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Evidence: HighPeptideDiscontinuedNatriuretic peptide (NPR-A agonist)Investigational · never approvedAcute heart failure

Ularitide

A synthetic copy of urodilatin, the kidney's own natriuretic peptide: it lowered cardiac filling pressures in heart failure, then failed its 2,157-patient outcome trial

Ularitide is the chemically synthesised form of urodilatin, a 32-amino-acid natriuretic peptide the kidney makes from the same precursor as atrial natriuretic peptide (ANP). Given as a continuous intravenous infusion, it lowered pulmonary capillary wedge pressure and eased breathlessness in phase 2 heart-failure trials. In TRUE-AHF, a 48-hour infusion in 2,157 people with acute heart failure lowered blood pressure and NT-proBNP but did not reduce cardiovascular death or improve the early clinical course. No regulator has approved it.

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Overview

What is it?

Urodilatin was first isolated from human urine, and by 1989 reviewers were describing it as a new member of the atrial natriuretic peptide family. It comes from the same gene and precursor as ANP, but cells in the distal tubule of the kidney cut the precursor four amino acids further towards its start, giving a 32-residue peptide that is released into the tubule and acts on receptors in the collecting duct to make the kidney excrete sodium. Ularitide is the same peptide made synthetically. In the laboratory, purified neprilysin, the enzyme that inactivates natriuretic peptides, broke it down far more slowly than ANP.

Its promise was the idea that a kidney-derived peptide would favour the kidney. In healthy volunteers, infusions raised sodium excretion and urine flow at rates that left blood pressure unchanged, and a bolus lowered pulmonary artery pressure more, and for longer, than the same dose of ANP. In phase 2 trials in decompensated heart failure, 24-hour infusions lowered wedge pressure by 10 to 15 mm Hg within six hours, raised cardiac index and improved breathlessness, and serum creatinine did not rise through day 3. The main adverse effect was the one the mechanism predicts: falls in blood pressure that grew with the dose.

TRUE-AHF was designed to settle whether that effect on the circulation changed outcomes. It enrolled patients soon after they arrived, a median of six hours after their first evaluation, gave 15 ng/kg per minute for 48 hours on top of usual treatment, and followed everyone for a median of 15 months. Cardiovascular death occurred in 21.7% on ularitide and 21.0% on placebo (hazard ratio 1.03), and the hierarchical composite of the first 48 hours did not differ. Ularitide lowered systolic blood pressure and NT-proBNP more than placebo, but troponin T, the marker used to look for heart-muscle injury, did not differ.

Later work moved away from the heart and found no better result. A randomised trial in refractory cirrhotic ascites was stopped at an interim analysis: on ularitide, urine output fell rather than rose, sodium excretion did not improve, and adverse reactions were 8.5 times as frequent as on placebo, driven by serious falls in blood pressure. Earlier trials in kidney failure after abdominal surgery and after liver transplantation had found trends but no significant benefit. No regulator has approved ularitide: FDA's Drugs@FDA database holds no application for it, and EMA's register of centrally authorised medicines has no entry.

2,157
TRUE-AHF participants
acute heart failure, 48-hour infusion vs placebo
1.03
Hazard ratio for cardiovascular death
21.7% vs 21.0% over a median 15 months
10 to 15 mm Hg
Fall in wedge pressure at 6 hours
15 and 30 ng/kg/min vs baseline, phase 2
5.6 min
Plasma half-life
healthy volunteers, intravenous infusion
Science

Mechanism of Action

Ularitide acts on the same receptor as ANP and BNP. What differs is where the natural hormone works and how quickly enzymes break it down.

⚙

NPR-A and cyclic GMP

Binding natriuretic peptide receptor A activates its guanylyl cyclase and raises cyclic GMP. In the ascending-dose heart-failure trial, plasma cyclic GMP stayed above placebo between 1 and 12 hours at 15 and 30 ng/kg per minute, and in healthy volunteers a bolus raised urinary cyclic GMP excretion seven-fold.

💧

Sodium and water excretion

In healthy people, infusions increased sodium excretion and urine flow by raising glomerular filtration and blocking sodium reabsorption in the distal nephron; in cirrhosis, with or without ascites, they also sent more fluid out of the proximal tubule. Renal plasma flow fell rather than rose, and blocking angiotensin II receptors or prostaglandin synthesis changed neither effect.

⬇

Vasodilation and lower filling pressures

Urodilatin relaxes blood vessels, lowering pulmonary capillary wedge pressure, right atrial pressure and systemic vascular resistance while cardiac index rises. The same action lowers systemic blood pressure, which limited the dose in the heart-failure and cirrhosis trials.

