In the Journals

Investigational GH drug increased muscle mass in older adults

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 group (P=.003).

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 DiMarcantonio

Ann Intern Med. 2008;149:601-611.

PERSPECTIVE

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 Clinic,
and Professor of Pediatrics, Mayo Medical School, Jacksonville, Fla.

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 group (P=.003).

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 DiMarcantonio

Ann Intern Med. 2008;149:601-611.

PERSPECTIVE

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 Clinic,
and Professor of Pediatrics, Mayo Medical School, Jacksonville, Fla.