Investigating the Relationship Between Acne and Vasodilatory Medications in a Hospital-Wide Adult Population.

Acne vulgaris is a common chronic dermatological condition characterized by obstruction and inflammation of pilosebaceous units. Recent research on a different dermatologic condition has demonstrated that the use of vasodilatory medications is associated with a decreased relative risk of rosacea. This finding is significant due to the overlapping inflammatory pathways involved in rosacea and acne. Herein, a retrospective cohort study was designed to determine the correlation between vasodilator usage and the risk of developing acne within 5 years, contrasting it with thiazide diuretics, chosen as a control due to its non-vasodilatory antihypertensive mechanism and availability of data. Angiotensin-converting enzyme (ACE) inhibitors (RR, 0.775; 95% CI, 0.727-0.826; P<0.05), angiotensin receptor blockers (ARBs) (RR, 0.739; 95% CI, 0.685-0.797; P<0.05), beta-blockers (BB) (RR, 0.829; 95% CI, 0.777-0.885; P<0.05), and calcium channel blockers (CCB) usage (RR, 0.821, 95% CI, 0.773-0.873; P<0.05) were associated with a significantly lower risk of developing acne within 5 years of initiating therapy compared to thiazide diuretics. It is unclear if thiazide diuretics are more likely to cause acne within the adult population or if vasodilators are protective against the development of acne. Finding mechanisms and therapeutics that lower the risk of developing acne is of significant public health interest, and this study provides a step toward this endeavor. Further research is required to uncover the underlying mechanisms for this reduction in the development of acne.  J Drugs Dermatol. 2024;23(6):446-449.     doi:10.36849/JDD.8362.

Integrated metabolomics analysis reveals mechanistic insights into variability in blood pressure response to thiazide diuretics and beta blockers.

Hypertensive patients with a higher proportion of genetic West African ancestry (%GWAA) have better blood pressure (BP) response to thiazide diuretics (TDs) and worse response to ß-blockers (BBs) than those with lower %GWAA, associated with their lower plasma renin activity (PRA). TDs and BBs are suggested to reduce BP in the long term through vasodilation via incompletely understood mechanisms. This study aimed at identifying pathways underlying ancestral differences in PRA, which might reflect pathways underlying BP-lowering mechanisms of TDs and BBs. Among hypertensive participants enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, we previously identified 8 metabolites associated with baseline PRA and 4 metabolic clusters (including 39 metabolites) that are different between those with GWAA <45% versus ≥45%. In the current study, using Ingenuity Pathway Analysis (IPA), we integrated these signals. Three overlapping metabolic signals within three significantly enriched pathways were identified as associated with both PRA and %GWAA: ceramide signaling, sphingosine 1- phosphate signaling, and endothelial nitric oxide synthase signaling. Literature indicates that the identified pathways are involved in the regulation of the Rho kinase cascade, production of the vasoactive agents nitric oxide, prostacyclin, thromboxane A2, and endothelin 1; the pathways proposed to underlie TD- and BB-induced vasodilatation. These findings may improve our understanding of the BP-lowering mechanisms of TDs and BBs. This might provide a possible step forward in personalizing antihypertensive therapy by identifying patients expected to have robust BP-lowering effects from these drugs.

Effects of thiazides and new findings on kidney stones and dysglycemic side effects.

Thiazide and thiazide-like diuretics (thiazides) belong to the most frequently prescribed drugs worldwide. By virtue of their natriuretic and vasodilating properties, thiazides effectively lower blood pressure and prevent adverse cardiovascular outcomes. In addition, through their unique characteristic of reducing urine calcium, thiazides are also widely employed for the prevention of kidney stone recurrence and reduction of bone fracture risk. Since their introduction into clinical medicine in the early 1960s, thiazides have been recognized for their association with metabolic side effects, particularly impaired glucose tolerance, and new-onset diabetes mellitus. Numerous hypotheses have been advanced to explain thiazide-induced glucose intolerance, yet underlying mechanisms remain poorly defined. Regrettably, the lack of understanding and unpredictability of these side effects has prompted numerous physicians to refrain from prescribing these effective, inexpensive, and widely accessible drugs. In this review, we outline the pharmacology and mechanism of action of thiazides, highlight recent advances in the understanding of thiazide-induced glucose intolerance, and provide an up-to-date discussion on the role of thiazides in kidney stone prevention.

