GDF15
The hormone that makes you stop eating, now a drug target in cancer wasting
GDF15 rises with cellular stress, pregnancy, exercise and metformin, and acts on one receptor in the brainstem to suppress appetite. The most advanced medicine built on it does the opposite of supplying it: an antibody that blocks it reversed weight loss in cancer cachexia.
What is it?
GDF15 is released when cells are under stress, and for years its receptor was unknown. In 2017 it was identified as GFRAL, expressed in a small area of the brainstem and nowhere else that matters, signalling through the co-receptor RET. That narrowness is what makes it a tractable target: a single pathway, in one place, controlling food intake.
The obvious therapeutic idea was to supply it for obesity, and reviews still describe that direction. The result that actually reached a phase 2 trial went the other way. In cancer cachexia, where GDF15 is high and patients waste away, blocking it with the antibody ponsegromab increased weight at every dose.
That trial is the strongest human evidence on this page and it is about an antibody, not about GDF15 itself. Nobody is given GDF15; what is measured in people is how much of it they have.
Pregnancy is where its effect on appetite is easiest to see. GDF15 climbs steeply in the first seven weeks and is higher early in women who develop hyperemesis gravidarum. In nearly 1.45 million Danish pregnancies, using metformin, which raises GDF15, for at least six months before conception was associated with a lower rate of hyperemesis than shorter use (adjusted odds ratio 0.49). GDF15 gene variants also predicted nausea severity during breast cancer treatment.
Most other human data treat it as a stress marker. Higher levels predicted worse heart failure outcomes in DAPA-HF, death in a population cohort and shorter survival in fibrotic lung disease, and it rose during hypoglycaemia after bariatric surgery alongside symptoms. Treatment effects on it are inconsistent: exenatide nudged it up, dapagliflozin did not change it, and studies after bariatric surgery disagree on direction.
Mechanism of Action
GDF15 is a stress-induced hormone that acts on the GFRAL receptor, with the co-receptor RET, in a small area of the brainstem that controls food intake.
Brainstem GFRAL
A single receptor in one brainstem region mediates its effects, which makes it a tractable drug target.
Nausea and appetite
High levels go with hyperemesis in pregnancy and with appetite loss in cancer cachexia.
Stress marker
Levels rise with cellular stress and predict outcomes in heart failure, lung fibrosis and the general population.
Published Research
These are the studies in people, read from their PubMed abstracts: two trials of the antibody that blocks it, plus the work that found its receptor.
Blocking it reversed cancer wasting
In a phase 2 trial, 187 patients with cancer cachexia and GDF15 above 1,500 pg/mL received ponsegromab at 100, 200 or 400 mg or placebo every four weeks for 12 weeks. Weight gain beat placebo at every dose, by a median of 1.22 kg, 1.92 kg and 2.81 kg. Appetite, cachexia symptoms and physical activity improved at 400 mg. Adverse events were reported in 70% on the antibody and 80% on placebo.
The first-in-patient study
In a phase 1b study, ponsegromab drove unbound GDF15 below the limit of detection from three hours after the first dose through week 15, from a baseline of 2.269 ng/mL. Weight rose by a mean 4.63 kg at week 12, about 6.6%, with activity and appetite scores improving and no safety signal attributed to the drug.
How that trial was designed
The design paper for the phase 2 ponsegromab study in cancer cachexia, setting out the entry threshold on serum GDF15 and the weight-change endpoint.
Metformin raises it
In people given metformin, serum GDF15 rose from about 607 to 1,004 ng/mL alongside increased glycolysis, while FGF21 did not change; in gut cells, metformin increased GDF15 secretion directly.
Early pregnancy and hyperemesis
GDF15 rose sharply until week 7 and plateaued by week 9 in normal pregnancy, about 19% higher with female fetuses; it was higher early in hyperemesis gravidarum and lower, with a slower rise, in early pregnancy loss.
Metformin before conception
In 1,447,968 Danish pregnancies, preconception metformin overall did not change hyperemesis rates, but use for 6 months or more was associated with lower prevalence (1.1%, adjusted odds ratio 0.49).
Nausea during breast cancer treatment
In women treated for early breast cancer, a history of pregnancy nausea and GDF15 gene variants predicted more severe treatment-induced nausea.
Post-bariatric hypoglycaemia
GDF15 rose progressively during induced hypoglycaemia in people with post-bariatric hypoglycaemia and tracked symptoms; in mice, recombinant GDF15 reduced food intake during hypoglycaemia.
Rises on exenatide
In type 2 diabetes, GDF15 rose slightly after 16 weeks of add-on exenatide, and its link to HbA1c response did not survive adjustment for age.
Heart failure risk in DAPA-HF
In DAPA-HF, higher baseline GDF15 brought stepwise higher risk of worsening heart failure or cardiovascular death (top against bottom quartile, hazard ratio 2.30), and dapagliflozin did not change GDF15 over a year.
Population mortality
In a population cohort, elevated GDF15 predicted all-cause death (hazard ratio 2.47), though the effect weakened after adjustment for NT-proBNP.
Fibrotic lung disease
Serum GDF15 was more than double normal in fibrotic interstitial lung disease, and higher levels predicted shorter survival independent of a standard risk index.
Mitochondrial disease marker
In a metabolomic panel study, GDF15 with lactate helped distinguish primary mitochondrial disease from healthy controls.
Its receptor, found at last
GFRAL was identified as the receptor for GDF15, expressed in mice, rats, monkeys and humans. Deleting it abolished GDF15's ability to reduce food intake and body weight in mice, and GFRAL-deficient mice became more obese and insulin resistant on a high-fat diet. Signalling requires the co-receptor RET.
