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

Context The age-related decline of growth hormone secretion may play a role in sarcopenia and frailty. Content In this randomized trial, 65 healthy older adults were assigned to receive placebo or MK-677, an oral ghrelin mimetic that increased pulsat... show more

Context The age-related decline of growth hormone secretion may play a role in sarcopenia and frailty. Content In this randomized trial, 65 healthy older adults were assigned to receive placebo or MK-677, an oral ghrelin mimetic that increased pulsatile growth hormone secretion to young-adult levels. Over 1 year, lean fat-free mass increased 1.1 kg with MK-677 and decreased 0.5 kg with placebo. MK-677 did not affect strength and function, but insulin sensitivity declined and mean serum glucose levels increased 0.28 mmol/L (5 mg/dL). Caution This short-term trial was underpowered to detect functional changes and adverse events. Implication An oral ghrelin mimetic increases pulsatile growth hormone secretion and alters body composition in healthy older adults. The Editors Aging is an inevitable process across all species. In humans, muscle mass declines after reaching its peak in the third decade of life. Muscle mass is important for physical fitness and metabolic regulation; sarcopenia is a major risk factor for frailty, loss of independence, and physical disability in elderly persons (1) and is associated with shortened survival in critically ill patients (2). As lifespans increase, more adults are becoming frail and dependent on others, which creates challenges for them, their families, and society. The decrease in fat-free mass correlates with the aging-associated decrease in growth hormone secretion (3, 4). Aging adults show decreases in fat-free mass and growth hormone secretion similar to those seen in growth hormonedeficient young adults (5). By the eighth decade, men and women lose approximately 7 and 3.8 kg of muscle mass, respectively (3), and gain intra-abdominal fat (6, 7). Previous trials in which growth hormone was administered to elderly persons were small, poorly controlled, or too short (8); in addition, growth hormone replacement does not restore pulsatile growth hormone secretion. MK-677, the first orally active ghrelin mimetic (a growth hormone secretagogue and growth hormone secretagoguereceptor agonist), increases pulsatile growth hormone secretion in older adults to levels observed in young adults (9, 10). Our primary objectives were to determine whether 25 mg of oral MK-677 daily would increase growth hormone and insulin-like growth factor I (IGF-I) levels in healthy older adults, prevent the decline in fat-free mass, and decrease abdominal visceral fat, with acceptable tolerability. Methods Design The General Clinical Research Center (GCRC) and the University of Virginia institutional review boards approved this study. All participants gave written informed consent. We performed a 2-year, randomized, double-blind, modified crossover trial in which healthy older men, women receiving hormone replacement therapy, and women not receiving hormone replacement therapy received oral MK-677, 25 mg, or placebo (in a 2:1 ratio) daily. After 1 year, participants receiving MK-677 were randomly assigned to continue receiving MK-677 (group 1) or change to placebo (group 2); participants receiving placebo were given MK-677 during year 2 (group 3). Appendix Figure 1 shows the study design. Supplement. Appendix Materials Setting and Participants We recruited healthy volunteers older than 60 years of age from the general population by advertisement and screened them by medical history, physical examination, and laboratory testing to rule out underlying disease. Exclusion criteria were body mass index greater than 35 kg/m2, strenuous exercise for more than 60 minutes per day, smoking, diabetes, history of cancer (other than some types of skin cancer), untreated hypertension or thyroid disease, or medications known to affect growth hormone secretion. We asked participants to maintain their typical diet and exercise throughout the study and to report any illnesses, medical procedures, or adverse effects. All participants were white, with the exception of 1 Hispanic and 1 African-American man. At baseline and every 6 months for 2 years, we admitted participants to the GCRC for measurement of body composition, body water, lipids, and bone mineral density; frequent blood sampling; and completion of quality-of-life questionnaires. We also performed tests of strength and function. During GCRC admissions, we standardized meals for caloric and nutrient content. Blood samples for growth hormone were drawn through an indwelling venous cannula every 10 minutes for 24 hours; participants were allowed to sleep after 9 p.m. Randomization and Intervention MK-677 and placebo tablets were provided by Merck Research Laboratories (Rahway, New Jersey) in a blinded manner and stored by a research pharmacist and dispensed in a blinded manner according to a randomization table with stratification for sex and hormone replacement therapy. Ten-mg tablets were provided for blinded back-titration. Participants were instructed to take the placebo or MK-677 tablets once daily between 7:00 and 9:00 a.m. (or at 9:00 a.m. during admissions). All research staff and volunteers remained blinded throughout the study and during data verification. We monitored adherence by pill counts. Outcome Measures We measured serum growth hormone and IGF-I levels in duplicate in the GCRC Core Laboratory. We assessed 24-hour mean growth hormone and endogenous growth hormone secretory dynamics by using the cluster method (11) and an automated multiple-parameter deconvolution method (9, 12). The Appendix provides details of all assay methods. We evaluated fat-free mass and total body fat by using a 4-compartment model (13) and dual x-ray absorptiometry (DXA) on a Hologic QDR-2000 (Hologic, Bedford, Massachusetts) in pencil-beam mode (14). Dual x-ray absorptiometry measurements included appendicular lean soft tissue of the arms and legs as an estimate of total appendicular skeletal muscle mass (TASM) (15); appendicular fat; and bone mineral density of the femoral neck, spine (L2L4), and total hip. We divided the DXA TASM estimates by heig show less