🛡

Resistance to neprilysin

With four extra residues at its start, urodilatin is a poorer substrate for neprilysin than ANP: the purified enzyme degraded ANP much faster, and in rats a neprilysin inhibitor cut ANP's clearance by 65% while leaving urodilatin's unchanged. Other routes still clear it quickly. In healthy volunteers total clearance was about 5.4 litres a minute, under 1% of the dose reached the urine, and the plasma half-life was 5.6 minutes.

Evidence

Published Research

These are the studies that shaped ularitide, read from their PubMed abstracts: the phase 2 heart-failure trials and TRUE-AHF, the physiology studies in healthy volunteers, the trials in kidney failure, liver transplantation and cirrhosis, and the laboratory work on how it is cleared. Most are small; TRUE-AHF is the only large trial.

Human2017

TRUE-AHF: 2,157 patients with acute heart failure

Patients were randomised to a 48-hour infusion of ularitide 15 ng/kg per minute or placebo on top of usual treatment, started a median of six hours after first evaluation. Cardiovascular death over a median 15 months occurred in 236 (21.7%) against 225 (21.0%): hazard ratio 1.03 (96% CI 0.85 to 1.25; P=0.75), and the hierarchical 48-hour clinical composite did not differ. Systolic blood pressure and NT-proBNP fell more on ularitide; troponin T changes did not differ in the 55% with paired samples.

PMID: 28402745
Human2017

How TRUE-AHF was designed

The design paper set two primary endpoints: cardiovascular death over the whole follow-up, with no truncation at an early time point, and a hierarchical composite that ranks symptoms, in-hospital worsening heart failure and death during the index admission. Patients were to be enrolled within 12 hours of presentation, with blood-pressure entry criteria and thresholds for adjusting the infusion rate to limit hypotension.

PMID: 27862700
Human2005

Phase 2 ascending-dose trial in 24 patients

In decompensated chronic heart failure (cardiac index 1.91 L/min/m², wedge pressure 26 mm Hg), 24-hour infusions of 7.5, 15 or 30 ng/kg per minute were compared with placebo. At 6 hours wedge pressure had fallen by 10 mm Hg at 15 ng and 15 mm Hg at 30 ng from baseline, right atrial pressure fell, and at 24 hours NT-proBNP was 40% and 45% lower. Adverse events did not differ between groups; three transient, asymptomatic hypotensions occurred on urodilatin.

PMID: 16338265
Human2006

SIRIUS II: 221 patients, three doses against placebo

Patients with decompensated heart failure received placebo (53) or 7.5 (60), 15 (53) or 30 ng/kg per minute (55) for 24 hours. At 6 hours wedge pressure fell (P=0.052, P=0.000004 and P=0.000002 by dose) and breathlessness improved in all three ularitide groups; systemic vascular resistance fell and cardiac index rose at 15 and 30 ng. Systolic blood pressure fell with dose, heart rate and creatinine were unchanged through day 3, and hypotension was the commonest drug-related adverse event.

PMID: 17074775
Human2008

SIRIUS II: the kidneys

Glomerular filtration, creatinine, creatinine clearance and urea were not impaired during the 24-hour infusion or the two days after it. At 24 hours, 15 ng/kg per minute lowered blood urea nitrogen against placebo (-4.07 against -0.20) and preserved the gradient between mean arterial and right atrial pressure, while 30 ng/kg per minute narrowed that gradient by 7.8 mm Hg against 2.4 on placebo at 6 hours.

PMID: 18513512
Human1992

Bolus injections in 18 healthy men, compared with ANP

Bolus doses of 1, 2 or 4 µg/kg raised heart rate, cardiac index and plasma cyclic GMP with dose, and increased urinary cyclic GMP, urine flow and sodium excretion seven-, five- and four-fold. At 2 µg/kg mean pulmonary artery pressure fell by 5.5 mm Hg against 1.8 with ANP(99-126), and the fall lasted from 2 to 90 minutes where ANP's was transient; wedge pressure fell from 9.3 to 3.8 mm Hg.

PMID: 1317296
Human1997

One-hour infusions in 12 healthy volunteers

In a double-blind crossover of 10, 20 and 40 ng/kg per minute against placebo, 20 ng increased sodium excretion, urine flow and glomerular filtration, lowered effective renal plasma flow, markedly reduced distal sodium reabsorption and suppressed renin, with blood pressure unchanged. At 40 ng responses varied widely, probably because blood pressure fell; the authors judged 20 ng the most effective dose.

