Mastering the Art of Diuretics

Educational Objectives

The goal of this program is to improve the management of heart failure using diuretic therapy. After hearing and assimilating this program, the clinician will be better able to:

1. Implement appropriate strategies for escalating and adjusting loop diuretic doses in patients with persistent congestion.
2. Explain the outcomes of the TRANSFORM-HF trial.
3. Compare bioavailability of torsemide with furosemide.

Summary

Heart failure (HF): getting patients on 4 pillars of guideline-directed medical therapy (GDMT) as early as possible is key because they help manage congestion, and improve survival; sodium glucose cotransporter 2 (SGLT2) inhibitors reduce morbidity and mortality in HF, and have a role in overcoming diuretic resistance; evidence suggests strong correlation among markers of congestion (brain natriuretic peptide), hemodynamic parameters (pulmonary capillary wedge pressure [PCWP]), and clinical signs and symptoms; significantly elevated PCWP (>20 mm Hg) may result in poor prognosis

Renal failure: the primary concern when treating HF with diuretics is worsening renal function; worsening renal function without residual congestion may lead to improved renal function after the fluid overload is resolved and is associated with a better prognosis; cardiorenal syndrome represents a complex subset of patients; the “rule of three” — a 0.3 mg/dL increase in creatinine ≤3 days in ≈30% of patients with acute decompensated HF, suggests that a transient rise in creatinine should not deter aggressive decongestion

Strategies for decongestion: loop diuretics are class 1 recommendation for decongesting patients across all types of HF, according to both European (2023) and American (2022) guidelines; combination therapies are used when loop diuretics are not effective; the options include acetazolamide, higher doses of spironolactone (>25 mg/day), thiazide diuretics (hydrochlorothiazide, metolazone), intravenous options (torsemide) and SGLT2 inhibitors (dapagliflozin, empagliflozin); the effectiveness of loop diuretics relies on their ability to be transported into the kidney tubules via organic transporters, where they then act on the sodium-potassium-chloride cotransporter; disruptions in this pathway may lead to diuretic resistance

Dose response relationship: loop diuretics are highly protein bound; the dose-response relationship is depicted as a sigmoidal curve with 3 key elements; the threshold is the minimum dose required to initiate diuresis; a common mistake is repeatedly administering doses below this threshold without achieving any effect; in HF, determining this threshold can be challenging; it is recommended to start with a moderate dose based on the patient’s volume overload and double it if there is no response; once threshold is crossed, increasing the dose leads to a significant increase in diuretic response; the ceiling dose is that dose beyond which increasing the dose does not lead to a greater rate of diuresis because all the relevant transporters in the kidney are saturated; the duration of diuresis may be prolonged, which is protective against rapid changes in renal function and serum creatinine; the patient’s diuresis is primarily determined by the medication’s half-life, which is longer for torsemide compared with furosemide; in HF, achieving the desired response might necessitate adjunctive therapies even at higher ceiling doses

Pharmacokinetic profiles: torsemide has the highest oral bioavailability; the potency ratio of furosemide to torsemide is 2:1 based on intravenous data applications; patients are switched from furosemide to torsemide when response is not adequate; evidence suggests that torsemide may possess antifibrotic myocardial effects, similar to mineralocorticoid receptor antagonists (MRAs), eg, spironolactone, eplerenone

Torsemide vs furosemide: the TRANSFORM HF trial (Mentz et al [2023]) enrolled 2859 patients across 60 hospitals in United States, and included a higher proportion of women (33%) and Black patients (33%) than typical HF trials; the majority (65%) had HF with reduced ejection fraction; at baseline, SGLT2 inhibitor use was low (6.4%); there was no significant difference in all-cause mortality or hospitalizations (including HF hospitalizations), although numerically there was a trend toward fewer hospitalizations in the torsemide group

Diuresis: symptoms of worsening congestion include weight gain, shortness of breath, abdominal fullness, and reduced effectiveness of diuretic; physical examination may reveal elevated jugular venous pressure, and pitting edema; to determine if a chosen diuretic dose is effective, clinicians must inquire about patients’ urine output; therapeutic diuresis manifests as frequent urination ≤4 to 6 hr window after medication intake, with a potential urine volume of 2 to 4 L; polyuria may indicate a subtherapeutic dose leading to continuous fluid retention rather than effective diuresis; the clinician may double the patient’s diuretic dose, and initiate GDMT in case of worsening congestion

