European Journal of Endocrinology (2006) 154 213–220 ISSN 0804-4643

CASE REPORT Elevated transaminases during medical treatment of acromegaly: a review of the German pegvisomant surveillance experience and a report of a patient with histologically proven chronic mild active H Biering1, B Saller4,*, J Bauditz1, M Pirlich1, B Rudolph2, A Johne3, M Buchfelder5,*, K Mann6,*, M Droste7,*, I Schreiber4, H Lochs1 and C J Strasburger1,* 1Department of Gastroenterology, Hepatology and Endocrinology, 2Institute of Pathology and 3Institute for Clinical Pharmacology, Charite´-Universita¨tsmedizin Berlin, 10117 Berlin, Germany, 4Pfizer Pharma GmbH, Karlsruhe, Germany, 5Department of Neurosurgery, University Hosiptal, Erlangen, Germany, 6Division of Endocrinology, Department of Medicine, University of Duisberg-Essen, Germany and 7Oldenburg, Germany (Correspondence should be addressed to C J Strasburger, Division of Clinical Endocrinology, Department of Medicine, Charite´-Universita¨tsmedizin Berlin, Schumannstr. 20/21, 10117 Berlin, Germany; Email: [email protected])

*On behalf of the German pegvisomant investigators

Abstract Objective: The new GH receptor antagonist pegvisomant is the most effective medical therapy to nor- malize IGF-I levels in patients with acromegaly. Based on currently available data pegvisomant is well tolerated; however, treatment-induced elevation of transaminases has been reported and led to the necessity for drug discontinuation in some patients in the pivotal studies. The aim of this study was to evaluate and characterize the prevalence of elevated transaminases and to describe in detail the findings in a single case who required drug discontinuation because of elevation of transaminases which emerged during treatment and who underwent biopsy. Design and methods: Retrospective safety analyses were carried out on 142 patients with acromegaly receiving pegvisomant treatment in Germany between March 2003 and the end of 2004. Of these patients, 123 were documented in a post-marketing surveillance study, one case of elevated transam- inases was reported spontaneously and the other patients were treated in a clinical study. Results: Mean treatment duration with pegvisomant in the ongoing observational study at the end of 2004 was 28.3^19.9 (S.D.) weeks. Twelve out of the 142 patients had elevated transaminases above three times the upper limit of normal, likely caused by biliary obstruction in five of the patients. All patients but one affected by elevated transaminases had been previously treated with somatostatin analogues. In six out of 142 (4%) of patients, pegvisomant was permanently withdrawn because of elevated transaminases. The same number of patients showed a transient increase of transaminases with either spontaneous remission without dose modification (n ¼ 4) or no re-increase of transamin- ases after temporary discontinuation and re-exposure (n ¼ 2). The liver biopsy of one patient who was permanently withdrawn showed a chronic mild hepatitis with a mixed portal inflammation including eosinophilic granulocytes. Conclusions: should be regularly followed on pegvisomant treatment. Biliary com- plications, which may arise from restitution of normal gall bladder motility after cessation of somato- analogue treatment, need to be differentiated from pegvisomant-induced abnormalities. The histological pattern of the liver biopsy performed in one of the patients showed a mild chronic active hepatitis. The lack of dose dependency and rather low frequency of elevated transaminases in those cases where a biliary disorder was excluded render this reaction an idiosyncratic drug toxicity.

European Journal of Endocrinology 154 213–220

Introduction disease is the principal cause of premature death. Treat- ment goals include relieving clinical symptoms, normal- Acromegaly is a debilitating condition, characterized by izations of biochemical markers, control of tumour mass excess of growth hormone (GH) from a pituitary tumour. and preservation/restoration of pituitary function. Average life expectancy in patients with active acro- Adequate control of GH and insulin-like growth factor-I megaly is reduced by approximately 10 years and cardiac (IGF-I) levels results in normalization of life expectancy

q 2006 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02079 Online version via www.eje-online.org

Downloaded from Bioscientifica.com at 09/30/2021 09:21:41PM via free access 214 H Biering and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 154

