title: Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial.
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.
  
  
  METHODS
  2-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial.
  
  
  METHODS
  General clinical research center study performed at a university hospital.
  
  
  METHODS
  65 healthy adults (men, women receiving hormone replacement therapy, and women not receiving hormone replacement therapy) ranging from 60 to 81 years of age.
  
  
  METHODS
  Oral administration of MK-677, 25 mg, or placebo once daily.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Study power (duration and participant number) was insufficient to evaluate functional end points in healthy elderly persons.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Ralf
authors.initials: R
authors.lastname: Nass
authors.forename: Suzan S
authors.initials: SS
authors.lastname: Pezzoli
authors.forename: Mary Clancy
authors.initials: MC
authors.lastname: Oliveri
authors.forename: James T
authors.initials: JT
authors.lastname: Patrie
authors.forename: Frank E
authors.initials: FE
authors.lastname: Harrell
authors.forename: Jody L
authors.initials: JL
authors.lastname: Clasey
authors.forename: Steven B
authors.initials: SB
authors.lastname: Heymsfield
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bach
authors.forename: Mary Lee
authors.initials: ML
authors.lastname: Vance
authors.forename: Michael O
authors.initials: MO
authors.lastname: Thorner
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D001066:Appetite / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D019382:Human Growth Hormone / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D007328:Insulin / Q000097:blood; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000033:anatomy & histology; D010146:Pain / Q000139:chemically induced; D013141:Spiro Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D013848:Thigh
chemical_list: D001786:Blood Glucose; D007211:Indoles; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D013141:Spiro Compounds; D019382:Human Growth Hormone; C094817:ibutamoren mesylate