Diuretic resistance: is defined as the inability to achieve the desired reduction in edema despite using full doses of diuretics; a normal individual may experience 3 to 4 L of urine output with 40 mg of furosemide; patients with HF often exhibit a significantly blunted response, with output as low as 300 cm³ to 400 cm³; the maximal fractional secretion of sodium is reduced to 10% to 15% in HF compared with 25% in healthy individuals; in acutely decompensated HF (ADHF), this threshold for diuretic effectiveness increases, potentially requiring intravenous diuretics or longer acting oral diuretics; clinicians often resort to increasing loop diuretic doses, administering them more frequently, or adding thiazide diuretics; azotemia, decreased renal blood flow, and hypoalbuminemia may contribute to poor diuretic response; compensatory mechanisms within the kidney, eg, upregulation of sodium reabsorption in the distal convoluted tubule (DCT) may counteract the effects of loop diuretics; this leads to hypertrophy of the DCT; loop diuretics are combined with thiazide diuretics, which work at the DCT, to overcome diuretic resistance; available thiazide diuretics include metolazone, hydrochlorothiazide, and chlorothiazide; while chlorothiazide can be expensive and hydrochlorothiazide often requires high doses, metolazone is frequently preferred; it is believed that metolazone may retain efficacy in renal failure and potentially has a longer duration of action; some clinicians believe that metolazone might have a proximal tubular effect, where a significant amount of sodium is absorbed; evidence suggests that the addition of thiazide diuretics may result in deterioration in renal function, and increased risk for hyponatremia and hypokalemia; potassium supplementation is important when using this combination, with a target potassium level of 4 to 4.5 mEq/L to mitigate the increased risk for arrhythmias associated with hypokalemia; a propensity-adjusted multivariate analysis (Brisco-Bacik et al [2018]) showed that metolazone was strongly associated with hyponatremia, hypokalemia, worsening renal function, and mortality; the same analysis did not find an association between higher doses of loop diuretics and mortality, suggesting that escalating the dose of loop diuretics may be safer than prematurely adding adjunctive thiazide therapy; it is recommended to optimize loop diuretic doses before adding other diuretics; the CLOROTIC trial by Truallas et al (2023) found that adding oral hydrochlorothiazide to intravenous furosemide improved diuretic response, as evidenced by greater weight loss, without a significant difference in dyspnea; worsening of renal function and increased hypokalemia were observed in the group receiving hydrochlorothiazide

Acetazolamide: this proximal tubule inhibitor is gaining attention because of the significant sodium reabsorption; aldosterone antagonists (spironolactone) have diuretic effects but are primarily used in HF for their morbidity and mortality benefits; SGLT2 inhibitors exhibit osmotic diuresis; the ATHENA trial by Butler et al (2017) investigated higher doses (100 mg) of spironolactone vs placebo or low-dose spironolactone (25 mg) in patients hospitalized with ADHF; the trial found no significant difference in N-terminal pro-B-type natriuretic peptide reduction or urine output between the 2 groups; the ADVOR trial by Mullens et al (2022) compared randomized ≈500 patients to receive intravenous acetazolamide (500 mg daily) or placebo for 3 days, in addition to furosemide; the results showed a 46% increase in decongestion, and increased diuresis and natriuresis with the addition of acetazolamide; SGLT2 inhibitors were excluded from this trial; a higher incidence of renal insufficiency in the acetazolamide arm was observed; some clinicians have anecdotally reported benefits of acetazolamide in HF with preserved ejection fraction

SGLT2 inhibitors: the DICTATE-AHF trial by Cox et al (2024) suggested that adding dapagliflozin increased natriuresis and diuresis per 40 mg of intravenous furosemide, reduced the total dose and duration of loop diuretics during hospitalization, and shortened the time to hospital discharge; the DAPA-RESIST trial by Yeoh al (2023) evaluated dapagliflozin in patients with diuretic resistance and found no significant difference in outcomes compared with metolazone

Strategy: loop diuretics are effective for decongestion; optimization is performed prior to combination with thiazides; acetazolamide with loop diuretics shows some decongestive benefits; SGLT2 inhibitors can enhance diuretic effectiveness, shorten hospital stays, and reduce morbidity and mortality; increasing the dose of MRAs beyond GDMT doses do not show additional decongestive benefits; the clinician must optimize GDMT, and may add diuretics and SGLT2 inhibitors; loop diuretic resistance is common; patients who do not respond to high doses of loop diuretics plus thiazides are rare and often very ill

