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

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.


Eligibility Criteria:
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.