Thiazide Research Articles

Use of Hydrochlorothiazide in the United States Following Label Update About Skin Cancer Risk.

On August 20, 2020, the United States (U.S.) Food and Drug Administration (FDA) issued a Drug Safety Communication (DSC) along with labeling updates to inform the public about a small increased risk of non-melanoma skin cancer (NMSC) associated with hydrochlorothiazide (HCTZ) use. This study aims to assess whether the DSC impacted HCTZ use in the U.S. We conducted a trend analysis in the Sentinel Distributed Database using national healthcare administrative data from January 2017 to November 2022. We identified two cohorts each month: An overall cohort of all enrollees and a skin cancer cohort of those with a history of NMSC. For each cohort, we plotted the monthly proportion of patients receiving HCTZ-containing products among those receiving any thiazide diuretics. We performed interrupted time series analyses to quantify the impact of the DSC on these monthly proportions. Secondary analyses were conducted on the proportion of HCTZ users among patients receiving any antihypertensives. In the overall cohort, the DSC was only associated with a statistically significant but clinically negligible trend change of monthly HCTZ proportion within this cohort (0.018%; 95% CI, 0.012%-0.025%). Similar results were observed in the skin cancer cohort. The secondary analysis found no significant level change or trend change in the monthly proportion of HCTZ use among antihypertensive users. We did not observe significant changes in HCTZ use following the DSC about its NMSC risk, among the overall population and those with a history of NMSC. Our findings were in accordance with the DSC recommendation.

Exploring The Relationship Between SSRIs, Falls, Fractures, And Bone Mineral Density In Older Irish Adults: Results From The TUDA Study

Abstract Background Selective Serotonin Reuptake Inhibitors (SSRIs) are associated with an increased risk of falls and fractures, though the results from studies are inconsistent. SSRIs may cause a decline in bone mineral density (BMD), but this remains unclear. We aimed to explore the relationship between SSRI use and falls, fractures and BMD in older Irish adults. Methods Study participants were from a cross-sectional study of adults aged >60 years; Trinity Ulster University Department of Agriculture (TUDA) study. Falls and falls resulting in fracture in the preceding year were self-reported so participants with an MMSE < 24 were excluded. The relationship between SSRIs and falls and falls with fractures was explored in multivariate logistic regression adjusting for relevant covariates and medications: loop and thiazide diuretics, alpha and beta blockers, calcium channel blockers, ACE-inhibitors, benzodiazepines, opioids. In a subgroup with no prior diagnosis of osteoporosis or on medications for same, the relationship with SSRI's and BMD (as assessed with DXA) was explored. Results There were 4521 participants, 67.6% female, mean age 73.3 ± 8.1 years, 9.4% (n=427) using SSRIs. SSRI use predicted an increased risk of falls in the last year both before and after multivariate adjustment (OR 1.71, 1.37-2.14, p<0.001). In participants with falls (n=1448), those who had a fall with fracture versus a fall with no fracture were no more likely to be using SSRIs. In a subsample, (n=2178) no relationship was found between SSRI use and BMD at the hip, neck of femur or spine. Conclusion SSRIs use was associated with a 71% increased risk of falls though did not predict BMD or fractures. However, duration of SSRI use was not known and there was no prospective follow up. It remains unclear whether increased fracture risk in SSRI users found elsewhere is explained solely by falls risk.

Multi- and poly-pharmacology of carbonic anhydrase inhibitors.