New use of thiazide diuretics vs. nonthiazide antihypertensive drugs was linked to hyponatremia over 2 y.

SOURCE CITATION: Andersson NW, Wohlfahrt J, Feenstra B, et al. Cumulative incidence of thiazide-induced hyponatremia: a population-based cohort study. Ann Intern Med. 2024;177:1-11. 38109740.

Thiazides for kidney stone recurrence prevention.

PURPOSE OF REVIEW: Kidney stones are the most common condition affecting the kidney, and characterized by a high rate of recurrence. Thiazide and thiazide-like diuretics (thiazides) are commonly prescribed to prevent the recurrence of kidney stones. This review offers a comprehensive up-to-date assessment of the evidence supporting the use of thiazides for kidney stone recurrence prevention, highlights potential harms associated with treatment, and identifies areas of knowledge that require further investigation. RECENT FINDINGS: The clinical routine to prescribe thiazides for kidney stone prevention has recently been challenged by the findings of the large NOSTONE trial that failed to show superiority of hydrochlorothiazide at doses up to 50 mg daily over placebo in preventing a composite of clinical or radiological recurrence in patients at high risk of recurrence. Yet, adverse events such as new onset diabetes mellitus and gout were more common in patients receiving hydrochlorothiazide compared to placebo. As demonstrated by a novel meta-analysis presented in this review encompassing all randomized placebo-controlled trials with thiazide monotherapy, current trial evidence does not indicate that thiazide monotherapy is significantly better than placebo in preventing kidney stone recurrence. SUMMARY: Given the limited efficacy and possible adverse effects, we advocate for a restrictive use of thiazides for kidney stone recurrence prevention. Clearly, there remains a high unmet medical need for effective, targeted therapies to prevent recurrence of kidney stones.

Prescribing cascades of antigout medications from thiazide diuretics in gout-naïve hypertensive adults receiving first-line pharmacological management.

Prescribing cascade is a significant clinical problem but is often overlooked. We explore the incidence of the prescribing cascades of antigout medications related to thiazide treatment in gout-naïve hypertensive adults newly exposed to the pharmacological treatment. This population-based, retrospective cohort study used the Taiwan National Health Insurance Registry Database. Gout-naïve hypertensive adults who were newly dispensed first-line antihypertensive drugs between January 1, 2000, and December 31, 2016, were enrolled. Patients were divided into the thiazide group (n = 4192) and the non-thiazide group (n = 81,083). The non-thiazide group included patients who received an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, calcium channel blocker, or beta-blocker. The study utilized propensity score matching and multivariable Cox regression models to investigate the prescribing cascade of antigout agents following antihypertensive treatment, adjusting for factors like age, sex, comorbidities, and concurrent medications. After propensity score matching, each group consisted of 4045 patients, with the thiazide group exhibiting a higher risk of being prescribed antigout medications across different time intervals post-treatment initiation. Specifically, adjusted hazard ratios (aHRs) for the thiazide group were 2.23, 2.07, and 2.41 for < 30 days, 31-180 days, and > 180 days, respectively, indicating a sustained and significant risk over time. Comparative analyses revealed thiazide diuretics were associated with a higher risk of antigout medication prescriptions compared to other antihypertensive classes, particularly evident after 180 days. Subgroup analyses across various demographics and comorbidities consistently showed an increased risk in the thiazide cohort. Gout-naïve hypertensive adults newly dispensed thiazide had a higher risk of subsequently adding antigout agents than those taking other first-line antihypertensive medications. The awareness and interruption of these prescribing cascades are critical to improving patient safety.

Preventive Pharmacological Therapy and Risk of Recurrent Urinary Stone Disease.

