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DOI: 10.1055/s-0034-1376988
Long-term Medical Treatment of Cushing’s Disease with Pasireotide: A Review of Current Evidence and Clinical Experience
Publikationsverlauf
received 31. Dezember 2013
first decision 28. April 2014
accepted 12. Mai 2014
Publikationsdatum:
08. Juli 2014 (online)
![](https://www.thieme-connect.de/media/eced/201408/lookinside/thumbnails/10.1055-s-0034-1376988-1.jpg)
Abstract
Cushing’s disease is a rare condition of chronic hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma and associated with debilitating complications and excess mortality. Transsphenoidal adenomectomy is generally first-line treatment but is contraindicated in some patients and associated with significant post-surgical recurrence. While there are few data to support long-term use of most pharmacologic treatments, pasireotide (a multireceptor-targeted somatostatin analog) recently demonstrated sustained benefit in a 12-month, multicenter, Phase III trial and in 2 long-term extension studies. The Phase III trial (N=162) demonstrated reductions in urinary free cortisol in most patients, with durable treatment effect over 12 months. Biochemical improvement was generally paralleled by reductions in Cushing’s-related signs and symptoms and enhanced health-related quality of life. Long-term treatment was evaluated in 58 patients who entered a planned 12-month extension phase. Reductions in urinary free cortisol remained stable throughout the extension, with further improvements noted in clinical signs and symptoms. Similar results were reported in the smaller Phase II extension (N=18; median treatment duration, 9.7 months; range, 2 months–4.8 years). Case reports have recently emerged demonstrating sustained disease control for upto 7 years in some patients. Safety considerations for long-term medical treatment with pasireotide are generally similar to those for other somatostatin analogs, except for the incidence and severity of hyperglycemia. Most patients experience new or worsening hyperglycemia with pasireotide treatment. Expert recommendations for treatment of pasireotide-associated hyperglycemia have recently been published and new studies are planned to elucidate the optimal treatment approach for pasireotide-associated hyperglycemia.
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References
- 1 Broder M, Neary M, Chang E et al. Incidence of Cushing’s Disease in the United States. Endocr Rev 2013;34:MON-91. Presented at ENDO 95th Annual Meeting, June 17, 2013, in San Francisco, CA, USA
- 2 Feelders RA, Pulgar SJ, Kempel A et al. The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol 2012; 167: 311-326
- 3 Biller BM, Grossman AB, Stewart PM et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2008; 93: 2454-2462
- 4 Kim JH, Shin CS, Paek SH et al. Recurrence of Cushing’s disease after primary transsphenoidal surgery in a university hospital in Korea. Endocr J 2012; 59: 881-888
- 5 European Medicines Authority. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. 2013 Available at http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/07/WC500146613.pdf Accessed December 18, 2013
- 6 FDA Drug Safety Communications. FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. 2013 Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM362444.pdf Accessed December 18, 2013
- 7 Korlym™ (mifepristone) full prescribing information. Corcept Therapeutics. Menlo Park, CA. Available at http://www.korlym.com/docs/KorlymPrescribingInformation.pdf Accessed December 18, 2013
- 8 Fleseriu M, Biller BM, Findling JW et al. SEISMIC Study Investigators. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab 2009; 97: 2039-2049
- 9 Illouz F, Dubois-Ginouves S, Laboureau S et al. Use of cabergoline in persisting Cushing’s disease. Annales d’Endocrinologie 2006; 67: 353-356
- 10 Godbout A, Manavela M, Danilowicz K et al. Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur J Endocrinol 2010; 163: 709-716
- 11 Pivonello R, De Martino MC, Cappabianca P et al. Lamberts SW, Colao A. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab 2009; 94: 223-230
- 12 Boscaro M, Ludlam WH, Atkinson B et al. Treatment of pituitary-dependent Cushing’s disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab 2009; 94: 115-122
- 13 Boscaro M, Bertherat J, Findling J et al. Extended treatment of Cushing’s disease with pasireotide: results from a 2-year, Phase II study. Pituitary 2013; Aug 14. [Epub ahead of print] DOI: 10.1007/s11102-013-0503-3.
