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

A Randomized Trial

  1. Ralf Nass, MD;
  2. Suzan S. Pezzoli, BA;
  3. Mary Clancy Oliveri, MS;
  4. James T. Patrie, MS;
  5. Frank E. Harrell, Jr., PhD;
  6. Jody L. Clasey, PhD;
  7. Steven B. Heymsfield, MD;
  8. Mark A. Bach, MD;
  9. Mary Lee Vance, MD; and
  10. Michael O. Thorner, MB, BS, DSc
  1. From the University of Virginia, Charlottesville, Virginia; Vanderbilt University School of Medicine, Nashville, Tennessee; University of Kentucky, Lexington, Kentucky; and Merck Research Laboratories, Rahway, New Jersey.

    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 g/dL [CI, 1.0 to 2.6 g/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.

    Article and Author Information

    • Grant Support: By National Institutes of Health grants DK-32632 (Dr. Thorner) and RR-00847 (GCRC). Dr. Nass was supported in part by a grant from Deutsche Forschungsgemeinschaft (Na 317/1-1, Na 317/1-2). Merck Research Laboratories provided MK-677 and placebo. Additional support for assays was provided by grants NIH P30-DK 56336 (University of Alabama at Birmingham, Birmingham, Alabama) and NIH PO1-DK42618 (Columbia University, New York, New York).

    • Acknowledgment: The authors thank Mark L. Hartman, MD, and Arthur Weltman, PhD, for their contributions; Stephanie Studenski, MD, MPH, and Bette Ann Harris, DPT, MS, for review of the strength and function data; and Sue Brown, MD, for review of the bone data. They also thank Michael Johnson, PhD, and Paula Veldhuis for analysis of pulsatile GH secretion; Isao Eto, PhD; Alexandra Vyazovkina; Barbara Gower, PhD; Timothy R. Nagy, PhD; Jack Wang; and Jean Bergeron, MD, for laboratory work; and Shigehiro Oishi, PhD, for quality-of-life analyses. Finally, the authors thank the GCRC staff for care of our volunteers and the nurses; the Core Laboratory and Metabolic Kitchen personnel; and the staff of the Exercise Physiology Laboratory for performing body composition, strength, and function testing.

    • Potential Financial Conflicts of Interest: Employment: S.B. Heymsfield (Merck), M.A. Bach (Merck). Consultancies: M.O. Thorner (Merck). Honoraria: M.O. Thorner (Ipsen, Tercica, University of California Los Angeles, Duke University, New York Academy of Arts and Sciences). Stock ownership or options (other than mutual funds): M.A. Bach (Merck). Grants received: M.O. Thorner (National Institutes of Health, Bristol-Myers Squibb). Patents received: M.A. Bach (Merck). Patents pending: M.O. Thorner (methods for treating sarcopenia with a growth hormone secretagogue).

    • Reproducible Research Statement: Study protocol and statistical code: Available from Dr. Thorner (mot{at}virginia.edu). Data set: Not available.

    • Requests for Single Reprints: Michael O. Thorner, MB, BS, DSc, Department of Medicine, Box 801411, University of Virginia Health System, 450 Ray C. Hunt Drive, Aurbach Building, Room 2323, Charlottesville, VA 22908; e-mail, mot{at}virginia.edu.

    • Current Author Addresses: Drs. Nass and Thorner, Ms. Pezzoli, and Ms. Oliveri: Department of Medicine, Box 801411, University of Virginia Health System, 450 Ray C. Hunt Drive, Aurbach Building, Room 2323, Charlottesville, VA 22908.

    • Mr. Patrie: Department of Public Health Sciences, University of Virginia Health System, Box 800717, Charlottesville, VA 22908.

    • Dr. Harrell: Department of Biostatistics, Vanderbilt University School of Medicine, S2323 MCN, 1161 21st Avenue South, Nashville, TN, 37235.

    • Dr. Clasey: Department of Kinesiology and Health Promotion, University of Kentucky, 216 Seaton Center, Lexington, KY 40506.

    • Drs. Heymsfield and Bach: Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, NJ 07065.

    • Dr. Vance: Department of Medicine, University of Virginia Health System, Box 800601, Charlottesville, VA 22908.

    • Author Contributions: Conception and design: R. Nass, S.S. Pezzoli, F.E. Harrell, M.A. Bach, M.L. Vance, J.L. Clasey, M.O. Thorner.

    • Analysis and interpretation of the data: R. Nass, S.S. Pezzoli, J.T. Patrie, F.E. Harrell, J.L. Clasey, S.B. Heymsfield, M.O. Thorner.

    • Drafting of the article: R. Nass, S.S. Pezzoli, J.T. Patrie, M.L. Vance, M.O. Thorner.

    • Critical revision of the article for important intellectual content: R. Nass, S.S. Pezzoli, J.T. Patrie, S.B. Heymsfield, M.A. Bach, M.L. Vance, M.O. Thorner.

    • Final approval of the article: R. Nass, S.S. Pezzoli, M. C. Oliveri, J.T. Patrie, F.E. Harrell, J.L. Clasey, S.B. Heymsfield, M.A. Bach, M.L. Vance, M.O. Thorner.

    • Provision of study materials or patients: R. Nass, M.C. Oliveri, M.O. Thorner.

    • Statistical expertise: J.T. Patrie, F.E. Harrell.

    • Obtaining of funding: M.A. Bach, M.O. Thorner.

    • Administrative, technical, or logistic support: R. Nass, S.S. Pezzoli, M.C. Oliveri, M.L. Vance, M.O. Thorner.

    • Collection and assembly of data: R. Nass, S.S. Pezzoli, M.C. Oliveri, M.L. Vance, M.O. Thorner.

    • ClinicalTrials.gov registration number: NCT00474279.

    Responses to this article

    • Effects of an Oral Ghrelin Mimetic on Body Composition and Clinical Outcomes in Healthy Older Adults
      • Michael O. Thorner and
      • Ralf M. Nass, Mary Lee Vance
      Ann Intern Med published online October 26, 2009
    • Aging process is a disease
      • Hernando Rafael
      Ann Intern Med published online October 26, 2009
    • To proof a concept of a drug without side effects
      • Markus Gaugg and
      • Markus Gaugg
      Ann Intern Med published online October 26, 2009
    • Strategies for remaining as healthy adults
      • Jim Webster and
      • N/A
      Ann Intern Med published online October 26, 2009

    Summary for Patients

    • Summaries for Patients:Effects of an Oral Ghrelin Mimetic on Body Composition and Clinical Outcomes in Healthy Older Adults Ann Intern Med November 4, 2008 149:I-36
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