sensitivity and energy expenditure, one can infer that relatively low NP levels are an important biological contributor to the high prevalence rates of cardiometabolic disease in African Americans.

Sacubitril/valsartan is an FDA-approved inhibitor of neprilysin that augment NP levels. NP augmentation using sacubitril/valsartan has been shown to improve insulin sensitivity and lipid metabolism in a small clinical trial among obese White individuals. It can be postulated that NP augmentation in populations with relatively low NP levels will help in improving their metabolic health. Improvement in the metabolic health following NP augmentation will also help us to outline the relationship between the NP system and the risk of cardiometabolic disease among Black individuals.

We hypothesize that NP augmentation among Black individuals will show an improvement in their metabolic health as measured by insulin sensitivity and energy expenditure. We hypothesize that African American individuals will show an improvement in their insulin sensitivity and their resting & exercise energy expenditure after treatment with sacubitril/valsartan versus valsartan alone.

Our study will have the following aims. The first aim is to assess the change in the insulin sensitivity after NP augmentation therapy (using sacubitril/valsartan) as compared with NP neutral therapy (using valsartan) among Black individuals. We will measure the change in insulin sensitivity (assessed using IVGTT) after 12 weeks of intervention. We will also assess the change in NP levels (a marker of NP augmentation) & cyclic guanylate monophosphate (cGMP) levels after intervention and evaluate their relationship with the change in insulin sensitivity.

The second aim of our study is to examine the change in the energy expenditure after sacubitril/valsartan as compared to valsartan alone among Black individuals. The individuals enrolled in the first aim will also be examined for the change in resting as well as exercise energy expenditure. This will be assessed using standardized protocol performed using the metabolic cart and an exercise treadmill, at baseline and after 12 weeks of either sacubitril/valsartan or valsartan alone.

The secondary aim of our study is to assess the GLP-1 response to meals after treatment with sacubitril/valsartan in Black individuals. We will evaluate the change in postprandial GLP-1 response to meals at baseline and after 12 weeks of either sacubitril/valsartan or valsartan alone.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Leigh Powell, MSN, RN; Phone Number: 205-975-9859; Email: lcpowell@uabmc.edu
• Study Contact Backup: Name: Nehal Vekariya, MS; Phone Number: 205-934-7173; Email: nvekariya@uabmc.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Recruiting
      • University of Alabama at Birmingham
      • Principal Investigator: Pankaj Arora, MD
      • Contact: Nehal Vekariya, MS; Phone Number: 205-934-7173; Email: nvekariya@uabmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Adults: Age more than or equal to 18 years of age
• Self-identified race/ethnicity as African-American or Black
• Blood pressure: 120-160/80-100 mmHg

Exclusion Criteria:

• Women who are pregnant or breastfeeding or who can become pregnant and not practicing an acceptable method of birth control during the study (including abstinence)
• Have any past or present history of cardiovascular diseases (stroke, myocardial infarction, heart failure, transient ischemic attack, angina, or cardiac arrhythmia)
• BP more than 160/100 mmHg
• BMI >45 kg/m2
• History of diabetes or fasting plasma glucose >=126 mg/dL or HbA1C>=6.5%
• History of angioedema
• Current or past (<12 months) history of smoking
• Estimated GFR < 60 ml/min/1.73 m2; albumin-creatinine ratio ≥30 mg/g
• Hepatic Transaminase (AST and ALT) levels >3x the upper limit of normal
• Significant psychiatric illness or seizure disorder
• More than 2 Alcoholic drinks daily
• Anemia (men, Hct < 38%, Hb<13 g/dL; women, Hct <36%, Hb <12 g/dL)
• Inability to exercise on a treadmill

