MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. — VialBase Research

Summary

The reversal of diet-induced negative nitrogen balance by GH suggested a possible therapeutic role for GH treatment in catabolic patients, and this double-blind, randomized, placebo-controlled, two-period crossover study asked whether MK-677 — an orally active nonpeptide mimic of GH-releasing peptide — could do the same. Eight healthy volunteers aged 24-39 years were calorically restricted to 18 kcal/kg.day for two 14-day periods, receiving either oral MK-677 25 mg or placebo once daily during the last 7 days of each diet period, with a 14- to 21-day washout between periods. During the first week of caloric restriction (diet alone) daily nitrogen losses were similar in both groups (MK-677 -2.67 +/- 0.40 g/day vs. placebo -2.83 +/- 0.26 g/day). During the second week, with diet plus study drug, mean daily nitrogen balance was 0.31 +/- 0.21 g/day on MK-677 versus -1.48 +/- 0.21 g/day on placebo (P < 0.01), and integrated over days 8-14 the area under the curve nitrogen balance response was +2.69 +/- 5.0 for MK-677 versus -8.97 +/- 5.26 g.day for placebo (P < 0.001). MK-677 produced a peak GH response of 55.9 +/- 31.7 micrograms/L after a single dose and 22.6 +/- 9.3 micrograms/L after a week of dosing, against placebo peaks of approximately 9 and approximately 7 micrograms/L. IGF-I, which had fallen in both groups during the first restricted week, rose significantly on MK-677 (264 +/- 31 vs. 188 +/- 19 ng/mL, P < 0.01), as did IGF binding protein-3 (3273 +/- 330 vs. 2604 +/- 253 ng/mL, P < 0.01), while IGF binding protein-2 did not differ. Neither cortisol nor prolactin response was significantly greater after 7 days of MK-677 than placebo, and 25 mg was generally well tolerated without clinically significant adverse experiences. The authors concluded that MK-677 reverses diet-induced nitrogen wasting and may be useful in catabolic conditions if these short-term effects are maintained in patients.

Key Findings

• Very small sample: 8 healthy volunteers (ages 24-39 yr), each serving as their own control in a two-period crossover with a 14- to 21-day washout
• Nitrogen balance during the drug week was positive on MK-677 (0.31 +/- 0.21 g/day) and negative on placebo (-1.48 +/- 0.21 g/day), P < 0.01; the day 8-14 AUC response was +2.69 +/- 5.0 vs. -8.97 +/- 5.26 g.day, P < 0.001
• GH response attenuated with continued dosing: peak 55.9 +/- 31.7 micrograms/L after a single dose fell to 22.6 +/- 9.3 micrograms/L after a week, versus placebo peaks of roughly 9 and 7 micrograms/L
• IGF-I increased significantly on MK-677 (264 +/- 31 vs. 188 +/- 19 ng/mL, P < 0.01) after having declined in both groups during the initial diet-only week; IGF binding protein-3 also rose (3273 +/- 330 vs. 2604 +/- 253 ng/mL, P < 0.01) while IGF binding protein-2 was unchanged
• Cortisol and prolactin responses were not significantly greater on MK-677 than placebo after 7 days, and the 25 mg dose was generally well tolerated without clinically significant adverse experiences over this one-week exposure
• The endpoint was nitrogen balance in calorically restricted healthy volunteers — a biochemical proxy, not muscle mass, strength, or any clinical outcome; the authors framed benefit in catabolic disease as conditional on whether these short-term effects are maintained in patients

Relevance to MK-677

This is the study most often invoked as human proof that MK-677 is anabolic, and it does show a real, statistically clean effect: nitrogen balance flipped from negative to positive during a week of dosing under caloric restriction, with corresponding rises in GH, IGF-I and IGFBP-3. The honest framing requires three qualifiers. First, the sample was 8 people — eight — which is small enough that the finding is best read as a pharmacological demonstration rather than a population-level estimate. Second, the exposure was 7 days, and within that week the GH response already fell by more than half from day 1 to day 7, which is a hint about how the effect behaves over the months or years that recreational users dose for. Third, the outcome measured was nitrogen balance in calorically restricted healthy volunteers, not muscle mass, strength, body composition, or any clinical benefit; the authors themselves made their therapeutic claim conditional on whether short-term effects persist in actual catabolic patients. When that question was later tested in a larger, longer, properly powered trial in hip fracture patients, IGF-1 rose but functional outcomes largely did not, and the trial was halted for a heart failure signal. Read this 1998 study as the mechanistic starting point, not as the answer.

Citation

Murphy MG, Plunkett LM, Gertz BJ, et al. MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. The Journal of clinical endocrinology and metabolism. 1998;83(2):320-5. doi:10.1210/jcem.83.2.4551.

See Also

• Parent compound: MK-677