Hypertension
Conditions
Keywords
Hypokalemia, Isoprostanes, Insulin resistance, Aldosterone, Hepatic fat, Muscle Magnesium, Liver fat
Brief summary
Chlorthalidone (CTD) may produce various metabolic disturbances, including hypokalemia, activation of Renin-Angiotensin- Aldosterone (RAA) system, oxidative stress, dyslipidemia, Fibroblast growth factor 23 (FGF23) synthesis, and magnesium depletion. These factors may interact with each other to contribute to the development of insulin resistances and metabolic syndrome. Smaller studies have suggested that Potassium magnesium Citrate (KMgCit) can ameliorate CTD- induced metabolic side effects independent of correction of hypokalemia. This study will tests if KMgCit ameliorates CTD induced metabolic effects independent of correction of hypokalemia.
Detailed description
CTD- induced metabolic side effects were though to be dependent on hypokalemia, but subsequent studies suggested that CTD - induced side effects were independent from hypokalemia. On the other hand, magnesium depletion has been linked to increased Renin-Angiotensin- Aldosterone (RAA) system, the development of metabolic syndrome and insulin resistance with magnesium supplementation ameliorating these effects. Participants will participate in a double-blinded, parallel design study. After baseline evaluation participants will take Chlorthalidone (CTD) alone for 2-3 weeks. They will then be randomized to two equal groups to take KMgCit powder or Potassium Chloride (KCl) powder along with CTD for 4 months. We speculate that Mg depletion is responsible for hepatic fat deposition, which then produces insulin resistance. Co-administration of KMgCit powder would avert magnesium (Mg) depletion, block hepatic fat deposition by restoring normal Mg status and direct intestinal binding of fat, thereby ameliorating insulin resistance. To test this hypothesis, we shall quantitate muscle Mg status and hepatic fat content by magnetic resonance spectroscopy (MRS) before and after KMgCit. Change in fasting glucose, insulin resistance, serum potassium, FGF23, and aldosterone will be compared between KCL and KMgCit groups after 4 months.
Interventions
KMgCit will be administer for 4 months with chlorthalidone.
KCl will be administer for 4 months with chlorthalidone.
DRUGChlorthalidone
Chlorthalidone will be administered for 2-3 weeks. Then either KCL or KMgCit will be added to Chlorthalidone and the combination will be taken for 4 months.
Sponsors
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
• Treated or untreated stage I hypertension
Exclusion criteria
* Diabetes mellitus, * Renal impairment (serum creatinine \> 1.4 mg/dL), * Any heart diseases such as congestive heart failure, sustained arrhythmia, or coronary heart disease, * Chronic regular NSAID use, * Allergy to thiazide diuretics, * Gastro-esophageal reflux disease (GERD) requiring treatment with acid reducing agents or antacid more than once a week, * Esophageal-gastric ulcer or history of gastrointestinal bleeding, * Chronic diarrhea, vomiting, * Excessive sweating, * Unprovoked hypokalemia (serum K \< 3.5 mmol/L) or hyperkalemia (serum K \> 5.3 mmol/L), * Abnormal liver function test (Aspartate transaminase (AST) or Alanine transaminase (ALT) above upper limit of normal range), * Subjects on any potassium supplement on a regular basis for any reason, such as patients with primary aldosteronism, * Pregnancy, * History of major depression, bipolar disorder, or schizophrenia, * History of substance abuse, * Gout, * Metabolic alkalosis, with serum bicarbonate \> 32 meq/L, * Severe dietary salt restriction, less than1/2 spoonful or 50 meq sodium/day. * Patient with Claustrophobia will not have MRI but can still participate in the study without MRI * Metal implants will not have MRI but can still participate in the study without MRI
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose From Week 4 to Week 16 | week 4 and week 16 | Fasting plasma glucose was measured from venous blood sample at week 4 and week 16 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Chang in Hepatic Fat Measured at Baseline and Week 16 | baseline to week 16 | Will be measured using hepatic magnetic resonance imaging at baseline and at week 16 |
| Change in Muscle Magnesium Content Measured at Baseline and Week 16 | baseline to week 16 | Will be measured using magnetic resonance imaging at baseline and at week 16 |
| Change in FGF23 From Week 4 to Week 16 | week 4 to week 16 | Will be measured from venous blood sample from week 4 to week 16 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| KMgCit + Chlorthalidone After a run-in period of 2-3 weeks on Chlorthalidone, patients will be randomized to the addition of KMgCit for 4 months.