Why it is attractive, and why that is unproven
A review of GDF15 biology for obesity and cardiometabolic disease: pregnancy, metformin and exercise raise it, it suppresses food intake through a single brainstem pathway, and it may have anti-inflammatory effects by mechanisms not fully understood.
After bariatric surgery
Across studies measuring GDF15 before and 12 months after bariatric surgery, the direction of change was inconsistent and not explained by population differences.
Dosing Data
GDF15 itself is not given to people. The rows below are for ponsegromab, an antibody that blocks it, in cancer cachexia trials.
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.
Side Effects & Contraindications
Reported Side Effects
From the trials of the antibody that blocks GDF15; the protein itself is not given to people.
Contraindications & Cautions
Not a medicine.
Legal Status
Neither the protein nor its antibody is approved.
Frequently Asked Questions
?What does GDF15 do?
It rises with cellular stress and acts on the GFRAL receptor in the brainstem to suppress appetite. Pregnancy, exercise and metformin raise it.
?Is it a weight-loss drug?
Not yet, and the furthest-advanced medicine goes the other way: an antibody that blocks GDF15 increased weight in patients with cancer cachexia.
?What is ponsegromab?
A humanised antibody that blocks GDF15. In 187 patients with cancer cachexia it beat placebo on weight gain at all three doses, by a median of 1.22 to 2.81 kg over 12 weeks.
?Why did its receptor take so long to find?
GFRAL is expressed in a small part of the brainstem and little else, so it was identified only in 2017, three decades after the protein.
?Is GDF15 behind morning sickness?
It appears to be involved. GDF15 rises steeply in early pregnancy and is higher early in hyperemesis gravidarum, and in Danish data at least six months of metformin before conception, which raises GDF15, was associated with a lower rate of hyperemesis (adjusted odds ratio 0.49).
?What does a high GDF15 level mean?
It signals stress rather than a specific disease. Higher levels predicted worse outcomes in heart failure, fibrotic lung disease and the general population.
References
- [pubmed] Groarke JD, et al. "Ponsegromab for the Treatment of Cancer Cachexia." N Engl J Med, 2024;391(24):2291-2303. PMID: 39282907.
- [pubmed] Crawford J, et al. "A Phase Ib First-In-Patient Study Assessing the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ponsegromab in Participants with Cancer and Cachexia." Clin Cancer Res, 2024;30(3):489-497. PMID: 37982848.
- [pubmed] Groarke JD, et al. "Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design." J Cachexia Sarcopenia Muscle, 2024;15(3):1054-1061. PMID: 38500292.
- [pubmed] Mullican SE, et al. "GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates." Nat Med, 2017;23(10):1150-1157. PMID: 28846097.
- [pubmed] Wang D, et al. "GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease." Nat Rev Endocrinol, 2021;17(10):592-607. PMID: 34381196.
- [pubmed] Kolnes KJ, et al. "Metformin increases glycolysis and the stress-induced cytokine GDF15 but not FGF21 in humans." Front Endocrinol (Lausanne), 2026;17:1797525. PMID: 41928890.
- [pubmed] Svenningsen JS, et al. "Early pregnancy GDF15 trajectories and their association with normal gestation, pregnancy loss, and hyperemesis gravidarum." EBioMedicine, 2026;131:106428. PMID: 42561814.
- [pubmed] van der Minnen LM, et al. "Preconception metformin and hyperemesis gravidarum in Denmark: clinical implications of growth differentiation factor 15's etiological role." Am J Obstet Gynecol, 2026;234(5):1502-1515. PMID: 41478545.
- [pubmed] Wesmiller SW, et al. "GDF15 and history of pregnancy-induced nausea as predictors of treatment-induced nausea severity in women following surgery for early-stage breast cancer." Support Care Cancer, 2025;33(8):714. PMID: 40699388.
- [pubmed] Ferraz-Bannitz R, et al. "Plasma GDF15 increases during hyperinsulinemic hypoglycemia in humans with post-bariatric hypoglycemia and after insulin exposure in mice." Cell Rep Med, 2026;7(3):102656. PMID: 41806840.
- [pubmed] Yassuda V, et al. "The impact of bariatric and metabolic surgery on the levels of circulating growth differentiation factor 15 in humans." J Physiol Biochem, 2026;82(1). PMID: 41915091.
- [pubmed] Wu Q, et al. "Circulating GDF15 and HbA1c Response to Add-On Exenatide Therapy in Type 2 Diabetes: A Post Hoc Analysis from a Multicenter Trial." Biomedicines, 2026;14(3). PMID: 41898219.
- [pubmed] Berg DD, et al. "Growth Differentiation Factor-15 and the Effect of Dapagliflozin in Heart Failure: Insights From the DAPA-HF Trial." J Card Fail, 2026;32(4):746-757. PMID: 40819681.
- [pubmed] Martín-Carro B, et al. "Growth Differentiation Factor 15 as a Biomarker of Cardiovascular Burden and Mortality in a Population-Based Cohort." Int J Mol Sci, 2026;27(7). PMID: 41977265.
- [pubmed] Suzuki Y, et al. "Serum GDF15 adds prognostic value to forced vital capacity in fibrotic interstitial lung disease." Respir Investig, 2026;64(6):101510. PMID: 42727311.
- [pubmed] Yildiz A, et al. "Diagnostic utility of FGF-21 and GDF-15 for differentiating primary mitochondrial diseases from lysosomal storage disorders associated with secondary mitochondrial dysfunction: a machine learning-based multimetabolite approach." Mol Genet Metab, 2026;149(1-2):110246. PMID: 42648230.
Sources & Citations
Studies were read from their PubMed abstracts; GDF15 and ponsegromab have no label. Read October 7, 2026.
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.