PMID: 9176040
Human1998

Pharmacokinetics in healthy volunteers

During 90-minute graded infusions (7.5, 15, then 30 ng/kg per minute) in 12 subjects, urodilatin had a volume of distribution of 43.7 L, total clearance of 5,383 mL/min and a plasma half-life of 5.57 minutes, and under 1% of the dose appeared in urine. Glomerular filtration rose 7.0% (placebo -1.9%), renal plasma flow fell 17%, and sodium excretion and urine flow rose, tracking the plasma concentration.

PMID: 9695722
Human1999

Four doses over two hours in eight healthy subjects

At 5, 10, 20 and 40 ng/kg per minute every dose lowered renal plasma flow (by 13 to 37%) and raised sodium excretion (by 30%, 76%, 136% and 99%), without a significant rise in glomerular filtration. The two lowest doses reduced cardiac output and stroke volume without changing blood pressure; the two highest lowered blood pressure by 6% and 14% and raised heart rate by 15% and 38%, and 40 ng activated the renin-angiotensin system that the three lower doses suppressed.

PMID: 10070128
Human2008

Losartan and indomethacin do not change its renal effects

In two crossover studies of 12 healthy volunteers each, a 15 ng/kg per minute infusion lowered effective renal plasma flow (for example from 540 to 432 mL/min after placebo) and raised sodium excretion whether subjects had been pretreated with losartan, indomethacin or placebo: its renal vasoconstrictive and natriuretic effects did not depend on angiotensin II receptors or prostaglandins.

PMID: 17852806
Human1998

Liver cirrhosis, with and without ascites

A one-hour infusion of 20 ng/kg per minute in 15 patients with ascites and 9 without raised sodium excretion (by 219% and 173% against placebo) and urine flow (42% and 94%). Fractional sodium excretion, filtration fraction and lithium clearance rose, pointing to more fluid leaving the proximal tubule as well as less sodium reabsorbed in the distal nephron.

PMID: 9697672
Human2024

Refractory cirrhotic ascites: a randomised trial stopped at interim analysis

Seventeen patients were randomised 2:1 to ularitide or placebo for up to 48 hours; the starting dose of 30 ng/kg per minute was cut to 20 for safety. Urine output fell after 24 hours instead of rising (22.8 against 47.5 mL/h at baseline) and fell more than on placebo, sodium excretion and weight did not improve, and adverse reactions were 8.5 times as frequent (95% CI 2 to 35), with serious falls in blood pressure.

PMID: 38934679
Human1997

Seven days after liver transplantation

Seventy liver-transplant recipients were randomised to 20 ng/kg per minute for 7 days (33) or placebo (37). Creatinine, urea and urine output did not differ, nor did the need for dialysis (4 against 6 patients); the urodilatin group needed less furosemide in the first two days, and no side effects were detected.

PMID: 9408691
Human1999

Acute kidney failure after abdominal surgery

In 12 ventilated intensive-care patients with established kidney failure, 20 ng/kg per minute for at least 96 hours on top of dopamine and furosemide gave a lower peak creatinine than placebo (4.65 against 5.78 mg/dL, P=0.148) and one anuric patient against four, but did not reduce the need for dialysis; the authors concluded that it failed to improve renal function.

PMID: 10192146
Review2018

Meta-analysis: filling pressures against other vasoactive drugs

Twelve randomised double-blind trials of 24- to 48-hour infusions in decompensated heart failure were pooled. At 6 hours ularitide's effect on wedge pressure against placebo was large (Hedges' g -0.979) and exceeded the pooled effect of the other agents (P=0.030), as did its effect on right atrial pressure (-0.797 against -0.304). It measured haemodynamics, not outcomes, and its first author also led the phase 2 trials.

PMID: 30246939
Review2001

The kidney's own natriuretic peptide

Urodilatin is expressed in distal tubular cells of the human kidney, is probably released into the tubule, and acts on guanylyl cyclase A receptors in the medullary collecting duct to inhibit sodium reabsorption. It comes from the same gene and precursor as ANP, and a more N-terminal cut in the kidney may explain its stability in urine. The review argues that it, rather than circulating ANP, mediates much of urinary sodium excretion.

PMID: 11320487
In Vitro1994

Neprilysin degrades it more slowly than ANP

With pure recombinant neutral endopeptidase (neprilysin), labelled ANP was degraded much faster than labelled urodilatin, and the inhibitors phosphoramidon and SQ-28,603 protected both. Circular dichroism showed the two peptides have very similar, largely unordered conformations.

PMID: 7812611
Animal1992

Clearance in rats with neprilysin blocked

In control rats urodilatin's volume of distribution, metabolic clearance and distribution half-life did not differ from ANP's. A neprilysin inhibitor (SQ-28,603) cut ANP's clearance by 65% and suppressed its breakdown products in blood, but did not change urodilatin's clearance; blocking clearance receptors raised intact levels of both peptides to the same extent.

