Glucagon-like Peptide-1 Metabolism in the Setting of Acute Neprilysin Inhibition
Overview
- Phase
- Phase 3
- Intervention
- Sacubitril/Valsartan 200mg (blinded)
- Conditions
- Diabetes Mellitus, Type 2
- Sponsor
- University of Pennsylvania
- Enrollment
- 25
- Locations
- 1
- Primary Endpoint
- Intact glucagon like peptide-1 (GLP-1) levels after the mixed meal
- Status
- Suspended
- Last Updated
- 7 months ago
Overview
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.
Detailed Description
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.
Investigators
Jessica R.Wilson, MD, MS
Instructor in Medicine Division of Endocrinology
University of Pennsylvania
Eligibility Criteria
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
Arms & Interventions
ARM 1: randomization order AB
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.
Intervention: Sacubitril/Valsartan 200mg (blinded)
ARM 1: randomization order AB
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.
Intervention: Valsartan 160mg (blinded)
ARM 2: randomization order BA
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.
Intervention: Sacubitril/Valsartan 200mg (blinded)
ARM 2: randomization order BA
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.
Intervention: Valsartan 160mg (blinded)
Outcomes
Primary Outcomes
Intact glucagon like peptide-1 (GLP-1) levels after the mixed meal
Time Frame: 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)
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.
Secondary Outcomes
- 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))