Eight genetically distinct families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) were described in organisms allover the phylogenetic tree. They catalyze the hydration of CO2 to bicarbonate and protons, and are involved in pH regulation, chemosensing and metabolism. The 15 α-CA isoforms present in humans are pharmacological drug targets known for decades, their inhibitors being used as diuretics, antiglaucoma, antiepileptic or antiobesity drugs, as well as for the management of acute mountain sickness, idiopathic intracranial hypertension and recently, as antitumor theragnostic agents. Other potential applications include the use of CA inhibitors (CAIs) in inflammatory conditions, cerebral ischemia, neuropathic pain, or for Alzheimer's/Parkinson's disease management. CAs from pathogenic bacteria, fungi, protozoans and nematodes started to be considered as drug targets in recent years, with notable advances registered ultimately. CAIs have a complex multipharmacology probably unique to this enzyme, which has been exploited intensely but may lead to other relevant applications in the future, due to the emergence of drug design approaches which afforded highly isoform-selective compounds for most α-CAs known to date. They belong to a multitude of chemical classes (sulfonamides and isosteres, (iso)coumarins and related compounds, mono- and dithiocarbamates, selenols, ninhydrines, boronic acids, benzoxaboroles, etc). The polypharmacology of CAIs will also be discussed since drugs originally discovered for the treatment of non-CA related conditions (topiramate, zonisamide, celecoxib, pazopanib, thiazide and high-ceiling diuretics) show efective inhibition against many CAs, which led to their repurposing for diverse pharmacological applications. Significance Statement Carbonic anhydrase inhibitors have multiple pharmacologic applications as diuretics, antiglaucoma, antiepileptic, antiobesity, anti-acute mountain sickness, anti-idiopathic intracranial hypertension and as antitumor drugs. Their use in inflammatory conditions, cerebral ischemia, neuropathic pain, or neurodegenerations started to be investigated recently. Parasite carbonic anhydrases are also drug targets for antiinfectives with novel mechanisms of action which can by pass drug resistance to commonly used such agents. Drugs discovered for the management of other conditions that effectively inhibit these enzymes exert interesting polypharmacologic effects.

Incidence of Idiosyncratic Drug-Induced Liver Injury Caused by Prescription Drugs.

The incidence of drug-induced liver injury (DILI) is not known for most prescription medications. We aimed to estimate the incidence of DILI for commonly prescribed outpatient drugs. To establish a baseline estimate of DILI incidence, we used the estimated incidence (EI) of amoxicillin/clavulanate DILI from a previous population-based study in Iceland. This was combined with the multicenter prospective DILI Network (DILIN) cohort and the US population-based Medical Expenditure Panel Survey (MEPS). From 2005 to 2019, prescription drugs with at least five bona fide DILIN cases and data from at least 10 of the 15years from MEPS during that timeframe were included. The EI for 'drug A' was calculated as follows: RESULTS: In total, 30 drugs met the inclusion criteria, of which 11 were antibiotics, 4 were antiepileptic drugs (AEDs), 4 were statins, and 11 were other drug types. The highest EI was seen with azathioprine and older AEDs, with one DILI case per 349-2329 new prescriptions. The EI of antibiotics ranged greatly, with the highest risk seen for minocycline, amoxicillin/clavulanate, and nitrofurantoin (approximately 1:1000-2400 new prescriptions), and lowest risk for clindamycin, doxycycline, azithromycin, and amoxicillin (approximately 1:40,000-170,000 new prescriptions). The EI for commonly prescribed statins was approximately 1:10,000-50,000. Important medication classes with > 5 million new prescriptions from 2005 to 2019 but fewer than five DILIN cases included β-blockers, thiazide diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, selective serotonin reuptake inhibitors, and metformin, which presumably have very low DILI incidence. The highest EI was found for azathioprine, older antiepileptics, and minocycline. In contrast, many widely used drugs are rare causes of DILI. These findings may help clinicians better weigh potential benefits of medications against hepatotoxicity risk.

A Pilot Project to Implement a Pharmacist-Managed Remote Blood Pressure Monitoring Service

Background: Clinicians often hesitate to adjust antihypertensive medications based solely on clinic blood pressure (BP) readings. Limitations to obtaining home readings include access to sphygmomanometers and ability to provide accurate, reliable readings upon follow-up. Objective: This study examined whether an online platform linked to remote BP monitoring improved BP management and facilitated effective clinical interventions by pharmacists. Methods: Thirty patients with uncontrolled hypertension were enrolled and provided a remote BP monitor for home use. BP data downloaded to an online platform were monitored by two clinic pharmacists. Daily BP checks were requested (up to twice daily), and pharmacists called patients approximately weekly for 6 months. Through approved protocols, pharmacists individualized interventions to improve patient care. Descriptive statistics were used for demographic and clinical data. Results: The average systolic BP reduction was 39 mmHg (IQR = 17-52.5) for the 21 patients included in analysis. A target BP <140/<90 was achieved by 67%, and 76% had improved BP control. Patients utilized the cuff 2-4 times (n = 10) or >5 times weekly (n = 11). Through 261 patient contact attempts, the pharmacists requested more BP checks (n = 62), changed medications (n = 57), or provided non-pharmacologic counseling (n = 24) most often. Medication changes commonly included dose increases (n = 35) and additional agents (n = 17) for BP control. Spironolactone (n = 5) and thiazide diuretics (n = 5) were the most added medications. Conclusions: Most patients were willing to check their BP when provided with devices. The majority achieved a clinically significant decrease in home BP readings, demonstrating that pharmacist-driven home-monitoring programs can improve the optimization of hypertension regimens.

