Obesity, Type 2 Diabetes
Conditions
Brief summary
The purpose of this study is to evaluate whether vitamin D receptor agonist therapy lowers renin-angiotensin system activity.
Detailed description
This study aims to evaluate whether vitamin D receptor agonist therapy (calcitriol) in diabetes lowers renin-angiotensin system (RAS) activity in a manner similar to an ACE inhibitor. This is a physiology study, focused on evaluating hormonal changes in the circulating and tissue RAS when compared to placebo. Subjects with type 2 diabetes and obesity and normal kidney function will undergo evaluation of their circulating and renal-vascular RAS activity and urinary protein at baseline, after withdrawing interfering medications, while on a controlled electrolyte diet, and in controlled posture settings. They will then randomly receive a study medication (calcitriol or placebo) for 3 weeks followed by a re-assessment of their RAS parameters. The main outcomes that will be evaluated following calcitriol/placebo include measures of the circulating renin activity (primary), as well as measures of the renal-vascular RAS (renal plasma flow) and urine protein (secondary) The primary outcome is the change in the plasma renin activity when sodium restricted, before and after intervention. Secondary outcomes include the change in renal plasma flow and urine protein when sodium loaded, before and after intervention.
Interventions
DRUGCalcitriol
Subjects will receive calcitriol (up to 0.75 mcg daily) for 3 weeks.
DRUGPlacebo
Subjects will receive placebo for 3 weeks.
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Type-Two Diabetes (treated with diet alone, with oral hypoglycemic agents, or with a single injection of basal insulin daily) 2. Normal blood pressure, or Mild (Stage 1) Hypertension that is either untreated, or adequately treated with a single anti-hypertensive drug. 3. Age \>18 years and \<70 years 4. Estimated GFR \> 60ml/min 5. Normal laboratory values for: Complete blood count, sodium, potassium, glucose, liver enzymes, urinalysis 6. Electrocardiogram without any signs of prior infarction, ventricular conduction abnormality, or supraventricular arrhythmia.
Exclusion criteria
1. Chronic Kidney Disease or eGFR\<60 2. History of nephrolithiasis (kidney stones) 3. Multiple (more than one) insulin injections daily (since insulin can alter the RAS) 4. Poorly controlled type 2 diabetes (That may require more aggressive therapy) as defined by an HbA1c\>8.5% 5. Type 1 diabetes 6. Stage 2 or Stage 3 hypertension or the use of more than 1 antihypertensive drug 7. Chronic inflammatory conditions (such as inflammatory bowel disease or arthritis) that are treated with prescribed doses of NSAIDs by a physician. 8. The use of prescribed doses of potassium supplements. 9. History of liver failure 10. History of parathyroid or granulomatous disorders 11. History of heart failure, cerebrovascular disease or coronary heart disease 12. History of known microvascular complications of diabetes (including retinopathy, neuropathy, nephropathy) 13. Illness requiring overnight hospitalization in the past 6 months 14. Active tobacco or recreational drug use 15. Pregnancy or current breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Change in Circulating RAS Activity After Calcitriol/Placebo Therapy | baseline and 2 weeks following calcitriol/placebo therapy | The below results represent the change in Plasma Renin Activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Renal Plasma Flow After Calcitriol/Placebo Therapy | baseline and 3 weeks following calcitriol/placebo therapy | Subjects had their renal plasma flow assessed at baseline while sodium loaded, and again after 3 weeks of randomized therapy with either calcitriol (up to 0.75 mcg daily) or placebo. |
| Change in Urine Protein After Calcitriol/Placebo Therapy | baseline and 3 weeks following calcitriol/placebo therapy | Subjects have their urine protein assessed at baseline while sodium loaded and again 3 weeks after randomized therapy with calcitriol or placebo. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the local Boston community A total of 41 participants were consented to participate. Subsequently, 13 were found ineligible, 5 withdrew participation, 3 were lost-to follow-up, and 2 were withdrawn for non-compliance with the washout. Therefore, 18 were randomized.
