Glucose Metabolism in Subjects With Aldosterone-Producing Adenomas
Primary Purpose
Primary Aldosteronism
Status
Completed
Phase
Locations
United States
Study Type
Observational
Intervention
Adrenalectomy
mineralocorticoid receptor antagonist
Sponsored by
About this trial
This is an observational trial for Primary Aldosteronism
Eligibility Criteria
Inclusion Criteria:
- Ambulatory subjects, 18 to 70 years of age, inclusive
For female subjects, the following conditions must be met:
- postmenopausal status for at least 1 year, or
- status-post surgical sterilization, or
- if of childbearing potential, utilization of adequate birth control and willingness to undergo urine beta-hcg testing on every study day.
Primary aldosteronism determined by both:
Biochemical hyperaldosteronism defined as either:
- Plasma aldosterone ≥15 ng/dL
- or aldosterone-to-renin ratio of ≥30 if on ACE inhibitor
- or aldosterone-to-renin ratio of ≥40 in absence of an ACE inhibitor
Positive suppression test defined as either:
- failure to suppress aldosterone to <7ng/dL after intravenous 0.9% saline infusion over 2 hours
- failure to suppress 24-hour urinary aldosterone excretion to <12 µcg with simultaneously documented urine sodium excretion >200 mmol.
Exclusion Criteria:
- Subjects presenting with any of the following will not be included in the study:
- Previously diagnosed type 1 Diabetes
Type II Diabetes, as defined by ADA criteria:
- Hemoglobin A1C ≥6.5%
- Fasting plasma glucose ≥126mg/dl (7.0mmol/l)
- 2-hour 75g oral glucose tolerance test (OGTT) plasma glucose ≥200mg/dl (11.1 mmol/l) d. Current treatment with anti-diabetic medication(s)
- Impaired renal function [estimated glomerular filtration rate (eGFR) of <30ml/min] as determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine (Scr) is expressed in mg/dl and age in years.
- Prior allergies to medications used in the study protocol (e.g. L-arginine, potassium chloride, insulin), or to drugs within the same class.
- Screening plasma potassium >5.5 mmol/L or sodium <135 mmol/L
- Cardiovascular disease such as recent (<6 months) myocardial infarction, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy
- Breast-feeding
- Treatment with anticoagulants
- History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack
- History or presence of immunological or hematological disorders
- Diagnosis of asthma requiring use of inhaled beta agonist >1 time per week
- Clinically significant gastrointestinal impairment that could interfere with drug absorption
- Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) >2.0 x upper limit of normal range]
- Hematocrit <35%
- 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 non-steroidal antiinflammatory drugs
- Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month)
- Treatment with lithium salts
- History of alcohol or drug abuse
- Treatment with any investigational drug in the 1 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
Sites / Locations
- Vanderbilt University Medical Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Arm Label
Adrenalectomy
Medical Therapy
Arm Description
Subjects will undergo assessment before and after adrenalectomy for treatment of primary aldosteronism
Subjects will undergo assessment before and after medical treatment of primary aldosteronism
Outcomes
Primary Outcome Measures
Change in Acute Glucose-stimulated Insulin Secretion
measured by hyperglycemic clamp
Change in Insulin Sensitivity Index
measured by hyperinsulinemic-euglycemic clamp
Change in Disposition Index (product of Insulin sensitivity index and acute insulin secretion)
Product of insulin sensitivity and insulin secretion
Secondary Outcome Measures
Suppression of Hepatic glucose production
suppression of hepatic glucose production during hyperinsulinemic clamp, determined using glucose tracer
Full Information
NCT ID
NCT02362308
First Posted
February 5, 2015
Last Updated
April 28, 2021
Sponsor
Vanderbilt University
Collaborators
Brigham and Women's Hospital, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
1. Study Identification
Unique Protocol Identification Number
NCT02362308
Brief Title
Glucose Metabolism in Subjects With Aldosterone-Producing Adenomas
Official Title
Glucose Metabolism in Subjects With Aldosterone-Producing Adenomas
Study Type
Observational
2. Study Status
Record Verification Date
April 2021
Overall Recruitment Status
Completed
Study Start Date
January 2015 (Actual)
Primary Completion Date
January 2020 (Actual)
Study Completion Date
January 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University
Collaborators
Brigham and Women's Hospital, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This observational study tests the hypothesis that endogenous aldosterone impairs insulin secretion and insulin sensitivity in subjects with primary aldosteronism.
Detailed Description
The week of each study period, subjects will be provided a standard 160mmol/d sodium diet for 6-8 days to control for inter-individual sodium intake.
In period 1, subjects will report after 5 days of controlled sodium diet for a hyperglycemic clamp study (to measure insulin secretion). Subjects will continue the study diet, and then return for a hyperinsulinemic-euglycemic clamp study (to measure insulin sensitivity).
After completion of period 1 assessment, subjects will undergo adrenalectomy by our endocrine surgeons or initiate medical treatment, according to routine clinical care.
