Thiazide diuretics alone or combined with potassium-sparing diuretics to treat hypertension: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: The magnitude of blood pressure (BP)-lowering effects and decrease of the adverse effects of thiazide diuretics provided by potassium-sparing diuretics remain uncertain. The aim of this study was to compare the BP-lowering efficacy and the incidence of adverse effects of high (T+) and low-dose (T-) thiazide diuretics, alone or combined with high (PS+) or low-dose (PS-) potassium-sparing diuretics in patients with primary hypertension. METHODS: A systematic literature search was performed in PubMed/MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, Web of Science, Scopus and LILACS. Randomized double-blind placebo or active-controlled trials (RCT) with 3 weeks to 1 year of follow-up were included. Sample size, mean and standard deviation from baseline, follow-up and change from baseline values were extracted by two independent reviewers. Pairwise random effect models and Bayesian network meta-analysis models were used to compare the effects of treatments. The risk of bias in individual studies was assessed using the Rob 1.0 tool. The primary outcome was the mean difference in office SBP. Secondary outcomes were the mean difference in biochemical parameters and the incidence of nonmelanoma skin cancer. RESULTS: Two hundred and seventy-six double-blind RCTs involving 58 807 participants (mean age: 55 years; 45% women) were included. All treatment groups were more effective than placebo in lowering BP, with mean differences (MDs) of change from baseline ranging from -7.66 mmHg [95% credible interval (95% CrI), -8.53 to -6.79] for T- to -12.77 mmHg (95% CrI, -15.22 to -10.31) for T+PS-. T+ alone or combined with potassium-sparing was more effective in reducing BP than T-. The surface under the cumulative ranking curve (SUCRA) estimated ranking showed that the best effectiveness in lowering SBP was found for T+PS- (0.69), T+PS+ (0.65) and T+ (0.54). Compared with placebo, all treatments (except T-PS-) were associated with more potassium reduction and T+ compared with all other treatments and T- when compared with T-PS-. Compared with placebo, all active treatments (except T+PS+) showed higher elevations of uric acid. The increase of plasma glucose promoted by thiazides alone was reduced by potassium-sparing agents. CONCLUSION: Thiazides with potassium-sparing diuretics are associated with increased BP-lowering efficacy compared with thiazides alone while minimizing hypokalaemia and hyperglycaemia. These findings demonstrate that thiazide and potassium-sparing diuretic combination is preferable to thiazide alone in treating hypertension.

Delayed Decline of Cognitive Function by Antihypertensive Agents: A Cohort Study Linked with Genotype Data.

BACKGROUND: Arterial hypertension is among factors with the potential for increasing the risk of cognitive impairment in elderly subjects. However, studies investigating the effects of antihypertensives on cognitive function have reported mixed results. METHODS: We have used the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) to investigate the effect of each class of antihypertensives, both as single and combined, in reducing the rate of conversion from normal to mild cognitive impairment (MCI). RESULTS: The use of antihypertensive drugs was associated with 21% (Hazard ratio: 0.79, p<01001) delay in the rate of conversion to MCI. This effect was modulated by age, gender, and genotypic APOE4 allele. Among different antihypertensive subclasses, calcium channel blockers (CCBs) (24%, HR: 0.76, P=0.004), diuretics (21%, HR: 0.79, P=0.006), and α1-adrenergic blockers (α1-ABs) (23%, HR: 0.77, P=0.034) significantly delayed the rate of MCI conversion. A significant effect was observed with the selective L-type voltage-gated CCBs, dihydropyridines, amlodipine (47%, HR=0.53, P<0.001) and nifedipine (49%, HR=0.51, P=0.012), whereas non-DHPs showed insignificant effect. Loop diuretics, potassium sparing diuretics, and thiazides all significantly reduced the rate of MCI conversion. Combination of α1-AB and diuretics led to synergistic effects; combination of vasodilators plus ß-blockers (ßBs), and α1-AB plus ßBs led to additive effect in delaying the rate of MCI conversion, when compared to a single drug. CONCLUSION: Our results could have implications for the more effective treatment of hypertensive elderly adults who are likely to be at high risk of cognitive decline and dementia. The choice of combination of antihypertensive therapy should also consider the combination which would lead to an optimum benefit on cognitive function.

Outcomes of a Specialized Clinic on Rates of Investigation and Treatment of Primary Aldosteronism.

