MK-677

MK-677 is a non-peptide, orally active ghrelin mimetic developed by Merck. It binds the growth hormone secretagogue receptor GHS-R1a in the pituitary and hypothalamus, a receptor separate from the one GHRH uses [6]. The result is more of the body's own growth hormone, released in its normal pulses [1]. It came out of a Merck programme that produced a series of such secretagogues [7].

Growth hormone and IGF-1. This part works, in every population tested. In 32 healthy adults aged 64-81, 25 mg daily raised mean 24-hour growth hormone by 97% and brought IGF-1 from 141 to 265 ug/L over four weeks, into the young-adult range [1]. The rise came from taller pulses and higher troughs, not from more pulses [1]. IGF-1 rose 60-73% in Alzheimer's disease [5], 84% after hip fracture [3], 39-45% in postmenopausal osteoporosis [8] and 65% over placebo in haemodialysis patients [9]. In children with growth hormone deficiency, 0.8 mg/kg for eight days raised growth hormone and IGF-1 in some but not all of the 18 children studied [6]. In adults with growth hormone deficiency, the response depended on how much pituitary function remained [10].

Body composition. The pivotal trial randomised 65 healthy adults aged 60-81 to 25 mg daily or placebo for two years. At 12 months fat-free mass had increased 1.1 kg on MK-677 and fallen 0.5 kg on placebo, with about half the gain in the limbs. Body weight rose 2.7 kg against 0.8 kg. Abdominal visceral fat did not differ, and total fat mass did not differ, though limb fat rose more on the drug (1.1 vs 0.24 kg). The changes were sustained through year 2, and reversed in people crossed back to placebo [2]. In obese men, eight weeks raised fat-free mass and briefly raised basal metabolic rate, with no change in total or visceral fat [11].

What it does not do. In the two-year trial there was no significant change in knee or shoulder strength, in 30-metre walking, six-minute walk, stair climbing or chair rises, or in any quality-of-life measure [2]. Two hip-fracture trials missed their functional endpoints, despite IGF-1 rising [3][4]. A 563-patient, 12-month trial in Alzheimer's disease found no effect on any cognitive or functional scale [5]. In osteoporosis, adding MK-677 to alendronate raised femoral neck bone density slightly more than alendronate alone (4.2% vs 2.5%) but did nothing extra at the spine, total hip or whole body [8].

Sleep. In a crossover study of 8 young men, 25 mg at bedtime for a week raised stage IV sleep by about 50% and REM sleep by over 20%. Six older adults on 25 mg for two weeks had nearly 50% more REM sleep and a shorter REM latency [12]. These are small, short studies, and sleep was not improved in the two-year trial's quality-of-life questionnaires [2].

Ghrelin is the stomach hormone that signals hunger and stimulates growth hormone release. MK-677 is a small molecule that copies it at GHS-R1a. Because the receptor sits upstream of the pituitary's own control loops, the growth hormone comes out in pulses rather than as the flat level injected growth hormone produces [1]. That pulsatility is the stated rationale for secretagogues over growth hormone itself [2].

Growth hormone raises IGF-1 from the liver, which is what drives the anabolic effects — and the metabolic ones. Growth hormone opposes insulin, and the two-year trial duly found fasting glucose up 0.3 mmol/L, HbA1c up 0.2% and a measurable fall in insulin sensitivity by the Quicki index [2]. In obese men an oral glucose tolerance test was already impaired at two weeks [11].

Ghrelin receptor activation also drives appetite, which is why two-thirds of people in the two-year trial reported eating more [2]. Effects on the other pituitary hormones are small: prolactin rose about 23% but stayed in range [1], and 24-hour cortisol rose modestly over a year [2], though shorter studies in obese men found no cortisol change [11].

The compound sold as MK-677 is ibutamoren mesylate, the methanesulfonic acid salt; all human trials used oral tablets [2]. It is not approved anywhere, and it has never been marketed as a medicine or a supplement.

Glucose. This is the consistent finding. Over 12 months, fasting glucose rose an average of 5 mg/dL and HbA1c 0.2%; 16 of 43 people on MK-677 moved from a normal fasting glucose into the 101-110 mg/dL band, and two reached 125-126 mg/dL. Eight had an HbA1c above 6% at 12 months. One 81-year-old man needed a dose reduction and a low-carbohydrate diet [2]. In obese men, glucose tolerance was impaired at both 2 and 8 weeks [11]. People with diabetes were excluded from the trials.

Common effects. Increased appetite (67% vs 36% on placebo, usually settling within three months), mild transient leg swelling (44% vs 27%) and transient muscle pain (33% vs 9%) [2]. Joint pain was common in both arms [2], and in the osteoporosis trial GH-mediated side effects were noted in the MK-677 groups [8].

Heart failure. The phase IIb hip-fracture trial in 123 patients was terminated early because of a congestive heart failure safety signal in a small number of patients, and its authors concluded MK-677 has an unfavourable safety profile in that population [4].

Bone. In healthy older adults, femoral neck bone mineral density fell slightly relative to placebo over 12 months, a pattern the authors read as increased bone remodelling [2]. MK-677 on its own raised both formation and resorption markers [8].

Cancer and other monitoring. Over two years in 65 people there were cancers in both arms (tongue and colon on MK-677, renal cell on placebo) — numbers far too small to interpret. Testosterone, PSA, mammograms and routine labs did not change [2]. There is no long-term safety data beyond two years, and none in young healthy people.

Secretagogues of this kind are sometimes proposed alongside testosterone for body composition in hypogonadal men, though the review that discusses this notes how thin the supporting evidence is [15]. Combined with alendronate for 12 months in postmenopausal osteoporosis, MK-677 blunted alendronate's suppression of bone formation markers and added a small amount of femoral neck bone density, without extra benefit elsewhere [8]. No interactions with other compounds on this site have been documented.