Ghrelin for Cachexia: The Hunger Hormone's Role
Ghrelin
1.10 kg lean mass gained
In ROMANA 1, patients with lung cancer cachexia gained a median 1.10 kg of lean body mass over 12 weeks with the ghrelin agonist anamorelin, while placebo patients lost 0.44 kg.
Temel et al., Lancet Oncology, 2016
Temel et al., Lancet Oncology, 2016
View as imageCachexia kills between 20% and 30% of all cancer patients, and it has no broadly approved treatment in the US or Europe. The syndrome is not simple weight loss. It involves skeletal muscle degradation driven by systemic inflammation, metabolic dysfunction, and appetite suppression that standard nutritional support cannot reverse. Ghrelin, the 28-amino-acid peptide hormone discovered in 1999 by Kojima and colleagues[1], attacks cachexia through three simultaneous pathways: stimulating appetite, releasing growth hormone, and suppressing pro-inflammatory cytokines. That triple mechanism has made it one of the most studied peptide-based approaches to a condition that has resisted decades of intervention.
Key Takeaways
- Ghrelin provides a triple-mechanism approach to cachexia: appetite stimulation, GH/IGF-1 anabolic signaling, and NF-kB-mediated anti-inflammatory effects (Li et al., Circulation, 2004)
- The oral ghrelin agonist anamorelin increased lean body mass by a median 1.10 kg in the ROMANA 1 phase III trial of 484 NSCLC patients with cachexia (Temel et al., 2016)
- In heart failure patients, ghrelin infusion improved left ventricular ejection fraction, increased lean body mass, and enhanced exercise capacity (Nagaya et al., 2003)
- A systematic review of 7 clinical trials (379 participants) found predominantly positive effects on GH levels, weight gain, and lean mass preservation (Mansson et al., Nutrition Reviews, 2016)
- 73.8% of 61 in vivo studies found null or inverse associations between ghrelin and cancer growth, suggesting ghrelin-based cachexia treatment does not promote tumors (Sever et al., 2016)
- Anamorelin received regulatory approval in Japan in 2021 for cancer cachexia, but the FDA has not approved any ghrelin-based therapy
What cachexia is and why standard nutrition fails
Cachexia is a metabolic syndrome characterized by involuntary loss of skeletal muscle mass, with or without fat loss, that cannot be fully reversed by conventional nutritional support. It occurs in up to 80% of advanced cancer patients, 16-42% of heart failure patients, and 20-40% of COPD patients. The distinction from simple malnutrition matters: cachexia involves active muscle proteolysis driven by inflammatory cytokines like TNF-alpha, IL-6, and IL-1beta that activate the ubiquitin-proteasome pathway in skeletal muscle. Feeding a cachectic patient more calories does not stop the muscle from breaking itself down.
This is why ghrelin attracted attention. Unlike appetite stimulants that only address caloric intake, ghrelin operates on the inflammatory and anabolic pathways that drive cachexia's core pathology. The same appetite-stimulating properties that make ghrelin central to food reward become therapeutically valuable when appetite itself is a casualty of disease.
Ghrelin's triple mechanism against wasting
Appetite stimulation via hypothalamic circuits
Wren et al. provided the first human evidence in 2001: intravenous ghrelin infusion increased both subjective appetite ratings and caloric intake in healthy volunteers[2]. Ghrelin activates neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus, the same circuit suppressed by the inflammatory cytokines elevated in cachexia. In cachectic patients, this appetite drive is particularly valuable because anorexia compounds the metabolic muscle wasting, creating a cycle where patients eat less while their bodies burn muscle faster.
Growth hormone and IGF-1 release
Ghrelin was originally discovered as the endogenous ligand of the growth hormone secretagogue receptor (GHS-R1a)[1]. Binding GHS-R1a in the pituitary triggers pulsatile GH release, which in turn stimulates hepatic IGF-1 production. The GH/IGF-1 axis promotes muscle protein synthesis and opposes the proteolytic signals driving cachexia. This is the same pathway targeted by growth hormone releasing peptides and synthetic secretagogues like MK-677, but ghrelin additionally provides the appetite and anti-inflammatory effects those compounds lack or deliver only partially.