(1). Standard treatment for acromegaly consists of pitu- phosphatase levels were seen in patients no. 2 and itary surgery and, if insufficient, adjuvant medical no. 9 (1.4- and 1.7-fold ULN respectively). therapy and/or pituitary irradiation. There was one case of elevated transaminases 80.6 A novel GH receptor antagonist (pegvisomant) has weeks after initiation of pegvisomant treatment. In been developed recently which, in clinical studies, is the other 11 patients, the interval between start of peg- capable of normalizing IGF-I in over 90% of visomant and onset of elevated transaminases was patients with active disease. Pegvisomant corrects the between 6.4 and 34.7 weeks (15.7^10.7 weeks, metabolic abnormalities of acromegaly, including insu- means^S.D.). The dosage of pegvisomant at the onset lin resistance and lipid (2–4). Normaliza- of transaminases abnormalities was between 10 and tion of serum IGF-I with pegvisomant is also 25 mg/day (15^5 mg/day).Ten out of the twelve associated with normalized bone metabolism (5). patients had previously received Sandostatin LAR Uniquely among treatments for acromegaly, pegviso- (Novartis Pharma, Basel, Switzerland) as medical mant neither acts on the pituitary nor attempts to inhi- therapy, except for patient no. 6 who received subcu- bit GH secretion but rather inhibits GH action. Based on taneous octreotide and patient no. 10 who was not the available data, pegvisomant is well tolerated. pretreated with somatostatin analogues. At the time Among the possible side-effects, elevation of transamin- of elevated transaminases, two patients were receiving ases seems to be the most relevant. In the first clinical a combination of pegvisomant with 30 mg long- studies with pegvisomant, a tenfold increase of alanine acting octreotide every 4 weeks within a clinical trial aminotransferase (ALT) and aspartate aminotransfer- (patients no. 8 and no. 9). Two patients had discontin- ase (AST) were observed in two patients (1.2%). How- ued Sandostatin LAR for more than 2 years (patients ever, since data regarding long-term safety with no. 11 and no. 12), in six other patients the last dose pegvisomant are limited, the aim of the present report of Sandostatin LAR was given between 7 and 36 is to summarize the cases with elevated transaminases weeks before the elevated transaminases. during pegvisomant treatment seen in Germany so far In five patients (patient nos 1, 2, 9, 11 and 12), sono- and to report details of one case who had a liver biopsy graphically proven gallstone disease was present and showed histological signs of chronic active together with elevated levels of g-GT and/or alkaline hepatitis. In line with the present approved indication, phosphatase or ; in patient no. 6 with sonogra- most patients were treated with pegvisomant only phically proven gallstones these laboratory data were after other forms of medical treatment were unable to unavailable. In two of these patients (patients no. 9 normalize the disease activity of acromegaly or were and no. 12), bile duct stones could be verified by endo- not tolerated. scopic retrograde cholangiography as the most obvious reason for laboratory abnormalities, suggesting biliary complications rather than a drug reaction as the Elevations of transaminases during reason for liver enzyme elevations. Additionally, in pegvisomant treatment patient no. 2 the leading enzyme was g-GT and gallstones were found. Up to the end of 2004, 35 acromegalic patients have During follow-up, transaminases returned to normal been treated in Germany with pegvisomant within in all patients after 4–32 weeks (mean 12 weeks). clinical trials and 123 acromegalic patients have been Interestingly, in four patients, transaminases spon- included in a non-interventional post-marketing sur- taneously normalized despite ongoing treatment with veillance study (including 17 patients who had already pegvisomant. participated in a clinical trial before entering the non- interventional surveillance study). In addition, patients with active acromegaly have been on the commercial Case study drug without being included in clinical trials. Up to December 2004 there have been reports of We report here in detail on a 43-year-old man (Table 1, elevated transaminases to more than three times the patient no. 8) who presented in May 1997 in our clinic upper limit of normal (ULN) in 12 patients (seven with typical clinical features of acromegaly and an elev- males, five females, age 44^9 years). Four cases were ated IGF-I. Magnetic resonance imaging demonstrated reported as adverse events from clinical trials, six a macroadenoma of the pituitary gland with suprasel- cases from the non-interventional surveillance study lar extension. Debulking of the tumour by trans-sphe- and two were reported spontaneously from patients noidal surgery in June 1997 as well as stereotactic not included in either. Table 1 summarizes the charac- radiotherapy of the residual pituitary adenoma in teristics as well as the clinical and biochemical data of 1999/2000 effectively reduced tumour mass but was these 12 patients. and bilirubin not sufficient to control the GH excess. Using several levels were available from only a minority of these medications (lanreotide, dopamine agonists), only tran- patients. An increased level of bilirubin to 2.1-fold sient and partial suppression of the residual acromegaly ULN was seen in patient no. 1. Elevated alkaline disease activity was achieved. Long-acting octreotide

www.eje-online.org

Downloaded from Bioscientifica.com at 09/30/2021 09:21:41PM via free access UOENJUNLO NORNLG (2006) ENDOCRINOLOGY OF JOURNAL EUROPEAN

Table 1 Clinical and biochemical characteristics of 12 patients with elevation of liver function tests (LFT) during pegvisomant treatment.

