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2 year study shows that MK677 is very effective!

GYMnTONIC

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[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 µg/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
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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.

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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 endogenous 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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Thabks for posting this. Ive been on the fence about peptides and gh but think Im about to order some
 
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