Importance: Primary aldosteronism (PA) is one of the most common causes of secondary hypertension but remains largely unrecognized and untreated. Objective: To understand the outcomes of a specialized clinic on rates of evaluation and treatment of PA in the context of secondary factors. Design, Setting, and Participants: This population-based cohort study was conducted in Alberta, Canada, using linked administrative data between April 1, 2012, and July 31, 2019, on adults identified as having hypertension. Main Outcomes and Measures: We evaluated each step of the diagnostic and care pathway for PA to determine the proportion of people with hypertension who received screening, subtyping, and targeted treatment for PA. Variations in diagnosis and treatment were examined according to individual-level, clinician-level, and system-level characteristics. Results: Of the 1.1 million adults with hypertension, 7941 people (0.7%) were screened for PA. Among those who were screened, 1703 (21.4%) had positive test results consistent with possible PA, and 1005 (59.0%) of these were further investigated to distinguish between unilateral and bilateral forms of PA. Only 731 individuals (42.9%) with a positive screen result received disease-targeted treatment. Geographic zones and clinician specialty were the strongest determinants of screening, subtyping, and treatment of PA, with the highest rates corresponding to the location of the provincial endocrine hypertension program. Conclusions and Relevance: In this cohort, less than 1% of patients expected to have PA were ever formally diagnosed and treated. These findings suggest that a system-level approach to assist with investigation and treatment of PA may be highly effective in closing care gaps and improving clinical outcomes.

Dysnatremias in emergency patients with acute kidney injury: A cross-sectional analysis.

PURPOSE: We aimed to investigate the prevalence, risk factors and outcome of hypo- and hypernatremia in emergency patients with acute kidney injury (AKI). METHODS: In this cross-sectional analysis all emergency patients between January 1st 2017 and December 31st 2018 with measurements of creatinine and sodium were included. Baseline characteristics, medication and laboratory data were gathered. Chart reviews were performed to identify patients with a diagnosis of chronic kidney disease (CKD) and to extract baseline creatinine. For all other patients the ADQI backformula was used to calculate baseline creatinine. AKI was graduated using creatinine criteria of the acute kidney injury network. Binary logistic regression analysis was used to identify risk factors for appearance of dysnatremias and outcome. RESULTS: AKI was found in 8% of patients. 392 patients (23.16%) had hyponatremia, 24 (1.4%) had hypernatremia. Use of potassium sparing diuretics, a medical cause for emergency referral, use of thiazide diuretics and AKI stage were the strongest risk factors for hyponatremia. Loop diuretics, a medical cause for emergency referral and AKI stage were risk factors for hypernatremia. In patients with all classes of hyponatremia, length of hospital stay was significantly longer compared to patients with a normal serum sodium. In the binary logistic regression analysis with death as outcome, hyponatremia as well as severe hypernatremia were independent risk factors for mortality. CONCLUSIONS: Dysnatremias are common in emergency patients with AKI. Diuretic medication is a major risk factor for hypo- and hypernatremia. Both hyponatremia and severe hypernatremia were independent risk factors for adverse outcome.

Potassium-sparing effects of furosemide in mice on high-potassium diets.

In individuals on a regular "Western" diet, furosemide induces a kaliuresis and reduction in plasma K concentration by inhibiting Na reabsorption in the thick ascending limb of Henle's loop, enhancing delivery of Na to the aldosterone-sensitive distal nephron. In the aldosterone-sensitive distal nephron, the increased Na delivery stimulates K wasting due to an exaggerated exchange of epithelial Na channel-mediated Na reabsorption of secreted K. The effects of furosemide are different in mice fed a high-K, alkaline (HK) diet: the large-conductance Ca-activated K (BK) channel, in conjunction with the BK ß4-subunit (BK-α/ß4), mediates K secretion from intercalated cells (IC) of the connecting tubule and collecting ducts. The urinary alkaline load is necessary for BK-α/ß4-mediated K secretion in HK diet-fed mice. However, furosemide acidifies the urine by increasing vacuolar ATPase expression and acid secretion from IC, thereby inhibiting BK-α/ß4-mediated K secretion and sparing K. In mice fed a low-Na, high-K (LNaHK) diet, furosemide causes a greater increase in plasma K concentration and reduction in K excretion than in HK diet-fed mice. Micropuncture of the early distal tubule of mice fed a LNaHK diet, but not a regular or a HK diet, reveals K secretion in the thick ascending limb of Henle's loop. The sites of action of K secretion in individuals consuming a high-K diet should be taken into account when diuretic agents known to waste K with low or moderate K intakes are prescribed.

