# 2 Year study show that MK677 is very effective



## GYMnTONIC (Jul 24, 2017)

[h=1]Effects of an Oral Ghrelin Mimetic on Body  Composition and Clinical Outcomes in Healthy Older Adults: A Randomized,  Controlled Trial[/h]*

Abstract*

*Background*

Growth  hormone (GH) secretion and muscle mass decline from mid-puberty  throughout life culminating in sarcopenia, frailty, decreased function  and loss of independence.

*Objective*

Determine  if an oral ghrelin mimetic (MK-677) would enhance GH secretion into the  young adult range without serious adverse effects, prevent the decline  of fat-free mass (FFM), and decrease abdominal visceral fat (AVF) in  healthy older adults.

*Design*

Two-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial.

*Setting*

General Clinical Research Center study performed at a University Hospital.

*Participants*

Sixty-five healthy men and women (on or off hormone replacement therapy) ages 60-81.

*Intervention*

Oral administration of MK-677 (25 mg) or placebo once daily.

*Measurements*

Growth  hormone and insulin-like growth factor-I (IGF-I); FFM and AVF were the  primary endpoints after one year of treatment. Other endpoints: weight,  fat mass, insulin sensitivity, lipid and cortisol levels, bone mineral  density, limb lean and fat mass, isokinetic strength, function and  quality of life; all endpoints were assessed at baseline and every 6  months.

*Limitations*

Study design (duration and subject number) not sufficient to evaluate functional endpoints in healthy elderly

*Results*

Daily  MK-677 significantly increased GH and IGF-I levels to those of healthy  young adults without serious adverse effects. With placebo, mean (95%  Cl) FFM decreased -0.5 (-1.1 to 0.2) kg, however, FFM increased 1.1 (0.7  to 1.5) kg with MK-677 (P<0.001, MK-677 _vs_. placebo); body cell mass as reflected by intracellular water _decreased_ -1.0 (-2.1 to 0.2) kg with placebo, but _increased_  0.8 (-0.1 to 1.6) kg with MK-677 (P=0.021). There were no significant  differences in AVF or total fat mass. However, the average increase in  limb fat in the MK-677 group (1.1 kg) was greater than with placebo  (0.24 kg); P=0.001. Body weight increased 0.8 (-0.3 to 1.8) kg with  placebo and 2.7 (2.0 to 3.5) kg with MK-677 (P=0.003). Fasting blood  glucose increased an average of 0.3 mmol/L (5 mg/dL) with MK-677  (P=0.015) and insulin sensitivity declined. The most frequent side  effects were an increase in appetite that subsided within a few months  and transient, mild lower extremity edema and muscle pain. Low density  lipoprotein cholesterol decreased -0.14 (-0.27 to -0.01) mmol/L [-5.4  (-10.4 to -0.4) mg/dL] with MK-677 (P=0.026); there were no differences  in total or high density lipoprotein cholesterol. Cortisol increased 47  (28 to 71) nmol/L [1.7 (1.0 to 2.6 ?g/dL)] with MK-677 (P=0.020).  Changes in bone mineral density consistent with increased bone  remodeling occurred in MK-677-treated subjects. Increased FFM did not  result in changes in strength or function. Two-year exploratory analyses  confirmed the 1-year results.

*Conclusions*

The  ghrelin mimetic MK-677 enhanced pulsatile GH secretion and  significantly increased FFM over 12 months and was generally well  tolerated. Long-term functional, and ultimately pharmaco-economic,  studies in elderly adults are indicated.


