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| https://doi.org/10.22541/au.159050681.10910720 | This a preprint and has not been peer reviewed. Data may be preliminary.

MAJOR APPROACHES THE USE OF GH SECRETAGOGUE

(MK-677) FOR MUSCLE MASS GAIN IN ELDERLY: A BRIEF
SYSTEMATIC REVIEW
Dr. Idiberto Jose Zotarelli Filho, MSc, Ph.D1
1
Affiliation not available

May 26, 2020

Abstract
Introduction: The number of disabilities due to age is expected to double by 2060. In this scenario, the development of
sarcopenia is an important risk factor for the development of frailty, loss of independence and physical disability in the elderly
and is associated with lower survival in critically ill patients. In this sense, the decline in fat-free mass correlates with the decline
associated with the age of growth hormone (GH) secretion. Thus, GH secretagogue (MK-677) as the first orally active ghrelin
mimetic may increase pulsatile GH secretion in the elderly. Objective: The main objectives were to determine whether oral
MK-677 in healthy elderly would increase GH and IGF-I levels, prevent the decline of FFM and decrease abdominal visceral
fat (AVF) with acceptable tolerability. Methods: A total of 18 articles were found involving MK-677, GH secretagogue,
sarcopenia, insulin-like growth factor-1, safety, and efficacy. Initially, it was held the existing exclusion title and duplications
following the interest described in this work. After this process, 5 articles were included and discussed in this study. The present
study was elaborated according to the rules of systematic review- PRISMA (Transparent reporting of systematic reviews and
meta-analysis- http://www.prisma-statement.org/). Results: In a clinical study, MK-677 neutralized three important factors
contributing to the development of sarcopenia, which is reduced GH secretion, fat-free mass loss, and inadequate food intake. A
recent study looked at the safety and efficacy of the oral GH secretagogue (MK-677) in humans, showing that MK-677 promotes
pulsatile GH release that is subject to negative feedback and may prevent supra-therapeutic levels. of GH and its sequelae.
Available studies indicate that MK-677 is well tolerated, however, there is a bias in decreased insulin sensitivity. There were no
adverse effects attributable to MK-677. However, MK-677 had an unfavorable safety profile in individuals with congestive heart
failure. Conclusion: The most confirmed sarcopenia treatment methods are nutritional overfeeding and resistance training,
but studies have shown that supplementation with MK-677 can significantly reduce three important factors contributing to
the development of sarcopenia, which is reduced secretion. GH loss, fat-free mass loss, and inadequate food intake, safely and
effectively. However, it is imperative to increase randomized clinical trials to establish a consensus treatment.

Keywords: MK-677. Ibutamoren. GH secretagogue. Sarcopenia. Elderly.

José Wilson Ribas1 , Priscilla Carlos Ribeiro Teotonio1 , Idiberto José Zotarelli Filho2,3

1
Reviv Clinic, Advanced Center for Integrative Medicine, Brasilia DF, Brazil.
2
Doctor of the Zotarelli-Filho Scientific Work, São José do Rio Preto/SP, Brazil.
3
Bentham Science Ambassador, Brazil.

Corresponding Author: José Wilson Ribas, Reviv Clinic, Advanced Center for Integrative Medicine,
Brasilia DF, Brazil.
Introduction

1
 In humans, muscle mass decreases after its peak in the third decade of life [1]. Muscle mass is important
for physical and metabolic fitness regulation. The development of sarcopenia is an important risk factor for
the development of frailty, loss of independence and physical disability in the elderly and is associated with
Posted on Authorea 26 May 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159050681.10910720 | This a preprint and has not been peer reviewed. Data may be preliminary.