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sacubitril/Valsartan; We will enroll 100 adult Black individuals. Each participant will take the assigned dose of medication twice daily for 12 weeks. We evaluate insulin sensitivity and energy expenditure at baseline and after 12 weeks of intervention.	Drug: Sacubitril, Valsartan 97-103 mg Oral Tablet; The subject will be randomized, in a double-blind manner to sacubitril/valsartan 97/103 mg twice daily for a period of 12 weeks.; Other Names: Sacubitril/Valsartan arm; Other: Intravenous Glucose Tolerance Test; An assessment of the insulin sensitivity will be done using the IVGTT, at baseline and after 12 weeks of pharmacological interventions.; Dietary supplement: Standardized Meals; Participants will consume the standardized study mixed meal for the assessment of postprandial GLP-1 response to the meal.; Other: Exercise capacity VO2 maximum determination; Each participant's maximal oxygen capacity will be determined using modified Bruce treadmill protocol.
Active Comparator: Valsartan; We will enroll 100 adult Black individuals. Each participant will take the assigned dose of medication twice daily for 12 weeks. We evaluate insulin sensitivity and energy expenditure at baseline and after 12 weeks of intervention.	Other: Intravenous Glucose Tolerance Test; An assessment of the insulin sensitivity will be done using the IVGTT, at baseline and after 12 weeks of pharmacological interventions.; Dietary supplement: Standardized Meals; Participants will consume the standardized study mixed meal for the assessment of postprandial GLP-1 response to the meal.; Other: Exercise capacity VO2 maximum determination; Each participant's maximal oxygen capacity will be determined using modified Bruce treadmill protocol.; Drug: Valsartan 160 mg; The subject will be randomized, in a double-blind manner to valsartan 160 mg twice daily for a period of 12 weeks.; Other Names: Valsartan arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in insulin sensitivity after natriuretic peptide augmentation	An assessment of the insulin sensitivity will be done at baseline and after 12 weeks of pharmacological intervention.	12 weeks
Change in energy expenditure after natriuretic peptide augmentation	An assessment of the resting energy expenditure will be done at baseline and after 12 weeks of pharmacological intervention.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in exercise energy expenditure after 12 weeks of pharmacological intervention.	During standardized protocol after 12 weeks of intervention, the energy expenditure will be calculated using metabolic cart.	12 weeks
Change in post-meal increase in GLP-1 levels	Change in GLP-1 levels after a standardized meal after 12 weeks of pharmacological intervention	12 weeks
Change in peak oxygen consumption after 12 weeks of pharmacological intervention.	Change in the peak oxygen consumption (VO2 max) after 12 weeks of intervention.	12 weeks
Change in fasting GLP-1 levels	Change in fasting GLP-1 levels after 12 weeks of pharmacological intervention	12 weeks
Change in natriuretic peptide levels	Change in natriuretic peptide levels (ANP, MRproANP, BNP, NTproBNP) after 12 weeks of pharmacological intervention	12 weeks
Change in measures of insulin sensitivity	Change in measures of insulin sensitivity (AIRg, Sg, Kg, Disposition Index) after 12 weeks of pharmacological intervention	12 weeks
Change in HBA1c levels	Change in HBA1c levels after 12 weeks of pharmacological intervention	12 weeks
Change in fasting blood glucose levels	Change in fasting blood glucose levels after 12 weeks of pharmacological intervention	12 weeks
Change in HOMA-IR	Change in HOMA-IR after 12 weeks of pharmacological intervention	12 weeks
Change in fasting insulin levels	Change in fasting insulin levels after 12 weeks of pharmacological intervention	12 weeks
Change in measures of body mass index	Change in the measures of body mass index after 12 weeks of pharmacological intervention	12 weeks
Change in measures of hip circumference	Change in the measures of hip circumference after 12 weeks of pharmacological intervention	12 weeks
Change in measures of waist circumference	Change in the measures of waist circumference after 12 weeks of pharmacological intervention	12 weeks
Change in measures of adipose tissue mass	Change in the measures of adipose tissue mass after 12 weeks of pharmacological intervention	12 weeks
Change in total cholesterol levels	Change in the total cholesterol levels after 12 weeks of pharmacological intervention	12 weeks
Change in LDL-C levels	Change in LDL-C levels after 12 weeks of pharmacological intervention	12 weeks
Change in HDL-C levels	Change in HDL-C levels after 12 weeks of pharmacological intervention	12 weeks
Change in triglyceride levels	Change in triglyceride levels after 12 weeks of pharmacological intervention	12 weeks
Correlation of change in MR-pro atrial natriuretic peptide levels with change in insulin sensitivity after 12 weeks of pharmacological intervention.	The exposure-response relationship of change in MR-pro atrial natriuretic peptide levels with change in insulin sensitivity after 12 weeks of intervention will be examined.	12 weeks
Correlation of change in MR-pro atrial natriuretic peptide levels with change in energy expenditure after 12 weeks of pharmacological intervention.	The exposure-response relationship of change in MR-pro atrial natriuretic peptide levels with change in resting and exercise energy expenditure after 12 weeks of intervention will be examined.	12 weeks
Correlation of change in B-type natriuretic peptide levels with change in insulin sensitivity after 12 weeks of pharmacological intervention.	The exposure-response relationship of change in B-type natriuretic peptide levels with change in insulin sensitivity after 12 weeks of intervention will be examined.	12 weeks
Correlation of change in B-type natriuretic peptide levels with change in resting energy expenditure after 12 weeks of pharmacological intervention.	The exposure-response relationship of change in B-type natriuretic peptide levels with change in resting energy expenditure after 12 weeks of intervention will be examined.	12 weeks
Correlation of change in NT-pro B-type natriuretic peptide levels with change in insulin sensitivity after 12 weeks of pharmacological intervention.	The exposure-response relationship of change in NT-pro B-type natriuretic peptide levels with change in insulin sensitivity after 12 weeks of intervention will be examined.	12 weeks
Correlation of change in NT-pro B-type natriuretic peptide levels with change in energy expenditure after 12 weeks of pharmacological intervention.	The exposure-response relationship of change in NT-pro B-type natriuretic peptide levels with change in resting and exercise energy expenditure after 12 weeks of intervention will be examined.	12 weeks
Impact of Natriuretic Peptide Genotype on Study Endpoints	All study outcomes will be analyzed by natriuretic peptide genotypes	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Metabolomic Profile	The change in the metabolomic profile examined using standardized platforms after 12 weeks of intervention.	12 weeks

