Apelin
Apelin (endogenous ligand of the APJ receptor; apelin-36, apelin-17 and pyroglutamated apelin-13)
Written by Aaron CuhaReviewed Sep 2026
Also known as: (Pyr1)apelin-13, Pyroglutamated apelin-13, Apelin-13, Apelin-36, APJ endogenous ligand
A vasodilator and cardiac inotrope in humans, shown by infusion in about 50 people including 18 with heart failure, where its effect was preserved when acetylcholine's was not. The sarcopenia-reversal claim is mouse work; three completed human studies of apelin and insulin sensitivity or cardiovascular effects have never posted results.
Overview
Apelin is a family of peptides cut from a 77 amino acid precursor: apelin-36, apelin-31, apelin-28 and apelin-13, with pyroglutamated apelin-13 usually reported as the dominant circulating form. All of them activate the APJ receptor, a class A G protein-coupled receptor also targeted by a second, unrelated ligand called ELABELA. Apelin is made in endothelium, heart, fat and brain, and it is degraded by ACE2, the same enzyme that produces angiotensin-(1-7).
The human data are acute cardiovascular physiology in small groups, and they are of good quality. In 24 healthy volunteers, intrabrachial apelin-36 and (Pyr1)apelin-13 caused reproducible, nitric oxide-dependent arterial vasodilatation with no effect on veins. In a series of randomised double-blind placebo-controlled studies in 18 patients with NYHA class II to III heart failure, 6 patients at angiography and 26 healthy volunteers, apelin dilated forearm vessels equally in patients and controls (whereas the response to acetylcholine was blunted in heart failure, p 0.01), intracoronary apelin-36 increased coronary flow and the rate of rise of left ventricular pressure, and systemic (Pyr1)apelin-13 raised cardiac index and lowered arterial pressure and vascular resistance. The preserved response in failing hearts is the strongest argument for APJ as a heart failure target.
That argument has been tested only as far as safety. Novartis's APJ agonist CLR325 completed a 26-patient phase 2 in chronic stable heart failure in 2019 with adverse events as the primary outcome; results were posted in 2020. Three other completed human studies, a 16-person and a 9-person phase 1 of apelin and insulin sensitivity in Toulouse and a 14-person Edinburgh study of subcutaneous and intravenous apelin, have posted no results as of 11 September 2026. A 15-person Basel study of intravenous apelin-13 in induced hyponatraemia completed in 2025, results not yet posted.
The claim that brings most searchers here is different. A 2018 Nature Medicine paper titled 'The exerkine apelin reverses age-associated sarcopenia' showed that apelin production falls with age in humans and rodents and associates with the benefits of exercise in older people; every intervention in it, the knockouts, the restoration of apelin signalling, the improvement in muscle function through mitochondrial biogenesis, autophagy and muscle stem cells, was in mice. PubMed labels that record a phase 3 randomised trial because of the human cohort embedded in it; it is not an apelin administration trial. No trial has given apelin or an APJ agonist to a human for muscle, ageing or performance. No apelin product is approved anywhere.
Mechanism of action
Established in humans by infusion: apelin peptides cause arterial vasodilatation that depends on nitric oxide (abolished by a nitric oxide clamp, unaffected by aspirin), have no effect on venous tone, increase coronary blood flow and left ventricular contractility, and raise cardiac output while lowering blood pressure and peripheral resistance, in healthy people and in heart failure alike. Established in mice: apelin is induced by muscle contraction, declines with age, and its absence or its receptor's absence produces marked age-related muscle deterioration; restoring it improves muscle function through mitochondrial biogenesis, autophagy, anti-inflammatory signalling and muscle stem cell effects. Apelin is a substrate of ACE2. Native apelin peptides have a very short circulating half-life, the figure for which we could not verify from a primary human pharmacokinetic paper and do not state; this is the practical obstacle that drove development of PEGylated and small-molecule APJ agonists.
Human evidence
Acute infusion physiology in roughly 50 people across two published Edinburgh studies, plus one 26-patient industry safety trial of an APJ agonist and four small completed academic studies of apelin itself, three of which have never posted results. No human study has measured any clinical outcome, and none has tested apelin for muscle, ageing or performance.
- JACC 2008: 24 healthy volunteers, nitric oxide-dependent arterial vasodilatation to apelin-36 and (Pyr1)apelin-13, no venodilatation.