Erectile dysfunction in the hypertensive patient

Hypertensive patients are frequently affected by erectile dysfunction (20-25%). This is often a manifestation of atherosclerosis, a systemic disease that itself requires management. Dietary measures and physical activity are beneficial for these patients. Regarding pharmacological options, these include modifying the antihypertensive treatment or using a phosphodiesterase type 5 inhibitor (PDE5 inhibitor) in males. The preferred antihypertensive treatments are angiotensin 2 receptor antagonists, ACE inhibitors, calcium channel blockers, and if necessary, a vasodilating beta-blocker (nébivolol). Thiazide and thiazide-like diuretics (with the exception of indapamide), traditional beta-blockers, and central antihypertensive agents should be avoided.

Antihypertensive drug-associated adverse events in osteoarthritis: a study of a large real-world sample based on the FAERS database.

Hypertension is a common complication in patients with osteoarthritis (OA). There is increasing interest in the relationship between hypertension and OA. However, hypertension has been reported to negatively affect symptoms and quality of life in patients with OA. Therefore, treating hypertension is crucial for patients with OA. However, there is a lack of real-world studies on the effects of medications for treating hypertension on OA. Data from the FAERS database from January 2004 to December 2023 were extracted for disproportionality analyses, and proportional reporting ratios (PRRs) were used to assess the association between medications for hypertension and all types of arthritis. Adverse event signals were identified and determined using reporting odds ratios (RORs) Adverse event signals were considered to have occurred if a drug-induced adverse event was recorded more than or equal to 3 and the lower limit of the ROR confidence interval was more than 1. We selected five classes of drugs including, calcium channel blockers (CCBs), angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), thiazide diuretics and β-blockers and representative drugs were analysed for osteoarthritis-related adverse reactions, and age and gender subgroups were analysed for drugs of significance. We also analysed the occurrence of AEs in relation to time using the Weibull distribution. In terms of overall data, we found significant OA adverse reaction signals only for ARBs among the five drug classes.ARB AEs for spinal osteoarthritis (ROR 4.64, 95% CI 3.62-5.94), osteoarthritis (ROR 3.24 95% CI 2.82-3.72) and gouty arthritis (ROR 3.27 95% CI 1.22-8.75) were the three adverse reactions with the loudest signals. Next, we found that valsartan had strong osteoarthritis adverse reaction signals among the three ARBs, namely, irbesartan, cloxartan, and valsartan. We also analysed age and gender subgroups and found that osteoarthritis signals were strongest in the 18-65 and 65+ population, while females seem to be more prone to valsartan-related OA AEs. ARBs, especially valsartan, have significant positive signals for OA AEs. Therefore, ARB drugs, especially valsartan, should be used with caution when treating patients with OA combined with hypertension.

P104 MEDICAL TREATMENT IN PATIENTS WITH HEART FAILURE WITH REDUCED EJECTION FRACTION HOSPITALIZED AT RESEARCH INSTITUTE OF CARDIOLOGY DURING 1 YEAR (FROM SEPTEMBER 2022 TO SEPTEMBER 2023)