Readings

Bikdeli B, Strait KM, Dharmarajan K, et al. Dominance of furosemide for loop diuretic therapy in heart failure: time to revisit the alternatives?. J Am Coll Cardiol. 2013;61(14):1549-1550. doi:10.1016/j.jacc.2012.12.043; Bozkurt B, Ahmad T, Alexander KM, et al. Heart failure epidemiology and outcomes statistics: a report of the Heart Failure Society of America. J Card Fail. 2023;29(10):1412-1451. doi:10.1016/j.cardfail.2023.07.006; Brisco-Bacik MA, Ter Maaten JM, Houser SR, et al. Outcomes associated with a strategy of adjuvant metolazone or high-dose loop diuretics in acute decompensated heart failure: a propensity analysis. J Am Heart Assoc. 2018;7(18):e009149. doi:10.1161/JAHA.118.009149; Butler J, Anstrom KJ, Felker GM, et al. Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial. JAMA Cardiol. 2017;2(9):950-958. doi:10.1001/jamacardio.2017.2198; Cox ZL, Collins SP, Hernandez GA, et al. Efficacy and safety of dapagliflozin in patients with acute heart failure. J Am Coll Cardiol. 2024;83(14):1295-1306. doi:10.1016/j.jacc.2024.02.009; Felker GM, Ellison DH, Mullens W, et al. Diuretic therapy for patients with heart failure: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(10):1178-1195. doi:10.1016/j.jacc.2019.12.059; Fudim M, Loungani R, Doerfler SM, et al. Worsening renal function during decongestion among patients hospitalized for heart failure: findings from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. Am Heart J. 2018;204:163-173. doi:10.1016/j.ahj.2018.07.019; Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America Guideline for the Management of Heart Failure: executive summary. J Card Fail. 2022;28(5):810-830. doi:10.1016/j.cardfail.2022.02.009; McDonagh TA, Metra M, Adamo M, et al. 2023 Focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure [published correction appears in Eur Heart J. 2024 Jan 1;45(1):53. doi: 10.1093/eurheartj/ehad613.]. Eur Heart J. 2023;44(37):3627-3639. doi:10.1093/eurheartj/ehad195; Mentz RJ, Anstrom KJ, Eisenstein EL, et al. Effect of torsemide vs furosemide after discharge on all-cause mortality in patients hospitalized with heart failure: the TRANSFORM-HF randomized clinical trial. JAMA. 2023;329(3):214-223. doi:10.1001/jama.2022.23924; Mullens W, Dauw J, Martens P, et al. Acetazolamide in acute decompensated heart failure with volume overload. N Engl J Med. 2022;387(13):1185-1195. doi:10.1056/NEJMoa2203094; Siddiqi TJ, Packer M, Ezekowitz JA, et al. Diuretic potentiation strategies in acute heart failure. JACC Heart Fail. 2025;13(1):14-27. doi:10.1016/j.jchf.2024.09.017; Testani JM, Brisco MA, Turner JM, et al. Loop diuretic efficiency: a metric of diuretic responsiveness with prognostic importance in acute decompensated heart failure. Circ Heart Fail. 2014;7(2):261-270. doi:10.1161/CIRCHEARTFAILURE.113.000895; Trullàs JC, Morales-Rull JL, Casado J, et al. Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial. Eur Heart J. 2023;44(5):411-421. doi:10.1093/eurheartj/ehac689; Trullàs JC, Casado J, Cobo-Marcos M, et al. Combinational diuretics in heart failure. Curr Heart Fail Rep. 2024;21(4):1-11. doi:10.1007/s11897-024-00659-9; Yeoh SE, Osmanska J, Petrie MC, et al. Dapagliflozin vs. metolazone in heart failure resistant to loop diuretics. Eur Heart J. 2023;44(31):2966-2977. doi:10.1093/eurheartj/ehad341.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Singh was recorded at the 56th Annual Primary Care Review, held February 10-14, 2025, in Portland, OR, and presented by Oregon Health and Science University. For information on upcoming CME activities from this presenter, please visit ohsu.edu/school-of-medicine/cpd. Audio Digest thanks the speakers and the presenters their cooperation in the production of this program.

CME/CE INFO

Accreditation:

Lecture ID:

FP732201

Qualifies for:

Clinical Pharmacology

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.