A teenage patient with autosomal recessive polycystic kidney disease, a splenorenal shunt, and congenital hepatic fibrosis: a case report.

A 16-year-old female patient previously diagnosed with autosomal recessive polycystic kidney disease (ARPKD) presented with acute bilateral pneumonia, upper gastrointestinal bleeding caused by ruptured esophageal varices, ascites, and lower limb edema. She required intensive care and an endoscopic procedure to treat the gastrointestinal bleeding. The analysis of the differential diagnosis for chronic liver disease indicated she had a spontaneous splenorenal shunt. Ultrasound-guided biopsy revealed the patient had cirrhosis, as characteristically seen in individuals with ARPKD. She had no symptoms at discharge and was referred for review for a combined transplant.

Hydrochlorothiazide vs chlorthalidone, indapamide, and potassium-sparing/hydrochlorothiazide diuretics for reducing left ventricular hypertrophy: A systematic review and meta-analysis.

Left ventricular hypertrophy develops in 36%-41% of hypertensive patients and independently predicts cardiovascular events and total mortality. Moreover, drug-induced reduction in left ventricular mass (LVM) correlates with improved prognosis. The optimal thiazide-type diuretic for reducing LVM is unknown. Evidence regarding potency, cardiovascular events, sodium, and potassium suggested the hypothesis that "CHIP" diuretics (CHlorthalidone, Indapamide, and Potassium-sparing diuretic/hydrochlorothiazide [PSD/HCTZ]) would reduce LVM more than HCTZ. Systematic searches of five databases were conducted. Among the 38 randomized trials, a 1% reduction in systolic blood pressure (SBP) predicted a 1% reduction in LVM, P = 0.00001. CHIP-HCTZ differences in reducing LVM differed across trials (ie, heterogeneity), making interpretation uncertain. However, among the 28 double-blind trials, heterogeneity was undetectable, and HCTZ reduced LVM (percent reduction [95% CI]) by -7.3 (-10.4, -4.2), P < 0.0001. CHIP diuretics surpassed HCTZ in reducing LVM: chlorthalidone -8.2 (-14.7, -1.6), P = 0.015; indapamide -7.5 (-12.7, -2.3), P = 0.005; and all CHIP diuretics combined -7.7 (-12.2, -3.1), P < 0.001. The comparison of PSD/HCTZ with HCTZ had low statistical power but favored PSD/HCTZ: -6.0 (-14.1, +2.1), P = 0.149. Thus, compared to HCTZ, CHIP diuretics had twice the effect on LVM. CHIP diuretics did not surpass HCTZ in reducing systolic or diastolic blood pressure: -0.3 (-5.0, +4.3) and -1.6 (-5.6, +2.4), respectively. The strength of evidence that CHIP diuretics surpass HCTZ for reducing LVM was high (GRADE criteria). In conclusion, these novel results have demonstrated that CHIP diuretics reduce LVM 2-fold more than HCTZ among hypertensive patients. Although generally related to LVM, blood pressure fails to explain the superiority of CHIP diuretics for reducing LVM.

Pediatric calculi: cause, prevention and medical management.

PURPOSE OF REVIEW: The incidence of pediatric nephrolithiasis is on the rise, with a significant related morbidity and a concomitant relevant increase in healthcare costs. The purpose of this review is to portray the current epidemiology and cause of renal stones in children, to provide a framework for appropriate clinical evaluation on an individual basis, and a guidance regarding treatment and prevention for the significant risk of lifelong recurrence and deriving complications. RECENT FINDINGS: The early identification of modifiable risk factors and other abnormalities is essential, to prevent related morbidity, the onset of chronic kidney disease, and the associated increased risk of developing other diseases. The implementation of risk reduction strategies, including dietary modifications and targeted pharmacological therapies, will significantly influence stone recurrences and preserve renal function. SUMMARY: Future research is desirable, with the aim to strengthen personalized conservative management of pediatric nephrolithiasis as first-line treatment.

Hydrochlorothiazide and alternative diuretics versus renin-angiotensin system inhibitors for the regression of left ventricular hypertrophy: a head-to-head meta-analysis.