*Keywords: *Ghrelin, ghrelin mimetic, body composition, aging, sarcopenia, frailty, healthspan, growth hormone, growth hormone secretagogue
Go to:
*INTRODUCTION*

Aging  is an inevitable process across all species. In humans, muscle mass  declines following its peak in the third decade of life. Muscle mass is  important for physical fitness and metabolic regulation; development of  sarcopenia is a major risk factor for developing frailty, loss of  independence and physical disability in the elderly (1) and is associated with shortened survival in critically-ill patients (2).  With increased lifespan, increasing numbers of adults are becoming  frail and dependent upon others, creating challenges for them, their  families and society.
The decline in fat-free mass (FFM) correlates with the aging-associated decline of growth hormone (GH) secretion (3, 4). Rudman _et al._ noted that aging adults show similar declines in FFM and GH secretion as seen in GH-deficient young adults (5). By the 8th decade, men and women have lost about 7 and 3.8 kg of muscle mass, respectively (3), with an increase in intra-abdominal fat (6, 7).
Previous trials using GH in the elderly were small, poorly controlled and/or too short (8);  in addition, GH replacement does not restore pulsatile GH secretion.  MK-677, the first orally-active ghrelin mimetic (GH secretagogue; GH  secretagogue-receptor agonist), increases pulsatile GH secretion in  older adults to that observed in young adults (9, 10).  The primary objectives were to determine if oral MK-677 (25 mg daily)  in healthy older adults would increase GH and IGF-I levels, prevent the  decline of FFM and decrease abdominal visceral fat (AVF) with acceptable  tolerability.

Go to:
*METHODS*

*Study Design*

This  study was approved by the General Clinical Research Center (GCRC) and  the University of Virginia Institutional Review Boards under IND #  54,041. All subjects gave written informed consent. A two-year,  randomized, double-blind, modified-crossover trial of once-daily oral  administration of 25 mg MK-677 or placebo (2:1 ratio) to healthy older  adults (men, women on and women off hormone replacement therapy) was  performed. After 1 year, MK-677-treated subjects were randomized to  continue on MK-677 (Group 1) or change to placebo (Group 2); the  placebo-treated subjects were given MK-677 during year 2 (Group 3). A  schematic of the study design is provided in APPENDIX FIGURE 1.

*Setting and Participants*

Healthy  older volunteers ≥ 60 years were recruited from the general population  by advertisement and were screened by medical history, physical  examination and laboratory testing to rule out underlying disease.  Exclusion criteria included body mass index ≥ 35 kg/m[SUP]2[/SUP],  strenuous exercise > 60 minutes per day, smoking, diabetes, history  of malignancy (other than some skin cancers), untreated hypertension,  thyroid disease or medications known to affect GH secretion.  Participants were asked to maintain their typical diet and exercise  throughout the study and to report any illnesses, medical procedures or  adverse effects. All subjects were Caucasian, with the exception of 1  Hispanic and 1 African-American man.
At  baseline and every 6 months for 2 years, subjects were admitted to the  GCRC for body composition, body water, lipid and bone mineral density  measurements, frequent blood sampling and completion of quality of life  questionnaires. Tests of strength and function also were performed.  During GCRC admissions, meals were standardized for caloric and nutrient  content. Blood samples for GH were drawn from an indwelling venous  cannula every 10 minutes for 24 hours; subjects were allowed to sleep  after 21:00.

*Randomization and Intervention*

Blinded  supplies of MK-677 and placebo tablets were provided by Merck Research  Laboratories, Inc., stored by a research pharmacist, and were dispensed  in a blinded manner according to a randomization table with  stratification for gender and hormone replacement therapy. Ten mg  tablets were provided for blind back-titration. Placebo or MK-677 (25  mg) tablets were taken once daily between 7 and 9:00 AM (at 9:00 AM  during admissions). All research staff and the volunteers remained  blinded throughout the study and during data verification. Compliance  was monitored by pill counts.

*Outcome Measures*

*Growth Hormone and IGF-I*

Serum GH and IGF-I levels were measured in duplicate in the GCRC Core Laboratory. 24-h mean GH and _e_ndogenous GH secretory dynamics were assessed by Cluster (11) and an automated (12) multiple-parameter deconvolution method (9). Details of all assay methods are provided in APPENDIX 1.