In period 2, the investigators will repeat the studies in the same manner as period 1, 3 to 12 months after adrenalectomy or initiation of medical treatment.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Aldosteronism
7. Study Design
Enrollment
10 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Adrenalectomy
Arm Description
Subjects will undergo assessment before and after adrenalectomy for treatment of primary aldosteronism
Arm Title
Medical Therapy
Arm Description
Subjects will undergo assessment before and after medical treatment of primary aldosteronism
Intervention Type
Other
Intervention Name(s)
Adrenalectomy
Intervention Description
Adrenalectomy for treatment of primary aldosteronism, according to standard of care
Intervention Type
Drug
Intervention Name(s)
mineralocorticoid receptor antagonist
Other Intervention Name(s)
spironolactone, eplerenone
Intervention Description
Subjects will be treated with a mineralocorticoid receptor antagonist according to standard of care
Primary Outcome Measure Information:
Title
Change in Acute Glucose-stimulated Insulin Secretion
Description
measured by hyperglycemic clamp
Time Frame
Change from Baseline vs. 3-12 months after intervention
Title
Change in Insulin Sensitivity Index
Description
measured by hyperinsulinemic-euglycemic clamp
Time Frame
Change from Baseline vs. 3-12 months after intervention
Title
Change in Disposition Index (product of Insulin sensitivity index and acute insulin secretion)
Description
Product of insulin sensitivity and insulin secretion
Time Frame
Change from Baseline vs. 3-12 months after intervention
Secondary Outcome Measure Information:
Title
Suppression of Hepatic glucose production
Description
suppression of hepatic glucose production during hyperinsulinemic clamp, determined using glucose tracer
Time Frame
Change from Baseline vs. 3-12 months after intervention
Other Pre-specified Outcome Measures:
Title
Urinary exosomal biomarkers
Description
Urinary biomarkers of renal sodium channels and sodium transporters
Time Frame
Change from Baseline vs. 3-12 months after intervention
Title
Associative learning Memory testing
Description
Associative learning task matching images and words
Time Frame
Change from Baseline vs. 3-12 months after intervention
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Ambulatory subjects, 18 to 70 years of age, inclusive
For female subjects, the following conditions must be met:
postmenopausal status for at least 1 year, or
status-post surgical sterilization, or
if of childbearing potential, utilization of adequate birth control and willingness to undergo urine beta-hcg testing on every study day.
Primary aldosteronism determined by both:
Biochemical hyperaldosteronism defined as either:
Plasma aldosterone ≥15 ng/dL
or aldosterone-to-renin ratio of ≥30 if on ACE inhibitor
or aldosterone-to-renin ratio of ≥40 in absence of an ACE inhibitor
Positive suppression test defined as either:
failure to suppress aldosterone to <7ng/dL after intravenous 0.9% saline infusion over 2 hours
failure to suppress 24-hour urinary aldosterone excretion to <12 µcg with simultaneously documented urine sodium excretion >200 mmol.
Exclusion Criteria:
- Subjects presenting with any of the following will not be included in the study:
Previously diagnosed type 1 Diabetes
Type II Diabetes, as defined by ADA criteria:
Hemoglobin A1C ≥6.5%
Fasting plasma glucose ≥126mg/dl (7.0mmol/l)
2-hour 75g oral glucose tolerance test (OGTT) plasma glucose ≥200mg/dl (11.1 mmol/l) d. Current treatment with anti-diabetic medication(s)
Impaired renal function [estimated glomerular filtration rate (eGFR) of <30ml/min] as determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine (Scr) is expressed in mg/dl and age in years.
Prior allergies to medications used in the study protocol (e.g. L-arginine, potassium chloride, insulin), or to drugs within the same class.
Screening plasma potassium >5.5 mmol/L or sodium <135 mmol/L
Cardiovascular disease such as recent (<6 months) myocardial infarction, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy
Breast-feeding
Treatment with anticoagulants
History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack
History or presence of immunological or hematological disorders
Diagnosis of asthma requiring use of inhaled beta agonist >1 time per week
Clinically significant gastrointestinal impairment that could interfere with drug absorption
Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) >2.0 x upper limit of normal range]
Hematocrit <35%
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 non-steroidal antiinflammatory drugs
Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month)
Treatment with lithium salts
History of alcohol or drug abuse
Treatment with any investigational drug in the 1 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
James M Luther, MD
Organizational Affiliation
Vanderbilt University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
33583202
Citation
Luther JM, Wei DS, Ghoshal K, Peng D, Adler GK, Turcu AF, Nian H, Yu C, Solorzano CC, Pozzi A, Brown NJ. Treatment of Primary Aldosteronism Increases Plasma Epoxyeicosatrienoic Acids. Hypertension. 2021 Apr;77(4):1323-1331. doi: 10.1161/HYPERTENSIONAHA.120.14808. Epub 2021 Feb 15.
Results Reference
result
PubMed Identifier
32172621
Citation
Adler GK, Murray GR, Turcu AF, Nian H, Yu C, Solorzano CC, Manning R, Peng D, Luther JM. Primary Aldosteronism Decreases Insulin Secretion and Increases Insulin Clearance in Humans. Hypertension. 2020 May;75(5):1251-1259. doi: 10.1161/HYPERTENSIONAHA.119.13922. Epub 2020 Mar 16.
Results Reference
result
Learn more about this trial
Glucose Metabolism in Subjects With Aldosterone-Producing Adenomas
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