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Pasireotide treatment reduces cardiometabolic risk in Cushing’s disease patients: an Italian, multicenter study

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Abstract

Purpose

Patients with Cushing’s disease (CD) experience metabolic alterations leading to increased cardiovascular mortality. Recently, the visceral adiposity index (VAI) has been proposed as a marker of visceral adipose tissue dysfunction (ATD) and of the related cardiometabolic risk. We aimed to evaluate the impact of 12-month pasireotide treatment on cardiometabolic risk in CD patients.

Methods

This is a multicentre, prospective, and observational study. Sixteen CD patients, referred to the Endocrine Units of the University Hospitals of Messina, Napoli, Padova, and Palermo (Italy), successfully treated with pasireotide for 12 month have been enrolled. In all patients, we assessed anthropometric, clinical, and biochemical parameters and calculated VAI, ATD severity, Framingham, and atherosclerotic cardiovascular disease (ASCVD) risk scores, before and after 6 and 12 months of treatment with pasireotide (1200–1800 mcg/daily).

Results

Before starting pasireotide treatment, ATD was present in 7/16 patients (mild in 2/16, moderate in 3/16, and severe 2/16). After 12 months of treatment: (i) 24h-urinary free cortisol levels (p = 0.003), BMI (p < 0.001), waist circumference (p = 0.001), LDL-cholesterol (p = 0.033), total-cholesterol (p = 0.032), triglycerides (p = 0.030), VAI (p = 0.015), and ATD severity (p = 0.026) were significantly decreased as compared to baseline; (ii) ATD was present in only 1/16 patients; (iii) prevalence of diabetes mellitus (p = 0.015) and HbA1c levels (p = 0.001) were significantly increased as compared to baseline; (iv) Framingham and ASCVD risk scores were not significantly different from pre-treatment values.

Conclusions

Twelve-month pasireotide treatment significantly reduces VAI and ATD in CD patients. These positive effects on cardiometabolic risk occur despite no change in Framingham and ASCVD risk scores and the increase in the prevalence of diabetes mellitus.

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References

  1. R. Pivonello, M. De Leo, A. Cozzolino, A. Colao, The treatment of Cushing’s disease. Endocr. Rev. 36(4), 385–486 (2015). https://doi.org/10.1210/er.2013-1048

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. R.N. Clayton, P.W. Jones, R.C. Reulen, P.M. Stewart, Z.K. Hassan-Smith, G. Ntali, N. Karavitaki, O.M. Dekkers, A.M. Pereira, M. Bolland, I. Holdaway, J. Lindholm, Mortality in patients with Cushing’s disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study. Lancet Diabetes Endocrinol. 4(7), 569–576 (2016).https://doi.org/10.1016/S2213-8587(16)30005-5

    Article  PubMed  Google Scholar 

  3. O.M. Dekkers, N.R. Biermasz, A.M. Pereira, F. Roelfsema, M.O. van Aken, J.H. Voormolen, J.A. Romijn, Mortality in patients treated for Cushing’s disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma. J. Clin. Endocrinol. Metab. 92(3), 976–981 (2007). https://doi.org/10.1210/jc.2006-2112

    Article  PubMed  CAS  Google Scholar 

  4. G. Ntali, A. Asimakopoulou, T. Siamatras, J. Komninos, D. Vassiliadi, M. Tzanela, S. Tsagarakis, A.B. Grossman, J.A. Wass, N. Karavitaki, Mortality in Cushing’s syndrome: systematic analysis of a large series with prolonged follow-up. Eur. J. Endocrinol. 169(5), 715–723 (2013). https://doi.org/10.1530/EJE-13-0569

    Article  PubMed  CAS  Google Scholar 

  5. R. Pivonello, M.C. De Martino, M. De Leo, C. Simeoli, A. Colao, Cushing’s disease: the burden of illness. Endocrine (2016). https://doi.org/10.1007/s12020-016-0984-8

  6. R. Pivonello, A.M. Isidori, M.C. De Martino, J. Newell-Price, B.M. Biller, A. Colao, Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol. 4(7), 611–629 (2016). https://doi.org/10.1016/S2213-8587(16)00086-3