BACKGROUND: Found in 36-41% of hypertension, elevated left ventricular mass (LVM) independently predicts cardiovascular events and total mortality. Conversely, drug-induced regression of LVM predicts improved outcomes. Previous studies have favored renin-angiotensin system inhibitors (RASIs) over other antihypertensives for reducing LVM but ignored differences among thiazide-type diuretics. From evidence regarding potency, cardiovascular events, and electrolytes, we hypothesized a priori that 'CHIP' diuretics [CHlorthalidone, Indapamide and Potassium-sparing Diuretic/hydrochlorothiazide (PSD/HCTZ)] would rival RASIs for reducing LVM. METHOD AND RESULTS: Systematic review yielded 12 relevant double-blind randomized trials. CHIPs were more closely associated with reduced LVM than HCTZ (P = 0.004), indicating that RASIs must be compared with each diuretic separately. Publication bias favoring RASIs was corrected by cumulative analysis. For reducing LVM, HCTZ tended to be less effective than RASIs. However, the following surpassed RASIs: chlorthalidone Hedge's G: -0.37 (95% CI -0.72 to -0.02), P = 0.036; indapamide -0.20 (-0.39 to -0.01), P = 0.035; all CHIPs combined (with 61% of patients in one trial) -0.25 (-0.41to -0.09), P = 0.002. Statistical significance (P < 0.05) did not depend on any one trial. CHIPs reduction in LVM was 37% greater than that from RASIs. CHIPs superiority tended to increase with trial duration, from a negligible effect at 0.5 year to a maximal effect at 0.9-1.0 years: -0.26 (-0.43 to -0.09), P = 0.003. Fifty-eight percent of patients had information on echocardiographic components of LVM: relative to RASIs, CHIPs significantly reduced end-diastolic LV internal dimension (EDLVID): -0.18 (-0.36 to -0.00), P = 0.046. Strength of evidence favoring CHIPs over RASIs was at least moderate. CONCLUSION: In these novel results in patients with hypertension, CHIPs surpassed RASIs for reducing LVM and EDLVID.

Review of the Diagnosis and Treatment of Periodic Paralysis.

Periodic paralyses (PPs) are rare neuromuscular disorders caused by mutations in skeletal muscle sodium, calcium, and potassium channel genes. PPs include hypokalemic paralysis, hyperkalemic paralysis, and Andersen-Tawil syndrome. Common features of PP include autosomal dominant inheritance, onset typically in the first or second decades, episodic attacks of flaccid weakness, which are often triggered by diet or rest after exercise. Diagnosis is based on the characteristic clinic presentation then confirmed by genetic testing. In the absence of an identified genetic mutation, documented low or high potassium levels during attacks or a decrement on long exercise testing support diagnosis. The treatment approach should include both management of acute attacks and prevention of attacks. Treatments include behavioral interventions directed at avoidance of triggers, modification of potassium levels, diuretics, and carbonic anhydrase inhibitors. Muscle Nerve 57: 522-530, 2018.

Neonatal bartter syndrome in an extremely low birth weight baby.

Early diagnosis of Bartter syndrome (BS) in the neonatal period is a clinical challenge, more so in an extremely low birth weight (ELBW) baby because of the inherent renal immaturity and the associated difficulty in fluid management. However, once a diagnosis is made, the disorder is known to respond well to fluid and electrolyte management, prostaglandin inhibitors, and potassium-sparing diuretics. Herein, we report a case of neonatal BS in a very premature ELBW infant.

Diuretic, natriuretic and potassium-sparing effect of nothofagin isolated from Leandra dasytricha (A. Gray) Cogn. leaves in normotensive and hypertensive rats.

Active constituents from natural origin have long been used for the treatment of patients suffering from cardiovascular and renal diseases. This study therefore aimed to investigate the diuretic and natriuretic properties of nothofagin, a dihydrochalcone isolated from Leandra dasytricha (A. Gray) Cogn. leaves in normotensive and hypertensive rats. Male Wistar normotensive rats were orally treated with vehicle (1 ml/kg); hydrochlorothiazide (HCTZ; 25 mg/kg); ethyl acetate fraction from L. dasytricha (EALD; 3-30 mg/kg) and nothofagin (NOT; 0.3-3 mg/kg). Spontaneously hypertensive rats (SHR) received NOT (1 mg/kg), HCTZ (25 mg/kg) or vehicle. The cumulative diuretic index, urinary electrolytes excretion (Na+ and K+), pH, density and conductivity were measured at the end of the experiment (after 8 h). A7r5 and L929 cell lines were used to measure cell viability after exposure to NOT. Nitric oxide generation was quantified in A7r5 cell supernatant, and DPPH assay was used for evaluating the antioxidant properties of NOT. The urinary volume of normotensive rats were increased after the treatment with EALD, without any changes in Na+ or K+ excretion. NOT was able to induce diuresis and natriuresis, but not kaliuresis, in both normotensive and hypertensive rats. The reduction in prostanoids generation through cyclooxygenase inhibition, as well as the muscarinic receptor antagonism, fully avoided NOT-induced increases in diuretic index. NOT, which did not interfere with L929 or A7r5 cell viability, was able to stimulate nitric oxide generation in A7r5 cell, besides showing an antioxidant effect in scavenging the free-radical DPPH. Taken together, our study shows, for the first time, the diuretic, natriuretic and potassium-sparing effect of nothofagin in rats, which was associated with prostanoids generation, muscarinic receptor activation and antioxidant properties.

