Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial.
Level 2 - randomized trial
Individual randomized, double-blind, placebo-controlled clinical trial
PubMed 18981485 · doi:10.7326/0003-4819-149-9-200811040-00003
What was done
This 2-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial evaluated the effect of MK-677 (25 mg orally once daily) versus placebo in 65 healthy older adults aged 60 to 81 years (men, women receiving HRT, and women not receiving HRT) at a university general clinical research center. Primary 1-year endpoints were fat-free mass, abdominal visceral fat, and levels of growth hormone (GH) and insulin-like growth factor I (IGF-1). Secondary endpoints assessed at baseline and every 6 months included body weight, limb lean and fat mass, insulin sensitivity, lipid and cortisol levels, bone mineral density, isokinetic strength, physical function, and quality of life.
What was found
MK-677 increased GH and IGF-1 levels to those of healthy young adults without serious adverse effects. Fat-free mass increased in the MK-677 group compared with a decrease in placebo (+1.1 kg [95% CI, 0.7 to 1.5 kg] vs. -0.5 kg [95% CI, -1.1 to 0.2 kg]; P < 0.001), as did body cell mass measured by intracellular water (+0.8 kg vs. -1.0 kg; P = 0.021). Body weight rose by 2.7 kg (95% CI, 2.0 to 3.5 kg) in the MK-677 group versus 0.8 kg (95% CI, -0.3 to 1.8 kg) in placebo (P = 0.003). No significant differences were seen in abdominal visceral fat or total fat mass, though limb fat increased more in the MK-677 group (1.1 kg vs. 0.24 kg; P = 0.001). Fasting glucose increased by an average of 0.3 mmol/L (5 mg/dL; P = 0.015) and insulin sensitivity decreased. Cortisol rose by 47 nmol/L (P = 0.020), LDL cholesterol fell by 0.14 mmol/L (P = 0.026), and bone remodeling markers increased. The increase in fat-free mass did not translate to changes in isokinetic strength or functional measures.
Why it matters
MK-677 reliably activates the GH/IGF-1 axis and reverses age-related loss of fat-free mass through oral dosing. However, increased lean mass did not yield improvements in physical function or muscle strength, and treatment impaired insulin sensitivity.
Limits
The sample size was small (n = 65) and explicitly underpowered to detect changes in functional endpoints. The cohort comprised healthy older adults, precluding direct generalization to frail or sarcopenic populations. Adverse metabolic changes, specifically elevated fasting blood glucose and decreased insulin sensitivity, represent important safety limitations.
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