Peak LFT elevation

Time between last dose Time between start Pegvisomant # of long-acting octreotide of pegvisomant and dose at onset of Patient Age and LFT elevation LFT elevation LFT elevation ALT AST g-GT Gallstone no. Sex (years) (weeks) (weeks) (mg/day) ( £ ULN) ( £ ULN) ( £ ULN) disease? Follow-up 154 1 M 41 21.6 15.6 10 25.7 20.2 4.6 Biliary sludge Drug withdrawn, normalization of LFTs, re-exposure 3 months later, now 8 months on treatment without LFT elevations 2 M 55 7.6 2.3 10 4.9 — 8.7 Gall stones Drug withdrawn, normalization of LFTs 3 F 27 21.0 8.9 15 4.7 3.3 — No drug continued, spontaneous Normalization of LFTs 4** F 40 12.0 7.3 10 9.8 4.1 7.6 No Drug withdrawn, normalization of LFTs 5 M 46 23.1 12.3 15 3.8 0.9 3.1 No Drug withdrawn, normalization of LFTs 6 F 31 34.7* 34.7 20 10.9 2.9 — Gall stones Drug continued, spontaneous Normalization of LFTs

7** F 45 35.7 27.0 25 3.6 2.0 1.7 No Drug continued, spontaneous treatment pegvisomant during transaminases Elevated Normalization of LFTs 8*** M 43 Continued*** 9.0 10 4.9 3.1 — No Drug withdrawn, normalization of LFTs 9*** F 44 Continued*** 8.9 15 20.8 11.1 — Cholecystectomy, Drug withdrawn, normalization of LFTs extrahepatic duct cholelithiasis 10 M 53 No previous octreotide 12.7 15 4.5 2.7 — No Drug withdrawn, normalization of LFTs 11 M 42 108 80.6 25 3.1 2.7 6.7 Gall stones Drug continued, spontaneous normalization of LFTs 12 M 61 177 6.4 15 4.0 2.1 5.1 Cholelithiasis Drug withdrawn, normalization of LFTs, re-exposure 5 months later, now 4 months on treatment without LFT Downloaded fromBioscientifica.com at09/30/202109:21:41PM elevations

g-GT, g-glutamyltranspeptidase. * Patient was treated with octreotide daily s.c. ** Patients received concomitant medications which are potentially hepatotoxic. *** Patients were treated with a combination of daily pegvisomant and 30 mg long-acting octreotide, given every 4 weeks. www.eje-online.org 215 via freeaccess 216 H Biering and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 154

(Sandostatin LAR, 30 mg every 28 days) also failed to injections at monthly intervals was continued. g-GT reduce IGF-I levels to the normal range. The patient was only mildly affected. No concurrent increase in was then treated within a clinical trial with Somavert serum alkaline phosphatase was observed. Diagnostic (pegvisomant) in combination with Sandostatin LAR work-up for exclusion of other hepatic diseases, includ- (30 mg). Treatment with Somavert was initiated at a ing and haemochromatosis, Wilson’s dis- dose of 10 mg/day s.c. and was adjusted to 15 mg/day ease, autoimmune hepatitis and a-1 anti-trypsin because of incomplete suppression of IGF-I. Treatment deficiency was performed. Ultrasound examination was well tolerated and resulted in significant improve- showed normal echogenicity of the liver parenchyma ment of clinical symptoms. The patient reported an without signs of steatosis. In addition, there was no evi- improved sense of well-being, disappearance of par- dence of gallstone disease. A liver biopsy was performed esthesias and reduced soft tissue swelling of the for further diagnostic evaluation. Histology demon- hands. Biochemical evaluation demonstrated normali- strated discrete portal fibrosis without bridging and dis- zation of IGF-I which was reduced to the age-related crete lobular hepatitis with fatty droplets in 30% of . hepatocytes. The majority of the portal tracts showed a Eight weeks after the start of treatment we noticed a mixed inflammatory infiltrate and discrete interface gradual increase of the transaminases. After ALT hepatitis. Inflammatory cells were composed of lympho- increased fivefold above the ULN, which persisted over cytes, histiocytes, mast cells and eosinophilic granulo- several weeks, we decided to discontinue treatment cytes consistent with chronic mild active hepatitis with Somavert. Treatment with Sandostatin LAR (Fig. 1 and 2). Two months after discontinuation of