Objective: Patients with heart failure remain most challenging group of patients with cardiovascular diseases. Hospital period of these patients is important period of their life. Therefore evaluation of the level of in- hospital care and treatment options represents valuable information. Design and method: 477 patients (pts), 13% female,87% male with HFrEF hospitalized at Research Institute of Cardiology during 1 year (September 2022 – September 2023) represented study population. Consecutive patients’ data was extracted from the archive of Institute and evaluated. Results: Majority of pts had NYHA III-IV and mean ejection fraction (EF) of 35% (26-43%).Atrial fibrillation (AF) observed in 17,8% out of 477 pts. Myocardial infarction (MI) in anamnesis was in 82%. Systolic Blood Pressure (SBP) – mean 137 mm.Hg(min 80-max 240),Diastolic Blood Pressure(DBP) – mean 84 mm.Hg(min 50 – max 140).Arterial Hypertension(AH) had 61,4%. Type 2 Diabetes (T2D) – 51%.Chronic Kidney Disease had 22,9%.Pulmonary artery hypertension – 33%.Hb<12 g/l had 22,4%.ACE inhibitors or ARB mainly in form of fix combination with thiazide diuretics received 34% out of 477pts. ARNI were used in 27,7% of pts.B-blockers-55%. MRA – 89%. SGLT2 inh – 17,4%.Loop diuretics-86,2%.Digoxin-28,8%.Amiodarone – 22,9%.Ivabradine – 6%. Lab, tests: К+ mean 4,4 (2,9-6,2). Na+, mean 140,4 (133- 155). NT-proBNP, mean 2246.39 pg/ml (10.0-30000.0). Conclusion: In significant number of patients with HFrEF hospitalized to Research Institute of Cardiology during the period from September 2022- September 2023 medical therapy was almost adequately adherent to modern international guidelines on management of heart failure. In some cases’ limitations for indication because of low blood pressure, low eGFR and high serum kalium level took place.

Thiazide diuretics versus loop diuretics in stage 3-5 CKD: impact on cardiorenal outcomes

ABSTRACT Objectives The association between diuretic use and cardiorenal outcomes remains limited in patients with stage 3–5 chronic kidney disease (CKD) and hypertension. To address this gap, we aim to investigate the long-term clinical impact of diuretic use with its pharmacological classification in Taiwanese patients with stage 3–5 CKD and hypertension who were concurrently received angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs). Methods Using data from the National Health Insurance Research Database (January 2008 to December 2019), we focused on individuals with stage 3–5 CKD receiving ACEIs/ARBs between 2010 and 2018. We categorized the cohort into non-diuretic, loop diuretic (furosemide), thiazide diuretic, and combination diuretic groups. We used a Cox proportional hazards regression model with propensity score matching to analyze the influence of diuretics on all-cause mortality, cardiovascular (CV) death, and cardiorenal adverse outcomes. Results The study included 59,719 patients, with 17,585 in the non-diuretic group and 42,134 in the diuretic group. Diuretics including furosemide use was significantly associated the risks of hospitalization for decompensated congestive heart failure (CHF), acute renal failure (ARF), end-stage renal disease (ESRD) requiring dialysis, CV mortality, and all-cause mortality (p-value <0.001). Thiazide diuretics showed no such adverse outcomes associations. The group receiving both thiazide and furosemide was more associated with all-cause mortality than the nondiuretic, thiazide, and furosemide monotherapy groups (all p-value <0.001). Conclusion Among stage 3–5 CKD patients on ACEIs/ARBs, loop diuretics exposure was associated with increased mortality and hospitalization for cardiorenal events, while thiazide diuretics exposure in isolation had no such associations. In the present data, we cannot evaluate the relationship between furosemide-associated adverse outcomes and worse renal function. These findings highlight the need for randomized controlled trials to assess the safety of loop diuretics in this population, urging caution in their prescription without a clear clinical indication.

Mechanisms of thiazide-induced hypertension treatment: insights from gene expression and histological analysis in malignant stroke-prone spontaneously hypertensive rats.

