The GH receptor antagonist Pegvisomant in the treatment of acromegaly

Abstract

Understanding the mechanisms by which growth hormone (GH) interacts with its receptor has led to the design of compounds that function as GH receptor antagonists. One such compound has been conjugated to polyethylene glycol (PEG) to produce a drug, pegvisomant, which has been extensively investigated as a treatment for acromegaly and is now available for clinical use in the United States and Europe. Studies have shown that the drug is able to normalise circulating concentrations of insulin-like growth factor I (IGF-I), the principal mediator of GH action, in 97% of patients with active acromegaly, as well as improve the symptoms and signs associated with GH excess. Unlike other medical therapies, pegvisomant does not have as its target the somatotroph pituitary tumour responsible for excess GH secretion. All patients have therefore undergone regular surveillance imaging to ensure that interruption of the GH/IGF-I feedback loop is not associated with accelerated tumour growth. Overall, there is no evidence that pegvisomant therapy is associated with an increase in pituitary tumour volume but periodic radiological surveillance is clearly mandatory. The fact that pegvisomant does not act on other endocrine systems has facilitated careful dissection of many of the metabolic consequences of GH excess and documentation of the effect of GH receptor blockade. Active acromegaly is associated with a variety of metabolic derangements, including abnormal lipoprotein metabolism, accelerated cortisol metabolism and insulin resistance (IR). In this talk, particular focus will be given to insulin resistance and glucose homeostasis, which are believed to be important contributory factors in the increased cardiovascular morbidity and mortality associated with acromegaly. Although the IR of acromegaly is well documented, it does not, per se, predict glucose tolerance, as measurements of insulin sensitivity (IS) are equivalent in patients with or without carbohydrate intolerance. Compensatory β-cell hyperfunction is seen in patients with normal glucose tolerance but not in those with diabetes mellitus. The effect of somatostatin analogs on glucose tolerance is complex and unpredictable; glucose tolerance improves in some patients by virtue of better control of the GH-IGF-I axis but often worsens by virtue of inhibition of pancreatic insulin release. No published data exist regarding the effect of cabergoline on IR and glucose tolerance, although experience with bromocriptine would suggest that dopamine agonists improve glycaemic control in proportion to the degree of control of GH hypersecretion. Significant decreases in plasma glucose and insulin concentrations have been observed in acromegalic patients treated with pegvisomant; and there are anecdotal reports of patients with acromegaly and diabetes treated with pegvisomant in whom it has been necessary to reduce the dose of oral hypoglycemic agents. However, to date, studies of pegvisomant have included a substantial proportion of patients with complete or partial OT resistance, such that the improvements in IS may, in part, have been consequent upon better biochemical control of acromegaly. No randomised, comparative studies of pegvisomant and SST are currently available, although preliminary data from a recent observational study of patients converted from depot OT to pegvisomant suggest that treatment with pegvisomant may be associated with improved IS and overall glucose tolerance.