A Consensus on the Diagnosis and Treatment of Acromegaly Comorbidities

An Update

Andrea Giustina; Ariel Barkan; Albert Beckers; Nienke Biermasz; Beverly M. K. Biller; Cesar Boguszewski; Marek Bolanowski; Vivien Bonert; Marcello D. Bronstein; Felipe F. Casanueva; David Clemmons; Annamaria Colao; Diego Ferone; Maria Fleseriu; Stefano Frara; Monica R. Gadelha; Ezio Ghigo; Mark Gurnell; Anthony P. Heaney; Ken Ho; Adriana Ioachimescu; Laurence Katznelson; Fahrettin Kelestimur; John Kopchick; Michal Krsek; Steven Lamberts; Marco Losa; Anton Luger; Pietro Maffei; Monica Marazuela; Gherardo Mazziotti; Moises Mercado; Pietro Mortini; Sebastian Neggers; Alberto M. Pereira; Stephan Petersenn; Manel Puig-Domingo; Roberto Salvatori; Ilan Shimon; Christian Strasburger; Stylianos Tsagarakis; A. J. van der Lely; John Wass; Maria Chiara Zatelli; Shlomo Melmed

Disclosures

J Clin Endocrinol Metab. 2020;105(4)

Abstract and Introduction

Abstract

Objective: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013.

Participants: The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration.

Evidence: This evidence-based consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities.

Consensus Process: Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the Scientific Committee graded the quality of the supporting evidence and the consensus recommendations using the GRADE system.

Conclusions: Evidence-based approach consensus recommendations address important clinical issues regarding multidisciplinary management of acromegaly-related cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders and their sequelae, as well as their effects on quality of life and mortality.

Introduction

Excess levels of circulating GH and IGF-I in acromegaly have deleterious effects on a wide range of tissues and physiologic processes.^[1,2] Patients commonly experience abnormal growth of bone and soft tissue^[3,4] and have dysregulated glucose metabolism^[5,6] with increased risk for cardiovascular disease,^[7] all of which may affect mortality risk.^[8] Treatment of patients with acromegaly is aimed at controlling excess GH and/or IGF-I levels, but signs and symptoms of the disease often persist despite achievement of biochemical control.^[1,9,10] The diagnosis and optimal management of acromegaly comorbidities is critical to ensuring the best long-term outcome for this chronic illness.

The Acromegaly Consensus Group published the first set of recommendations on diagnosis and treatment of disease complications in 2003^[11] and updated them in 2013.^[12] In concert with development of new disease management protocols,^[9] and the conceptualization of the Pituitary Tumor Center of Excellence,^[13] investigators have increasingly been focusing on defining and optimizing management strategies for acromegaly comorbidities and disease-related sequelae. In June 2018, 45 experts in acromegaly management reviewed the literature and critically assessed new research findings and changes in clinical practice standards and clinical opinion since the 2013 consensus publication. Discussions focused on: cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders, as well as the impact of these disease sequelae on quality of life (QoL) and mortality. Updated consensus recommendations on diagnosis and treatment of acromegaly comorbidities were graded using the Grading of Recommendations Assessment, Development and Evaluation system (GRADE; Table 1)^[14,15] and key consensus recommendations are presented in Table 2.

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Next Section

Abstract and Introduction
Materials and Methods
Cardiovascular Disease
Endocrine and Metabolic Disorders
Musculoskeletal Disorders
Impact of Comorbidities on Therapeutic Approaches
Conclusions
References

Table 1. Grading of Evidence and Recommendations
Evidence	Recommendations
• Very low quality (VLQ): expert opinion supported by 1 or a few small uncontrolled studies • Low quality (LQ): supported by large series of small uncontrolled studies • Moderate quality (MQ): supported by 1 or a few large uncontrolled studies or meta-analyses • High quality (HQ): supported by controlled studies or large series of large uncontrolled studies with sufficiently long follow-up	• Discretionary recommendation (DR): based on VLQ or LQ evidence • Strong recommendation (SR): based on MQ or HQ evidence

From Giustina et al (16).

