Oral Ghrelin Mimetic May Improve Body Composition, Clinical Outcomes

November 7, 2008 — Growth hormone secretion and fat-free mass were increased in elderly patients with use of the oral ghrelin mimetic MK-677, according to the results of a 2-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial reported in the November 4 issue of theAnnals of Internal Medicine.

“Growth hormone secretion and muscle mass decline from midpuberty throughout life, culminating in sarcopenia, frailty, decreased function, and loss of independence,” write Ralf Nass, MD, from the University of Virginia in Charlottesville, and colleagues. “The decline of growth hormone in the development of sarcopenia is one of many factors, and its etiologic role needs to be demonstrated…. 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.”

At a general clinical research center of a university hospital, 65 healthy adults were randomly assigned to receive oral administration of 25 mg of either MK-677 or placebo once daily. Participants were aged 60 to 81 years and included men, women receiving hormone replacement therapy, and women not receiving hormone replacement therapy.

The main outcomes were fat-free mass and abdominal visceral fat after 1 year of treatment. Other study measurements, determined at baseline and every 6 months, included levels of growth hormone and IGF-I, 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.

Participants who received daily administration of MK-677 had significant increases in growth hormone and IGF-I levels, matching those of healthy young adults. No serious adverse effects were observed.

Although mean fat-free mass decreased in the placebo group, it increased in the MK-677 group (change, −0.5 kg [95% confidence interval (CI), −1.1 to 0.2 kg] vs 1.1 kg [95% CI, 0.7 – 1.5 kg], respectively; P < .001). Similar trends were noted for body cell mass, as reflected by intracellular water (change, −1.0 kg [95% CI, −2.1 to 0.2 kg] vs 0.8 kg [95% CI, −0.1 to 1.6 kg], respectively; P = .021).

Abdominal visceral fat and total fat mass were not significantly different between groups. However, the average increase in limb fat was greater in the MK-677 group than in the placebo group (1.1 kg vs 0.24 kg; P = .001). Increase in body weight was 0.8 kg (95% CI, −0.3 to 1.8 kg) with placebo and 2.7 kg (95% CI, 2.0 – 3.5 kg) with MK-677 (P = .003).

In the MK-677 group, fasting blood glucose level increased 0.3 mmol/L (5 mg/dL) on average (P = .015), and insulin sensitivity decreased. The most common adverse effects were transient increase in appetite that resolved in a few months and mild, self-limited lower-extremity edema and muscle pain.

Compared with baseline values, low-density lipoprotein cholesterol levels decreased in the MK-677 group by −0.14 mmol/L (95% CI, −0.27 to −0.01 mmol/L [−5.4 mg/dL; 95% CI, −10.4 to −0.4 mg/ dL]; P = .026).

Total or high-density lipoprotein cholesterol levels did not differ between groups. In the MK-677 group, cortisol levels increased 47 nmol/L (95% CI, 28 – 71 nmol/L;1.7 mcg/dL [95% CI, 1.0 – 2.6 mcg/dL; P = .020), and changes in bone mineral density occurred that were consistent with increased bone remodeling. Increased fat-free mass was not associated with changes in strength or function. The 1-year findings were confirmed by 2-year exploratory analyses.

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

Limitations of this study include its relatively short duration, small sample size, insufficient power to determine functional end points in healthy elderly persons, and combining the results for men and women, which may have missed important sex effects.

“The promise of MK-677 is that it seems to restore endogenous growth hormone levels in a physiologic secretory pattern, unlike the single high-amplitude pulse observed after exogenous growth hormone administration,” the study authors conclude. “We believe that our study sets the stage for an adequately powered clinical trial of sufficient duration in a population vulnerable to frailty.”

The National Institutes of Health and Deutsche Forschungsgemeinschaft supported this study. Merck Research Laboratories provided MK-677 and placebo and employs 2 of the authors. One of the authors reports various financial relationships with Merck, Ipsen, Tercica, University of California–Los Angeles, Duke University, New York Academy of Arts and Sciences, and Bristol-Myers Squibb and has a patent pending for methods for treating sarcopenia with a growth hormone secretagogue.

Ann Intern Med. 2008;149:601–611.

Source: Oral Ghrelin Mimetic May Improve Body Composition, Clinical Outcomes

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