Correspondence *3920 Taubman Center, Box 5354, University of Michigan Medical Center, Ann Arbor, MI 48109–5354, USA

Email abarkan@umich.edu

Introduction

Acromegaly is caused by excessive growth hormone (GH) secretion, predominantly from pituitary macroadenomas. Consequently, the objectives of treatment are twofold: abrogation of tumor expansion and management of GH concentrations to control secretion of insulin-like growth factor 1 (IGF-I). Biochemical control is deemed to be achieved if IGF-I concentrations can be reduced to within the normal range for healthy individuals of the same age and sex.¹ Consistent suppression of random GH concentrations to below 2.5 mIU/l is thought to reduce mortality to within normal values.^{2, 3, 4, 5} Despite the application of various therapeutic approaches—such as surgery, radiotherapy, dopamine or somatostatin agonists—about 25% of patients continue to exhibit florid acromegaly.⁶

Pegvisomant is a highly selective, recombinant, GH-receptor antagonist that modifies the action of GH and inhibits production of IGF-I. The mechanisms of action of this drug have been previously described.⁷ Briefly, a Gly120Arg mutation prevents this recombinant protein to bind to the GH receptor, which abolishes receptor activation and signal transduction.^{8, 9, 10, 11, 12, 13} To prolong the half-life and decrease the immunogenicity of pegvisomant, the drug is pegylated to generate a stable 42–46 kDa molecule.^{14, 15} Pegvisomant seems to be highly efficacious in the treatment of acromegaly. Here, we present the long-term data on this therapy, discuss the related risks and benefits, and frame a potential therapeutic approach.

Efficacy of pegvisomant therapy

Pegvisomant can be used alone or in combination with somatostatin analogs. Estimation of plasma GH concentrations cannot be used to monitor pegvisomant therapy, mainly because GH crossreacts with pegvisomant in many GH assays. Normalization of plasma IGF-I concentration is, therefore, the biochemical criterion by which efficacy is assessed in all studies.

Pegvisomant as a single agent

Data are available from three prospective studies and one observational study on the long-term efficacy of pegvisomant monotherapy (Table 1). The three prospective studies followed up a total of 280 patients with acromegaly for up to 18 months.^{16, 17, 18} Following washout periods off other pharmacologic agents, patients were given pegvisomant at doses of 10–40 mg daily. Normalization of IGF-I was seen in 75–97% of patients and was dose-dependent. Of note, the study that reported the highest efficacy for pegvisomant had the least-stringent definition of sustained IGF-I normalization.¹⁷

Table 1 Long-term studies of pegvisomant monotherapy.

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Schreiber et al.¹⁹ conducted an observational study that described 2 years' treatment experience in more than 85% of all German patients with acromegaly who received pegvisomant therapy in 2004–2005. Of 229 participants, more than 71% achieved normal IGF-I concentrations. This level of efficacy was attributed to a lack of treatment standardization, owing to limitations of the study design.

Overall, pegvisomant monotherapy at daily doses of up to 40 mg seems efficacious in patients with acromegaly.

Glucose metabolism

Diabetes affects about 50% of patients with acromegaly^{26, 27, 28, 29} and is associated with hypertension and correlates with the severity of cardiomyopathy.^{30, 31} In seven nondiabetic patients, 4 weeks of pegvisomant monotherapy decreased basal serum insulin levels without attenuating fasting glucose levels.³² Moreover, patients' peripheral and hepatic insulin sensitivities improved. Changes in insulin sensitivity (according to the homeostasis model assessment index) were not demonstrated in patients who received only one dose of pegvisomant,³³ which underscores the importance of sustained treatment in achieving metabolic improvement.

Three trials evaluated changes in carbohydrate metabolism during pegvisomant monotherapy.^{17, 18, 19} Overall, in 280 patients who were followed up for up to 24 months, mean fasting glucose improved significantly, concurrently with reduced mean serum insulin levels. Nonetheless, only Schreiber et al.¹⁹ and Barkan et al.³⁴ demonstrated significant improvements in glycated hemoglobin levels, of about 0.5–1.0%.