Diuretics, including thiazides and thiazide-like drugs, are commonly recommended for treating hypertension, though their precise mechanism of action is not fully understood. This study aimed to investigate the pharmacological effects of trichloromethiazide (TCM) in malignant stroke-prone spontaneously hypertensive rats (M-SHRSP). M-SHRSPs were treated with varying doses of TCM. Prognosis, histological changes, and mRNA expression related to hypertension and stroke were assessed. The high-dose TCM group (3%) exhibited significantly lower SBP compared with the untreated group, whereas the low-dose group (0.3%) did not show a significant reduction in SBP. The survival rate was 54% in the low-dose group, whereas all rats in the high-dose group survived without experiencing a stroke by 16 weeks of age. Organ weights in both TCM-treated groups were lower than those in the control group, without severe histological abnormalities, including stroke and sclerosis. Plasma levels of thiobarbituric acid-reactive substances (TBARS) were significantly reduced in both TCM-treated groups. Additionally, 20 genes related to tissue protection, repair, proliferation, maintenance, and function were significantly expressed. TCM administration in M-SHRSPs significantly modulated the expression of 20 genes associated with tissue protection and maintenance, and reduced plasma TBARS levels. These findings suggest that TCM, a thiazide diuretic, may protect against tissue impairment in hypertension by modulating gene expression and exhibiting antioxidant activity.

Hyponatremia in geriatric patients.

Hyponatremia is the most frequent electrolyte imbalance in geriatric medicine. Causes of hyponatremia were retrospectively analyzed in all in-patients treated in 2016 (N = 2267, 1564 women, 703 men, mean age± standard deviation 81.9 ± 7.6years). Any form of hyponatremia on admission, during the stay or on discharge was noted in 308 patients (13.6%, 231 women, 77men; mean age± standard deviation 83.1 ± 7.3 years, p = 0.009 vs. age of all patients). Women had ahigher probability of developing hyponatremia compared to men (p = 0.019), 131 patients were hypovolemic, and dyspnea as an indicator of hypervolemia was noted in 71patients.Only 12patients suffering from hyponatremia (3.9%) did not receive any of the potentially sodium-lowering drugs assessed (diuretics, angiotensin-converting enzyme inhibitors, angiotensinII receptor antagonists, antidepressants, neuroleptics, nonsteroidal antirheumatics, carbamazepine, oxcarbazepine). The median number of drugs per patient potentially lowering the plasma sodium level was3 and the maximum number was7.Hypovolemic hyponatremia and the syndrome of inadequate antidiuretic hormone secretion were the most important causes of hyponatremia. Adverse drug effects were the main origins of both conditions. In patients with hyponatremia the drug load influencing plasma sodium level should be minimized, thiazide diuretics should be avoided and older individuals should receive adiet with sufficient salt content.

Structural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases

The Na+-Cl− cotransporter (NCC) drives salt reabsorption in the kidney and plays a decisive role in balancing electrolytes and blood pressure. Thiazide and thiazide-like diuretics inhibit NCC-mediated renal salt retention and have been cornerstones for treating hypertension and edema since the 1950s. Here we determine NCC co-structures individually complexed with the thiazide drug hydrochlorothiazide, and two thiazide-like drugs chlorthalidone and indapamide, revealing that they fit into an orthosteric site and occlude the NCC ion translocation pathway. Aberrant NCC activation by the WNKs-SPAK kinase cascade underlies Familial Hyperkalemic Hypertension, but it remains unknown whether/how phosphorylation transforms the NCC structure to accelerate ion translocation. We show that an intracellular amino-terminal motif of NCC, once phosphorylated, associates with the carboxyl-terminal domain, and together, they interact with the transmembrane domain. These interactions suggest a phosphorylation-dependent allosteric network that directly influences NCC ion translocation.

Renin-angiotensin system inhibitors and risk of hepatocellular carcinoma among patients with hepatitis B virus infection.

Hepatitis B virus (HBV) infection is a common cause of liver-related morbidity and mortality. Evidence suggests that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) decrease liver fibrosis, an intermediate step between liver injury and hepatocellular carcinoma (HCC). Our aim was to investigate the association between the use of ACEIs and ARBs on incident HCC and liver-related mortality among patients with HBV infection. We conducted a population-based study on a new-user cohort of patients seen at 24 hospitals across China. We included adult patients with HBV infection who started ACEIs or ARBs (ACEIs/ARBs), or calcium channel blockers or thiazide diuretics (CCBs/THZs) from January 2012 to December 2022. The primary outcome was incident HCC; secondary outcomes were liver-related mortality and new-onset cirrhosis. We used propensity score matching and Cox proportional hazards regression to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of study outcomes. Among 32 692 eligible patients (median age 58 [interquartile range (IQR) 48-68] yr, and 18 804 male [57.5%]), we matched 9946 pairs of patients starting ACEIs/ARBs or CCBs/THZs. During a mean follow-up of 2.3 years, the incidence rate of HCC per 1000 person-years was 4.11 and 5.94 among patients who started ACEIs/ARBs and CCBs/THZs, respectively, in the matched cohort. Use of ACEIs/ARBs was associated with lower risks of incident HCC (HR 0.66, 95% CI 0.50-0.86), liver-related mortality (HR 0.77, 95% CI 0.64-0.93), and new-onset cirrhosis (HR 0.81, 95% CI 0.70-0.94). In this cohort of patients with HBV infection, new users of ACEIs/ARBs had a lower risk of incident HCC, liver-related mortality, and new-onset cirrhosis than new users of CCBs/THZs.