shorter survival in critically ill patients [2]. In the 8th decade, men and women can lose about 7 and 3.8 kg
of muscle mass, respectively, with increased intra-abdominal fat [3].
In this context, the number of disabilities due to age is expected to double by 2060. Muscle mass is im-
portant for physical fitness and metabolic regulation [4]. In this scenario, the development of sarcopenia
is an important risk factor for the development of frailty, loss of independence and physical disability in
the elderly and is associated with lower survival in critically ill patients. The pathophysiology of sarcopenia
is multifactorial and may be influenced by reduced caloric intake, neurodegenerative diseases, intracellular
oxidative stress, hormonal disorders, and others. In this sense, the decline in fat-free mass correlates with
the decline associated with the age of growth hormone (GH) secretion. Thus, GH secretagogue (Ibutamoren
- MK-677) as the first orally active ghrelin mimetic may increase pulsatile GH secretion in the elderly [5].
Therefore, the present study aimed to determine whether oral MK-677 in healthy elderly would increase GH
and insulin-like growth factor I (IGF-I) levels, prevent the decline of muscle mass, and decrease abdominal
visceral fat (AVF) with acceptable tolerability.
Methods
Data sources and search strategy
A total of 24 articles were found involving MK-677, GH secretagogue, sarcopenia, insulin-like growth factor-
1, safety, and efficacy. Initially, it was held the existing exclusion title and duplications following the in-
terest described in this work. After this process, 14 articles were included and discussed in this study
(Figure 1). PUBMED, EMBASE, OVID AND COCHRANE LIBRARY databases were searched. Initial-
ly, the descriptors were determined by searching the DeCS tool and later verified and validated by the
MeSH Terms System (US National Library of Medicine).The present study was elaborated according to
the rules of systematic review- PRISMA (Transparent reporting of systematic reviews and meta-analyses-
http://www.prisma-statement.org/).
Study selection and risk of bias in each study
Two independent reviewers (1 and 2) performed research and study selection. The data extraction was
performed by reviewer 1 and fully reviewed by reviewer 2. A third investigator decided some conflicting
points and made the final decision to choose the articles. Only studies reported in Portuguese and English
were evaluated. The Cochrane instrument was adopted to assess the quality of the included studies.
Risk of bias
Considering the Cochrane tool for risk of bias, the overall evaluation resulted in 4 studies with a high risk of
bias and 2 studies with uncertain risk. Five studies had a limited number of participants. Also, the absence
of the source of financing in 1 studies. Further, 2 studies did not disclose the information on the conflict of
interest statement.
Figure 1. Flow Chart of the article selection process.

2
Posted on Authorea 26 May 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159050681.10910720 | This a preprint and has not been peer reviewed. Data may be preliminary.

Development and Discussion

In the stimulating scenario of GH production, the long-term safety of growth hormone (GH) treatment is an
area of much debate. Healthy elderly subjects who took the MK-677 ghrelin mimetic experienced a sustained
increase in the amplitude of GH and IGF-I pulsatile secretion to levels observed in young adults [7,8].
The likely mechanism was ghrelin receptor activation by MK-677, with feedback from IGF-I. MK-677 in-
creased the Fat-Free Mass (FFM) by 1.6 kg compared to placebo. To provide perspective, the average life
loss in an adult’s average lifespan is ~ 5.5 kg. A concomitant increase in intracellular water, which reflects
body cell mass, is the likely mechanism for increased FFM [9].
Ghrelin stimulates GH secretion but also has effects that are not attributable to GH increase. In this study, a
ghrelin mimetic transiently increased appetite, a new effect that can counteract physiological anorexia, which
is a cause of weight loss in the elderly, ghrelin increases fat stores, unlike lipolytic GH. Bodyweight was found
to increase more after MK-677 than the placebo. Although total fat mass increased in both groups, lean fat
and limb lean mass increased more with MK-677 than with placebo. Surprisingly, the cross-sectional area
of the thigh muscle did not increase, although the study was not designed to detect small but potentially
important differences with the inaccurate single slice CT method we use [9].
GH reduces abdominal visceral fat (AVF) in GH-deficient and obese adults, postmenopausal women (29),
but not in normal elderly. Despite increased GH levels, MK-677 did not affect AVF, perhaps because its
combined orexigenic and adipogenic effects neutralized the lipolytic effects of increased GH. Finally, although
MK-677 did not reduce AVF, it reduced LDL levels at 12 months, and the unobserved effect on GH in normal
elderly [9].
Although strength has improved in elderly hypopituitary patients following daily GH injections for two
to three years, GH alone does not increase strength in healthy elderly. In fact, strength has improved in
healthy older men who take GH alone in combination with testosterone for 26 weeks. Finally, the relationship