The advantage of pegvisomant over somatostatin analogs with respect to carbohydrate metabolism was established in an open-label, crossover study of seven healthy individuals.³⁵ During a short treatment period of 7 days, pegvisomant did not affect fasting glucose levels, insulin levels or response to an oral glucose-tolerance test, as opposed to octreotide, which impaired insulin secretion and augmented glucose levels.

Three studies assessed the influence of pegvisomant on the suppressive effect of somatostatin analogs on insulin secretion.^{22, 24, 34} A total of 96 patients were treated with a combination of pegvisomant and somatostatin analogs or switched from somatostatin to pegvisomant and were followed up for up to 138 weeks. Values for fasting glucose, oral glucose tolerance test results and glycated hemoglobin levels all improved with the combined therapy compared with somatostatin analogs alone. Similarly, when patients were switched from long-acting release octreotide to pegvisomant, glucose metabolism greatly improved, especially in those who already had diabetes.

Cardiovascular risk factors

Bone metabolism

Bone and soft-tissue changes in acromegaly are linked to increased bone turnover and excessive renal synthesis of 1,25-dihyroxy vitamin D, which leads to reduced parathyroid hormone secretion, hypercalciuria and hyperphosphatemia.⁵⁰ Normalization of IGF-I concentrations in 16 patients with pegvisomant-responsive acromegaly led to normalization of levels of bone-resorption markers (e.g. C-terminal crosslinked telopeptide of type I collagen), bone-formation markers (e.g. type I procollagen N-terminal propeptide) and parathyroid hormone.⁵¹

Glucocorticoid axis

In patients with acromegaly, excess GH suppresses 11-hydroxysteroid dehydrogenase type 1, which converts inactive cortisone to active cortisol in peripheral tissues (i.e. adipose, liver, and gonadal tissue). This suppression could worsen glucocorticoid insufficiency. Trainer et al.⁵² have shown that improvement of IGF-I levels achieved with pegvisomant therapy resulted in an increase in the ratio of cortisol to cortisone. Accordingly, when IGF-I is suppressed by pegvisomant, cortisol-replacement therapy should be reduced to avoid iatrogenic glucocorticoid excess.⁵³

Tachyphylaxis

Low levels of antibodies to pegvisomant were detected in 35 of 232 patients;^{16, 17} however, no evidence of tachyphylaxis was detected during follow-up of up to 18 months.

Safety

Tumor size

The first description of tumor growth during pegvisomant therapy in 2001 prompted surveillance by repeated pituitary imaging.⁵⁵ Review of the evaluable literature revealed that 21 cases of tumor growth during pegvisomant treatment had been reported (Table 2).^{17, 18, 19, 22, 23, 24, 34, 56} Only one case of tumor growth was identified in trials that evaluated the combination of pegvisomant and somatostatin analogs;²² the remaining 20 cases occurred in pegvisomant monotherapy trials.

Table 2 Cases of increase in pituitary tumor size on pegvisomant treatment.

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In the study conducted by Schreiber et al.¹⁹ 12 patients had reported increases in tumor size during therapy. Careful case-by-case review demonstrated that in five patients tumor expansion could not be verified by repeated imaging, and in another three patients slow tumor growth was apparent even before the initiation of pegvisomant; growth continued at the same pace during therapy. Another three cases were probably caused by regrowth of the tumor after cessation of somatostatin-analog therapy. In only one case tumor regrowth coincided with the initiation of pegvisomant. In other studies, two cases of tumor enlargement were described, but pegvisomant was continued with no further growth.¹⁷ In addition, despite early impressions to the contrary, tumor growth did not exclusively affect nonirradiated patients; five of the patients had received radiotherapy before pegvisomant initiation.^{19, 34}

Tumor growth might result from a disturbance to the IGF-I negative-feedback loop or a direct (although as yet unknown) effect of the drug on the tumor. Alternatively, in some cases discontinuation of somatostatin analogs might result in tumor regrowth, regardless of pegvisomant therapy. Most importantly, some tumors exhibit a highly aggressive growth pattern and their enlargement might be due to their inherent growth potential rather than any influence of pegvisomant.

