Preventing Metabolic Side Effects of Thiazide Diuretics With KMgCitrate

NCT ID: NCT02665117

Last Updated: 2023-10-25

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

61 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-01-31

Study Completion Date

2022-11-04

Brief Summary

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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

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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.

Conditions

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Hypertension

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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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.

Group Type ACTIVE_COMPARATOR

Potassium Magnesium Citrate (KMgCit)

Intervention Type DRUG

KMgCit will be administer for 4 months with chlorthalidone.

Chlorthalidone

Intervention Type DRUG

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.

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.

Group Type ACTIVE_COMPARATOR

Potassium Chloride (KCl)

Intervention Type DRUG

KCl will be administer for 4 months with chlorthalidone.

Chlorthalidone

Intervention Type DRUG

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.

Interventions

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Potassium Magnesium Citrate (KMgCit)

KMgCit will be administer for 4 months with chlorthalidone.

Intervention Type DRUG

Potassium Chloride (KCl)

KCl will be administer for 4 months with chlorthalidone.

Intervention Type 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.

Intervention Type DRUG

Other Intervention Names

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KMgCit KCl

Eligibility Criteria

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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
Minimum Eligible Age

21 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University of Texas Southwestern Medical Center

OTHER

Sponsor Role lead

Responsible Party

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Wanpen Vongpatanasin

Professor

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Wanpen Vongpatanasin, MD

Role: PRINCIPAL_INVESTIGATOR

UT Southwestern Medical Center

Locations

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University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States

Site Status

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Site Status

UT Southwestern Medical Center

Dallas, Texas, United States

Site Status

Countries

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United States

References

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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.

Reference Type BACKGROUND
PMID: 22939974 (View on PubMed)

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. No abstract available.

Reference Type BACKGROUND
PMID: 18504319 (View on PubMed)

Guerrero-Romero F, Rodriguez-Moran M. Hypomagnesemia, oxidative stress, inflammation, and metabolic syndrome. Diabetes Metab Res Rev. 2006 Nov-Dec;22(6):471-6. doi: 10.1002/dmrr.644.

Reference Type BACKGROUND
PMID: 16598698 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23758216 (View on PubMed)

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. doi: 10.1016/s0022-5347(17)38330-1.

Reference Type BACKGROUND
PMID: 1988724 (View on PubMed)

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. doi: 10.1097/01.mjt.0000149922.16098.c0.

Reference Type BACKGROUND
PMID: 16645424 (View on PubMed)

Pak CY. Correction of thiazide-induced hypomagnesemia by potassium-magnesium citrate from review of prior trials. Clin Nephrol. 2000 Oct;54(4):271-5.

Reference Type BACKGROUND
PMID: 11076102 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23837919 (View on PubMed)

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. doi: 10.1016/s0272-6386(99)70115-0.

Reference Type BACKGROUND
PMID: 10401023 (View on PubMed)

Vongpatanasin W, Giacona JM, Pittman D, Murillo A, Khan G, Wang J, Johnson T, Ren J, Moe OW, Pak CCY. Potassium Magnesium Citrate Is Superior to Potassium Chloride in Reversing Metabolic Side Effects of Chlorthalidone. Hypertension. 2023 Dec;80(12):2611-2620. doi: 10.1161/HYPERTENSIONAHA.123.21932. Epub 2023 Oct 17.

Reference Type DERIVED
PMID: 37846572 (View on PubMed)

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

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STU 092015-058

Identifier Type: -

Identifier Source: org_study_id

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