    Article  PubMed  CAS  Google Scholar 

  7. F. Ferrau, M. Korbonits, Metabolic comorbidities in Cushing’s syndrome. Eur. J. Endocrinol. 173(4), M133–M157 (2015). https://doi.org/10.1530/EJE-15-0354

    Article  PubMed  CAS  Google Scholar 

  8. D. Ferone, C. Pivonello, G. Vitale, M.C. Zatelli, A. Colao, R. Pivonello, Molecular basis of pharmacological therapy in Cushing’s disease. Endocrine 46(2), 181–198 (2014). https://doi.org/10.1007/s12020-013-0098-5

    Article  PubMed  CAS  Google Scholar 

  9. A. Colao, S. Petersenn, J. Newell-Price, J.W. Findling, F. Gu, M. Maldonado, U. Schoenherr, D. Mills, L.R. Salgado, B.M. Biller, B.S.G. Pasireotide, A 12-month phase 3 study of pasireotide in Cushing’s disease. N. Engl. J. Med 366(10), 914–924 (2012). https://doi.org/10.1056/NEJMoa1105743

    Article  PubMed  CAS  Google Scholar 

  10. R. Pivonello, S. Petersenn, J. Newell-Price, J.W. Findling, F. Gu, M. Maldonado, A. Trovato, G. Hughes, L.R. Salgado, A. Lacroix, J. Schopohl, B.M. Biller, B.S.G. Pasireotide, Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing’s disease: results from a Phase III study. Clin. Endocrinol. 81(3), 408–417 (2014). https://doi.org/10.1111/cen.12431

    Article  CAS  Google Scholar 

  11. J. Schopohl, F. Gu, R. Rubens, L. Van Gaal, J. Bertherat, M. Ligueros-Saylan, A. Trovato, G. Hughes, L.R. Salgado, M. Boscaro, R. Pivonello, B.S.G. Pasireotide, Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing’s disease: results from an open-ended, open-label extension trial. Pituitary 18(5), 604–612 (2015). https://doi.org/10.1007/s11102-014-0618-1

    Article  PubMed  CAS  Google Scholar 

  12. S. Petersenn, L.R. Salgado, J. Schopohl, L. Portocarrero-Ortiz, G. Arnaldi, A. Lacroix, C. Scaroni, S. Ravichandran, A. Kandra, B.M.K. Biller, Long-term treatment of Cushing’s disease with pasireotide: 5-year results from an open-label extension study of a Phase III trial. Endocrine 57(1), 156–165 (2017). https://doi.org/10.1007/s12020-017-1316-3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. R. Pivonello, G. Arnaldi, C. Scaroni, C. Giordano, S. Cannavò, D. Iacuaniello, L. Trementino, M. Zilio, V. Guarnotta, A. Albani, A. Cozzolino, G. Michetti, M. Boscaro, A. Colao, Pasireotide medical treatment in Cushing’s disease: an Italian multicenter experience based on “real world evidence”. Endocrine (2018)

  14. M.C. Amato, C. Giordano, Visceral adiposity index: an indicator of adipose tissue dysfunction. Int J. Endocrinol. 2014, 730827 (2014). https://doi.org/10.1155/2014/730827

    Article  PubMed  PubMed Central  Google Scholar 

  15. M.C. Amato, C. Giordano, M. Galia, A. Criscimanna, S. Vitabile, M. Midiri, A. Galluzzo; AlkaMeSy Study, G., Visceral adiposity index: a reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care 33(4), 920–922 (2010). https://doi.org/10.2337/dc09-1825

    Article  PubMed  PubMed Central  Google Scholar 

  16. A. Ciresi, M.C. Amato, V. Guarnotta, F. Lo Castro, C. Giordano, Higher doses of cabergoline further improve metabolic parameters in patients with prolactinoma regardless of the degree of reduction in prolactin levels. Clin. Endocrinol. 79(6), 845–852 (2013). https://doi.org/10.1111/cen.12204

    Article  CAS  Google Scholar 

  17. A. Ciresi, M.C. Amato, G. Pizzolanti, C. Giordano Galluzzo, Visceral adiposity index is associated with insulin sensitivity and adipocytokine levels in newly diagnosed acromegalic patients. J. Clin. Endocrinol. Metab. 97(8), 2907–2915 (2012). https://doi.org/10.1210/jc.2012-1518