- Circulation 2010: 18 heart failure patients, 6 angiography patients, 26 healthy volunteers. Vasodilatation preserved in heart failure; intracoronary apelin-36 raised coronary flow and contractility; systemic apelin-13 raised cardiac index and lowered blood pressure and resistance.
- Nature Medicine 2018, human component: muscle apelin production declines with age and associates with exercise response in older people. Observational; the interventions are in mice.
- CLR325 (NCT02696967): Novartis APJ agonist, 26 heart failure patients, phase 2 safety study, completed 2019, results posted 2020.
- Apelin and insulin sensitivity (NCT02033473, 16 healthy volunteers; NCT02724566, 9 with type 2 diabetes): Toulouse phase 1 studies completed 2014 and 2017, no results posted.
- Subcutaneous and intravenous apelin (NCT02259686): 14 healthy volunteers, Edinburgh, completed 2015, no results posted.
- Intravenous apelin-13 in induced hyponatraemia (NCT06277336): 15 healthy volunteers, Basel, completed March 2025, results not yet posted.
What this does not tell you: Every published human measurement is haemodynamic and lasts minutes to hours. Nothing shows that apelin or an APJ agonist improves symptoms, exercise capacity, hospitalisation or survival in heart failure, and the one industry trial in patients measured only safety in 26 people. The insulin sensitivity question was asked twice in humans and the answers were never published, which could mean a null, a formulation problem or simply an unpublished thesis; we cannot tell. There is no human data on apelin and muscle mass, strength or ageing beyond the observation that its production declines with age. Nobody has studied repeated dosing of native apelin in people, and the dosing patterns used by research-chemical buyers have no pharmacokinetic basis in the literature.
Reading the research record
Apelin's record has the shape of a good target that never became a drug. The Edinburgh physiology from 2008 to 2010 is careful, randomised, placebo-controlled work in about 50 people, and the finding that failing hearts respond to apelin when they no longer respond normally to acetylcholine is exactly the kind of result that justifies a programme. The obstacle is pharmacokinetic: native apelin peptides are cleared within minutes, so the effort went into PEGylated apelins and small molecules like BMS-986224 and Novartis's CLR325. CLR325 got as far as a 26-patient safety study and, as far as the public record shows, no further. Bristol-Myers Squibb's compound is at the animal stage in the literature we resolved. An oral APJ agonist is in clinical development for muscle and is covered on its own page. None of this has produced an efficacy trial in patients.
The sarcopenia claim rides on a different paper and needs to be read carefully. The 2018 Nature Medicine study is a strong piece of mouse biology with an observational human cohort attached, and PubMed's metadata labels it a phase 3 randomised trial, which it is not in any sense relevant to apelin. The human part shows that older people who produce more apelin in response to exercise do better; the reversal of sarcopenia is entirely in mice. Nothing in humans supports apelin for body composition or performance, and the three small trials that did try to ask a metabolic question in people, the Toulouse insulin sensitivity studies and the Edinburgh dosing study, finished years ago without reporting.
The evidence, charted
Fig. 1 · evidence composition
6of 10 citations (60%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 7 distinct years, 2008 to 2024, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Not approved
CA
Not approved
Approved in 1 of 4, prescription route in 0, not approved in 3. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Human2008
Vascular effects of apelin in vivo in man
24 healthy volunteers. Apelin-36 and (Pyr1)apelin-13 infused intrabrachially at 0.1 to 30 nmol/min caused reproducible forearm arterial vasodilatation (p < 0.0001), attenuated by a nitric oxide clamp (p 0.004) and unaffected by aspirin; neither peptide dilated dorsal hand veins where sodium nitroprusside did. Non-US government funded.
Journal of the American College of Cardiology - Human2010
Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure
18 patients with NYHA II to III heart failure, 6 at coronary angiography and 26 healthy volunteers in randomised double-blind placebo-controlled studies. Forearm vasodilatation to apelin was preserved in heart failure (p 0.3) while the acetylcholine response was attenuated (p 0.01); intracoronary apelin-36 increased coronary flow and left ventricular dP/dt max and lowered filling pressures; systemic (Pyr1)apelin-13 at 30 to 300 nmol/min raised cardiac index and lowered mean arterial pressure and vascular resistance in both groups, raising heart rate only in controls. Non-US government funded.