The effect of co-trimoxazole on serum potassium concentration: safety evaluation of a randomized controlled trial.

AIMS: Co-trimoxazole maintains a well-established role in the treatment of Pneumocystis jirovecii and Toxoplasma gondii, as well as urinary tract infections. Observational studies report hyperkalaemia to be associated with co-trimoxazole, which may stem from an amiloride-like potassium-sparing effect. The current study investigated changes in serum potassium in patients without acute infections, and the influence of concomitant antikaliuretic drugs on this effect. METHODS: A post hoc analysis was carried out of a randomized controlled trial in patients with interstitial lung disease who were assigned to placebo or 960 mg co-trimoxazole twice daily. Serum potassium and creatinine were measured at baseline, 6 weeks, and 6, 9 and 12 months. The primary outcome was the difference in mean serum potassium concentrations between co-trimoxazole and placebo at 6 weeks. RESULTS: Mean serum potassium levels were similar at baseline: 4.24 (± 0.44) mmol l-1 in the 87 co-trimoxazole group participants and 4.25 (± 0.39) mmol l-1 in the 83 control participants. Co-trimoxazole significantly increased mean serum potassium levels at 6 weeks, with a difference between means compared with placebo of 0.21 mmol l-1 [95% confidence interval (CI) 0.09, 0.34; P = 0.001). This significant increase in serum potassium was detectable even after exclusion of patients on antikaliuretic drugs, with a difference between means for co-trimoxazole compared with placebo of 0.23 mmol l-1 (95% CI 0.09, 0.38; P = 0.002). There were 5/87 (5.7%) patients on co-trimoxazole whose serum potassium concentrations reached ≥5.5 mmol l-1 during the study period. CONCLUSIONS: Co-trimoxazole significantly increases serum potassium concentration, even in participants not using antikaliuretic drugs. While the magnitude of increase was often minor, a small proportion in our outpatient cohort developed hyperkalaemia of clinical importance.

Clinical Utility of Potassium-Sparing Diuretics to Maintain Normal Serum Potassium in Peritoneal Dialysis Patients.

♦ BACKGROUND: Hypokalemia is a vexing problem in end-stage renal disease patients on peritoneal dialysis (PD), and oral potassium supplements (OPS) have limited palatability. Potassium-sparing diuretics (KSD) (spironolactone, amiloride) may be effective in these patients. ♦ METHODS: We performed a cross-sectional review of 75 current or past (vintage > 6 months) PD patients with regard to serum potassium (K+), OPS, and KSD utilization. We reviewed charts for multiple clinical and laboratory variables, including dialysis adequacy, residual renal function, nutritional status and co-existing medical therapy. ♦ RESULTS: The cohort was middle-aged with a mean age of 49.2 years (standard deviation [SD] = 14.7) and overweight with a body mass index of 29.5 (6.7) kg/m2. Of all the participants, 57.3% were female, 73.3% African-American, and 48% diabetic with an overall PD vintage of 28.2 (24.3) months at the time of enrollment. Weekly Kt/V was 2.12 (0.43), creatinine clearance was 73.5 (33.6) L/week/1.73 m2 with total daily exchange volume of 10.8 (2.7) L. Residual urine output (RUO) measured at 440 (494) mL (anuric 30.6%). Three-month averaged serum K+ measured at 4 (0.5) mmol/L with 36% of the participants receiving K+ supplements (median: 20 [0;20] mmol/day) and 41.3% KSD (spironolactone dose: 25 - 200 mg/day; amiloride dose: 5 - 10 mg/day). Serum K+ correlated positively with weekly Kt/V (r = 0.239; p = 0.039), PD vintage (r = 0.272; p = 0.018) but not with PD modality, daily exchange volume, RUO, or KSD use. However, KSD use was associated with decreased use of OPS (r = -0.646; p < 0.0001). ♦ CONCLUSIONS: Potassium-sparing diuretics were effective in this cohort of PD patients and decreased the need for OPS utilization.

