Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial
Nass R, Pezzoli SS, Oliveri MC, Patrie JT, Harrell FE Jr, Clasey JL, Heymsfield SB, Bach MA, +2 more
Annals of Internal Medicine (2008) · n=65
Daily oral MK-677 raised GH and IGF-1 to young-adult levels and added 1.1 kg of fat-free mass over a year — but the gain did not translate into measurable strength or functional improvement.
This is the most rigorous human trial of MK-677 to date and the cleanest single source for what daily ghrelin-mimetic dosing actually does in humans over a meaningful timeframe. Investigators randomized 65 healthy adults aged 60 to 81 (men, women on hormone replacement, women not on HRT) to 25 mg of oral MK-677 daily or placebo in a two-year double-blind, modified-crossover design at the University of Virginia. Pulsatile growth hormone secretion and IGF-1 both rose to levels typical of young adults during MK-677 treatment. Fat-free mass increased by 1.1 kg on MK-677 versus a 0.5 kg decrease on placebo at one year (P<0.001); body weight increased more on the active drug (2.7 kg vs. 0.8 kg). Limb fat also increased modestly. Crucially, the increased fat-free mass did not translate into measurable improvements in strength or physical function. Fasting glucose rose by 0.3 mmol/L (P=0.015), insulin sensitivity decreased, cortisol levels rose, and bone-remodeling markers shifted. The most common adverse events were transient increased appetite, mild lower-extremity edema, and muscle pain. Two-year exploratory analyses were consistent with the one-year endpoints.
The population is healthy older adults, not the lean-mass-seeking biohacker demographic that drives most current MK-677 use; generalizability across age and baseline body composition is not established. The lean-mass-gain-without-strength-gain finding is subtle and clinically important — readers translating MK-677 to recomposition use should weight the strength data over the scale data. The glycemic shift is small in magnitude but reproducible and matters for anyone with metabolic risk. Bone-remodeling changes were measured but their long-term clinical significance is not characterized. The trial used a single fixed dose (25 mg daily) and does not characterize the dose-response curve. Industry funding is disclosed; the primary endpoint is robust, but the limit of the evidence base is two years and one population.