3
 between strength and physical strength performance is nonlinear. Increasing physical capacity has been found
to substantially improve performance in fragile adults, but not in healthy adults [10].
Posted on Authorea 26 May 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159050681.10910720 | This a preprint and has not been peer reviewed. Data may be preliminary.

In this sense, sarcopenia is a characteristic of frailty and is associated with increased mortality in the
elderly. In our study of healthy older adults, MK-677 neutralized three important factors contributing to the
development of sarcopenia: reduced GH secretion, loss of FFM, and inadequate food intake. Both GH and
MK-677 increase insulin resistance and blood glucose in the elderly [11]. Small increases in fasting glucose
and HbA1c were found at 12 months. Based on the results of short-term studies with MK-677, which did
not find a statistically significant increase in serum cortisol, it cannot be stated that the small increase in
serum cortisol found in our study may underlie the increase in fasting glucose. [11]
In patients treated with GH, bone mineral density initially decreases and treatment is required for at least 18
months to demonstrate increased bone density. Femoral neck bone mineral density decreased at 12 months
with MK-677, which is consistent with increased bone remodeling, as with GH. The risk of fracture would be
the best measure of the effects of MK-677 on bone, but this result would require studies of a large number
of individuals over many years [8].
In addition, in one clinical study, MK-677 neutralized three important factors contributing to the development
of sarcopenia, which is reduced GH secretion, fat-free mass loss and inadequate food intake [10]. A recent
study looked at the safety and efficacy of the oral GH secretagogue (MK-677) in humans, showing that MK-
677 promotes pulsatile GH release that is subject to negative feedback and may prevent supra-therapeutic
levels of GH and its sequelae. Available studies indicate that MK-677 is well tolerated, however, there is a
bias in decreased insulin sensitivity [11].
In addition, a randomized double-blind crossover study evaluated the effect of MK-677 versus placebo on
IGF-1 levels in 22 hemodialysis patients. The average IGF-1 was 1.07 times higher after placebo (p> 0.001).
In patients receiving MK-0677, the mean IGF-1 was 1.76 times higher after MK-677 (p <0.001). These
data demonstrate a 65% greater increase in IGF-1 in subjects treated with MK-677 compared with placebo.
There were no adverse effects attributable to MK-677 [11].
Another randomized, double-blind study looked at 123 elderly hip fracture patients assigned to receive
25mg/day of MK-677 (n = 62) or placebo (n = 61). After 24 weeks, the average power of climbing stairs
at 12.5 W in the MK-677 group increased considerably compared to placebo, as well as increased gait speed
with a 0.7 point difference in averages. Also, the MK-677 group experienced fewer falls during the study
compared to the placebo. Also, IGF-1 levels in treated patients increased by 51.4 ng/mL compared to
placebo. However, MK-677 had an unfavorable safety profile in individuals with congestive heart failure [12].
In this context, it was necessary to evaluate the effects of MK-677 on hip fracture functional recovery in
previously mobile elderly individuals. Thus, it conducted a placebo-controlled, randomized, double-blind
study. Thirteen medical centers in England, Sweden, Denmark, Belgium, Switzerland, Canada, and the
United States. Patients were recruited between 3 and 14 days postoperatively, or at most 18 days after
fracture, in acute care hospitals and rehabilitation centers. One hundred and sixty-one (161) hip fracture
patients were included. Entry criteria included hip fracture patients with consent aged 65 years and older and
outpatient clinically stable postoperative fractures and mentally competent [13]. Patients were excluded if
they had multiple fractures or severe trauma, diabetes mellitus, cancer, uncontrolled hypertension, congestive
heart failure or total hip replacement at the involved extremity. Random assignment to 6 months of daily
treatment with MK-677 or placebo. Patients were followed for a further 6 months after the end of therapy.
MK-677 treatment increased serum IGF-I levels by 84% (95% confidence interval (CI) = 63-107) compared
with a 17% increase (95% CI = 8-28) in placebo. There were no significant differences between MK-677 and
placebo in improving functional performance measures or overall SIP-NH scores [13].
In this study, although patients MK-677 showed greater improvement over placebo in three of the four
measures of lower limb functional performance, physical domain and ability to live independently, these
differences were not statistically significant. Although treatment with MK-677 increased serum IGF-I, it
is not known whether clinically significant effects on physical function have been achieved. Measurement

