THE 30-SECOND OVERVIEW
At a glance
MK-677 and ipamorelin are the two ghrelin-receptor compounds most often set side by side, usually as if one were a stronger version of the other. They are not versions of anything. One is a small molecule taken by mouth with a deep clinical record. The other is a five-amino-acid peptide with a preclinical selectivity finding and a discontinued human programme. They share a receptor and very little else.
One receptor
Both compounds are agonists at GHS-R1a, the growth hormone secretagogue receptor that the stomach hormone ghrelin acts on. Stimulating it prompts the pituitary to release growth hormone by amplifying the pulses it already produces, and in the MK-677 trials that amplification showed up as taller pulses and higher troughs without a change in pulse count (Chapman et al., 1996).
That shared mechanism is why the two appear in the same literature and why they are compared. Everything downstream of the receptor, though, is set by the molecule, and the molecules could hardly be more different.
Two molecules
MK-677, also called ibutamoren, is a spiroindoline small molecule. It is not a peptide. It survives the gut, which is why every one of its trials used oral administration, and why it is stocked as a 25mg per mL oral liquid and as 15mg tablets rather than as a lyophilised vial.
Ipamorelin is a synthetic pentapeptide, Aib-His-D-2-Nal-D-Phe-Lys, from Novo Nordisk's growth hormone-releasing peptide programme in the 1990s. As a peptide it is degraded if swallowed, so the published work used injection, and its plasma kinetics were characterised by modelling in human volunteers (Gobburu et al., 1999). It is also available as a nasal spray for research programmes that want a needle-free route.
The practical consequence is duration. MK-677 was dosed once daily in every trial, and once-daily bedtime dosing raised 24-hour growth hormone and IGF-1 for as long as it was continued, up to two years in the Nass trial (2008). Ipamorelin's peptide half-life is short, and protocols in that class are built around timing rather than a single daily figure.
Selectivity, and who measured it
Ipamorelin's reputation rests on one property. The older growth hormone-releasing peptides, GHRP-6 and GHRP-2, raised cortisol and prolactin alongside growth hormone. Raun and colleagues (1998) characterised ipamorelin in rats and swine as releasing growth hormone with far less effect on those hormones, and titled the paper accordingly: the first selective growth hormone secretagogue. That finding is preclinical, and it has not been reproduced across human dose ranges in the published record.
MK-677's trials measured the same hormones in people. In the 1996 Chapman study, cortisol did not change and prolactin rose 23 percent while staying within the normal range. Copinschi (1996) found no effect on 24-hour cortisol profiles apart from a shift in their timing. Svensson (1998) saw growth hormone and prolactin rise after the first dose, with the prolactin peak not persisting at two and eight weeks, and no cortisol increase at those points. The two-year Nass trial, though, recorded a cortisol increase of 47 nanomoles per litre. So MK-677 has human selectivity data, and it is mixed; ipamorelin has animal selectivity data, and it is clean. Those are not equivalent statements.
The evidence bases
This is where the comparison stops being close.
MK-677 has randomised, placebo-controlled trials from 1996 onward: dose-ranging in the elderly, seven-day crossovers in young men, an eight-week obesity study, caloric-restriction and bone-turnover studies, a 161-patient and a 123-patient hip-fracture trial, a 563-patient Alzheimer's trial, a two-year body-composition trial, a haemodialysis crossover, and an ongoing paediatric programme under the name LUM-201. The record includes negative results, which is part of what makes it a record.
Ipamorelin entered human trials for postoperative ileus, the slowing of gut motility after abdominal surgery, on the basis that ghrelin-receptor agonism affects gastric emptying. The phase 2 trial infused 0.03mg per kg twice daily after bowel resection, found the compound well tolerated, and found no significant benefit over placebo on its motility endpoints (Beck et al., 2014). The programme was discontinued. There is no long-duration human data and no published protocol for the uses ipamorelin is now discussed for.
What the MK-677 trials found
Two decades of 25mg once-daily dosing produced consistent IGF-1 increases, in the range of 40 to 90 percent depending on the population, and a consistent rise in fat-free mass in the studies that measured it. They also produced consistent metabolic signals: higher fasting glucose in the Chapman and Nass studies, impaired oral glucose tolerance in Svensson, reduced insulin sensitivity in Nass, and an early termination of the 2010 hip-fracture trial over a heart-failure signal. Clinical endpoints, strength, function, and cognitive progression, generally did not move. Our MK-677 dosage research article covers the trial designs in detail.
Where each one fits
A programme studying oral delivery, sustained IGF-1 elevation, sleep architecture, or any question that needs a compound with human safety data to compare against, has an MK-677 literature to design from.
A programme studying ghrelin-receptor agonism with minimal cortisol and prolactin involvement, in an animal model, has the Raun characterisation and the selectivity property ipamorelin was made for.
A programme that wants ghrelin-receptor stimulation combined with a GHRH-receptor agonist has a different question, and blends such as CJC-1295 with ipamorelin exist for it.
The takeaway
MK-677 and ipamorelin hit the same receptor by different means. MK-677 is oral, long-acting, and studied to a clinical standard, with results that are pharmacologically consistent and clinically modest. Ipamorelin is injected or intranasal, short-acting, selective in animals, and unstudied in humans for the endpoints it is discussed for. Comparing potency between them is not meaningful; comparing the evidence is, and the evidence is lopsided.
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References
1. Chapman, I. M., Bach, M. A., Van Cauter, E., et al. (1996). Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects. Journal of Clinical Endocrinology and Metabolism, 81(12), 4249-4257.
2. Copinschi, G., Van Onderbergen, A., L'Hermite-Balériaux, M., et al. (1996). Effects of a 7-day treatment with a novel, orally active, growth hormone (GH) secretagogue, MK-677, on 24-hour GH profiles, insulin-like growth factor I, and adrenocortical function in normal young men. Journal of Clinical Endocrinology and Metabolism, 81(8), 2776-2782.
3. Raun, K., Hansen, B. S., Johansen, N. L., et al. (1998). Ipamorelin, the first selective growth hormone secretagogue. European Journal of Endocrinology, 139(5), 552-561.
4. Svensson, J., Lönn, L., Jansson, J. O., et al. (1998). Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure. Journal of Clinical Endocrinology and Metabolism, 83(2), 362-369.
5. Gobburu, J. V., Agersø, H., Jusko, W. J., & Ynddal, L. (1999). Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharmaceutical Research, 16(9), 1412-1416.
6. Nass, R., Pezzoli, S. S., Oliveri, M. C., et al. (2008). Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Annals of Internal Medicine, 149(9), 601-611.
7. Beck, D. E., Sweeney, W. B., McCarter, M. D., et al. (2014). Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. International Journal of Colorectal Disease, 29(12), 1527-1534.
