11.17.2008

Growth Hormone and Beta Amyloid: Merck Study
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Insulin growth factor 1

Sometimes research leads to unexpected results. For example, stimulating growth hormone secretion in Alzheimer's patients did not help clear protein-containing beta-amyloid plaques or halt disease progression, as was hypothesized, particularly in APOEe4 carriers. Researchers used an experimental growth hormone secretion booster known as MK-677.

While the growth hormone dramatically increased levels of insulin-like growth factor-1 (IGF-1), which in animal studies had been shown to increase clearance of beta-amyloid, there was no incipient trend of beta-amyloid clearance in a subgroup of patients.

"Given that multiple pathways contribute to the clinical Alzheimer's disease phenotype," the scientists wrote, "it is possible that selectively altering the IGF-1 system alone is insufficient to slow the overall rate of disease progression."

563 patients age 50 or older were analyzed at 45 sites. Participants were randomized to double-blind treatment with the growth hormone-stimulating agent MK-677 at a dose of 25 mg or placebo for 12 months.

Growth hormone secretagogue therapy had the expected effect on serum IGF-1 levels -- a 60.1% increase at six weeks and a 72.9% increase at 12 months -- that were significantly greater than in the placebo group (difference 61.4 ng/mL at 12 months, P<0.001).

But the researchers noted that the effect was small and substantially less than reported for FDA-approved cholinesterase inhibitors.

The only subgroup that appeared to potentially benefit from growth hormone treatment were noncarriers of the apolipoprotein E (APOE) epsilon (e) 4 allele gene, that is, individuals with APOE2 or APOE3 biomarkers. (the link provides a general overview of APOE)

This group had a marginally significant improvement in global clinical status measured by CIBIC-plus (P≤0.05) and some numerical but nonsignificant effects on the other efficacy outcomes.

The researchers noted that this was not a prespecified subgroup analysis and should be interpreted with caution.

Source reference:

Sevigny JJ, et al "Growth hormone secretagogue MK-677: No clinical effect on AD progression in a randomized trial" Neurology 2008; 71:1702-1708.

Note: The research was funded by Merck and the authors have been financially supported by, and/or own stock-options of Merck, Inc.

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