BACKGROUND: Healthcare providers should balance the potential risks and benefits of chronic diuretic use, particularly in older adults, as with age, diuretic benefits may decline and risks increase. A comprehensive synthesis and critical evaluation of the available evidence on chronic diuretic treatment effects is currently lacking. METHODS: We conducted an umbrella review of systematic reviews and meta-analyses published since 2018 on health outcomes associated with diuretic use in randomized-controlled trials (RCTs). We conducted random-effects meta-analysis for pooled effect estimates and narratively summarized data that could not be pooled. RESULTS: We included 741 effect estimations from 117 systematic reviews (SRs) on 1566 RCTs in individuals aged 62 ± 6 years. Of our 33 meta-analyses, 11 provided convincing, high-quality evidence: finerenone reduced the risk of cardiovascular (CV) mortality and end-stage kidney disease in individuals with chronic kidney disease (CKD) and/or type 2 diabetes (T2D). Torasemide reduced the risk of heart failure-related hospitalization (HFH) more than furosemide in individuals with HF. Thiazides reduced CV events in individuals with hypertension. Mineralocorticoid receptor antagonists (MRAs) reduced HFH, but also increased hyperkalemia risk in individuals with HF. MRAs also reduced the risk of atrial fibrillation in those with HF or CVD, and reduced HFH, major adverse cardiovascular events (MACEs), > 40% eGFR decrease, and composite kidney outcomes in individuals with CKD and/or T2D. Lower quality evidence suggests that in older (≥ 65 years), but not in younger adults, diuretics may reduce CV mortality, but also increase adverse event (AE) risk. CONCLUSIONS: Our umbrella review offers a comprehensive and up-to-date evaluation of the benefits and harms of diuretics. However, further research is needed to establish their efficacy and safety in populations commonly seen in clinical practice, especially older adults living with multimorbidity and frailty.

Amsterdam Public Health Research Institute Aging and Later Life Amsterdam The Netherlands

Amsterdam University Medical Center Amsterdam The Netherlands

Department of Anesthesiology Pharmacology and Therapeutics Faculty of Medicine University of British Columbia Vancouver Canada

Department of Cardiology University Medical Center Utrecht Transplantation Center UMC Utrecht Utrecht The Netherlands

Department of Clinical and Molecular Sciences Università Politecnica delle Marche Ancona Italy

Department of Geriatric and Intensive Care Medicine Careggi Hospital University of Florence Florence Italy

Department of Geriatrics and Internal Medicine 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Internal Medicine and Gerontology Jagiellonian University Medical College Kraków Poland

Department of Musculoskeletal and Ageing Science Institute of Life Course and Medical Sciences University of Liverpool Liverpool UK

Division of Geriatric and Palliative Medicine McGovern Medical School University of Texas Health Science Center at Houston Houston TX USA

Division of Geriatrics Department of Internal Medicine Health Sciences University Tepecik Training and Research Hospital İzmir Turkey

Division of Geriatrics Department of Internal Medicine Istanbul Medical Faculty Istanbul University Istanbul Turkey

Division of Geriatrics Department of Internal Medicine Istanbul University Istanbul Medical School Istanbul Turkey

Division of Geriatrics Department of Internal Medicine Liv Hospital Vadistanbul Istanbul Turkey

General Faculty Hospital Prague Faculty of Health and Social Sciences University of South Bohemia Ceske Budejovice Czech Republic

Geriatria Accettazione geriatrica e Centro di ricerca per l'invecchiamento IRCCS INRCA Ancona Italy

Geriatric Center Medical Faculty Heidelberg Heidelberg University Heidelberg Germany

Hellenic Society for the Study and Research of Ageing Athens Greece

Medical Library Amsterdam University Medical Center University of Amsterdam Amsterdam The Netherlands

Pharmacy Department IRCCS San Raffaele Hospital Milan Italy

Program for the Care and Study of the Aging Heart Department of Medicine Weill Cornell Medicine New York NY USA

Saint Camillus International University of Health Sciences Rome Italy

Section of Geriatrics Department of Internal Medicine Amsterdam University Medical Center Location University of Amsterdam Meibergdreef 9 Amsterdam The Netherlands

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