Evaluation of antihypertensive drug-induced changes in mandibular bone using fractal analysis

ObjectivesThe aim was to evaluate changes in trabecular and cortical mandibular bone caused by antihypertensive (AHT) drugs through fractal analysis. MethodsThis retrospective study included 230 patients who were taking AHT medication and had no conditions affecting bone metabolism other than hypertension. A control group of 230 healthy, sex-matched individuals was also included. Patients were divided into subgroups according to AHT drugs: thiazide diuretics (TDs), beta-blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and a combination of drugs. The fractal dimension (FD) was calculated bilaterally in 5 regions of interest (ROI 1 – ROI 5) including 4 trabecular regions and 1 cortical region using Image J software. ResultsMean FD values were significantly higher in all ROIs for the study group compared to the control group (P<0.001). FDs were significantlty higher for BB, ACEI, ARB, CCB, and combined subgroups compared to controls in ROIs 1, 2, and 4; for ACEI and CCB subgroups compared to controls in ROI 3; and for TD, BB, ACEI, ARB, CCB, and combined subgroups compared to controls in ROI 5 (P<0.001). ConclusionAHTs may increase FD values of the trabecular and cortical structures. Assessment of the effects of AHT drugs is essential for predicting the prognosis for bone healing after tooth extraction, osseointegration after implant surgery or other surgical procedures.

Combination diuretic therapies in heart failure: Insights from GUIDE-IT

IntroductionDiuretics are the mainstay of maintaining and restoring euvolemia in the management of heart failure. Loop diuretics are often preferred, however, combination diuretic therapy (CDT) with a thiazide diuretic is often used to overcome diuretic resistance and increase diuretic effect. We performed an analysis of the GUIDE-IT study to assess all-cause mortality and time to first hospitalizations in patients necessitating CDT. MethodsPatients from the GUIDE-IT dataset were stratified by their requirement for CDT with a thiazide to achieve euvolemia. A total of 894 patients were analyzed, 733 of which were treated with loop diuretics alone vs 161 used either chlorothiazide or metolazone in addition to loop diuretics. Kaplan-Meir curves were derived with log-rank p-values to evaluate for differences between the groups. ResultsThere was no significant difference in all-cause mortality regardless of CDT utilization status (mean survival of 612.704 days vs 603.326 days, p = 0.083). On subgroup analysis, there was no significant difference in all-cause mortality amongst those using loop diuretics compared to CDT in the BNP-guided therapy group, (mean survival time 576.385 days vs 620.585 days, p = 0.0523), nor the control group (614.1 days vs 588.9 days; p = 0.5728). Time to first hospitalization was reduced in all using CDT compared to loop diuretics alone (280.5 days vs 407.2 days, p < 0.0001). On subgroup analysis, both the BNP-guided group as well as the control group had reduced time to first hospitalization in the CDT group compared to those who did not require CDT (BNP group: 287.503 days vs 402.475 days, p ≤0.0001; control group 248.698 days vs 399.035 days, p = 0.0009). ConclusionUse of CDT is associated with earlier time to hospitalization, though no association was identified with increased all-cause mortality. Further prospective studies are likely needed to determine the true risk and benefits of combination diuretic therapy.

Home blood pressure-lowering effect of a non-steroidal mineralocorticoid receptor blocker, esaxerenone, versus trichlormethiazide for uncontrolled hypertension: the EXCITE-HT randomized controlled study.

