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Endocrine

, Volume 62, Issue 2, pp 448–455 | Cite as

Efficacy and safety of long-acting pasireotide in patients with somatostatin-resistant acromegaly: a multicenter study

  • Ilan ShimonEmail author
  • Zaina Adnan
  • Alexander Gorshtein
  • Lior Baraf
  • Nariman Saba Khazen
  • Michal Gershinsky
  • Yulia Pauker
  • Ali Abid
  • Mark J Niven
  • Carmela Shechner
  • Yona Greenman
Original Article

Abstract

Introduction

Pasireotide, a multi-somatostatin receptor (SSTR)-ligand with high affinity for SSTR5 was recently approved for acromegaly treatment.

Patients and methods

A retrospective multicenter study investigating the efficacy and safety of long-acting (LAR) pasireotide treatment in 35 patients (20 males) with active acromegaly (28 macroadenomas).

Results

Mean baseline insulin-like growth factor-1 (IGF-1) at diagnosis was 3.1 ± 1.3 × ULN. All but five patients have undergone pituitary surgery and six received sellar radiotherapy. All remained with active acromegaly despite first-generation somatostatin analogue (SSA) treatment. Immediately before pasireotide-LAR initiation, eighteen patients were under SSA monotherapy and one with pegvisomant. The remaining patients received combination therapy with SSA and pegvisomant, n = 9 (two received cabergoline also); SSA and cabergoline, n = 4; pegvisomant and cabergoline, n = 1. Two were untreated. Mean IGF-1 was 1.76 ± 0.9 ULN before pasireotide. Pasireotide-LAR starting dose was 40 mg/4 weeks in most patients. IGF-1 normalized in 19 patients, IGF-1 between 1-1.2 × ULN was reached in five, and in additional two patients IGF-1 was significantly suppressed. No effect was seen in nine patients. Pasireotide dose was reduced by 20 mg in six patients with excellent response, with preserved IGF-1 control in five. Severe headaches in six patients disappeared or improved with pasireotide. Side effects consisted of symptomatic cholelithiasis in one patient and deterioration of glucose control in 22 patients, requiring initiation or intensification of antidiabetic treatment in seventeen. One patient developed diabetic ketoacidosis.

Conclusions

In the real-life scenario ~54% of patients with acromegaly resistant to first-generation SSA, may normalize IGF-1 with pasireotide; however, 63% experienced glucose control deterioration.

Keywords

Acromegaly GH IGF-1 Pasireotide Somatostatin 

Notes

Compliance with ethical standards

Conflict of interest

I.S. has received research grants, consulting and lectureship fees from Novartis, Medison, and Pfizer. Y.G. received research grant from Pfizer, and research grant, travel support, and speaker fees from Novartis. The remaining authors declare that they have no conflict of interest.

Ethical approval

The study was conducted according to best clinical practice directives after being approved by the institutional ethical review board, with the 1964 Helsinki declaration and its later amendments.

Informed consent

Due to the retrospective design of the study, formal informed consent is not required. This article does not contain any studies with animals performed by any of the authors