Figure 1 Portal tract (haematoxylin–eosin): mixed portal inflammation with eosinophilic granulocytes and interface hepatitis.

www.eje-online.org

Downloaded from Bioscientifica.com at 09/30/2021 09:21:41PM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 154 Elevated transaminases during pegvisomant treatment 217

Figure 2 Lobule (haematoxylin–eosin): hepatocytes with fatty droplets and discrete lobular hepatitis with inflammatory demarcation. pegvisomant treatment liver transaminases returned to ubinaemia, which was present before the increase of normal values without further specific therapy (Table 2). the transaminases, normalized during the hepatitis Gilbert’s syndrome had previously been diagnosed episode and reappeared after transaminases had in 1997 in this patient. Interestingly, mild hyperbilir- returned to normal values.

Table 2 Biochemical and hormonal parameters in patient no. 8 before, during and after treatment with pegvisomant.

January 04 April 04 June 04 Sandostatin LAR (30 mg)

Treatment Pegvisomant (15 mg)

IGF-I (70–230 ng/ml) 556 214 414 ALT (6–43 U/l) 26 210 32 AST (11–36 U/l) 26 112 34 Blood glucose fasting (3.9–6.4 mmol/l) 5.8 5.7 5.3 Blood glucose 2 h (mmol/l) 6.3 10.2 5 AUC glucose 15.3 16.9 16.5 Insulin fasting (mU/ml) 5.47 8.72 3.5 Insulin 2 h (mU/ml) 20.06 108.12 26.5 AUC insulin 47.7 74.1 60.7 HOMA (reference 25) (#2) 1.4 2.2 0.8

AUC, area under the curve; HOMA, homeostasis model assessment.

www.eje-online.org

Downloaded from Bioscientifica.com at 09/30/2021 09:21:41PM via free access 218 H Biering and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 154