Overall, among more than 400 studied patients, only a few have experienced clinically important tumor growth during pegvisomant therapy. Whether this growth occurred as a consequence of pegvisomant therapy or of other factors is uncertain. Nonetheless, until further data become available, regular pituitary imaging is warranted, regardless of whether the patient was irradiated or is taking somatostatin analogs.

Hepatotoxic effects

Hepatotoxic effects are the most serious systemic side effects associated with pegvisomant therapy (Table 3). Two types of hepatic dysfunctions have been reported: cholestatic and hepatocellular.

Table 3 Cases of elevated transaminase levels associated with pegvisomant treatment.

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Cholestatic dysfunction—indicated by elevated biliary enzyme levels, (alkaline phosphatase and -glutamyltranspeptidase) and radiological signs of biliary occlusion—is less common than hepatocellular dysfunction. Many patients form asymptomatic bile stones during somatostatin therapy, but active disease that requires biliary intervention (i.e. cholecystectomy or endoscopic cholangiography) is rare.^{23, 24, 57} As all patients who have developed cholestatic dysfunction during pegvisomant therapy have been previously treated with somatostatin analogs, this complication is probably a side effect related to the latter rather than the former therapy.

The second type of liver dysfunction involves a rise in transaminase levels that can be attributed directly to pegvisomant's effects. Mild elevation of transaminase concentrations is a side effect of many drug therapies and does not generally require treatment modification unless enzyme levels rise higher than three to five times their normal values, or plasma bilirubin levels increase (e.g. as seen with statins or isoniazid). A total of 37 cases of elevated transaminases have been described.^{16, 17, 18, 23, 24, 34, 57} In 24 cases the increases were less than five times normal and did not necessitate treatment modification.^{18, 23, 24, 34, 57} In four cases pegvisomant was continued or halted only transiently, despite alanine aminotransferase levels rising to 7–25 times normal, and no further clinical deterioration was seen.^{24, 34, 57} In the remaining nine patients, pegvisomant was stopped completely and liver abnormalities resolved within a few months.^{16, 17, 24, 57}

Although no severe synthetic liver dysfunction has ever been reported, further information on the long-term effects of pegvisomant administration is required before clear guidelines can be created.

Conclusions

We believe the data collected during the past 7 years indicate that pegvisomant offers an efficacious and safe treatment for acromegaly if patients are carefully selected for therapy and its use is tailored individually. Patients who have previously undergone surgery, particularly for tumor reduction, and those who are resistant or intolerant to somatostatin analogs will probably benefit most. Importantly, unlike somatostatin analogs, pegvisomant does not cause tumor shrinkage. Pegvisomant monotherapy might be considered for patients with glucose intolerance if clinically allowed. The key issues to consider before and throughout therapy are liver function and tumor size. Response to therapy should be assessed by measurement of IGF-I levels in plasma. Although the optimal dose is not yet clearly defined, a starting dose of 10 mg pegvisomant daily seems to be broadly suitable, and escalation up to 40 mg has been possible in most studies. Higher doses than 40 mg could be considered to normalize IGF-I in patients with very high GH levels. Coadministration of somatostatin analogs might improve the efficacy of treatment if pegvisomant doses need to be reduced.⁶¹ Adverse events might require permanent or temporary cessation of pegvisomant therapy; treatment with somatostatin analogs, repeated surgery or radiation therapy should also be discussed (Figure 1). These recommendations might change as more information becomes available.

Figure 1 Flow-chart of suggested options for pegvisomant treatment.

Abbreviations: IGF-I, insulin-like growth factor 1; LFTs, liver function test results; SRL, somatostatin receptor ligands.

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Acknowledgments

I Hodish and A Barkan have received grants from the NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases). Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Subject areas under which this article appears: Pituitary gland (including the pineal gland)