Glucagon-like Peptide-1 Metabolism and Acute Neprilysin Inhibition

Study Overview
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Brief Summary
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Type 2 diabetes is common, increases in prevalence with age, and patients with diabetes have an increased risk of cardiovascular disease. A relatively new cardiovascular medication currently used for the treatment of heart failure in the United States inhibits an enzyme that breaks down a variety of signaling hormones. This clinical trial tests if it may also be a target for the treatment of diabetes by decreasing the breakdown of a hormone that increases insulin release after a meal.

Detailed Description
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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.

Official Title
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Glucagon-like Peptide-1 Metabolism in the Setting of Acute Neprilysin Inhibition

Conditions
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Diabetes Mellitus, Type 2, Pre-diabetic, Hypertension, Elevated Blood Pressure

Intervention / Treatment
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* Drug: Sacubitril/Valsartan 200mg (blinded)
* Drug: Valsartan 160mg (blinded)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: prospective randomized, double-blind, crossover study, mechanistic/ translational study (not to change labeling or marketing, not classic phase 3 or 4 study), IND exempt
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARM 1: randomization order AB<br>Subjects will present for a baseline mixed meal study day 1 (no medication). Next they will be randomized to sacubitril/valsartan 200mg po and then valsartan 160 mg po with each medication given on study day 2 and 3, respectively (order AB). At each study day, subjects will present after fasting and receive blinded study medication on study days 2 and 3. After an IV is placed, neprilysin activity will be measured at baseline. Two hours later, subjects will have neprilysin activity collected again as well as baseline insulin, glucose, GLP-1, and triglycerides. Following this, subjects will ingest a mixed meal. Blood samples for insulin, glucose, GLP-1, and triglycerides will be collected after the meal for four hours total. Blood pressure and heart rate will be monitored. | Drug: Sacubitril/Valsartan 200mg (blinded)<br>* study day 2 for AB and study day 3 for BA<br>* Other names: Entresto;Drug: Valsartan 160mg (blinded)<br>* study day 3 for AB and study day 2 for BA<br>* Other names: Diovan;|
| Experimental: ARM 2: randomization order BA<br>Subjects will present for a baseline mixed meal study day 1 (no medication). Next they will be randomized to sacubitril/valsartan 200mg po and then valsartan 160 mg po with each medication given on study day 2 and 3, respectively (order BA). At each study day, subjects will present after fasting and receive blinded study medication on study days 2 and 3. After an IV is placed, neprilysin activity will be measured at baseline. Two hours later, subjects will have neprilysin activity collected again as well as baseline insulin, glucose, GLP-1, and triglycerides. Following this, subjects will ingest a mixed meal. Blood samples for insulin, glucose, GLP-1, and triglycerides will be collected after the meal for four hours total. Blood pressure and heart rate will be monitored. | Drug: Sacubitril/Valsartan 200mg (blinded)<br>* study day 2 for AB and study day 3 for BA<br>* Other names: Entresto;Drug: Valsartan 160mg (blinded)<br>* study day 3 for AB and study day 2 for BA<br>* Other names: Diovan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intact glucagon like peptide-1 (GLP-1) levels after the mixed meal | GLP-1 is a hormone released after a meal that has been shown to improve insulin and glucose dynamics. It is a target for diabetes therapies. We will compare GLP-1 levels during the different drug treatments and at baseline. | This will be measured just before the meal and after the meal at pre-specified time points for a total of four hours. (Time points 0 to 4 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin levels after the mixed meal | Insulin is a hormone released from the pancreas that helps with blood glucose control. We will measure insulin levels during the different drug treatments and at baseline. | This will be measured just before the meal and after the meal at pre-specified time points for a total of four hours. (Time points 0 to 4 hours) | 
| Blood glucose levels after the mixed meal | We will compare blood glucose levels during the different drug treatments and at baseline. | This will be measured just before the meal and after the meal at pre-specified time points for a total of four hours. (Time points 0 to 4 hours) | 
| Triglyceride levels after the mixed meal | Triglycerides are a component of a routine lipid/ cholesterol panel. They rise in the setting of increased fat intake. GLP-1 is thought to decrease triglyceride levels. We will compare triglyceride levels during the different drug treatments and at baseline. | This will be measured just before the meal and after the meal at pre-specified time points for a total of four hours. (Time points 0 to 4 hours) | 
| Neprilysin enzyme (drug) activity at baseline, during sacubitril/valsartan, and during valsartan | Neprilysin is an enzyme that breaks down several proteins, including glucagon-like peptide-1 (GLP-1). Sacubitril in sacubitril/valsartan is a pro-drug of a neprilysin inhibitor. This assay level will help to determine if the changes seen after the meal are related to alterations in this enzyme activity and administration of the drug sacubitril/valsartan compared to valsartan. We will measure this before the medication is administered (thus at baseline) and two hours after the drug is administered and just prior to the mixed meal. | Time points -120 min (before drug given) and 0 min (2 hours after drug dose, just prior to the meal) |