Clinical trial NCT04055428: NAUTICAL: Effect of Natriuretic Peptide Augmentation on Cardiometabolic Health in Black Individuals
Official title: The Effects of Natriuretic Peptide Augmentation on Cardiometabolic Health in Black Individuals (NAUTICAL)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Diabetes Mellitus
Cardiovascular Diseases
Insulin Sensitivity/Resistance
Metabolic Disease
Natriuretic Peptides
Metabolism
Energy Expenditure
Keywords: Natriuretic Peptides
Diabetes
Insulin Sensitivity
Energy Expenditure
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2019-08-13
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in insulin sensitivity after natriuretic peptide augmentation
timeFrame: 12 weeks
measure: Change in energy expenditure after natriuretic peptide augmentation
timeFrame: 12 weeks
Secondary outcomes:
measure: Change in exercise energy expenditure after 12 weeks of pharmacological intervention.
timeFrame: 12 weeks
measure: Change in post-meal increase in GLP-1 levels
timeFrame: 12 weeks
measure: Change in peak oxygen consumption after 12 weeks of pharmacological intervention.
timeFrame: 12 weeks
measure: Change in fasting GLP-1 levels
timeFrame: 12 weeks
measure: Change in natriuretic peptide levels
timeFrame: 12 weeks
measure: Change in measures of insulin sensitivity
timeFrame: 12 weeks
measure: Change in HBA1c levels
timeFrame: 12 weeks
measure: Change in fasting blood glucose levels
timeFrame: 12 weeks
measure: Change in HOMA-IR
timeFrame: 12 weeks
measure: Change in fasting insulin levels
timeFrame: 12 weeks
measure: Change in measures of body mass index
timeFrame: 12 weeks
measure: Change in measures of hip circumference
timeFrame: 12 weeks
measure: Change in measures of waist circumference
timeFrame: 12 weeks
measure: Change in measures of adipose tissue mass
timeFrame: 12 weeks
measure: Change in total cholesterol levels
timeFrame: 12 weeks
measure: Change in LDL-C levels
timeFrame: 12 weeks
measure: Change in HDL-C levels
timeFrame: 12 weeks
measure: Change in triglyceride levels
timeFrame: 12 weeks
measure: Correlation of change in MR-pro atrial natriuretic peptide levels with change in insulin sensitivity after 12 weeks of pharmacological intervention.
timeFrame: 12 weeks
measure: Correlation of change in MR-pro atrial natriuretic peptide levels with change in energy expenditure after 12 weeks of pharmacological intervention.
timeFrame: 12 weeks
measure: Correlation of change in B-type natriuretic peptide levels with change in insulin sensitivity after 12 weeks of pharmacological intervention.
timeFrame: 12 weeks
measure: Correlation of change in B-type natriuretic peptide levels with change in resting energy expenditure after 12 weeks of pharmacological intervention.
timeFrame: 12 weeks
measure: Correlation of change in NT-pro B-type natriuretic peptide levels with change in insulin sensitivity after 12 weeks of pharmacological intervention.
timeFrame: 12 weeks
measure: Correlation of change in NT-pro B-type natriuretic peptide levels with change in energy expenditure after 12 weeks of pharmacological intervention.
timeFrame: 12 weeks
measure: Impact of Natriuretic Peptide Genotype on Study Endpoints
timeFrame: 12 weeks
Other outcomes:
measure: Change in Metabolomic Profile
timeFrame: 12 weeks
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
Study officials:
affiliation: University of Alabama at Birmingham
name: Pankaj Arora, MD, FAHA
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.