Before commencement of pegvisomant treatment an g-GT, alkaline phosphatase or bilirubin suggest biliary oral glucose-tolerance test showed completely normal complications rather than a pegvisomant-induced reac- glucose metabolism. During the period of elevation of tion as the reason for liver enzyme elevations. In two of transaminases we observed an impaired glucose toler- these patients, cholelithiasis was clearly identified as ance according to WHO criteria (6) despite normal IGF- the reason for liver enzyme elevations; these patients I levels (Table 2). Two months after discontinuation of underwent an endoscopic retrograde cholangiograpy pegvisomant treatment IGF-I levels were again increased with a therapeutical papillotomy. twofold above the upper limit and transaminases had After discontinuation of pegvisomant treatment, returned to normal values. At that time glucose toler- transaminases returned to normal in all patients. Inter- ance testing again showed normal results. estingly, in four patients, transaminases spontaneously Concentrations of haemoglobin A1c,, normalized despite ongoing treatment with pegviso- , lipid electrophoresis, lipoprotein a, C-reactive mant. Additionally, in patients no. 1 and no. 12 protein levels, erythrocyte sedimentation rate, haemato- treatment was recommenced, after temporary discon- crit, white blood cell count, platelet counts, blood urea tinuation of pegvisomant for 3–5 months, and no nitrogen, and were further increase of transaminases was observed. within normal limits at baseline and did not change The mechanism of pegvisomant-induced deranged during treatment. transaminases remains the subject of conjecture. In order to increase the antagonist’s half-life and to reduce antibody formation, a pegylated formula of the Discussion substance was developed. has not been Safety and tolerability reported with other pegylated compounds in clinical use, and no such adverse events have been evident in Based on the available data, pegvisomant is well toler- any of the animal toxicology studies to date (11, 12). ated. In the first two double-blind, placebo-controlled Moreover, attachment of polyethyleneglycol polymers trials of pegvisomant for treatment of acromegaly of to polypeptides is thought to reduce immunogenicity. It 46 and 112 patients, respectively, were randomized seems unlikely therefore that the drug formulation of (7, 8). Many of the patients from these studies have sub- pegvisomant has contributed to the hepatotoxicity sequently been transferred to a long-term daily dosing observed in our patient. regimen, with normalization of serum IGF-I in 97% of Gilbert’s syndrome is a benign disorder caused by patients. In these studies, a tenfold increase of ALT insufficient enzymatic conjugation of bilirubin without and AST was observed in two patients (1.2%). Both alteration of liver function. Bilirubin levels normalized patients experienced mild fatigue and had normal during the phase of acute hepatitis in the described bilirubin concentrations. Liver transaminases returned case. It is unlikely therefore that Gilbert’s syndrome to normal several months after drug discontinuation. contributed to the development of hepatitis. As induc- In one patient, a liver biopsy was performed revealing tion of enzymes, e.g. by barbiturates, normalizes chronic active hepatitis of unknown aetiology. The bilirubin, normalization of bilirubin levels during hepa- second patient was rechallenged and transaminases titis was possibly secondary to inflammation-induced rose again, proving a causative role of pegvisomant. induction of hepatic enzymes. No other significant adverse events were observed during long-term treatment (9). Glucose metabolism Presently available data showed that the incidence of slight increases of transaminases was not different Pegvisomant was not found to induce a glycaemic effect between pegvisomant- and placebo-treated patients. in animal studies (13, 14). Furthermore, in a recent The increases in transaminases did not appear to be study of healthy subjects, pegvisomant was not associ- dose-related, usually occurred within 3 month of ated with deterioration in glucose tolerance (15). GH initiation of therapy and were not associated with any infusion in normal subjects stimulates gluconeogenesis identifiable biochemical, phenotypic or genetic predic- and lipolysis, which are mediated by the GH receptor, tors. Concurrent increases in serum total bilirubin resulting in increased blood glucose and fatty acid and alkaline phosphatase, which are established as levels, causing enhanced insulin secretion and sus- indicators of serious drug-induced hepatic injury, tained hyperglycaemia (16, 17). Similarly, acromegaly were not observed. In many cases, increases in trans- is characterized by increased glucose turnover, insulin aminases were sporadic and returned to normal with- resistance and hyperinsulinaemia (18, 19). Adequate out discontinuation of pegvisomant therapy (10). control of acromegaly disease activity therefore results The present report adds data from 12 patients treated in improvement in glucose tolerance by normalization in Germany with elevations of transaminases to more of GH excess. than three times ULN during pegvisomant treatment. Van der Lely et al. (9) investigated glucose metab- In five of these patients, the presence of sonographically olism in 160 patients treated with pegvisomant. proven gallstone disease together with elevated levels of The improvement in serum IGF-I was associated