BACKGROUND: Urinary stone disease is a prevalent condition associated with a high recurrence risk. Preventive pharmacological therapy has been proposed to reduce recurrent stone episodes. However, limited evidence exists regarding its effectiveness, contributing to its underutilization by physicians. This study aimed to evaluate the association between preventive pharmacological therapy (thiazide diuretics, alkali therapy, and uric acid-lowering medications) and clinically significant urinary stone disease recurrence. METHODS: Using data from the Veterans Health Administration, adults with an index episode of urinary stone disease from 2012 through 2019 and at least one urinary abnormality (hypercalciuria, hypocitraturia, or hyperuricosuria) on 24-hour urine collection were included. The primary outcome was a composite variable representing recurrent stone events that resulted in emergency department visits, hospitalizations, or surgery for urinary stone disease. Cox proportional hazards regression was performed to estimate the association between preventive pharmacological therapy use and recurrent urinary stone disease while adjusting for relevant baseline patient characteristics. RESULTS: Among the cohort of patients with urinary abnormalities ( n =5637), treatment with preventive pharmacological therapy was associated with a significant 19% lower risk of recurrent urinary stone disease during the 12-36-month period after the initial urine collection (hazard ratio, 0.81; 95% confidence interval, 0.65 to 1.00; P = 0.0496). However, the effectiveness of preventive pharmacological therapy diminished over longer follow-up periods (12-48 and 12-60 months after the urine collection) and did not reach statistical significance. When examining specific urinary abnormalities, only alkali therapy for hypocitraturia was associated with a significant 26% lower recurrence risk within the 12-36-month timeframe (hazard ratio, 0.74; 95% confidence interval, 0.56 to 0.97; P = 0.03). CONCLUSIONS: When considering all urinary abnormalities together, this study demonstrates that the use of preventive pharmacological therapy is associated with a lower risk of clinically significant recurrent episodes of urinary stone disease in the 12-36 month timeframe after urine collection, although only the association with the use of alkali therapy for hypocitraturia was significant when individual abnormalities were examined.

Circulating microRNA Biomarkers of Thiazide Response in Hypertension.

BACKGROUND: Thiazide diuretics are the second most frequently prescribed class of antihypertensives, but up to 50% of patients with hypertension have minimal antihypertensive response to thiazides. We explored circulating microRNAs (miRNAs) in search of predictive biomarkers of thiazide response. METHODS AND RESULTS: We profiled 754 miRNAs in baseline plasma samples of 36 hypertensive European American adults treated with hydrochlorothiazide, categorized into responders (n=18) and nonresponders (n=18) on the basis of diastolic blood pressure response to hydrochlorothiazide. miRNAs with ≥2.5-fold differential expression between responders and nonresponders were considered for validation in 3 cohorts (n=50 each): hydrochlorothiazide-treated European Americans, chlorthalidone-treated European Americans, and hydrochlorothiazide-treated Black individuals. Different blood pressure phenotypes including categorical (responder versus nonresponder) and continuous diastolic blood pressure and systolic blood pressure were tested for association with the candidate miRNA expression using multivariate regression analyses adjusting for age, sex, and baseline blood pressure. After quality control, 74 miRNAs were available for screening, 19 of which were considered for validation. In the validation cohort, miR-193b-3p and 30d-5p showed significant associations with continuous SBP or diastolic blood pressure response or both, to hydrochlorothiazide in European Americans at Benjamini-Hochberg adjusted P<0.05. In the combined analysis of validation cohorts, let-7g (odds ratio, 0.6 [95% CI, 0.4-0.8]), miR-142-3p (odds ratio, 1.1 [95% CI, 1.0, 1.2]), and miR-423-5p (odds ratio, 0.7 [95% CI, 0.5-0.9]) associated with categorical diastolic blood pressure response at Benjamini-Hochberg adjusted P<0.05. Predicted target genes of the 5 miRNAs were mapped to key hypertension pathways: lysine degradation, fatty acid biosynthesis, and metabolism. CONCLUSIONS: The above identified circulating miRNAs may have a potential for clinical use as biomarkers for thiazide diuretic selection in hypertension. REGISTRATION: URL: ClinicalTrials.gov. Unique identifiers: NCT00246519, NCT01203852, NCT00005520.

[Thiazid diuretics : some useful considerations in clinical practice]. / Diurétiques thiazidiques. Quelques considérations utiles en pratique clinique.

Thiazide diuretics are an essential part of the treatment of hypertension, which affects nearly a third of the world's population. Hydrochlorothiazide is the most widely used member of this class, due to its long availability on the market and the many combinations available with other substances. Other analogues of this class exist, with notable advantages from a clinical point of view, recognized under the name of thiazide-like. This article reviews some of the considerations in clinical practice concerning the different types of thiazides currently available in Switzerland.