The EXCITE-HT study aimed to evaluate the efficacy and safety of esaxerenone versus thiazide diuretics (trichlormethiazide) as second-line treatment for Japanese patients with uncontrolled essential hypertension. This was a 12-week, multicenter, randomized, open-label, parallel-group study. The non-inferiority of esaxerenone to trichlormethiazide was confirmed if the upper limit of the two-sided 95% confidence interval (CI) for the difference in systolic blood pressure (SBP)/diastolic blood pressure (DBP) change between groups was below 3.9/2.1 mmHg. A total of 295 and 290 patients were included in the esaxerenone and trichlormethiazide groups, respectively. The non-inferiority of esaxerenone to trichlormethiazide was demonstrated: least squares mean change differences in morning home SBP/DBP at end of treatment (EOT) were -2.2 (95% CI, -3.6, -0.8) mmHg for SBP/-0.6 (-1.4, 0.2) mmHg for DBP. Morning home, bedtime home, and office BP significantly decreased (all p < 0.001) from baseline to EOT in both groups. The urinary albumin-to-creatinine ratio and N-terminal pro-brain natriuretic peptide level decreased from baseline to Week 12 in both groups, with no notable intergroup difference. Serum potassium elevations occurred more frequently with esaxerenone, while serum potassium reductions occurred more with trichlormethiazide. Uric acid elevations were observed in both groups, but more frequently with trichlormethiazide than esaxerenone. No cases of gout occurred in this study. Reductions in estimated glomerular filtration rate were similarly observed in both groups. EXCITE-HT is the first randomized controlled study to demonstrate evidence that esaxerenone is non-inferior to trichlormethiazide as second-line treatment for Japanese patients with uncontrolled essential hypertension, with no new safety concerns. The EXCITE-HT study demonstrated the non-inferiority of esaxerenone to trichlormethiazide in its morning home blood pressure lowering effect and safety profile in Japanese patients with uncontrolled essential hypertension who were previously treated with an angiotensin II receptor blocker or calcium channel blocker.

Evolving the Role of Black Race in Hypertension Therapeutics.

Black race has been used to guide antihypertensive drug selection for Black patients based on predominant between race (same drug) and intra-race (different drugs) blood pressure (BP) response patterns. Accordingly, thiazide diuretics and calcium antagonists have been recommended over renin-angiotensin system (RAS) inhibitors (angiotensin-receptor blockers, angiotensin-converting enzyme inhibitors) and beta blockers for Black patients. Current antihypertensive drug prescribing reflects historical guidance as calcium antagonists and thiazide diuretics are prescribed more and RAS blockers less in Black than White patients. Hypertension control rates in Blacks, lag those for Whites despite their greater use of combination drug therapy and lesser use of monotherapy. This is also true across drug regimens containing any of the 4 recommended classes for initial therapy as well as for evidence-based combination drug therapy (calcium antagonist or thiazide diuretic + RAS blocker) regimens for which there is no known racial disparity in BP response. Current recommendations acknowledge the need for combination drug therapy in most, especially in Black patients. One exemplary comprehensive hypertension control program achieved >80% control rates in Black and White patients with minimal racial disparity while utilizing a race-agnostic therapeutic algorithm. Black patients manifest robust, if not outsized, BP responses to diet/lifestyle modifications. Importantly, race neither appears to be a necessary nor sufficient consideration for the selection of effective drug therapy. Accordingly, we urge the initiation of adequately intense race-agnostic drug therapy coupled with greater emphasis on diet/lifestyle modifications for Black patients as the cornerstone of a race-informed approach to hypertension therapeutics.

Pathophysiological role of Na-Cl cotransporter in kidneys, blood pressure, and metabolism.

