MK-677, an Orally Active Growth Hormone Secretagogue, Reverses Diet-Induced Catabolism

This 1998 *JCEM* paper is the early human-volunteer trial that demonstrated MK-677's potential to reverse catabolic metabolism in caloric deficit and helped establish the molecule's plausibility as a clinical intervention beyond diabetes-related GH-secretagogue research. The double-blind, randomized, placebo-controlled, two-period crossover study enrolled eight healthy volunteers (ages 24–39) and subjected them to two 14-day periods of caloric restriction (18 kcal/kg/day, well below maintenance for adults). During the last 7 days of each diet period, participants received either oral MK-677 25 mg daily or placebo. The primary metabolic readout was nitrogen balance, measured continuously through the 7-day dosing window. MK-677 reversed the diet-induced negative nitrogen balance — the cumulative nitrogen retention difference versus placebo across the dosing window indicated MK-677 produced a clinically meaningful anabolic effect even under significant caloric restriction. IGF binding protein-3 rose to 3,273 ± 330 ng/mL on MK-677 versus 2,604 ± 253 ng/mL on placebo, consistent with the GH-axis activation expected from a ghrelin-receptor agonist. Tolerability was unremarkable. The paper supplied an early proof-of-concept that the orally bioavailable design could produce clinically interpretable anabolic effects — a finding that helped justify the subsequent two-year Nass et al. trial in older adults that became the molecule's main long-duration human dataset.

The sample size is very small (eight volunteers), and the trial design is short-duration (7 active dosing days within a 14-day caloric-restriction period). The findings establish a positive nitrogen-balance signal under caloric restriction in healthy young adults; generalization to chronic dosing in older adults, to populations with disease-related catabolism (cancer cachexia, postoperative recovery, age-related sarcopenia), or to the recreational body-composition use cases that drive most current MK-677 interest is not directly supported by this paper. Nitrogen balance is a useful but imperfect proxy for protein anabolism — total body protein turnover or muscle protein synthesis measurements would be more directly informative for clinical translation. Industry sponsorship by Merck (the original MK-677 developer) is disclosed; the methodology is appropriate for a Phase 1/2 design.