www.eje-online.org

Downloaded from Bioscientifica.com at 09/30/2021 09:21:41PM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 154 Elevated transaminases during pegvisomant treatment 219 with a significant fall in mean fasting insulin and glu- References cose, indicating improved insulin sensitivity. These results were confirmed by Rose & Clemmons (20) 1 Holdaway IM, Rajasoorya RC & Gamble GD. Factors influencing who reported a significant progressive increase in mortality in acromegaly. Journal of Clinical Endocrinology and Metabolism 2004 89 667–674. insulin sensitivity, which was related to both dose 2 Trainer PJ, Drake WM, Perry LA, Taylor NF, Besser GM & and duration of pegvisomant treatment. Improvement Monson JP. Modulation of cortisol metabolism by the growth of insulin sensitivity did not appear to be due to hormone receptor antagonist pegvisomant in patients with changes in body composition or a reduction of lipoly- acromegaly. Journal of Clinical Endocrinology and Metabolism 2001 86 2989–2992. sis respectively (20, 21). 3 Parkinson C, Drake WM, Wieringa G, Yates AP, Besser GM & Increased insulin resistance in the case described was Trainer PJ. Serum lipoprotein changes following IGF-I normaliza- possibly caused by the toxic hepatitis caused by tion using a growth hormone receptor antagonist in acromegaly. pegvisomant. Insulin resistance is found in inflamma- Clinical Endocrinology 2002 56 303–311. tory liver diseases (22), which are characterized by 4 Sesmilo G, Fairfield WP, Katznelson L, Pulaski K, Freda PU, Bonert V, Dimaraki E, Stavrou S, Vance ML, Hayden D & increased production of tumour necrosis factor-a Klibanski A. Cardiovascular risk factors in acromegaly before (TNF-a) (23). As TNF-a induces insulin resistance by and after normalization of serum IGF-I levels with the GH antag- directly inhibiting signalling from the insulin receptor onist pegvisomant. Journal of Clinical Endocrinology and Metabolism (24), the metabolic changes in this patient are likely to 2002 87 1692–1699. 5 Parkinson C, Kassem M, Heickendorff L, Flyvbjerg A & Trainer PJ. be primarily related to inflammation-mediated effects. Pegvisomant-induced serum insulin-like growth factor-I normal- ization in patients with acromegaly returns elevated markers of bone turnover to normal. Journal of Clinical Endocrinology and Conclusion Metabolism 2003 88 5650–5655. As pegvisomant is the most effective medical therapy 6 World Health Organization, Definition, diagnosis and classification of diabetes mellitus and its complications. In Report of a World Health for normalizing serum IGF-I levels, the drug represents Organization Consultation, part I: Diagnosis and Classification of a major advance in the treatment of acromegaly. Based Diabetes Mellitus. Geneva: World Health Organization, 1999. on currently available data, pegvisomant is well toler- 7 van der Lely AJ, Lamberts SW, Barkan A, Pandya N, Besser G, ated. However, in a minority of patients increases in Trainer PJ, Bonert V, Melmed S, Clemmons DR, Rose R, Vance ML, Thorner M, Zib K, Davis RJ, Bennett WF & Scarlett JAA. A transaminases are observed. six-week, double blind, placebo controlled study of a growth hor- The present series summarizes clinical and labora- mone antagonist B2036–PEG (Troverte) in acromegalic tory data from 12 German patients with elevated patients. Proceedings of the 80th Annual Meeting of the Endocrine transaminases during pegvisomant treatment. It illus- Society, New Orleans, LA, USA, 1988. Abstract OR4-1. trates that in any individual case pegvisomant-induced 8 Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, Dimaraki EV, Stewart PM, Friend KE, Vance ML, abnormalities have to be differentiated from biliary Besser GM, Scarlett JA, Thorner MO, Parkinson C, Klibanski A, complications seen in these patients. These may Powell JS, Barkan AL, Sheppard MC, Malsonado M, Rose DR, occur as a consequence of cholecystolithiasis which, Clemmons DR, Johannsson G, Bengtsson BA, Stavrou S, after resumption of normal gall bladder contractility Kleinberg DL, Cook DM, Phillips LS, Bidlingmaier M, Strasburger CJ, Hackett S, Zib K, Bennett WF & Davis RJ. Treat- following discontinuation of long-acting somatostatin ment of acromegaly with the growth hormone-receptor antagon- analogue treatment, may be moved into the ist pegvisomant. New England Journal of Medicine 2000 342 biliary duct. The mechanism of pegvisomant- 1171–1177. induced deranged transaminases remains the subject 9 van der Lely AJ, Hutson RK, Trainer PJ, Besser GM, Barkan AL, of conjecture. Because of the low frequency and the Katznelson L, Klibanski A, Herman-Bonert V, Melmed S, Vance ML, Freda PU, Stewart PM, Friend KE, Clemmons DR, dose independence of the untoward reaction, idiosyn- Johannsson G, Stavrou S, Cook DM, Phillips LS, Strasburger CJ, cratic drug toxicity has to be assumed. Drug surveil- Hackett S, Zib KA, Davis RJ, Scarlett JA & Thorner MO. Long- lance as well as basic research is needed to clearly term treatment of acromegaly with pegvisomant, a growth hor- define the association between the use of pegvisomant mone receptor antagonist. Lancet 2001 358 1754–1759. 10 CDER. Center for Drug Evaluation and Research Approval Pack- and hepatitis. Monitoring of liver transaminases is age for: application number 21–106. Medical review(s) (for peg- required during pegvisomant therapy and, beyond visomant). Center for Drug Evaluation and Research, Food and assessment of ALT and AST, monitoring should Drug Administration web site 2003. Available at: http://www. include g-GT, alkaline phosphatase and potentially fda.gov/cder/foi/nda/2003/21-106_Somavert_Medr_P1.pdf. bilirubin levels to facilitate differentiation between Accessed 23 July 2003. 11 Drake WM, Parkinson C, Besser GM & Trainer PJ. Clinical use of a hepatotoxicity and cholestatic causes of transaminase growth hormone receptor antagonist in the treatment of acro- elevations. megaly. Trends in Endocrinology and Metabolism 2001 12 408–413. 12 Harris JM & Chess RB. Effect of pegylation on pharmaceuticals. Acknowledgements Nature Reviews Drug Discovery 2003 2 214–221. 13 Flyvbjerg A, Bennett WF, Rasch R, Kopchick JJ & Scarlett JA. Inhibitory effect of a growth hormone receptor antagonist The German Pegvisomant Observational Study is (G120K-PEG) on renal enlargement, glomerular hypertrophy, supported by a grant from Pfizer Pharma GmbH and urinary albumin excretion in experimental diabetes in Karlsruhe, Germany. mice. Diabetes 1999 48 377–382.

