Preventing Metabolic Side Effects of Thiazide Diuretics With KMgCitrate
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: 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. |
Drug: Potassium Magnesium Citrate (KMgCit)
KMgCit will be administer for 4 months with chlorthalidone.
Other Names:
Drug: 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.
|
| Active Comparator: 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. |
Drug: Potassium Chloride (KCl)
KCl will be administer for 4 months with chlorthalidone.
Other Names:
Drug: 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.
|
Outcome Measures
Primary Outcome Measures
- Change in fasting plasma glucose [4 months]
Will be measured from venous blood sample
Secondary Outcome Measures
- Hepatic fat [4 months]
Will be measured using hepatic magnetic resonance imaging
- Muscle magnesium content [4 months]
Will be measured using magnetic resonance imaging.
- Serum Aldosterone [4 months]
Will be measured from serum sample
- FGF23 [4 months]
Will be measured from serum sample
- Urinary Isoprostanes [4 months]
Will be measured before and after treatment regimen containing potassium salt.
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Texas Southwestern Medical Center at Dallas | Dallas | Texas | United States | 75390 |
| 2 | University of Texas Southwestern Medical Center | Dallas | Texas | United States | 75390 |
| 3 | UT Southwestern Medical Center | Dallas | Texas | United States | 75390 |
Sponsors and Collaborators
- University of Texas Southwestern Medical Center
Investigators
- Principal Investigator: Wanpen Vongpatanasin, MD, UT Southwestern Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
- Ahmed LA. Protective effects of magnesium supplementation on metabolic energy derangements in lipopolysaccharide-induced cardiotoxicity in mice. Eur J Pharmacol. 2012 Nov 5;694(1-3):75-81. doi: 10.1016/j.ejphar.2012.07.036. Epub 2012 Aug 23. Erratum in: Eur J Pharmacol. 2013 Aug 15;714(1-3):526.
- Carter BL, Einhorn PT, Brands M, He J, Cutler JA, Whelton PK, Bakris GL, Brancati FL, Cushman WC, Oparil S, Wright JT Jr; Working Group from the National Heart, Lung, and Blood Institute. Thiazide-induced dysglycemia: call for research from a working group from the national heart, lung, and blood institute. Hypertension. 2008 Jul;52(1):30-6. doi: 10.1161/HYPERTENSIONAHA.108.114389. Epub 2008 May 26. Review.
- Guerrero-Romero F, Rodríguez-Morán M. Hypomagnesemia, oxidative stress, inflammation, and metabolic syndrome. Diabetes Metab Res Rev. 2006 Nov-Dec;22(6):471-6.
- Hata A, Doi Y, Ninomiya T, Mukai N, Hirakawa Y, Hata J, Ozawa M, Uchida K, Shirota T, Kitazono T, Kiyohara Y. Magnesium intake decreases Type 2 diabetes risk through the improvement of insulin resistance and inflammation: the Hisayama Study. Diabet Med. 2013 Dec;30(12):1487-94. doi: 10.1111/dme.12250. Epub 2013 Jun 29.
- Koenig K, Padalino P, Alexandrides G, Pak CY. Bioavailability of potassium and magnesium, and citraturic response from potassium-magnesium citrate. J Urol. 1991 Feb;145(2):330-4.
- Odvina CV, Mason RP, Pak CY. Prevention of thiazide-induced hypokalemia without magnesium depletion by potassium-magnesium-citrate. Am J Ther. 2006 Mar-Apr;13(2):101-8.
- Pak CY. Correction of thiazide-induced hypomagnesemia by potassium-magnesium citrate from review of prior trials. Clin Nephrol. 2000 Oct;54(4):271-5.
- Price AL, Lingvay I, Szczepaniak EW, Wiebel J, Victor RG, Szczepaniak LS. The metabolic cost of lowering blood pressure with hydrochlorothiazide. Diabetol Metab Syndr. 2013 Jul 9;5(1):35. doi: 10.1186/1758-5996-5-35.
- Ruml LA, Pak CY. Effect of potassium magnesium citrate on thiazide-induced hypokalemia and magnesium loss. Am J Kidney Dis. 1999 Jul;34(1):107-13.
- STU 092015-058