4
 function in clinical trials in hip fracture patients is difficult due to the lack of validated outcome measures, high
variability and lack of initial evaluation. Current functional performance measures may not be sufficiently
responsive for use as the primary objective of small intervention studies; alternatively, GH stimulation may
Posted on Authorea 26 May 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159050681.10910720 | This a preprint and has not been peer reviewed. Data may be preliminary.

not result in significant functional improvement [13].

In this sense, growth hormone (GH) stimulates osteoblasts in vitro and increases bone turnover and stim-
ulates osteoblast activity when administered to elderly individuals. Probably a large effect of GH on bone
is mediated by stimulation of circulating or locally produced IGF-I. We determined the effect of chronic
administration of GH secretagogue MK-677 on serum IGF-I and bone turnover markers in 187 elderly (65
years and over) enrolled in three randomized, double-blind, placebo-controlled clinical trials. 2-9 weeks.
Urine was collected for determination of N-telopeptide (NTXs) cross-links, a bone resorption marker, and
blood was collected for determination of serum osteocalcin and bone-specific alkaline phosphatase (BSAP)
as markers of bone formation and IGF. - Pre and post-treatment levels. Dose-response data were initially
obtained in healthy elderly subjects who received oral doses of 10 mg or 25 mg MK-677 or placebo for 2
weeks (n = 10-12/group). Treatment with 10 mg and 25 mg MK-677 for 2 weeks increased average urinary
NTXs by 10% and 17%, respectively (p <0.05 vs. placebo). In addition, 50 healthy elderly people received
a placebo (n = 20) for 4 weeks or 25 mg of MK-677 (n = 30) daily for 2 weeks, followed by 50 mg daily for
2 weeks. MK-677 increased mean serum osteocalcin by 8% (p <0.05 vs. placebo) [14].
Thus, in both studies, MK-677 significantly increased serum IGF-I levels (55-94%). Subsequently, the biolog-
ical effects of MK-677 were studied in 105 elderly people who met objective criteria for functional impairment.
Subjects were randomized to receive oral placebo doses for 9 weeks or 5, 10 or 25 mg of MK-677 daily for
the initial 2 weeks, followed by 25 mg of MK-677 daily for the next 7 weeks (n = 63 in MK-677). 677 and n
= 28 in placebo completed 9 weeks of therapy). Treatment with MK-677 (all combined MK-677 groups) for
9 weeks increased mean serum osteocalcin by 29.4% and BSAP by 10.4% (p <0.001 vs. placebo) and mean
urinary excretion of NTX at 22.6% (p <0.05 vs. placebo). The change in basal serum osteocalcin correlated
with the change in basal serum IGF-I in the MK-677 group (r = 0.37; p<0.01). In conclusion, a daily dose
of MK-677, an orally active GH secretagogue, stimulates bone turnover in the elderly based on elevations in
biochemical markers of bone resorption and formation [14].
Thus, more significant increases in IGF-1 levels were observed in the ibutamoren group compared to placebo
(84% vs. 17%, respectively). In assessing functional outcomes, the ibutamoren group did not show a signif-
icant impact on quality of life, although three out of four lower extremity performance measures improved
in this group. There was also a tendency towards a more independent life in the ibutamoren group in all
patients, and in particular in 70% of those who were independent before hip fracture (p=0.036). A second
smaller study (n=123), with a similar design assessing ibutamoren compared to placebo in hip fracture
recovery, found an improvement in stair climbing power and gait speed in the ibutamoren group. How-
ever, these increases were so small that they were not considered a significant improvement. Although the
above work suggests a positive impact of ibutamoren on anabolism, further studies are needed to determine
whether slowing down ibutamoren catabolism affects mortality, length of hospital stay or results in functional
improvements, reducing protein breakdown and increasing anabolism [15].
Within the limits of current literature, growth hormone secretagogues appear to be safe, with few studies
cited in this review looking at serious adverse events with the use of ibutamoren. However, safety data are
limited due to the short overall lengths and small sizes of most studies. Long term studies with ibutamoren
are available. Adunsky et al. [12] examined the role of ibutamoren in hip fracture recovery in 123 elderly
patients during 24 weeks of treatment and was the only randomized, double-blind, placebo-controlled study
that was discontinued early due to concerns that ibutamoren could increase the rate of congestive heart
failure (CHF). Four patients in the ibutamoren group (6.5%) and one in the placebo group (1.7%) developed
CHF during the study, although the higher rate of CHF in the ibutamoren group may have been due in part
to lower basal blood pressures. high in this group [15].
These findings contrast with a similar, randomized, double-blind, placebo-controlled study by Bach et al. [13]