    Article  PubMed  CAS  Google Scholar 

  18. C. Giordano, V. Guarnotta, R. Pivonello, M.C. Amato, C. Simeoli, A. Ciresi, A. Cozzolino, A. Colao, Is diabetes in Cushing’s syndrome only a consequence of hypercortisolism? Eur. J. Endocrinol. 170(2), 311–319 (2014). https://doi.org/10.1530/EJE-13-0754

    Article  PubMed  CAS  Google Scholar 

  19. D.C. Goff Jr., D.M. Lloyd-Jones, G. Bennett, S. Coady, R.B. D’Agostino Sr., R. Gibbons, P. Greenland, D.T. Lackland, D. Levy, C.J. O’Donnell, J.G. Robinson, J.S. Schwartz, S.T. Shero, S.C. Smith Jr., P. Sorlie, N.J. Stone, P.W. Wilson; American College of Cardiology/American Heart Association Task Force on Practice, G., 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63(25 Pt B), 2935–2959 (2014). https://doi.org/10.1016/j.jacc.2013.11.005

    Article  PubMed  Google Scholar 

  20. Standards of Medical Care in Diabetes-2016, Summary of revisions. Diabetes Care 39(Suppl 1), S4–S5 (2016). https://doi.org/10.2337/dc16-S003

    Article  CAS  Google Scholar 

  21. S.M. Grundy, H.B. Brewer Jr., J.I. Cleeman, S.C. Smith Jr., C. Lenfant; American Heart, A., National Heart, L., Blood, I., Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 109(3), 433–438 (2004). https://doi.org/10.1161/01.CIR.0000111245.75752.C6

    Article  PubMed  Google Scholar 

  22. M.C. Amato, C. Giordano, M. Pitrone, A. Galluzzo, Cut-off points of the visceral adiposity index (VAI) identifying a visceral adipose dysfunction associated with cardiometabolic risk in a Caucasian Sicilian population. Lipids Health Dis. 10, 183 (2011). https://doi.org/10.1186/1476-511X-10-183

    Article  PubMed  PubMed Central  Google Scholar 

  23. A.M. Isidori, C. Graziadio, R.M. Paragliola, A. Cozzolino, A.G. Ambrogio, A. Colao, S.M. Corsello, R. Pivonello, A.B.C.S. Group, The hypertension of Cushing’s syndrome: controversies in the pathophysiology and focus on cardiovascular complications. J. Hypertens. 33(1), 44–60 (2015). https://doi.org/10.1097/HJH.0000000000000415

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. M.G. Baroni, F. Giorgino, V. Pezzino, C. Scaroni, A. Avogaro; Italian Society for Study of, D., Italian Endocrinological, S., Italian Society for the Study of Diabetes (SID)/Italian Endocrinological Society (SIE) guidelines on the treatment of hyperglycemia in Cushing’s syndrome and acromegaly. Nutr. Metab. Cardiovasc Dis. 26(2), 85–102 (2016). https://doi.org/10.1016/j.numecd.2016.02.001

    Article  PubMed  CAS  Google Scholar 

  25. A. Colao, C. De Block, M.S. Gaztambide, S. Kumar, J. Seufert, F.F. Casanueva, Managing hyperglycemia in patients with Cushing’s disease treated with pasireotide: medical expert recommendations. Pituitary 17(2), 180–186 (2014). https://doi.org/10.1007/s11102-013-0483-3

    Article  PubMed  CAS  Google Scholar 

  26. M.C. Amato, G. Pizzolanti, V. Torregrossa, G. Misiano, S. Milano, C. Giordano, Visceral adiposity index (VAI) is predictive of an altered adipokine profile in patients with type 2 diabetes. PLoS One 9(3), e91969 (2014). https://doi.org/10.1371/journal.pone.0091969

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. M.C. Amato, M. Verghi, A. Galluzzo, C. Giordano, The oligomenorrhoic phenotypes of polycystic ovary syndrome are characterized by a high visceral adiposity index: a likely condition of cardiometabolic risk. Hum. Reprod. 26(6), 1486–1494 (2011). https://doi.org/10.1093/humrep/der088