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Pankaj Arora, MD, FAHA, University of Alabama at Birmingham

Publications and helpful links

General Publications

• Jordan J, Stinkens R, Jax T, Engeli S, Blaak EE, May M, Havekes B, Schindler C, Albrecht D, Pal P, Heise T, Goossens GH, Langenickel TH. Improved Insulin Sensitivity With Angiotensin Receptor Neprilysin Inhibition in Individuals With Obesity and Hypertension. Clin Pharmacol Ther. 2017 Feb;101(2):254-263. doi: 10.1002/cpt.455. Epub 2016 Nov 17.
• Arora P, Reingold J, Baggish A, Guanaga DP, Wu C, Ghorbani A, Song Y, Chen-Tournaux A, Khan AM, Tainsh LT, Buys ES, Williams JS, Heublein DM, Burnett JC, Semigran MJ, Bloch KD, Scherrer-Crosbie M, Newton-Cheh C, Kaplan LM, Wang TJ. Weight loss, saline loading, and the natriuretic peptide system. J Am Heart Assoc. 2015 Jan 16;4(1):e001265. doi: 10.1161/JAHA.114.001265.
• Seferovic JP, Claggett B, Seidelmann SB, Seely EW, Packer M, Zile MR, Rouleau JL, Swedberg K, Lefkowitz M, Shi VC, Desai AS, McMurray JJV, Solomon SD. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol. 2017 May;5(5):333-340. doi: 10.1016/S2213-8587(17)30087-6. Epub 2017 Mar 18.
• Patel N, Cushman M, Gutierrez OM, Howard G, Safford MM, Muntner P, Durant RW, Prabhu SD, Arora G, Levitan EB, Arora P. Racial differences in the association of NT-proBNP with risk of incident heart failure in REGARDS. JCI Insight. 2019 Jun 4;5(13):e129979. doi: 10.1172/jci.insight.129979.

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2020
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): May 31, 2027

Study Registration Dates

• First Submitted: August 7, 2019
• First Submitted That Met QC Criteria: August 10, 2019
• First Posted (Actual): August 13, 2019

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Diabetes; Insulin Sensitivity; Energy Expenditure; Natriuretic Peptides
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Immune System Diseases; Hyperinsulinism; Hypersensitivity; Cardiovascular Diseases; Insulin Resistance; Metabolic Diseases; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: 300003702; R01HL163852 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No