References

  1. 1.
    S. Melmed, Acromegaly. N. Engl. J. Med. 355, 2558–2573 (2006)CrossRefPubMedGoogle Scholar
  2. 2.
    I.M. Holdaway, M.J. Bolland, G.D. Gamble, A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. Eur. J. Endocrinol. 159, 89–95 (2008)CrossRefPubMedGoogle Scholar
  3. 3.
    L. Katznelson, E.R. Laws Jr., S. Melmed, M.E. Molitch, M.H. Murad, A. Utz, J.A. Wass; Endocrine Society, Acromegaly: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 99, 3933–3951 (2014)CrossRefPubMedGoogle Scholar
  4. 4.
    C. Schöfl, H. Franz, M. Grussendorf, J. Honegger, C. Jaursch-Hancke, B. Mayr, J. Schopohl; participants of the German Acromegaly Register, Long-term outcome in patients with acromegaly: analysis of 1344 patients from the German Acromegaly Register. Eur. J. Endocrinol. 168, 39–47 (2013)CrossRefPubMedGoogle Scholar
  5. 5.
    A. Colao, R.S. Auriemma, M. Galdiero, G. Lombardi, R. Pivonello, Effects of initial therapy for five years with somatostatin analogs for acromegaly on growth hormone and insulin-like growth factor-I levels, tumor shrinkage, and cardiovascular disease: a prospective study. J. Clin. Endocrinol. Metab. 94, 3746–3756 (2009)CrossRefPubMedGoogle Scholar
  6. 6.
    M.R. Gadelha, L.E. Wildemberg, M.D. Bronstein, F. Gatto, D. Ferone, Somatostatin receptor ligands in the treatment of acromegaly. Pituitary 20, 100–108 (2017)CrossRefPubMedGoogle Scholar
  7. 7.
    A.J. van der Lely, B.M. Biller, T. Brue, M. Buchfelder, E. Ghigo, R. Gomez, J. Hey-Hadavi, F. Lundgren, N. Rajicic, C.J. Strasburger, S.M. Webb, M. Koltowska-Häggström, Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY. J. Clin. Endocrinol. Metab. 97, 1589–1597 (2012)CrossRefPubMedGoogle Scholar
  8. 8.
    C. Bruns, I. Lewis, U. Briner, G. Meno-Tetang, G. Weckbecker, SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur. J. Endocrinol. 146, 707–716 (2002)CrossRefPubMedGoogle Scholar
  9. 9.
    A. Colao, M.D. Bronstein, P. Freda, F. Gu, C.C. Shen, M. Gadelha, M. Fleseriu, A.J. van der Lely, A.J. Farrall, K. Hermosillo Reséndiz, M. Ruffin, Y. Chen, M. Sheppard; Pasireotide C2305 Study Group, Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J. Clin. Endocrinol. Metab. 99, 791–799 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    M. Gadelha, M. Bronstein, T. Brue, M. Coculescu, M. Fleseriu, M. Guitelman, V. Pronin, G. Raverot, I. Shimon, K.K. Lievre, J. Fleck, M. Aout, A.M. Pedroncelli, A. Colao; Pasireotide C2402 Study Group, Superior efficacy of pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly: randomized prospective Phase III study. Lancet. Diabetes. Endocrinol 2, 875–884 (2014)Google Scholar
  11. 11.
    I. Shimon, W. Saeger, L.E. Wildemberg, M.R. Gadelha, Somatotropinomas inadequately controlled with octreotide may over-respond to pasireotide: the importance of dose adjustment to achieve long-term biochemical control. Hormones 16, 84–91 (2017)PubMedGoogle Scholar
  12. 12.
    M.D. Bronstein, M. Fleseriu, S. Neggers, A. Colao, M. Sheppard, F. Gu, C.C. Shen, M. Gadelha, A.J. Farrall, K. Hermosillo Reséndiz, M. Ruffin, Y. Chen, P. Freda; Pasireotide C2305 Study Group, Switching patients with acromegaly from octreotide to pasireotide improves biochemical control: crossover extension to a randomized, double-blind, Phase III study. BMC Endocr. Disord. 16, 16 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    S. Tahara, M. Murakami, T. Kaneko, A. Shimatsu, Efficacy and safety of long-acting pasireotide in Japanese patients with acromegaly or pituitary gigantism: results from a multicenter, open-label, randomized, phase 2 study. Endocr. J. 64, 735–747 (2017)CrossRefPubMedGoogle Scholar
  14. 14.
    A. Muhammad, A.J. van der Lely, P.J.D. Delhanty, A.H.G. Dallenga, I.K. Haitsma, J.A.M.J.L. Janssen, S.J.C.M.M. Neggers, Efficacy and safety of switching to pasireotide in acromegaly patients controlled with pegvisomant and first-generation somatostatin analogues (PAPE study). J. Clin. Endocrinol. Metab. 103, 586–595 (2018)CrossRefPubMedGoogle Scholar
  15. 15.
    P. Petrossians, L. Borges-Martins, C. Espinoza, A. Daly, D. Betea, H. Valdes-Socin, A. Stevenaert, P. Chanson, A. Beckers, Gross total resection or debulking of pituitary adenomas improves hormonal control of acromegaly by somatostatin analogs. Eur. J. Endocrinol. 152, 61–66 (2005)CrossRefPubMedGoogle Scholar
  16. 16.
    I. Donangelo, M. Rodacki, M.C. Peixoto, M. Vaisman, N.R. Caldas, M.R. Gadelha, Dependency and analgesia related to treatment with subcutaneous octreotide in patients with growth hormone-secreting tumors. Endocr. Pract. 10, 107–111 (2004)CrossRefPubMedGoogle Scholar
  17. 17.
    M. Fleseriu, E. Rusch, E.B. Geer; ACCESS, Study Investigators Safety and tolerability of pasireotide long-acting release in acromegaly-results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study. Endocrine 55, 247–255 (2017)CrossRefPubMedGoogle Scholar
  18. 18.
    Y. Zambre, Z. Ling, M.C. Chen, X. Hou, C.W. Woon, M. Culler, J.E. Taylor, D.H. Coy, C. Van Schravendijk, F. Schuit, D.G. Pipeleers, D.L. Eizirik, Inhibition of human pancreatic islet insulin release by receptor-selective somatostatin analogs directed to somatostatin receptor subtype 5. Biochem. Pharmacol. 57, 1159–1164 (1999)CrossRefPubMedGoogle Scholar
  19. 19.
    R.R. Henry, T.P. Ciaraldi, D. Armstrong, P. Burke, M. Ligueros-Saylan, S. Mudaliar, Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J. Clin. Endocrinol. Metab. 98, 3446–3453 (2013)CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ilan Shimon
    • 1
    Email author
  • Zaina Adnan
    • 2
  • Alexander Gorshtein
    • 1
  • Lior Baraf
    • 3
  • Nariman Saba Khazen
    • 4
  • Michal Gershinsky
    • 4
  • Yulia Pauker
    • 4
  • Ali Abid
    • 2
  • Mark J Niven
    • 5
  • Carmela Shechner
    • 6
  • Yona Greenman
    • 7
  1. 1.Rabin Medical Center, Petah Tikva and Sackler School of MedicineTel-Aviv UniversityTel-AvivIsrael
  2. 2.Zvulun Medical CenterClalit Medical ServicesKiryat BialikIsrael
  3. 3.Soroka University Medical CenterBeer ShevaIsrael
  4. 4.Linn Medical CenterClalit Medical ServicesHaifaIsrael
  5. 5.Laniado Hospital, NetanyaThe Rappaport Faculty of MedicineThe TechnionIsrael
  6. 6.Bnai-Zion Medical CenterHaifaIsrael
  7. 7.Tel-Aviv Sourasky Medical Center and Sackler School of MedicineTel-Aviv UniversityTel-AvivIsrael

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