Les diurétiques thiazidiques font partie des traitements de premier choix dans la prise en charge de l'hypertension artérielle, touchant près d'un tiers de la population mondiale. L'hydrochlorothiazide est le représentant de cette classe médicamenteuse le plus utilisé dans les combinaisons antihypertensives en Suisse. D'autres analogues de cette classe existent sur le marché, avec des avantages notables du point de vue clinique, reconnus sous la dénomination de thiazides-like. Le choix de l'utilisation d'un diurétique thiazidique repose avant tout sur les indications et les contre-indications relatives à cette classe. Cet article propose une revue de quelques considérations en pratique clinique sur les différents types de thiazides actuellement disponibles en Suisse.

Role of Diuretics in Cardiovascular Events and Mortality in Systolic Blood Pressure Intervention Trial: A Post Hoc Analysis.

BACKGROUND: In a post hoc analysis, we examined whether postrandomization diuretics use can explain and/or mediate the beneficial effects of intensive systolic BP lowering on cardiovascular disease and all-cause mortality in the Systolic Blood Pressure Intervention Trial (SPRINT). METHODS: SPRINT was a randomized, controlled trial of 9361 participants comparing the effects of intensive (systolic BP target <120 mm Hg) versus standard (systolic BP target <140 mm Hg) BP control on a primary composite cardiovascular end point in participants aged 50 years or older with systolic BP of 130-180 mm Hg. In time-varying multivariable Cox analyses, we assessed hazard ratios (HRs) of cardiovascular end points and all-cause mortality in participants on thiazide type, loop and/or potassium (K) sparing, or no diuretics. We also conducted mediation analysis to formally assess the role of diuretics in the effects of intensive systolic BP lowering. RESULTS: At baseline, diuretics were prescribed in 46% and 48% of participants in standard and intensive systolic BP-lowering groups, respectively, and in 46% and 74% in the corresponding groups during the trial. The lower risk of cardiovascular end points in the intensive group (HR, 0.75; 95% confidence interval [CI], 0.64 to 0.89) persisted after adjustment for postrandomization time-varying diuretics use (HR, 0.74; 95% CI, 0.62 to 0.89). Across the entire study population, time-varying diuretics use was not associated with cardiovascular end points (compared with no diuretics, HR for thiazide type, 0.89; 95% CI, 0.73 to 1.10, and loop/K sparing, 1.29; 95% CI, 0.97 to 1.73). However, thiazide-type diuretics were associated with lower risk of cardiovascular end points in the intensive (HR, 0.62; 95% CI, 0.46 to 0.85) but not in the standard (HR, 1.07; 95% CI, 0.82 to 1.39) group. In mediation analysis, HRs for total effect, direct effect (not mediated through diuretics use), and indirect effect (mediated through diuretics) of the intervention on cardiovascular end points were 0.66 (95% CI, 0.54 to 0.79), 0.67 (95% CI, 0.54 to 0.81), and 0.98 (95% CI, 0.88 to 1.10), respectively. The results were largely similar for all-cause mortality. CONCLUSIONS: The favorable effects of intensive systolic BP lowering on cardiovascular end points and all-cause mortality in SPRINT were independent of and not mediated by time-varying diuretics use. However, thiazide-type diuretics use associated with benefit if intensive systolic BP lowering was targeted.

Sex differences in clinical characteristics and outcomes in the CLOROTIC (combining loop with thiazide diuretics for decompensated heart failure) trial.

AIMS: The addition of hydrochlorothiazide (HCTZ) to furosemide improved the diuretic response in patients with acute heart failure (AHF) in the CLOROTIC trial. Our aim was to evaluate if there were differences in clinical characteristics and outcomes according to sex. METHODS: This is a post-hoc analysis of the CLOROTIC trial, including 230 patients with AHF randomized to receive HCTZ or placebo in addition to an intravenous furosemide regimen. The primary and secondary outcomes included changes in weight and patient-reported dyspnoea 72 and 96 h after randomization, metrics of diuretic response and mortality/rehospitalizations at 30 and 90 days. The influence of sex on primary, secondary and safety outcomes was evaluated. RESULTS: One hundred and eleven (48%) women were included in the study. Women were older and had higher values of left ventricular ejection fraction. Men had more ischemic cardiomyopathy and chronic obstructive pulmonary disease and higher values of natriuretic peptides. The addition of HCTZ to furosemide was associated to a greatest weight loss at 72/96 h, better metrics of diuretic response and higher 24-h diuresis compared to placebo without significant differences according to sex (all p-values for interaction were not significant). Worsening renal function occurred more frequently in women (OR [95%CI]: 8.68 [3.41-24.63]) than men (OR [95%CI]: 2.5 [0.99-4.87]), p = 0.027. There were no differences in mortality or rehospitalizations at 30/90 days. CONCLUSION: Adding HCTZ to intravenous furosemide is an effective strategy to improve diuretic response in AHF with no difference according to sex, but worsening renal function was more frequent in women. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT01647932; EudraCT Number: 2013-001852-36.

