Glucagon-like Peptide-1 Metabolism and Acute Neprilysin Inhibition

This study will test the hypothesis that neprilysin inhibition with sacubitril/valsartan will increase endogenous glucagon-like peptide-1 (GLP-1) after a mixed meal compared to valsartan. The primary statistical analysis will be within subject comparison (paired t-test or nonparametric equivalent) of area under the curve intact GLP-1 after the meal during sacubitril/valsartan compared to valsartan. Neprilysin inhibition may be a new drug target for the treatment of type 2 diabetes by increasing intact GLP-1 and may be of particular benefit to individuals with increased risk of hypoglycemia and cardiovascular disease.

Inclusion criteria

• Men and women ages 18-80 years
• Type 2 diabetes mellitus (T2DM) or pre-diabetes, controlled by diet alone or metformin therapy and elevated blood pressure

• Pre-diabetes is defined as fasting plasma glucose of 100-125 mg/dL, plasma glucose of 140-199 mg/dL two hours after 75g oral glucose load, or hemoglobin A1C 5.7-6.4%. T2DM is defined as fasting plasma glucose of ≥126 mg/dL, plasma glucose of ≥200 mg/dL two hours after 75g oral glucose load, or hemoglobin A1C ≥6.5%.
• Elevated blood pressure is defined as systolic blood pressure (BP) ≥130 mmHg or diastolic BP ≥80 mmHg on three occasions or therapy with antihypertensive medication(s) for a minimum of three months.
• For female subjects, the following conditions must be met:

• Postmenopausal status for at least one year or
• Status post-surgical sterilization, or
• If childbearing potential, utilization of birth control (barrier methods, abstinence, hormonal contraception, etc) and willingness to undergo regular beta hCG monitoring prior to drug treatment and on each study day. (Valsartan is pregnancy category D.)

Exclusion criteria

• Type 1 diabetes
• Poorly controlled T2DM, defined as hemoglobin A1C ≥8.7%
• Use of anti-diabetic medications other than metformin for over 24 months prior to initiation of the study.
• Requiring the need for insulin therapy
• Secondary hypertension
• Severe hypertension requiring the use of more than two anti-hypertensive agents other than a stable dose of diuretic or blood pressure > 180/110 mmHg
• Subjects who have participated in a weight-reduction program during the last 6 months and whose weight has increased or decreased more than 5 kg over the preceding 6 months
• Pregnancy or breastfeeding
• History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, angiotensin converting enzyme inhibitors, ARBs, or NEP inhibitors, as well as known or suspected contraindications to the study drugs
• History of angioedema
• History of pancreatitis or known pancreatic lesions
• Clinically significant gastrointestinal impairment that could interfere with drug absorption
• Significant cardiovascular disease such as myocardial infarction or cardiovascular surgery or angioplasty within six months prior to enrollment, presence of angina pectoris, arrhythmia with history of or risk of syncopal episodes or need for antiarrhythmic therapy, congestive heart failure (LV hypertrophy and diastolic dysfunction acceptable), deep vein thrombosis, pulmonary embolism, second- or third-degree AV block, mitral valve stenosis, hypertrophic cardiomyopathy, or coronary or carotid artery disease likely to require surgical or percutaneous intervention within six months of screening
• Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >3 x upper limit of normal range)
• Impaired renal function (eGFR< 50mL/min/1.73m2 as determined by the MDRD equation)
• History or presence of immunological or hematological disorders
• Serum potassium >5.2 mmol/L at screening
• History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack within six months
• Hematocrit <35%
• Diagnosis of asthma requiring use of inhaled beta agonist more than once a week
• Clinically significant gastrointestinal impairment that could interfere with drug absorption
• Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult, such as arthritis treated with daily use of non-steroidal anti-inflammatory drugs
• Treatment with chronic systemic glucocorticoid therapy within the last year
• Treatment with systemic glucocorticoid therapy acutely within six weeks prior to enrollment
• Treatment with lithium salts
• History of alcohol or drug abuse
• Treatment with anticoagulation
• Treatment with any investigational drug in the one month preceding the study
• Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study
• Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study