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Randomized Controlled Trial
. 2008 Nov 4;149(9):601-11.
doi: 10.7326/0003-4819-149-9-200811040-00003.

Effects of an Oral Ghrelin Mimetic on Body Composition and Clinical Outcomes in Healthy Older Adults: A Randomized Trial

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Free PMC article
Randomized Controlled Trial

Effects of an Oral Ghrelin Mimetic on Body Composition and Clinical Outcomes in Healthy Older Adults: A Randomized Trial

Ralf Nass et al. Ann Intern Med. .
Free PMC article

Abstract

Background: Growth hormone secretion and muscle mass decline from midpuberty throughout life, culminating in sarcopenia, frailty, decreased function, and loss of independence. The decline of growth hormone in the development of sarcopenia is one of many factors, and its etiologic role needs to be demonstrated.

Objective: To determine whether MK-677, an oral ghrelin mimetic, increases growth hormone secretion into the young-adult range without serious adverse effects, prevents the decline of fat-free mass, and decreases abdominal visceral fat in healthy older adults.

Design: 2-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial.

Setting: General clinical research center study performed at a university hospital.

Participants: 65 healthy adults (men, women receiving hormone replacement therapy, and women not receiving hormone replacement therapy) ranging from 60 to 81 years of age.

Intervention: Oral administration of MK-677, 25 mg, or placebo once daily.

Measurements: Growth hormone and insulin-like growth factor I levels. Fat-free mass and abdominal visceral fat were the primary end points after 1 year of treatment. Other end points were body 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 end points were assessed at baseline and every 6 months.

Results: Daily administration of MK-677 significantly increased growth hormone and insulin-like growth factor I levels to those of healthy young adults without serious adverse effects. Mean fat-free mass decreased in the placebo group but increased in the MK-677 group (change, -0.5 kg [95% CI, -1.1 to 0.2 kg] vs. 1.1 kg [CI, 0.7 to 1.5 kg], respectively; P < 0.001), as did body cell mass, as reflected by intracellular water (change, -1.0 kg [CI, -2.1 to 0.2 kg] vs. 0.8 kg [CI, -0.1 to 1.6 kg], respectively; P = 0.021). No significant differences were observed in abdominal visceral fat or total fat mass; however, the average increase in limb fat was greater in the MK-677 group than the placebo group (1.1 kg vs. 0.24 kg; P = 0.001). Body weight increased 0.8 kg (CI, -0.3 to 1.8 kg) in the placebo group and 2.7 kg (CI, 2.0 to 3.5 kg) in the MK-677 group (P = 0.003). Fasting blood glucose level increased an average of 0.3 mmol/L (5 mg/dL) in the MK-677 group (P = 0.015), and insulin sensitivity decreased. The most frequent side effects were an increase in appetite that subsided in a few months and transient, mild lower-extremity edema and muscle pain. Low-density lipoprotein cholesterol levels decreased in the MK-677 group relative to baseline values (change, -0.14 mmol/L [CI, -0.27 to -0.01 mmol/L]; -5.4 mg/dL [CI, -10.4 to -0.4 mg/dL]; P = 0.026); no differences between groups were observed in total or high-density lipoprotein cholesterol levels. Cortisol levels increased 47 nmol/L (CI, 28 to 71 nmol/L (1.7 microg/dL [CI, 1.0 to 2.6 microg/dL]) in MK-677 recipients (P = 0.020). 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. Two-year exploratory analyses confirmed the 1-year results.

Limitation: Study power (duration and participant number) was insufficient to evaluate functional end points in healthy elderly persons.

Conclusion: Over 12 months, the ghrelin mimetic MK-677 enhanced pulsatile growth hormone secretion, significantly increased fat-free mass, and was generally well tolerated. Long-term functional and, ultimately, pharmacoeconomic, studies in elderly persons are indicated.