[Are thiazide diuretics ineffective with a glomerular filtration rate lower than 50 ml/min?] / Thiaziddiuretika unwirksam bei einer glomerulären Filtrationsrate kleiner als 50 ml/min?

Many treatment guidelines do not recommend the use of thiazide diuretics or thiazide-like diuretics in patients with impaired kidney function. The rationale is a presumed lack of efficacy of these diuretics in cases of a reduced glomerular filtration rate (GFR); however, this paradigm could not be verified in recent studies. Thiazide diuretics and thiazide-like diuretics are also effective in patients with substantially reduced GFR, which pertains to natriuresis, correction of volume overload and lowering of blood pressure; however, in patients with chronic kidney disease loop diuretics can control volume overload more rapidly. Particularly effective is the combination of loop diuretics with thiazide diuretics or thiazide-like diuretics in patients with markedly limited GFR. Therefore, thiazide diuretics and thiazide-like diuretics should also be prescribed even for patients with higher grade impairments of kidney function (chronic kidney disease in stages 3-5), except for anuric patients where they are ineffective.

Mortality and Morbidity Among Individuals With Hypertension Receiving a Diuretic, ACE Inhibitor, or Calcium Channel Blocker: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The long-term relative risk of antihypertensive treatments with regard to mortality and morbidity is not well understood. Objective: To determine the long-term posttrial risk of primary and secondary outcomes among trial participants who were randomized to either a thiazide-type diuretic, calcium channel blocker (CCB), or angiotensin-converting enzyme (ACE) inhibitor with up to 23 years of follow-up. Design, Setting, and Participants: This prespecified secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a multicenter randomized, double-blind, active-controlled clinical trial, followed up with participants aged 55 years or older with a diagnosis of hypertension and at least 1 other coronary heart disease risk factor for up to 23 years, from February 23, 1994, to December 31, 2017. Trial participants were linked with administrative databases for posttrial mortality (N = 32 804) and morbidity outcomes (n = 22 754). Statistical analysis was performed from January 2022 to October 2023. Interventions: Participants were randomly assigned to receive a thiazide-type diuretic (n = 15 002), a CCB (n = 8898), or an ACE inhibitor (n = 8904) for planned in-trial follow-up of approximately 4 to 8 years and posttrial passive follow-up for up to 23 years. Main Outcomes and Measures: The primary end point was mortality due to cardiovascular disease (CVD). Secondary outcomes included all-cause mortality, combined fatal and nonfatal (morbidity) CVD, and both mortality and morbidity for coronary heart disease, stroke, heart failure, end-stage renal disease, and cancer. Results: A total of 32 804 participants (mean [SD] age, 66.9 [7.7] years; 17 411 men [53.1%]; and 11 772 Black participants [35.9%]) were followed up for all-cause mortality and a subgroup of 22 754 participants (mean [SD] age, 68.7 [7.2] years; 12 772 women [56.1%]; and 8199 Black participants [36.0%]) were followed up for fatal or nonfatal CVD through 2017 (mean [SD] follow-up, 13.7 [6.7] years; maximum follow-up, 23.9 years). Cardiovascular disease mortality rates per 100 persons were 23.7, 21.6, and 23.8 in the diuretic, CCB, and ACE inhibitor groups, respectively, at 23 years after randomization (adjusted hazard ratio [AHR], 0.97 [95% CI, 0.89-1.05] for CCB vs diuretic; AHR, 1.06 [95% CI, 0.97-1.15] for ACE inhibitor vs diuretic). The long-term risks of most secondary outcomes were similar among the 3 groups. Compared with the diuretic group, the ACE inhibitor group had a 19% increased risk of stroke mortality (AHR, 1.19 [95% CI, 1.03-1.37]) and an 11% increased risk of combined fatal and nonfatal hospitalized stroke (AHR, 1.11 [95% CI, 1.03-1.20]). Conclusions and Relevance: In this secondary analysis of a randomized clinical trial in an adult population with hypertension and coronary heart disease risk factors, CVD mortality was similar between all 3 groups. ACE inhibitors increased the risk of stroke outcomes by 11% compared with diuretics, and this effect persisted well beyond the trial period. Trial Registration: ClinicalTrials.gov Identifier: NCT00000542.