5
 who also examined the use of ibutamoren for 6 months in 161 elderly patients recovering from hip fracture.
However, more patients discontinued treatment due to a clinical adverse effect in the ibutamoren group
than in the placebo group (p<0.05). Nevertheless, a randomized, double-blind, placebo-controlled study
Posted on Authorea 26 May 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159050681.10910720 | This a preprint and has not been peer reviewed. Data may be preliminary.

evaluating the 4-week effects of ibutamoren administration in 32 healthy elderly patients did not observe
adverse effects [15].
There are currently few studies examining the effects of ibutamoren, although existing studies support
beneficial roles for these drugs in elevating GH levels and impacting patient outcomes. There are currently
few studies evaluating large cohorts for prolonged durations of ibutamoren treatments [8]. Available data
support increases in GH and IGF-1 levels with ibutamoren treatment, but provide little objective insight into
the effects of these drugs on body composition or other important parameters. Although available studies
support a beneficial effect of ibutamoren on growth velocity in children, appetite stimulation, positive effects
on states of loss and in obese individuals, bone turnover, MLG, and sleep, the parameters that should
be further investigated include hospital recovery, functional muscle parameters or adiposity changes in the
context of an exercise program and large long-term safety data [8].
In this sense, the current literature supports an increased risk of hyperglycemia in the context of ibutamoren
use, with few other adverse effects directly attributable to ibutamoren use. However, larger safety studies
are needed to accurately compare the safety of ibutamoren with exogenous GH. Future work should also
focus on determining the effects of ibutamoren on patient outcomes under a variety of conditions, as well as
on body composition in the catabolic exercise and recovery scenario.
Therefore, based on the literature, current indications for the use of ibutamoren include waste treatment
and as treatment for GH deficiency. An initial dose of 25 mg orally daily is recommended for ibutamoren,
as this is the dose studied in randomized controlled trials. These patients should be followed with regular
examinations for changes in body composition and IGF-1 levels during treatment with ibutamoren, as well
as glycemia and HbA1c monitoring [10].
Conclusion
The most confirmed methods of treating sarcopenia are nutritional overfeeding and resistance training, but
studies have shown that supplementation with MK-677 can significantly reduce three important factors
contributing to the development of sarcopenia, which are reduced GH secretion. , fat-free mass loss and
inadequate food intake, safely and effectively. However, it is imperative to increase randomized clinical trials
to establish a consensus treatment.
Declaration of conflicts of interest
The authors declare nothing.
References
1. Melmed S. Physiology of growth hormone. UpToDate. In: Rose BD, editor. UpToDate. 2008.
Waltham, MA.
2. Brooks AJ, Waters MJ. The growth hormone receptor: mechanism of activation and clinical implica-
tions. Nature reviews Endocrinology. 2010;6(9):515–25.
3. FDA. FDA Drug Safety Podcast for Healthcare Professionals: Ongoing safety review of Recombinant
Human Growth Hormone (somatropin) and possible increased risk of death.
4. Plotkin D, Ng J, Farmer M, Gelato M, Kaiser F, Kiel D, Korenman S, McKeever C, Munoz, Schwartz
R, Krupa D, Gormley G, Bach MA. Use of MK-677, an oral GH secretagogue in frail elderly subjects.
Endocrinol Metab 1997;4(SupplA):35–36.
5. Blackman MR, Sorkin JD, Munzer T, Bellantoni MF, Busby-Whitehead J, Stevens TE, et al. Growth
hormone and sex steroid administration in healthy aged women and men: a randomized controlled
trial. JAMA 2002;288:2282–92.
6. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [up-
dated March 2011]. The Cochrane Collaboration; 2011.