Anti-inflammatory action through NF-kB inhibition
Li et al. demonstrated in 2004 that ghrelin directly inhibited TNF-alpha-induced pro-inflammatory responses in human endothelial cells by blocking NF-kB nuclear translocation[3]. Ghrelin preserved IkBalpha, preventing the NF-kB signaling cascade that upregulates VCAM-1, ICAM-1, and MCP-1. Dixit and Taub extended this finding, showing ghrelin suppresses IL-1beta, IL-6, and TNF-alpha while promoting IL-10 in immune cells[4]. Since NF-kB activation drives the expression of muscle-specific ubiquitin ligases MuRF1 and atrogin-1, ghrelin's anti-inflammatory action directly opposes the proteolytic machinery of cachexia at the molecular level.
Cancer cachexia: the most studied application
Cancer cachexia has been the primary clinical target for ghrelin-based therapies. Molfino et al. reviewed the evidence in 2014, noting that ghrelin's pleiotropic effects involve both systemic anti-inflammatory action and muscle-specific activation of antiatrophic molecular cascades[5].
The landmark clinical data come from the ROMANA trials. ROMANA 1 enrolled 484 patients with stage III/IV non-small-cell lung cancer and cachexia (defined as 5% or greater weight loss within 6 months or BMI below 20). Patients received anamorelin 100 mg orally once daily or placebo for 12 weeks. Anamorelin-treated patients gained a median 1.10 kg of lean body mass (95% CI: 0.76-1.42) versus a loss of 0.44 kg in the placebo group. ROMANA 2 (495 patients) replicated this: 0.75 kg gain versus 0.96 kg loss. Body weight and patient-reported appetite symptoms also improved significantly.
The critical limitation: neither trial showed improvement in handgrip strength. Patients gained lean tissue but did not demonstrate functional muscle improvement over 12 weeks. Whether longer treatment or combined exercise interventions would translate mass gains into strength remains unanswered.
Anamorelin received regulatory approval in Japan in 2021 for cancer cachexia in non-small-cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer[6]. No regulatory body in the US or Europe has approved it, partly because the FDA requires functional endpoints (like grip strength or physical performance) rather than body composition changes alone. For more on ghrelin agonist development for cancer cachexia, including anamorelin's full trial history, see our dedicated review.
Cardiac cachexia: ghrelin's dual cardiac-metabolic action
Nagaya and Kangawa published a series of studies showing ghrelin's unique value in heart failure, where cachexia carries particularly poor prognosis. In patients with chronic heart failure and left ventricular ejection fraction below 40%, ghrelin infusion (0.1 microg/kg/min for 60 minutes) reduced mean arterial pressure by 9 mmHg, increased cardiac index by 25%, and increased stroke volume index by 30%[7].
Crucially, ghrelin's cardiac effects appear to involve both GH-dependent and GH-independent pathways. Baldanzi et al. showed that even des-acyl ghrelin, which does not bind GHS-R1a or stimulate GH release, protected cardiomyocytes and endothelial cells from apoptosis through ERK1/2 and PI3K/Akt survival pathways[8]. This means ghrelin's cardiac protection extends beyond its hormonal effects, which links directly to why ghrelin has unexpected cardioprotective properties.
In longer-term studies, three weeks of daily ghrelin administration to heart failure patients with cachexia increased food intake and body weight, improved exercise capacity, reduced muscle wasting, and improved left ventricular function[9]. These are small studies, and no large randomized trial has tested ghrelin specifically for cardiac cachexia. The cardiology field has been slower to pursue ghrelin-based therapies than oncology, despite the mechanistic rationale being arguably stronger given ghrelin's direct cardiac effects.
COPD cachexia: the respiratory evidence
Miki et al. conducted a multicenter, randomized, double-blind, placebo-controlled trial of ghrelin in 33 cachectic COPD patients. Participants received intravenous ghrelin (2 microg/kg) or placebo twice daily for 3 weeks during pulmonary rehabilitation. Ghrelin-treated patients showed improvements in respiratory symptoms and respiratory muscle strength, though the primary endpoint of 6-minute walk distance did not reach statistical significance between groups[10].
The COPD data illustrate a recurring pattern: ghrelin consistently improves appetite, body weight, and patient-reported symptoms, but proving functional improvement in short trials with small sample sizes has proven difficult. The biological plausibility is clear, and the safety profile has been acceptable, but definitive evidence of functional benefit remains elusive.