PMID: 1443119
Animal2000

Reperfusion injury in isolated rat hearts

Given during the first 15 minutes of reperfusion after 40 or 60 minutes of no-flow ischaemia, urodilatin limited the fall in heart cyclic GMP, improved contractile recovery after 40 minutes, and reduced the rise in diastolic pressure, LDH release and contraction-band necrosis after 60 minutes; a cell-permeable cyclic GMP analogue reproduced the effect.

PMID: 10728355
Dosing

Dosing Data

Ularitide was never approved, so the only doses are trial doses, all given as continuous intravenous infusions in hospital with blood pressure monitored.

Investigational only. Ularitide has no approved use anywhere, and anything sold under this name outside a registered trial is not a studied product. Its main risk in trials was a fall in blood pressure.
ProtocolDoseFrequencyDurationRoute
TRUE-AHF (2017) Human studyPMID 2786270015 ng/kg/minContinuous infusion48 hoursIntravenous
SIRIUS II (2006) Human studyPMID 170747757.5, 15 or 30 ng/kg/minContinuous infusion24 hoursIntravenous
Refractory ascites (2024) Human studyPMID 3893467930, reduced to 20 ng/kg/minContinuous infusionUp to 48 hoursIntravenous
Liver transplantation (1997) Human studyPMID 940869120 ng/kg/minContinuous infusion7 daysIntravenous

Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.

An infusion, not an injection
Ularitide was dosed by body weight as an infusion-pump rate in hospital, which a vial reconstitution calculator does not model.
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Safety

Side Effects & Contraindications

Reported Side Effects

From the trials above.

● Low blood pressure — dose-dependent falls and hypotension were the commonest drug-related adverse events in SIRIUS II
● Serious blood-pressure falls in cirrhosis — adverse reactions 8.5 times as frequent as on placebo in refractory ascites, where urine output fell
● Faster heart rate at higher doses — up 15% and 38% at 20 and 40 ng/kg per minute in healthy volunteers
● Lower renal plasma flow — every dose studied in healthy volunteers reduced it, even as sodium excretion rose

Contraindications & Cautions

Ularitide has no label. These cautions follow from its trials; they are not instructions.

● Low or unstable blood pressure — TRUE-AHF used blood-pressure entry criteria and infusion-adjustment thresholds for this reason
● Refractory cirrhotic ascites — the one trial in this group was stopped, with falling urine output and more adverse reactions
● Established acute kidney failure — it did not improve renal function or reduce dialysis after abdominal surgery
● Products outside a trial — no approved product exists, so identity, dose and sterility are unverified
Questions

Frequently Asked Questions

?Is ularitide approved?

No. FDA's Drugs@FDA database holds no application for it and EMA's register has no entry. Its phase 3 trial, TRUE-AHF, met neither of its two primary endpoints.

?What happened in TRUE-AHF?

2,157 people with acute heart failure received a 48-hour infusion of ularitide or placebo. Cardiovascular death over a median 15 months was 21.7% against 21.0% (hazard ratio 1.03), and the early clinical composite did not differ, although blood pressure and NT-proBNP fell more on ularitide.

?How is ularitide related to ANP?

Both come from the same precursor. ANP is the 28-residue form the heart releases; urodilatin, which ularitide copies, is a 32-residue form cut in the kidney with four extra amino acids at its start. Both act on natriuretic peptide receptor A, but neprilysin breaks urodilatin down more slowly.

?Why did it lower blood pressure?

It relaxes blood vessels, which is how it lowered cardiac filling pressures. The same effect lowered systemic blood pressure in proportion to the dose, and hypotension was the commonest drug-related adverse event in the phase 2 trial.

?How long does it last in the body?

Minutes. In healthy volunteers its plasma half-life during an infusion was about 5.6 minutes and under 1% of the dose appeared in urine, which is why every trial gave it as a continuous intravenous infusion.

?Has it been tried outside heart failure?

Yes, in small trials in kidney failure after surgery, after liver transplantation and in cirrhosis. None found a significant benefit, and a 2024 trial in refractory cirrhotic ascites was stopped with urine output falling and more adverse reactions on ularitide.