Mendelian Randomization Analysis of Genetic Proxies of Thiazide Diuretics and the Reduction of Kidney Stone Risk.

Importance: Clinical trial data have called into question the efficacy of thiazide diuretics for the prevention of kidney stones. Objective: To identify whether there is an association between genetic proxies of thiazide diuretics and the risk of kidney stones. Design, Setting, and Participants: This genetic association study undertook a mendelian randomization analysis of derived exposures and outcomes from genome-wide association study summary statistics. Genetic proxies of thiazide diuretics were derived from the International Consortium for Blood Pressure. Kidney stone cases and controls were derived from the Million Veteran Program, UK Biobank, and the FinnGen study. These cross-sectional designs do not report a duration of follow-up. Data analysis was performed in May 2023. Exposure: Genetic proxies of thiazide diuretics were genetic variants in the thiazide-sensitive sodium chloride cotransporter gene associated with systolic blood pressure. Genetic proxies of ß-blockers and systolic blood pressure served as negative controls. Main Outcomes and Measures: The main outcome was the odds of kidney stones. The secondary outcomes were serum laboratory values relevant to the treatment of kidney stones. Results: The main analysis included up to 1 079 657 individuals, including 50 832 kidney stone cases and 1 028 825 controls. In a meta-analysis of all cohorts, genetic proxies of thiazide diuretics were associated with a lower odds of kidney stones (OR, 0.85; 95% CI, 0.81-0.89; P < .001). Genetic proxies of ß-blockers (OR, 1.02; 95% CI, 0.96-1.07; P = .52) and systolic blood pressure (OR, 1.00; 95% CI, 1.00-1.01; P = .49) were not associated with kidney stones. Genetic proxies of thiazide diuretics were associated with higher serum calcium (ß [SE], 0.051 [0.0092]; P < .001) and total cholesterol (ß [SE], 0.065 [0.015]; P < .001), but lower serum potassium (ß [SE], -0.073 [0.022]; P < .001). Conclusions and Relevance: In this genetic association study, genetic proxies of thiazide diuretics were associated with reduced kidney stone risk. This finding reflects a drug effect over the course of a lifetime, unconstrained by the limited follow-up period of clinical trials.

Potassium Magnesium Citrate Is Superior to Potassium Chloride in Reversing Metabolic Side Effects of Chlorthalidone.

BACKGROUND: Thiazide diuretics (TD) are the first-line treatment of hypertension because of its consistent benefit in lowering blood pressure and cardiovascular risk. TD is also known to cause an excess risk of diabetes, which may limit long-term use. Although potassium (K) depletion was thought to be the main mechanism of TD-induced hyperglycemia, TD also triggers magnesium (Mg) depletion. However, the role of Mg supplementation in modulating metabolic side effects of TD has not been investigated. Therefore, we aim to determine the effect of potassium magnesium citrate (KMgCit) on fasting plasma glucose and liver fat by magnetic resonance imaging during TD therapy. METHODS: Accordingly, we conducted a double-blinded RCT in 60 nondiabetic hypertension patients to compare the effects of KCl versus KMgCit during chlorthalidone treatment. Each patient received chlorthalidone alone for 3 weeks before randomization. Primary end point was the change in fasting plasma glucose after 16 weeks of KCl or KMgCit supplementation from chlorthalidone alone. RESULTS: The mean age of subjects was 59±11 years (30% Black participants). Chlorthalidone alone induced a significant rise in fasting plasma glucose, and a significant fall in serum K, serum Mg, and 24-hour urinary citrate excretion (all P<0.05). KMgCit attenuated the rise in fasting plasma glucose by 7.9 mg/dL versus KCl (P<0.05), which was not observed with KCl. There were no significant differences in liver fat between the 2 groups. CONCLUSIONS: KMgCit is superior to KCl, the common form of K supplement used in clinical practice, in preventing TD-induced hyperglycemia. This action may improve tolerability and cardiovascular safety in patients with hypertension treated with this drug class.