The Safety and Efficacy of Growth Hormone Secretagogues. — VialBase Research

Summary

This is a narrative review of the clinical literature on growth hormone secretagogues (GHSs), the class that includes the GH-releasing peptides and the orally available small-molecule drug ibutamoren mesylate (MK-677). The authors set the context with growth hormone itself: GH increases lean body mass, decreases fat mass, increases exercise tolerance and maximum oxygen uptake, enhances muscle strength and improves linear growth, but long-term studies of GH administration offer conflicting results on its safety, which has led to strict Food and Drug Administration criteria for GH use. The potential drawbacks of exogenous GH are believed to be due in part to impaired regulatory feedback, and this is the mechanistic case for secretagogues: GHSs promote pulsatile release of GH that remains subject to negative feedback and can therefore prevent supra-therapeutic GH levels and their sequelae. Reviewing clinical studies in human subjects, the authors report that GHSs might improve growth velocity in children, stimulate appetite, improve lean mass in wasting states and in obese individuals, decrease bone turnover, increase fat-free mass and improve sleep — while stating plainly that to date few long-term, rigorously controlled studies have examined GHS efficacy and safety. Available studies indicate GHSs are well tolerated, with some concern for increases in blood glucose because of decreases in insulin sensitivity. The review closes by identifying what is missing: further work is needed to understand the long-term impact of GHSs on human anatomy and physiology across a diversity of clinical scenarios, and safety with long-term use, including evaluation of cancer incidence and mortality, is needed.

Key Findings

• Few long-term, rigorously controlled studies have examined the efficacy and safety of growth hormone secretagogues — the class evidence base is thin, and the review says so directly
• Available studies indicate GHSs are well tolerated, with the qualifier of some concern for increases in blood glucose because of decreases in insulin sensitivity
• The class rationale is pulsatile GH release that remains subject to negative feedback, which can prevent supra-therapeutic GH levels and their sequelae; the drawbacks of exogenous GH are believed to stem in part from impaired regulatory feedback
• Reported effects across the class: improved growth velocity in children, appetite stimulation, improved lean mass in wasting states and in obese individuals, decreased bone turnover, increased fat-free mass, improved sleep — all reported with “might” rather than as established outcomes
• Long-term safety is explicitly unresolved, and the authors specifically name evaluation of cancer incidence and mortality as needed work
• Long-term GH administration studies themselves offer conflicting safety results, which is why the FDA maintains strict criteria for GH use

Relevance to MK-677

This is the class-level reference for MK-677, and it is worth reading for what it does and does not license. It supports the strongest mechanistic argument in MK-677’s favour: because a secretagogue works by stimulating the body’s own pulsatile GH release, that release stays under negative feedback control, which distinguishes it from injecting exogenous GH and can prevent supra-therapeutic GH levels. It also supports the “well tolerated” framing found in short-term studies. But the review is a review, not a trial, and it is candid about the foundation underneath it — few long-term, rigorously controlled studies exist. Two specific cautions carry over to anyone actually taking MK-677. Blood glucose increases secondary to decreased insulin sensitivity are flagged as a real concern for the class, which matters for a compound taken continuously for months by people who are not being monitored. And the authors state outright that long-term safety, including cancer incidence and mortality, has not been evaluated — for a compound that raises IGF-1, an unstudied cancer question is not a neutral gap. “Well tolerated in short studies” and “safe long-term” are different claims, and only the first is supported here.

Citation

Sigalos JT, Pastuszak AW. The Safety and Efficacy of Growth Hormone Secretagogues. Sexual medicine reviews. 2018;6(1):45-53. doi:10.1016/j.sxmr.2017.02.004.

See Also

• Parent compound: MK-677