Bibliography

References

  1. [pubmed] Packer M, et al. "Effect of Ularitide on Cardiovascular Mortality in Acute Heart Failure." N Engl J Med, 2017;376(20):1956-1964. PMID: 28402745.
  2. [pubmed] Packer M, et al. "Rationale for and design of the TRUE-AHF trial: the effects of ularitide on the short-term clinical course and long-term mortality of patients with acute heart failure." Eur J Heart Fail, 2017;19(5):673-681. PMID: 27862700.
  3. [pubmed] Mitrovic V, et al. "Effects of the renal natriuretic peptide urodilatin (ularitide) in patients with decompensated chronic heart failure: a double-blind, placebo-controlled, ascending-dose trial." Am Heart J, 2005;150(6):1239. PMID: 16338265.
  4. [pubmed] Mitrovic V, et al. "Haemodynamic and clinical effects of ularitide in decompensated heart failure." Eur Heart J, 2006;27(23):2823-32. PMID: 17074775.
  5. [pubmed] Lüss H, et al. "Renal effects of ularitide in patients with decompensated heart failure." Am Heart J, 2008;155(6):1012.e1-8. PMID: 18513512.
  6. [pubmed] Kentsch M, et al. "Haemodynamic and renal effects of urodilatin in healthy volunteers." Eur J Clin Invest, 1992;22(5):319-25. PMID: 1317296.
  7. [pubmed] Carstens J, et al. "Effect of urodilatin infusion on renal haemodynamics, tubular function and vasoactive hormones." Clin Sci (Lond), 1997;92(4):397-407. PMID: 9176040.
  8. [pubmed] Carstens J, et al. "Metabolism and action of urodilatin infusion in healthy volunteers." Clin Pharmacol Ther, 1998;64(1):73-86. PMID: 9695722.
  9. [pubmed] Bestle MH, et al. "Cardiovascular, endocrine, and renal effects of urodilatin in normal humans." Am J Physiol, 1999;276(3):R684-95. PMID: 10070128.
  10. [pubmed] Carstens J, et al. "Renal effects of urodilatin in healthy subjects are independent of blockade of the cyclooxygenase and angiotensin II receptor." Scand J Clin Lab Invest, 2008;68(1):2-10. PMID: 17852806.
  11. [pubmed] Carstens J, et al. "Renal effects of a urodilatin infusion in patients with liver cirrhosis, with and without ascites." J Am Soc Nephrol, 1998;9(8):1489-98. PMID: 9697672.
  12. [pubmed] Gantzel RH, et al. "Randomized clinical trial on safety of the natriuretic peptide ularitide as treatment of refractory cirrhotic ascites." Hepatol Commun, 2024;8(7). PMID: 38934679.
  13. [pubmed] Langrehr JM, et al. "Prophylactic use of low-dose urodilatin for prevention of renal impairment following liver transplantation: a randomized placebo-controlled study." Clin Transplant, 1997;11(6):593-8. PMID: 9408691.
  14. [pubmed] Herbert MK, et al. "Concomitant treatment with urodilatin (ularitide) does not improve renal function in patients with acute renal failure after major abdominal surgery--a randomized controlled trial." Wien Klin Wochenschr, 1999;111(4):141-7. PMID: 10192146.
  15. [pubmed] Mitrovic V, et al. "Randomized double-blind clinical studies of ularitide and other vasoactive substances in acute decompensated heart failure: a systematic review and meta-analysis." ESC Heart Fail, 2018;5(6):1023-1034. PMID: 30246939.
  16. [pubmed] Drummer C. "Involvement of the renal natriuretic peptide urodilatin in body fluid regulation." Semin Nephrol, 2001;21(3):239-43. PMID: 11320487.
  17. [pubmed] Abassi ZA, et al. "Hydrolysis of iodine labelled urodilatin and ANP by recombinant neutral endopeptidase EC. 3.4.24.11." Br J Pharmacol, 1994;113(1):204-8. PMID: 7812611.
  18. [pubmed] Abassi ZA, et al. "Pharmacokinetics of ANF and urodilatin during cANF receptor blockade and neutral endopeptidase inhibition." Am J Physiol, 1992;263(5 Pt 1):E870-6. PMID: 1443119.
  19. [pubmed] Inserte J, et al. "Urodilatin limits acute reperfusion injury in the isolated rat heart." Cardiovasc Res, 2000;45(2):351-9. PMID: 10728355.
  20. [fda] FDA. Drugs@FDA (openFDA): no application for ularitide or urodilatin. Read September 30, 2026.
  21. [other] European Medicines Agency. Medicines register (centrally authorised human medicines): no entry for ularitide or urodilatin. Read September 30, 2026.

Sources & Citations

Every study on this page was read from its PubMed record. Approval status comes from FDA's Drugs@FDA database and EMA's register of authorised medicines, read September 30, 2026. Grey Peptides sells nothing and links to no vendor.

Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.

Last reviewed: 2026-09-30