MK-677, an oral ghrelin mimetic, increased growth hormone secretion and
fat-free mass in healthy older adults, according to study data.
Researchers from the University of Virginia in Charlottesville,
Vanderbilt University in Nashville, Tenn., the University of Kentucky in
Lexington and Merck Research Laboratories conducted a two-year, double blind,
randomized, placebo-controlled trial. They enrolled 65 healthy men and women
aged 60 to 81 years. Forty-three participants were randomly assigned to receive
25 mg MK-677 daily and 22 were assigned to placebo.
At one year, GH and insulin-like growth factor I levels of participants
receiving MK-677 increased to levels of that of healthy young adults. GH levels
increased 1.8-fold from baseline, and IGF-I levels increased 1.5-fold. Mean
fat-free mass increased by 1.1 kg in the MK-677 group, but decreased by
–0.5 kg in the placebo group (P<.001). Body cell mass also
increased in the MK-677 group by 0.8 kg compared with a –1 kg decrease in
the placebo group (P=.021).
The researchers observed no significant differences in abdominal
visceral fat or total fat mass, but the MK-677 group had a greater increase in
limb fat — 1.1 kg vs. 0.24 kg in the placebo group (P=.001). Body
weight increased by 2.7 kg in the MK-677 group and by 0.8 kg in the placebo
According to the study, the most frequent adverse effects of MK-677 were
increased appetite; transient, mild lower-extremity edema; and muscle pain.
“Changes in bone mineral density consistent with increased bone remodeling
occurred in MK-677 recipients. Increased fat-free mass did not result in
changes in strength or function,” the researchers wrote. – by Tina
Ann Intern Med. 2008;149:601-611.
In this paper, Nass et al reported their results of a two-year
randomized crossover trial in a group of 65 healthy adults aged 60 and 81 years
treated with the GH secretagogue MK-677 or placebo (2:1 ratio) for one year,
followed by three arms for year two, ie, continuation of MK-677, crossing over
to placebo from MK-677 or crossing over to MK-677 from placebo. These studies
were detailed and thorough, and the researchers ought to be commended for the
tremendous amount of work the studies represent. The striking result is the
very substantial increase in GH pulsatility sustained at 12 months as well as
the sizable increase in IGF-I concentrations observed in the MK-677 group.
Their key outcome of changes in fat-free mass was positive for the participants
randomly assigned to MK-677 who gained 1.5 kg (along with total body water)
whereas those receiving placebo lost 0.5 kg (P<.001). However, there
was no difference in the abdominal visceral fat mass between the groups, and
appetite and total body weight increased more in the MK-677 group. There was no
improvement on any functional measures of muscle strength in the groups
studied. Other factors were not favorable, including an increase in BMD of the
femoral neck in the placebo group and a decrease in the MK-677 group. LDL
decreased for those who received MK-677 vs. placebo; however, measures of
insulin sensitivity declined with MK-677. Assessment of quality of life did not
change in either group. The tolerance of the drug was adequate.
Overall, I think these data are important as they show the establishment
of 'younger' GH pulsatility and IGF-I generation in the elderly with the use of
MK-677. However, the issue remains: Is a 'younger' GH profile healthy in the
elderly? The increase in fat-free mass was mostly secondary to total body water
and was not accompanied by measurable increases in muscle strength.
Intra-abdominal adiposity did not decrease, and total body weight and insulin
resistance increased on the medication. It would be intriguing to explore
whether the increase in fat-free mass observed could translate into increased
muscle strength if accompanied by concomitant increase in exercise activity. It
would also be important to assess the changes in the participants that ended up
receiving the drug for two years (data not shown). Based on the data presented
thus far, the benefits of MK-677 do not outweigh the risks, and MK-677 does not
seem to be a 'fountain of youth' in elderly patients.
– Nelly Mauras, MD
Chief, Division of Endocrinology, Nemours Children's
and Professor of Pediatrics, Mayo Medical School, Jacksonville,