- 14 Colao A, Petersenn S, Newell-Price J et al. Pasireotide B2305 Study Group . A 12-Month Phase 3 study of pasireotide in Cushing’s disease. N Engl J Med 2012; 366: 914-924
- 15 Schopohl J, Bertherat J, Ludlam WH et al. on behalf of the Pasireotide B2305 Study Group. Long-term pasireotide use leads to improvements in the biochemical parameters of Cushing’s disease: 24-month results from a randomized Phase III study. Abs P1410. Presented at the joint 15th International Congress of Endocrinology and the 14th European Congress of Endocrinology (ICE/ECE), Florence, Italy, 5–9 May 2012
- 16 MacKenzie Feder J, Bourdeau I, Vallette S et al. Pasireotide monotherapy in Cushing’s disease: a single-centre experience with 5-year extension of Phase III trial. Pituitary 2013; Nov 28. [Epub ahead of print] DOI: 10.1007/s11102-013-0539-4.
- 17 Libé R, Groussin L, Bertherat J. Pasireotide in Cushing’s Disease. N Engl J Med 2012; 366: 2134-2135
- 18 Feelders RA, de Bruin C, Pereira AM et al. Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. N Engl J Med 2010; 362: 1846-1848
- 19 van der Pas R, de Bruin C, Pereira AM et al. Cortisol diurnal rhythm and quality of life after successful medical treatment of Cushing’s disease. Pituitary 2013; 16: 536-544
- 20 Signifor ® (pasireotide) full prescribing information . Novartis Pharmaceuticals Corporation. Basel; Switzerland: Available at http://www.pharma.us.novartis.com/product/pi/pdf/signifor.pdf Accessed December 18, 2013
- 21 Paserchia LA, Hewett J, Woosley RL. Effects of ketoconazole on QTc [abstr]. Clin Pharmacol Ther 1994; 55: 146
- 22 Bertherat J, Ludlam WH, Pivonello R et al. on behalf of the Pasireotide B2305 Study Group . Long-Term Use of Pasireotide in Cushing’s Disease: 24-Month Safety Results from a Randomized Phase III Study. Abs P1405. Presented at the joint 15th International Congress of Endocrinology and the 14th European Congress of Endocrinology (ICE/ECE), Florence, Italy, 5–9 May 2012
- 23 Shenouda M, Maldonado M, Wang Y et al. An open-label dose-escalation study of once-daily and twice-daily pasireotide in healthy volunteers: Safety, tolerability, and effects on glucose, insulin, and glucagon levels. Am J Ther 2012; Jun 16. [Epub ahead of print] DOI: 10.1097/MJT.0b013e31824c3eb4.
- 24 Henry RR, Mudaliar S, Hermosillo Reséndiz K et al. Mechanism and Management of Hyperglycemia Associated with Pasireotide: Results from Studies in Healthy Volunteers. Abs. P260. Presented at the 13th European Congress of Endocrinology (ECE), Rotterdam, The Netherlands, 30 April – 4 May 2011
- 25 Chisholm C, Greenberg GR. Somatostatin-28 regulates GLP-1 secretion via somatostatin receptor subtype 5 in rat intestinal cultures. Am J Physiol Endocrinol Metab 2002; 283: E311-E317
- 26 Hansen L, Hartmann B, Bisgaard T et al. Somatostatin restrains the secretion of glucagon-like peptide-1 and -2 from isolated perfused porcine ileum. Am J Physiol Endocrinol Metab 2000; 278: E1010-E1018
- 27 Schmid HA, Brueggen J. Effects of somatostatin analogs on glucose homeostasis in rats. Journal of Endocrinology 2012; 212: 49-60
- 28 Colao A, De Block C, Gaztambide MS et al. Managing hyperglycemia in patients with Cushing’s disease treated with pasieotide: medical expert recommendations. Pituitary 2013; 7. Apr 7 [Epub ahead of print] DOI: 10.1007/s11102-013-0483-3.
- 29 Shah P, Mudaliar S.. Pioglitazone: side effect and safety profile. Expert Opin Drug Saf 2010; 9: 347-354
- 30 Truong HL, Nellesen D, Ludlam WH et al. Budget impact of pasireotide for the treatment of Cushing’s disease, a rare endocrine disorder associated with considerable comorbidities. J Med Econ 2014; 17: 288-295
- 31 ClinicalTrials.gov. Efficacy and Safety of Pasireotide Administered Monthly in Patients With Cushing’s Disease. NCT01374906. Available at http://www.clinicaltrials.gov/ct2/show/NCT01374906 Accessed December 18, 2013