Pre-assignment details
An anti-hypertensive medication washout was conducted to minimize confounding of the renin-angiotensin system. ACE inhibitors, angiotensin-receptor blockers, and mineralocorticoid receptor antagonists, beta blockers, diuretics, and calcium-channel blockers were withdrawn for 2 weeks to 2 months prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Calcitriol Subjects will receive calcitriol (titrated up to 0.75 mcg daily) for 3 weeks.
Subjects have their renin-angiotensin system, renal plasma flow, and urine protein assessed at baseline while sodium restricted and sodium loaded. They will then be randomized to receive calcitriol (up to 0.75 mcg daily) or placebo for 3 weeks, and repeat assessments again while sodium restricted and sodium loaded. | 9 |
| Placebo Subjects will receive placebo for 3 weeks.
Subjects have their renin-angiotensin system, renal plasma flow, and urine protein assessed at baseline while sodium restricted and sodium loaded. They will then be randomized to receive calcitriol (up to 0.75 mcg daily) or placebo for 3 weeks, and repeat assessments again while sodium restricted and sodium loaded. | 9 |
| Total | 18 |
Baseline characteristics
| Characteristic | Total | Calcitriol | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 8 Participants | 9 Participants |
| Age, Continuous | 50.8 years STANDARD_DEVIATION 7.9 | 51.0 years STANDARD_DEVIATION 10.4 | 50.7 years STANDARD_DEVIATION 5 |
| Region of Enrollment United States | 18 Participants | 9 Participants | 9 Participants |
| Sex: Female, Male Female | 7 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 11 Participants | 7 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 0 / 9 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 |
Outcome results
Primary
The Change in Circulating RAS Activity After Calcitriol/Placebo Therapy
The below results represent the change in Plasma Renin Activity.
Time frame: baseline and 2 weeks following calcitriol/placebo therapy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Calcitriol | The Change in Circulating RAS Activity After Calcitriol/Placebo Therapy | 0 ng/mL/h |
| Placebo | The Change in Circulating RAS Activity After Calcitriol/Placebo Therapy | -1.3 ng/mL/h |
Comparison: The hypothesis was that calcitriol therapy would lower plasma renin activity (PRA), when sodium restricted, when compared to placebo.p-value: 0.69ANOVA
Secondary
Change in Renal Plasma Flow After Calcitriol/Placebo Therapy
Subjects had their renal plasma flow assessed at baseline while sodium loaded, and again after 3 weeks of randomized therapy with either calcitriol (up to 0.75 mcg daily) or placebo.
Time frame: baseline and 3 weeks following calcitriol/placebo therapy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Calcitriol | Change in Renal Plasma Flow After Calcitriol/Placebo Therapy | -16.4 mL/min/1.73m2 | Standard Deviation 180.5 |
| Placebo | Change in Renal Plasma Flow After Calcitriol/Placebo Therapy | -0.6 mL/min/1.73m2 | Standard Deviation 142.2 |
Comparison: The hypothesis was that calcitriol therapy would raise renal plasma flow, when sodium loaded, when compared to placebo.p-value: 0.89ANOVA
Secondary
Change in Urine Protein After Calcitriol/Placebo Therapy
Subjects have their urine protein assessed at baseline while sodium loaded and again 3 weeks after randomized therapy with calcitriol or placebo.
Time frame: baseline and 3 weeks following calcitriol/placebo therapy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Calcitriol | Change in Urine Protein After Calcitriol/Placebo Therapy | 21.1 mg/24h | Standard Deviation 95.7 |
| Placebo | Change in Urine Protein After Calcitriol/Placebo Therapy | 8.1 mg/24h | Standard Deviation 51 |
Comparison: The hypothesis was that calcitriol therapy would lower urine protein, when sodium loaded, when compared to placebo.p-value: 0.8ANOVA