# Cardio-Renal Effects of Torsemide vs. Furosemide: A TRANSFORM-HF Mechanistic Sub-Study

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $791,162

## Abstract

Despite being the cornerstone of decongestive therapy in heart failure (HF), loop diuretics are paradoxically
one of the least well-studied classes of HF medications and substantial differences exist between members of
the class. Compared to furosemide, torsemide has 1) superior bioavailability and absorption, 2) significantly
longer half-life and 3) potential broad spectrum “anti-aldosterone” effects. These theoretical advantages of
torsemide, in part, motivated the NIH funded 6000 participant TRANSFORM-HF study, which will definitively
establish the value of torsemide on hard outcomes. At first glance, the above differences would imply a self-
evident superiority of torsemide. However, it is also known that severe within-dose diuretic resistance occurs in
healthy subjects administered torsemide during its long half-life; indeed, animal studies have demonstrated
massive adverse structural remodeling of the distal tubule with prolonged loop diuretic exposure. We have
recently demonstrated that distal tubular compensation is in fact the dominant mechanism of loop diuretic
resistance in human HF and pharmacokinetic defects are relegated to a minor role. Additionally, while there
may be in vitro anti-aldosterone effects, it is unclear if this translates into clinically relevant effects in HF
patients on contemporary medical therapy. Lastly, furosemide also has unique properties such as promiscuous
antagonism of sodium channels proximal and distal to the loop of Henle and a paradoxical improvement in
relative potency with progressive renal dysfunction. As such, with currently available data, a biologically
plausible case for superiority or inferiority of torsemide can be made. The overarching goal of this proposal
is to rigorously characterize candidate mechanisms by which torsemide may influence outcome within
the TRANSFORM-HF population. To achieve this goal, we propose a three center, 150 patient mechanistic
sub study of TRANSFORM-HF which will query a detailed set of mechanistic parameters both at randomization
and again at 30 days to answer the following questions: 1) What are the net effects of known and unknown
differences between torsemide and furosemide on the ultimate target of diuretic therapy- volume status? We
will address this by evaluating changes in gold standard body fluid space measurements (plasma volume,
extra cellular water, total body water). 2) Are there clinically relevant pleiotropic anti-aldosterone effects of
torsemide? We will address this with functional and structural readouts of tissue level aldosterone activity;
potassium excretion and urinary exosomal levels of the aldosterone regulated protein γENaC. 3) Does
torsemide, with its long half-life, result in adverse structural remodeling of the kidney and redistribution of intra-
renal sodium handling? We will address this by evaluating structural changes with urinary exosomal levels of
the distal tubular transporter NCC and functionally by evaluating changes in endogenou...

## Key facts

- **NIH application ID:** 10199884
- **Project number:** 5R01HL148354-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** JEFFREY M TESTANI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $791,162
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10199884

## Citation

> US National Institutes of Health, RePORTER application 10199884, Cardio-Renal Effects of Torsemide vs. Furosemide: A TRANSFORM-HF Mechanistic Sub-Study (5R01HL148354-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10199884. Licensed CC0.

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