    Article  PubMed  Google Scholar 

  28. I.I. Androulakis, E. Kandaraki, C. Christakou, A. Karachalios, E. Marinakis, T. Paterakis, E. Diamanti-Kandarakis, Visceral adiposity index (VAI) is related to the severity of anovulation and other clinical features in women with polycystic ovary syndrome. Clin. Endocrinol. 81(3), 426–431 (2014). https://doi.org/10.1111/cen.12447

    Article  CAS  Google Scholar 

  29. A. Ciresi, S. Radellini, V. Guarnotta, C. Giordano, The visceral adiposity index is associated with insulin sensitivity and IGF-I levels in adults with growth hormone deficiency. Endocrine 56(3), 579–588 (2017). https://doi.org/10.1007/s12020-016-1076-5

    Article  PubMed  CAS  Google Scholar 

  30. C. Di Somma, A. Ciresi, M.C. Amato, S. Savastano, M.C. Savanelli, E. Scarano, A. Colao, C. Giordano, Alteration of the growth hormone axis, visceral fat dysfunction, and early cardiometabolic risk in adults: the role of the visceral adiposity index. Endocrine 49(2), 492–502 (2015). https://doi.org/10.1007/s12020-014-0471-z

    Article  PubMed  CAS  Google Scholar 

  31. A. Giandalia, G.T. Russo, E.L. Romeo, A. Alibrandi, P. Villari, A.A. Mirto, G. Armentano, S. Benvenga, D. Cucinotta, Influence of high-normal serum TSH levels on major cardiovascular risk factors and Visceral Adiposity Index in euthyroid type 2 diabetic subjects. Endocrine 47(1), 152–160 (2014). https://doi.org/10.1007/s12020-013-0137-2

    Article  PubMed  CAS  Google Scholar 

  32. R.S. Auriemma, L. Granieri, M. Galdiero, C. Simeoli, Y. Perone, P. Vitale, C. Pivonello, M. Negri, T. Mannarino, C. Giordano, M. Gasperi, A. Colao, R. Pivonello, Effect of cabergoline on metabolism in prolactinomas. Neuroendocrinology 98(4), 299–310 (2013). https://doi.org/10.1159/000357810

    Article  PubMed  CAS  Google Scholar 

  33. F. Ferrau, F. Spagnolo, O.R. Cotta, L. Cannavo, A. Alibrandi, G.T. Russo, T. Aversa, F. Trimarchi, S. Cannavo, Visceral adiposity index as an indicator of cardiometabolic risk in patients treated for craniopharyngioma. Endocrine (2016). https://doi.org/10.1007/s12020-016-1196-y

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Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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Author notes

  1. A. Albani and F. Ferraù contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

    A. Albani

  2. Department of Human Pathology of Adulthood and Childhood ‘G. Barresi’, University of Messina, Messina, Italy

    F. Ferraù & S. Cannavo

  3. Section of Endocrinology, Diabetology and Metabolism, DIBIMIS, University of Palermo, Palermo, Italy

    A. Ciresi, V. Guarnotta & C. Giordano

  4. Department of Clinical Medicine and Surgery, Endocrinology Unit, University of Naples Federico II, Naples, Italy

    R. Pivonello, D. Iacuaniello & A. Colao

  5. Department of Medicine (DIMED), Endocrinology Unit, University-Hospital of Padua, Padova, Italy

    C. Scaroni, M. Zilio & M. Boscaro

  6. Department of Economics, University of Messina, Messina, Italy

    A. Alibrandi

  7. Unit of Endocrinology, University Hospital ‘G. Martino’, Messina, Italy

    E. Messina & S. Cannavo

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  1. A. Albani
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  2. F. Ferraù
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Corresponding author

Correspondence to F. Ferraù.

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Conflict of interest

R.P. and A.C. received unrestricted grants from Novartis; A.C. is a member of the international board for clinical trials of pasireotide in acromegaly patients; C.G. received scientific grants from Novartis and served in medical advisory boards of Novartis; S.C. received grants from Novartis and served in medical advisory boards of Novartis. The remaining authors declare that they have no conflict of interest.

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Albani, A., Ferraù, F., Ciresi, A. et al. Pasireotide treatment reduces cardiometabolic risk in Cushing’s disease patients: an Italian, multicenter study. Endocrine 61, 118–124 (2018). https://doi.org/10.1007/s12020-018-1524-5

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