6
 7. Del Rincon JP, Iida K, Gaylinn BD, McCurdy CE, Leitner JW, Barbour LA, et al. Growth hormone
regulation of p85 alpha expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism
for growth hormone-mediated insulin resistance. Diabetes 2007;56:1638–46.
Posted on Authorea 26 May 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159050681.10910720 | This a preprint and has not been peer reviewed. Data may be preliminary.

8. Turżańska K, Drelich M, Posturzyńska A. Protein and physical activity in prevention and treatment
of sarcopenia. Wiad Lek. 2019;72(9 cz 1):1660-1666.
9. Nass R, Pezzoli SS, Oliveri MC, et al. Effects of an oral ghrelin mimetic on body composition and
clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med . 2008;149(9):601–611.
doi:10.7326/0003-4819-149-9-200811040-00003.
10. Sigalos JT, Pastuszak AW. The Safety and Efficacy of Growth Hormone Secretagogues. Sex Med
Rev. 2018 Jan;6(1):45-53. doi: 10.1016/j.sxmr.2017.02.004. Epub 2017 Apr 8.
11. Campbell GA, Patrie JT, Gaylinn BD, Thorner MO, Bolton WK. Oral ghrelin receptor agonist MK-
0677 increases serum insulin-like growth factor 1 in hemodialysis patients: a randomized blinded study.
Nephrol Dial Transplant. 2018 Mar 1;33(3):523-530. doi: 10.1093/ndt/gfw474.
12. Adunsky A, Chandler J, Heyden N, Lutkiewicz J, Scott BB, Berd Y, Liu N, Papanicolaou DA. MK-
0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter,
randomized, placebo-controlled phase IIb study. Arch Gerontol Geriatr. 2011 Sep-Oct;53(2):183-9. doi:
10.1016/j.archger.2010.10.004. Epub 2010 Nov 9.
13. Bach MA, Rockwood K, Zetterberg C, Thamsborg G, Hébert R, Devogelaer JP, Christiansen JS, Rizzoli
R, Ochsner JL, Beisaw N, Gluck O, Yu L, Schwab T, Farrington J, Taylor AM, Ng J, Fuh V; MK 0677
Hip Fracture Study Group. The effects of MK-0677, an oral growth hormone secretagogue, in patients
with hip fracture. J Am Geriatr Soc. 2004 Apr;52(4):516-23.
14. Murphy MG, Bach MA, Plotkin D, Bolognese J, Ng J, Krupa D, Cerchio K, Gertz BJ. Oral adminis-
tration of the growth hormone secretagogue MK-677 increases markers of bone turnover in healthy and
functionally impaired elderly adults. The MK-677 Study Group. J Bone Miner Res. 1999 Jul;14(7):1182-
8.
15. Chapman IM, Bach MA, Van Cauter E, Farmer M, Krupa D, Taylor AM, et al. Stimulation of the
growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secre-
togogue (MK-677) in healthy elderly subjects. The Journal of clinical endocrinology and metabo-
lism. 1996;81(12):4249–57.