Serum Potassium, Mortality, and Kidney Outcomes in the Atherosclerosis Risk in Communities Study.

OBJECTIVES: To investigate the association between serum potassium, mortality, and kidney outcomes in the general population and whether potassium-altering medications modify these associations. PATIENTS AND METHODS: We studied 15,539 adults in the Atherosclerosis Risk in Communities Study. Cox proportional hazard regression was used to investigate the association of serum potassium at baseline (1987-1989), evaluated categorically (hypokalemia, <3.5 mmol/L; normokalemia, ≥3.5 and <5.5 mmol/L; hyperkalemia, ≥5.5 mmol/L) and continuously using linear spline terms (knots at 3.5 and 5.5 mmol/L), with mortality, sudden cardiac death, incident chronic kidney disease, and end-stage renal disease. The end date of follow-up for all outcomes was December 31, 2012. We also evaluated whether classes of potassium-altering medications modified the association between serum potassium and adverse outcomes. RESULTS: Overall, 413 (2.7%) of the participants had hypokalemia and 321 (2.1%) had hyperkalemia. In a fully adjusted model, hyperkalemia was significantly associated with mortality (hazard ratio, 1.24; 95% CI, 1.04-1.49) but not sudden cardiac death, chronic kidney disease, or end-stage renal disease. Hypokalemia as a categorical variable was not associated with any outcome; however, associations of hypokalemia with all-cause mortality and kidney outcomes were observed among those who were not taking potassium-wasting diuretics (all P for interaction, <.001). CONCLUSIONS: Higher values of serum potassium were associated with a higher risk of mortality in the general population. Lower levels of potassium were associated with adverse kidney outcomes and mortality among participants not taking potassium-wasting diuretics.

[News in blood pressure in 2015]. / Hypertension artérielle.

In this short review, we present 4 studies published in 2014-2015 which appear to important for clinicians. The results of the SPRINT trial are challenging the target systolic blood pressure (BP) to be achieved in non-diabetic hypertensive. It shows that a target BP <120 mmHg provides clear mortality and morbidity advantages over a <140 mmHg target. The PATHWAY2 and 3 studies reemphasize the important role of potassium sparing diuretics in patients with resistant hypertension and in patients with metabolic syndrome. At last the DENERHTN study conducted in France suggests that renal denervation is not dead and that additional studies are needed to position this technique in management of resistant hypertension.

Diuretic antihypertensive drugs and incident dementia risk: a systematic review, meta-analysis and meta-regression of prospective studies.

OBJECTIVE: Diuretic drugs have been a mainstay of hypertension treatment in the elderly however their dementia sparing effects are under-reported. The objective was to quantify dementia risk in relation to diuretic antihypertensive drugs. METHODS: Electronic databases were searched until June 2015. ELIGIBILITY CRITERIA: population, adults without dementia from primary care, community cohort, residential/institutionalized, or randomized controlled trial; exposure, diuretic antihypertensive drug; comparison, no diuretic drug, other or no antihypertensive drug, placebo-control; outcome, incident dementia diagnosed by standardized criteria. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were pooled in fixed-effects models with RevMan 5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark) and the findings rated according to The Grading of Recommendations Assessment, Development and Evaluation criteria. RESULTS: A total of 15 articles were included (52 599 persons, 3444 dementia cases, median age 76.1 years) and median follow-up was 6.1 years. Diuretics were associated with reduced dementia risk (HR 0.83; 95% CI 0.76-0.91, P < 0.0001, I = 0) and Alzheimer's disease risk (HR 0.82; 95% CI 0.71-0.94, P = 0.004, I = 0). Stratified analysis indicated a difference between potassium sparing, thiazide and loop diuretics (P = 0.01). Risk estimates were generally consistent comparing monotherapy vs. combination therapy, study design and follow-up. Meta-regression showed that demographics, stroke, heart failure, diabetes, liver disease, attrition, mortality rate, cognitive function, and apolipoprotein E allele did not moderate the results. CONCLUSION: Diuretic antihypertensive drugs were associated with a consistent reduction in dementia risk without heterogeneity, pointing to generalizability of these findings. REGISTRATION: PROSPERO [CRD42015023428].