The ghrelin paradox: elevated levels in wasting patients
Circulating ghrelin levels are paradoxically elevated in cachectic patients. In heart failure patients with cachexia, plasma ghrelin measured 237 plus or minus 18 fmol/mL compared to 147 plus or minus 10 in non-cachectic heart failure patients. Cancer cachexia patients show similar elevations. This parallels the concept of ghrelin resistance in obesity, where high ghrelin levels fail to produce expected responses.
The elevated endogenous ghrelin likely represents a compensatory response to the energy deficit and muscle wasting. The body produces more hunger hormone in an attempt to counteract cachexia, but the inflammatory milieu, receptor desensitization, or downstream signaling disruption prevents adequate response. This is why pharmacological doses of ghrelin or potent receptor agonists can still produce effects that the body's own elevated ghrelin cannot.
From native ghrelin to oral agonists
Native ghrelin has a plasma half-life of approximately 30 minutes, requiring intravenous infusion for clinical use. This impracticality drove development of longer-acting alternatives[11].
Anamorelin (ONO-7643/RC-1291) is the most clinically advanced ghrelin agonist. It is an oral, non-peptide GHS-R1a agonist with a half-life of 7-12 hours, allowing once-daily dosing[12]. Other ghrelin-pathway compounds in development include macimorelin (approved for GH deficiency diagnosis, being tested for cachexia) and several peptide-based ghrelin analogs with improved stability[13].
The field is also exploring whether unacylated ghrelin (des-acyl ghrelin), which constitutes approximately 90% of circulating ghrelin, has therapeutic value. Des-acyl ghrelin does not activate GHS-R1a but shows independent anti-apoptotic and metabolic effects. A 2024 study demonstrated that unacylated ghrelin protected against muscle wasting, mitochondrial dysfunction, and neuromuscular junction disruption in tumor-bearing mice, suggesting that the non-classical ghrelin pathway may be therapeutically relevant for cachexia.
Safety: does ghrelin promote tumor growth?
The concern that a growth-promoting peptide might accelerate cancer has been directly addressed. Sever et al. conducted a systematic review of 61 in vivo studies examining ghrelin's relationship with cancer risk and progression[14]. Of these, 45 (73.8%), including all 11 studies involving exogenous ghrelin or ghrelin agonist treatment, reported either no association or an inverse association with cancer risk, presence, or growth. Only 10 studies (16.7%) reported positive associations, and 6 (10.0%) reported mixed results.
The clinical trial data from ROMANA 1, 2, and 3 showed no signal of tumor promotion with anamorelin treatment. Serious drug-related adverse events affected fewer than 3% of patients, primarily hyperglycemia and diabetes, consistent with ghrelin's known effects on glucose metabolism. This safety profile enabled regulatory approval in Japan.
However, the longest clinical trial duration has been 24 weeks (ROMANA 3 extension), and cancer cachexia patients have inherently short survival times, limiting the ability to detect long-term cancer-promoting effects. The preclinical and short-term clinical data are reassuring but not definitive for long-term safety.
Limitations across the evidence base
The systematic review by Mansson et al. of seven clinical trials involving 379 participants found predominantly positive effects on GH levels, weight gain, and lean mass preservation, but also identified consistent weaknesses[15]. Sample sizes are small. Trial durations are short (typically 3-12 weeks). Functional outcomes like grip strength, stair-climbing ability, and quality of life measures have been secondary endpoints at best. The gap between gaining lean tissue and gaining functional strength has not been bridged.
A Cochrane review identified only three randomized controlled trials that met inclusion criteria for ghrelin in cancer cachexia, and concluded there is insufficient evidence to support or refute ghrelin's clinical utility. The heterogeneity of cachexia definitions, treatment protocols, and outcome measures across studies makes meta-analysis difficult. Different underlying diseases (cancer, heart failure, COPD, renal failure) may respond differently to ghrelin, and trials grouping them together may obscure disease-specific effects.
The Bottom Line
Ghrelin's triple mechanism of appetite stimulation, GH-mediated anabolism, and NF-kB-dependent anti-inflammatory action makes it one of the most biologically rational approaches to cachexia. Clinical evidence from cancer, cardiac, and COPD cachexia trials consistently shows improvements in appetite, body weight, and lean body mass. The oral agonist anamorelin has achieved regulatory approval in Japan. However, no trial has convincingly demonstrated that ghrelin-based therapies improve functional outcomes like muscle strength or physical performance, and no US or European approval exists. The evidence is encouraging but incomplete.