*Body Composition and Bone Mineral Density*

FFM and total body fat were evaluated by a 4-compartment (4-C) model (13) and by dual x-ray absorptiometry (DXA) on a Hologic QDR-2000 (Hologic Inc., Bedford MA) in pencil beam mode (14).  DXA measurements included: i. appendicular lean soft tissue of the arms  and legs as an estimate of total appendicular skeletal muscle mass  (TASM) (15); ii. appendicular fat; iii. bone mineral density of the femoral neck, spine (L2-4) and total hip.

*T-score for TASM/ht[SUP]2[/SUP]*

The DXA TASM estimates were divided by height squared in meters [TASM (kg)/ht[SUP]2[/SUP]] (15). This index of relative limb muscle mass was used to compute a t-score for each individual, relating the TASM/ht[SUP]2[/SUP] to those of gender-concordant young adults (16). Sarcopenia was defined as ≤ 2 SD below young, gender-specific reference populations (17, 18).

*Computed Tomography*

Cross-sectional computed tomography images were used to measure the areas (cm[SUP]2[/SUP]) of abdominal visceral (AVF) and subcutaneous fat, and mid-thigh skeletal muscle at pre-defined anatomic locations (19);  data were not included when the subsequent scan location differed or  there were technical difficulties [N=4 placebo, N=3 MK-677].
DXA and CT scans were analyzed by a single blinded observer (J.L.C.)

*Body Water*

Total body water, using the deuterium oxide (D[SUP]2[/SUP]O) dilution technique (20), and extracellular water by bromide dilution (21)  were measured. Intracellular water was assessed as the difference  between total body water and extracellular water. To determine the  relative relationships of total-, extra- and intra-cellular water, each  component (in kg) was expressed per kg of FFM at each time point. The  scale of measure used in the analysis was chosen _a priori_; the raw data also were analyzed and are reported in typical units for comparison.

*Isokinetic Muscle Strength*

Concentric  force during flexion and extension of the knee and shoulder were  determined every 6 months using an isokinetic dynamometer (Cybex II,  CSM, Inc., Boston, MA). Six repetitions of maximal effort over 90  degrees at 60 degrees/second were performed with the mean of the last 5  repetitions computed by proprietary software (22). Total work (Newton.metres) was calculated by multiplying the mean per repetition by 5.

*Function*

Function  tests performed every 6 months included walking 30 meters as quickly as  possible (best of 2 trials), walking as far as possible in 6 minutes on  an indoor track, descending and ascending 4 flights of stairs, and  rising and sitting 5 times from an armless chair with an 18? seat  height.

*Correction for Height and Gender*

To  compensate for differences in muscle mass between men and women, all  strength and function measurements were analyzed per kg of baseline  appendicular skeletal muscle (lean) from DXA. Arm lean and leg lean were  used for shoulder and knee strength, respectively; baseline TASM (sum  of arms and legs) was used for the function tests. The scale of measure  used in the analysis was chosen _a priori_; the raw data also are reported.

*Quality of Life Assessments*

Subjects  completed 4 questionnaires every 6 months to assess quality of life and  general wellbeing: the 20-item Short Form Health Survey; Beck  Depression Inventory; Pittsburgh Sleep Quality Index; and the Body  Cathexis Scale.
Additional details of quality of life, muscle strength and function assessments are provided in APPENDIX 1.

*Clinical Outcomes*

Every  6 months, cholesterol, cortisol and insulin sensitivity, estimated by  fasting insulin and glucose using the Quicki Index method of Katz _et al_. (23), were measured.



*Read the entire report HERE:*
http://europepmc.org/articles/PMC2757071/


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## Derek Wilson (Jan 8, 2018)

MK 677 can help increase the users? muscle mass and It also improves the bone mineral density and promotes metabolism. These studies helped prove that MK 677 of Blackstone Labs are effective and legit. 

BY the way, such a great study! 

Thanks!


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## mikephilip (Jan 14, 2018)

Can anyone tell me TLDR?


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