Glucagon-like Peptide-1 Metabolism and Acute Neprilysin Inhibition

NCT03508739 | Suspended Phase 3 FDA Drug

• 1 other identifier: 828731
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Insulin levels after the mixed meal

  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

  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

  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

  Time points -120 min (before drug given) and 0 min (2 hours after drug dose, just prior to the meal)

Study Arms (2)

ARM 1: randomization order AB

EXPERIMENTAL

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); Drug: Valsartan 160mg (blinded)

ARM 2: randomization order BA

EXPERIMENTAL

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); Drug: Valsartan 160mg (blinded)

Interventions

Sacubitril/Valsartan 200mg (blinded) DRUG

study day 2 for AB and study day 3 for BA

Also known as: Entresto

ARM 1: randomization order AB; ARM 2: randomization order BA

Valsartan 160mg (blinded) DRUG

study day 3 for AB and study day 2 for BA

Also known as: Diovan

ARM 1: randomization order AB; ARM 2: randomization order BA

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.)

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Pennsylvania: lead

Study Sites (1)

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Glucose Intolerance; Hypertension

Interventions

sacubitril; Valsartan; sacubitril and valsartan sodium hydrate drug combination

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperglycemia; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Study Officials

• Jessica R Wilson, MD, MSCI

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Instructor in Medicine Division of Endocrinology

Model Details: prospective randomized, double-blind, crossover study, mechanistic/ translational study (not to change labeling or marketing, not classic phase 3 or 4 study), IND exempt

Study Record Dates

• First Submitted: November 7, 2017
• First Posted: April 26, 2018
• Study Start: June 1, 2018
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 30, 2026
• Last Updated: September 10, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)