Circulation - Human2016
A Study of CLR325 in Chronic Stable Heart Failure Patients
Novartis, phase 2, 26 enrolled, APJ receptor agonist CLR325 versus placebo in chronic stable heart failure, primary outcome adverse events, serious adverse events and death. Completed January 2019, results posted March 2020. The only industry trial of an APJ agonist in patients that has reported.
ClinicalTrials.gov - Human2014
Effect of Apelin on Insulin Sensitivity: Proof of Concept in Healthy Volunteers
University Hospital Toulouse, phase 1, 16 healthy volunteers, apelin versus placebo, completed October 2014, no results posted as of 11 September 2026. A companion 9-person phase 1 in type 2 diabetes (NCT02724566) completed April 2017, also with no results posted. Completed and unreported is a finding.
ClinicalTrials.gov - Human2014
Cardiovascular Effects of Apelin In Healthy Volunteers
University of Edinburgh, early phase 1, 14 healthy volunteers, apelin 1 mg subcutaneous, 1 mg intravenous or 5 mg subcutaneous. Completed May 2015, no results posted as of 11 September 2026.
ClinicalTrials.gov - Human2024
Effects of Intravenous [Pyr1]Apelin-13 on Healthy Volunteers With Artificially Induced SIAD
University Hospital Basel, 15 healthy volunteers, placebo versus low and high dose intravenous apelin-13 in induced syndrome of inappropriate antidiuresis, primary outcome urinary excretion. Completed March 2025, results not yet posted.
ClinicalTrials.gov - Animal2018
The exerkine apelin reverses age-associated sarcopenia
Apelin production by contracting muscle falls with age in humans and rodents and associates with exercise benefit in older people (observational). Mice lacking apelin or its receptor showed marked age-related muscle deterioration, and restoring apelin signalling improved muscle function via mitochondrial biogenesis, autophagy, anti-inflammatory pathways and muscle stem cells. The interventions are all in mice; PubMed's phase 3 trial label refers to the embedded human cohort, not to apelin administration. Non-US government funded.
Nature Medicine - Animal2024
Apelin regulates skeletal muscle adaptation to exercise in a high-intensity interval training model
Animal model of high-intensity interval training in which apelin signalling shaped muscle adaptation. Extends the 2018 mouse work; no human component.
American Journal of Physiology, Cell Physiology - Animal2021
In Vitro and In Vivo Evaluation of a Small-Molecule APJ (Apelin Receptor) Agonist, BMS-986224, as a Potential Treatment for Heart Failure
Rodent pharmacology of an orally available small-molecule APJ agonist developed to overcome the short half-life of native apelin. Preclinical.
Circulation: Heart Failure - Review2010
Apelin and ACE2 in cardiovascular disease
Review of the apelin-APJ system and its degradation by ACE2, the link between apelin and the angiotensin-(1-7) axis.
Current Opinion in Investigational Drugs
Frequently asked questions
Does apelin reverse sarcopenia?
In mice. The 2018 Nature Medicine paper of that title showed that restoring apelin signalling improved muscle function in ageing mice. Its human component was observational: apelin production falls with age and tracks the benefits of exercise in older people. No trial has given apelin or an APJ agonist to a human for muscle, and PubMed's 'phase 3 randomised trial' label on that paper refers to the embedded human cohort, not an apelin trial.
What does apelin do in humans?
By infusion in about 50 people: it dilates arteries through nitric oxide, does not dilate veins, increases coronary blood flow and heart contractility, and raises cardiac output while lowering blood pressure. In 18 heart failure patients the vasodilator response was preserved while the response to acetylcholine was blunted. All of this is acute physiology, not outcomes.
Is there an apelin drug?
No. Novartis's APJ agonist CLR325 completed a 26-patient phase 2 safety study in heart failure in 2019 and no efficacy trial followed. Native apelin has a half-life of minutes, which is why development moved to PEGylated peptides and small molecules. No apelin or APJ product is approved anywhere.
Does apelin improve insulin sensitivity?
In rodents, yes. In humans two phase 1 studies from Toulouse asked exactly that question, in 16 healthy volunteers and 9 people with type 2 diabetes, completed in 2014 and 2017 and have never posted results. The human answer is unpublished.