Figures

APPENDIX FIGURE 1
APPENDIX FIGURE 1. Study Design
Year 1: In each of 3 cohorts [23 men, 25 women on HRT and 17 women off HRT], 2/3 received oral MK-677 (25 mg daily) and 1/3 received placebo. At the end of year 1, 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 treatment in year 2 (Group 3).
APPENDIX FIGURE 2
APPENDIX FIGURE 2. Individual IGF-I Results
Serum IGF-I levels at baseline, 6 and 12 months in each subject. The lower limit of the IGF-I normal range is indicated: older adults (59-225 μg/L, lower dotted line); young adults aged 21-25 (116-358 μg/L, upper dashed line).IGF-I = insulin-like growth factor-I
APPENDIX FIGURE 3
APPENDIX FIGURE 3. Individual t-scores for TASM/ht2
Sarcopenia was defined as a t-score ≤ 2 SD below the young, gender-concordant population (17, 18). Dashed lines indicate -1 and -2 SD for t-score. TASM = total appendicular skeletal muscle mass by dual energy x-ray absorptiometry (DXA). TASM divided by height (meters) squared = an index of relative limb muscle mass used to compute a t-score by relating it to gender-concordant young adults
APPENDIX FIGURE 4
APPENDIX FIGURE 4. Individual FBG (Panels A and B) and HbA1c levels (Panels C and D)
Fasting blood glucose (FBG) and hemoglobin A1c (HBA1c) after 12 months of placebo (upper panels) and MK-677 (lower panels). FBG (lower dashed line=upper limit normal range, middle dashed line=prediabetic range, upper dotted line=diabetes mellitus); HbA1c (dashed line=upper limit of normal range).
APPENDIX FIGURE 5
APPENDIX FIGURE 5. Serum 24-h mean GH and IGF-I levels every 6 months over 2 years
GH (Panel A) and IGF-I (Panel B) data were not normally distributed and were analyzed on the natural logarithmic scale; line graphs show geometric means and 95% confidence intervals. An asterisk indicates that the fold change from baseline to 24 months was significant for that group (Bonferroni-adjusted P<0.001). In Panel A, the 24-h mean GH for young men and women combined (~1.3 μg/L) is indicated by a dashed line. In Panel B the lower limit of the IGF-I normal range is indicated: older adults (59-225 μg/L, lower dotted line); young adults aged 21-25 (116-358 μg/L, upper dashed line). GH=growth hormone, IGF-I=insulin-like growth factor-I
APPENDIX FIGURE 6
APPENDIX FIGURE 6. Changes from baseline in FFM and t-scores for TASM/ht2 every 6 months for 2 years
Data presented are arithmetic mean (SE) changes from baseline at 6, 12, 18 and 24 months; FFM (Panel A), t-scores for TASM/ht2 (Panel B). An asterisk indicates a significant difference in the change from baseline to 24 months within the group (Bonferroni-adjusted P values). In subjects treated with placebo followed by MK-677 in year 2 (Group 3), the change from baseline in FFM was significant (P=0.026), however, the t-score for TASM/ht2 was not significant compared with baseline (t-scores did increase in response to MK-677 in year 2, but had declined in year 1 during placebo). FFM = fat-free mass by DXA, TASM=total appendicular skeletal muscle mass from DXA, TASM divided by height (meters) squared = an index of relative limb muscle mass used to compute a t-score by relating it to gender-concordant young adults
APPENDIX FIGURE 7
APPENDIX FIGURE 7. Changes from baseline in body weight, total body fat, FBG and AVF every 6 months for 2 years
Data presented are arithmetic mean (SE) changes from baseline at 6, 12, 18 and 24 months; body weight (Panel A), total body fat mass by DXA (Panel B), FBG (Panel C) and AVF (Panel D). An asterisk indicates a significant difference in the change from baseline to 24 months within the group (Bonferroni-adjusted P values). In subjects treated with placebo followed by MK-677 in year 2 (Group 3), the change from baseline in body weight and FBG were significant (P=0.002 and P=0.001, respectively). In subjects treated with MK-677 for 2 years (Group 1), body weight was significantly increased (P=0.001), but fasting blood glucose was not (P=0.093). Total body fat mass by 4-C model was significantly increased (P=0.016) in Group 1, but body fat by DXA was not (P=0.062). There were no significant changes in AVF from baseline to 24 months in any group. FBG=fasting blood glucose), AVF=abdominal visceral fat from computed tomography (CT), DXA = dual energy x-ray absorptiometry
FIGURE 1
FIGURE 1
Participant Flow Through the Study
FIGURE 2
FIGURE 2. Serum 24-h mean GH and IGF-I results in pivotal year 1
GH and IGF-I data were not normally distributed and were analyzed on the natural logarithmic scale; line graphs show geometric means and 95% confidence intervals. Results of GH deconvolution analysis are included in APPENDIX TABLE 1. Panels A and B: 24-h mean GH and serum IGF-I levels at baseline, 6 and 12 months. An asterisk indicates P<0.001, MK-677 vs. placebo. In Panel A, the 24-h mean GH for young men and women combined (~1.3 μg/L) is indicated by a dashed line. In Panel B the lower limit of the IGF-I normal range is indicated: older adults (59-225 μg/L, lower dotted line); young adults aged 21-25 (116-358 μg/L, upper dashed line). GH=growth hormone, IGF-I=insulin-like growth factor-I. Panel C: Representative 24-h GH profiles in one 70-year-old man, BMI, 23.2 kg/m2, treated for one year with MK-677. 24-h mean GH levels were 0.37, 1.0 and 0.86 μg/L at baseline (open circles), 6 months (triangles) and 12 months (closed circles), respectively. Note that the pulsatile pattern of GH secretion at baseline is maintained and enhanced at 6 and 12 months, primarily as a result of increased secretion per peak rather than peak frequency.
FIGURE 3
FIGURE 3. Changes in body composition at 12 months
Graphs show arithmetic differences (95% CI). An asterisk indicates a significant difference (MK-677 vs. placebo) at 12 months. Panel A: Changes in fat-free mass (FFM, by 4-C model and by DXA) and TASM (total appendicular skeletal muscle mass by DXA). Panel B: Changes in TBW (total body water), ECW (extracellular water) and ICW (intracellular water). The increase in TBW and increase in ICW with active drug are consistent with the anabolic effects of MK-677. Panel C: Changes in abdominal visceral and abdominal subcutaneous fat cross-sectional areas measured by CT. Panel D: Changes in body weight and total fat mass (by 4-C model and DXA). CT = computed tomography; DXA = dual energy x-ray absorptiometry
FIGURE 4
FIGURE 4. Summary of mean changes in fat and FFM at 12 months
Fat mass (yellow) and fat-free mass (blue) from DXA; limb (solid bars) = appendicular lean soft tissue and appendicular fat; non-limb (hatched bars) = total minus limb. DXA = dual energy x-ray absorptiometry

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