Potassium Magnesium Citrate (KMgCit): KMgCit will be administer for 4 months with chlorthalidone.
Chlorthalidone: Chlorthalidone will be administered for 2-3 weeks. Then either KCL or KMgCit will be added to Chlorthalidone and the combination will be taken for 4 months. | 29 |
| KCl + Chlorthalidone After a run-in period of 2-3 weeks on Chlorthalidone, patients will be randomized to the addition of KCl for 4 months.
Potassium Chloride (KCl): KCl will be administer for 4 months with chlorthalidone.
Chlorthalidone: Chlorthalidone will be administered for 2-3 weeks. Then either KCL or KMgCit will be added to Chlorthalidone and the combination will be taken for 4 months. | 31 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | KMgCit + Chlorthalidone | KCl + Chlorthalidone | Total |
|---|---|---|---|
| Age, Continuous | 60.7 years STANDARD_DEVIATION 9.3 | 58.1 years STANDARD_DEVIATION 12.8 | 59.4 years STANDARD_DEVIATION 11.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 29 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 29 participants | 31 participants | 60 participants |
| Sex: Female, Male Female | 14 Participants | 11 Participants | 25 Participants |
| Sex: Female, Male Male | 15 Participants | 20 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 31 |
| other Total, other adverse events | 2 / 29 | 0 / 31 |
| serious Total, serious adverse events | 0 / 29 | 0 / 31 |
Outcome results
Primary
Change in Fasting Plasma Glucose From Week 4 to Week 16
Fasting plasma glucose was measured from venous blood sample at week 4 and week 16
Time frame: week 4 and week 16
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KMgCit + Chlorthalidone | Change in Fasting Plasma Glucose From Week 4 to Week 16 | -5.6 mg/dL | Standard Deviation 13.3 |
| KCl + Chlorthalidone | Change in Fasting Plasma Glucose From Week 4 to Week 16 | 2.3 mg/dL | Standard Deviation 9.9 |
Secondary
Change in FGF23 From Week 4 to Week 16
Will be measured from venous blood sample from week 4 to week 16
Time frame: week 4 to week 16
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KMgCit + Chlorthalidone | Change in FGF23 From Week 4 to Week 16 | 38.1 pg/ml | Standard Deviation 123.3 |
| KCl + Chlorthalidone | Change in FGF23 From Week 4 to Week 16 | 13.6 pg/ml | Standard Deviation 104.1 |
Secondary
Change in Muscle Magnesium Content Measured at Baseline and Week 16
Will be measured using magnetic resonance imaging at baseline and at week 16
Time frame: baseline to week 16
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KMgCit + Chlorthalidone | Change in Muscle Magnesium Content Measured at Baseline and Week 16 | -0.01 mM | Standard Deviation 0.1 |
| KCl + Chlorthalidone | Change in Muscle Magnesium Content Measured at Baseline and Week 16 | 0.02 mM | Standard Deviation 0.08 |
Secondary
Chang in Hepatic Fat Measured at Baseline and Week 16
Will be measured using hepatic magnetic resonance imaging at baseline and at week 16
Time frame: baseline to week 16
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KMgCit + Chlorthalidone | Chang in Hepatic Fat Measured at Baseline and Week 16 | 0.31 percent | Standard Deviation 2.74 |
| KCl + Chlorthalidone | Chang in Hepatic Fat Measured at Baseline and Week 16 | 1.59 percent | Standard Deviation 4.9 |