The Na-Cl cotransporter (NCC) is a well-recognized regulator of ion transportation in the kidneys that facilitates Na+ reabsorption in the distal convoluted tubule. It is also the pharmacologic inhibitory target of thiazide diuretics, a class of front-line antihypertensive agents that have been widely used for decades. NCC is a potent regulator of Na+ reabsorption and homeostasis. Hence, its overactivation and suppression lead to hypertension and hypotension, respectively. Genetic mutations that affect NCC function contribute to several diseases such as Gordon and Gitelman syndromes. We summarized the role of NCC in various physiologic processes and pathological conditions, such as maintaining ion and water homeostasis, controlling blood pressure, and influencing renal physiology and injury. In addition, we discussed the recent advancements in understanding cryo-EM structure of NCC, the regulatory mechanisms and binding mode of thiazides with NCC, and novel physiologic implications of NCC in regulating the cross-talk between the immune system and adipose tissue or the kidneys. This review contributes to a comprehensive understanding of the pivotal role of NCC in maintaining ion homeostasis, regulating blood pressure, and facilitating kidney function and NCC's novel role in immune and metabolic regulation.

Antihypertensive utilization patterns among pregnant persons with pre-existing hypertension in the US: A population-based study.

Hypertension among persons with childbearing potential is on the rise. Maintaining proper blood pressure during pregnancy is vital to prevent maternal and neonatal complications. Yet, limited evidence on the risk-benefit of various antihypertensives presents challenges for informed decision-making during this critical period. This study aimed to examine the utilization patterns of different classes of antihypertensives among persons with pre-existing hypertension before, during, and after pregnancy. We used MarketScan® Commercial Database 2011-2020 to analyze antihypertensive utilization among pregnant persons aged 12 to 55 identified via a validated algorithm. Pre-existing hypertension was defined as ≥1 inpatient or ≥2 outpatient encounters for hypertension within the 180 days preceding the LMP. Antihypertensive utilization was described during target periods: 0-3 months (0-3M) before pregnancy, 1st/2nd/3rd trimester (T1/2/3), 0-3M, and 4-6M after pregnancy. We identified 1,950,292 pregnancies, of which 20,576 (12,978 live and 7,598 non-live) had pre-existing hypertension. Both groups had similar antihypertensive use (80.1% and 81.0%, respectively) during the 6 months before pregnancy (baseline). For live-birth pregnancies, 13.9% of baseline users discontinued treatment during pregnancy, while 28.9% of non-users initiated antihypertensives during pregnancy, and 17.2% started postpartum. Before pregnancy, the predominant antihypertensives included thiazide diuretics (21.9%), combined α- and β-blockers (18.4%), and dihydropyridines (16.2%). During pregnancy, thiazide diuretics, cardioselective β-blockers, and ACE inhibitors declined (T3: 3.0%, 4.2%, and 0.8%). Dihydropyridine use was steady during pregnancy, but preference shifted from amlodipine to nifedipine in T3 (2.2.% vs.10.8%). Central α2-agonists increased during pregnancy (up to 15.2% in T3) compared to both pre- (9.8%) and post-pregnancy (5.7%). ARBs mirrored ACE inhibitors, with less than 1% utilization in later trimesters. Combination agents dropped from 10.8% pre-pregnancy to 0.8% in T3, then rebounded to 7.3% post-pregnancy. Research is warranted to evaluate the choice of antihypertensives and optimal timing to switch to safer alternatives, considering maternal and fetal outcomes.

The Evolving Role of Chlorthalidone and Hydrochlorothiazide as First-Line Treatments for Hypertensive Patients.

Hypertension is attributable long-term to various negative health outcomes, including atherosclerotic cardiovascular disease and, more broadly, to cardiovascular events such as congestive heart disease, myocardial infarction, heart failure, and stroke. Effective hypertension treatment is essential to lower the risk of these outcomes. Treatment of hypertension includes both nonpharmacologic and, if necessary, pharmacologic interventions. The drug classes proven in trials to decrease the risk of cardiovascular disease events in cases with hypertension include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, thiazide diuretics, and calcium channel blockers. When considering thiazide diuretics as a first-line treatment, chlorthalidone (CTD) is currently recommended by the American College of Cardiology over hydrochlorothiazide (HCTZ). Previous studies have demonstrated that CTD is superior to HCTZ in preventing cardiovascular disease events. However, more recent studies have revealed that there is no significant difference in the results of patients treated with HCTZ versus those treated with CTD. Additionally, studies have revealed CTD has worse outcomes regarding side effects when compared to HCTZ. In this regard, it is essential to carefully consider which medication will best improve the outcomes of patients with hypertension while also causing few or easily manageable side effects.