The Renin-Angiotensin-Aldosterone System in Adiposity, Blood Pressure and Glucose in African Americans

Study Overview
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Brief Summary
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The primary objective is to examine the impact of the Renin-Angiotensin-Aldosterone System (RAAS) blockade with medications (valsartan) or RAAS and neprilysin inhibition (valsartan/sacubitril) vs. placebo on changes in blood sugar and insulin secretion from the pancreas over 26 weeks assessed with glucose clamp studies among African Americans (AAs) with impaired glucose tolerance. The investigators hypothesize that combined RAAS/neprilysin inhibition will lead to greater improvement in insulin release from the pancreas and improved blood sugar compared to RAAS inhibition alone among AAs with impaired glucose tolerance.

Official Title
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The Role of the Renin-Angiotensin-Aldosterone System in Adiposity, Blood Pressure and Glucose Metabolism Among African Americans: Pilot Study

Conditions
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PreDiabetes, Impaired Glucose Tolerance, Obesity, Blood Pressure

Intervention / Treatment
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* Drug: Sacubitril-Valsartan Tab 97-103 MG
* Drug: Valsartan 160mg
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: African Americans aged 18-65 years old with a history of impaired fasting glucose, impaired glucose tolerance, hemoglobin A1c 5.7-6.4% or other risk factors for diabetes including metabolic syndrome, family history of type 2 diabetes in the parents or siblings or history of gestational diabetes will be invited to attend a formal screening visit. Participants with impaired glucose tolerance defined as 2-hour plasma glucose 140-199 mg/dl after a fasting 75-g oral glucose tolerance test and who meet other enrollment criteria will be enrolled. Exclusion Criteria: Type 2 Diabetes (American Diabetes Association Criteria) Hypertension with systolic blood pressure (SBP) > 150 mmHg or diastolic blood pressure (DBP) > 100 mmHg or taking anti-hypertensive medications SBP < 100 mmHg or DBP < 60 mmHg Pharmacologic treatment with statins, β-Blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, renin inhibitors, and/or mineralocorticoid antagonists Steroid use Hyperkalemia (Potassium > 5.0 milliequivalent/L) Abnormal renal function tests: Glomerular Filtration Rate calculated using the Chronic Kidney Disease Epidemiology Equation < 60 ml/min/1.73 m² Treatment with oral hypoglycemic medications, Use of antipsychotic medications or severe psychiatric disorders (severe mental illness) Severe Psychiatric Disorders: Schizophrenia Paranoid and other psychotic disorders Bipolar disorders (hypomanic, manic, depressive, and mixed) Major depressive disorders (single episode or recurrent) Schizoaffective disorders (bipolar or depressive) Pervasive developmental disorders Obsessive-compulsive disorders Depression in childhood and adolescence Panic disorder Post-traumatic stress disorders (acute, chronic, or with delayed onset) Bulimia Nervosa Anorexia Nervosa History of, or planned, bariatric surgery, Weight loss > 5% over the previous 6 months, Pregnancy, planning to conceive a child in the next 9 months, or progesterone based contraception and unable to switch to non-progesterone based contraception, Previous or current diagnosis of cardiac structural and functional abnormalities, history or current diagnosis of heart failure (New York Heart Association classes II-IV), history of myocardial infarction, coronary bypass surgery, or percutaneous coronary intervention during the 6 months prior to screening, History of angioedema, or known hypersensitivity to study drugs.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized prospective controlled clinical trial with three parallel arms, no crossover.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Valsartan<br>Valsartan 160 mg twice daily for 26 weeks | Drug: Valsartan 160mg<br>* Participant will take Valsartan for 26 weeks<br>* Other names: Diovan;|
| Experimental: Sacubitril/Valsartan<br>Sacubitril/Valsartan (97/103 mg) twice daily for 26 weeks | Drug: Sacubitril-Valsartan Tab 97-103 MG<br>* Participants will take Sacubitril-Valsartan for 26 weeks<br>* Other names: Entresto;|
| Placebo Comparator: Placebo<br>placebo (+/- amlodipine 2.5-5 mg twice daily if high blood pressure) | Drug: Placebo Oral Tablet<br>* Participant with take placebo for 26 weeks or if blood pressure elevated will receive standard of care blood pressure medication, amlodipine.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to 26 weeks in β-cell function (first-phase insulin secretion) | β-cell function will be assessed by first-phase insulin secretion, calculated as the mean insulin concentration (uIU/mL) over 10 minutes during the hyperglycemic clamp. | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Central Aortic Pressure (mmHg) from Baseline to 26 weeks | Central Aortic Pressure, measured via a non-invasive method using the SphygmoCor XCEL device, in mmHg. | 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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African American, Black, Prediabetes, Impaired Glucose Tolerance