www.eje-online.org

Downloaded from Bioscientifica.com at 09/30/2021 09:21:41PM via free access 220 H Biering and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 154

14 Segev Y, Landau D, Rasch R, Flyvbjerg A & Phillip M. Growth hor- 20 Rose DR & Clemmons DR. Growth hormone receptor antagonist mone receptor antagonism prevents early renal changes in non- improves insulin resistance in acromegaly. Growth Hormone and obese diabetic mice. Journal of the American Society of Nephrology IGF Research 2002 12 418–424. 1999 10 2374–2381. 21 Drake WM, Rowles SV,Roberts ME, Fode FK, Besser GM, Monson JP 15 Parkinson C, Drake WM, Roberts ME, Meeran K, Besser GM & & Trainer PJ. Insulin sensitivity and glucose tolerance improve in Trainer PJ. A comparison of the effects of pegvisomant and octreo- patients with acromegaly converted from depot octreotide to pegvi- tide on glucose, insulin, gastrin, cholecystokinin, and pancreatic somant. European Journal of Endocrinology 2003 149 521–527. polypeptide responses to oral glucose and a standard mixed 22 Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG, meal. Journal of Clinical Endocrinology and Metabolism 2002 87 McCaughan GW & George J. Insulin resistance is associated 1797–1804. with chronic infection and fibrosis progression. 16 Rizza RA, Mandarino LJ & Gerich JE. Effects of growth hor- Gastroenterology 2003 125 1695–1704. mone on insulin action in man. Mechanisms of insulin resist- 23 Nelson DR, Lim HL, Marousis CG, Fang JW, Davis GL, Shen L, ance, impaired suppression of glucose production, and Urdea MS, Kolberg JA & Lau JY. Activation of tumor necrosis impaired stimulation of glucose utilization. Diabetes 1982 31 factor-alpha system in chronic hepatitis C virus infection. Diges- 663–669. tive Diseases and Sciences 1997 42 2487–2494. 17 Rosenfeld RG, Wilson DM, Dollar LA, Bennett A & Hintz RL. Both 24 Hotamisligil GS, Murray DL, Choy LN & Spiegelman BM. Tumor human pituitary growth hormone and recombinant DNA-derived necrosis factor alpha inhibits signaling from the insulin receptor. human growth hormone cause insulin resistance at a postrecep- PNAS 1994 91 4854–4858. tor site. Journal of Clinical Endocrinology and Metabolism 1982 54 25 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF & 1033–1038. Turner RC. Homeostasis model assessment (HOMA): insulin 18 Roelfsema F & Frolich M. Glucose tolerance and plasma immuno- resistance and b-cell function from fasting plasma glucose and reactive insulin levels in acromegalics before and after selective insulin concentrations in man. Diabetologia 1985 28 412–419. transsphenoidal surgery. Clinical Endocrinology 1985 22 531–537. 19 Biering H, Knappe G, Gerl H & Lochs H. Diabetes-Ha¨ufigkeit bei Akromegalie und Cushing-Syndrom. Acta Medica Austriaca 2000 Received 5 August 2005 27 27–31. Accepted 25 October 2005

www.eje-online.org

Downloaded from Bioscientifica.com at 09/30/2021 09:21:41PM via free access