Table 2. Key Consensus Recommendations for Diagnosis and Treatment of Acromegaly Comorbidities
Assessment	Frequency
Cardiovascular disorders
Blood pressure measurement	At baseline and every 6 months or upon change of antihypertensive treatment
Echocardiography	Annually, if abnormal
Electrocardiogram	Annually, if abnormal
Endocrine and metabolic disorders
Epworth scale or sleep study	Baseline or before surgery if OSA is suspected
Fasting blood glucose or OGTT	Fasting blood glucose every 6 months, particularly in uncontrolled disease and during SRL therapy; HbA1c every 6 months if diabetes or prediabetes is present
Total testosterone, SHBG, and PRL (males)	Annually; consider testing free testosterone if there are doubts in interpretation of total testosterone
LH, FSH, 17β-estradiol, and PRL (females)	Annually, in premenopausal females with menstrual dysfunction and when pregnancy is desired
Serum free T4	Annually
Serum 8–9 am cortisol	If central adrenal insufficiency is suspected; cosyntropin stimulation test if serum cortisol is low
Musculoskeletal disorders
DXA	Every 2 years particularly if osteopenia/osteoporosis is present
Vertebral morphometry on thoracic x-ray, thoracic and lumbar spine x-ray	Annually, particularly if history of vertebral fracture, decrease in BMD, kyphosis, symptoms of vertebral fracture, untreated hypogonadism, and no biochemical control of acromegaly
Cancer
Colonoscopy	Every 10 years; more frequently if IGF-I remains persistently elevated or if abnormal colonoscopy or family history of colon cancer
Quality of life
AcroQoL	Annually

Abbreviations: BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; OGTT, oral glucose tolerance test; OSA, obstructive sleep apnea; PRL, prolactin; SHBG, sex hormone binding globulin; SRL, somatostatin receptor ligand.

Authors and Disclosures

Andrea Giustina¹, Ariel Barkan², Albert Beckers³, Nienke Biermasz⁴, Beverly M. K. Biller⁵, Cesar Boguszewski⁶, Marek Bolanowski⁷, Vivien Bonert⁸, Marcello D. Bronstein⁹, Felipe F. Casanueva¹⁰, David Clemmons¹¹, Annamaria Colao¹², Diego Ferone¹³, Maria Fleseriu¹⁴, Stefano Frara¹, Monica R. Gadelha¹⁵, Ezio Ghigo¹⁶, Mark Gurnell¹⁷, Anthony P. Heaney¹⁸, Ken Ho¹⁹, Adriana Ioachimescu²⁰, Laurence Katznelson²¹, Fahrettin Kelestimur²², John Kopchick²³, Michal Krsek²⁴, Steven Lamberts²⁵, Marco Losa²⁶, Anton Luger²⁷, Pietro Maffei²⁸, Monica Marazuela²⁹, Gherardo Mazziotti³⁰, Moises Mercado³¹, Pietro Mortini²⁶, Sebastian Neggers³², Alberto M. Pereira⁴, Stephan Petersenn³³, Manel Puig-Domingo³⁴, Roberto Salvatori³⁵, Ilan Shimon³⁶, Christian Strasburger³⁷, Stylianos Tsagarakis³⁸, A. J. van der Lely³², John Wass³⁹, Maria Chiara Zatelli⁴⁰ and Shlomo Melmed⁸

¹Division of Endocrinology and Metabolism, San Raffaele University Hospital, Milan, Italy; ²Division of Endocrinology, University of Michigan Health System, Ann Arbor, Michigan; ³Department of Endocrinology, University of Liège, Liège, Belgium; ⁴Division of Endocrinology and Center for Endocrine Tumors, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands; ⁵Neuroendocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; ⁶SEMPR, Endocrine Division, Department of Internal Medicine, Federal University of Parana, Curitiba, Brazil; ⁷Department of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, Wroclaw, Poland; ⁸Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; ⁹Division of Endocrinology and Metabolism, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil; ¹⁰Division of Endocrinology, Santiago de Compostela University and Ciber OBN, Santiago de Compostela, Spain; ¹¹Department of Medicine, University of North Carolina, Chapel Hill, North Carolina; ¹²Division of Endocrinologia, Universita' Federico II di Napoli, Naples, Italy; ¹³Endocrinology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy; ¹⁴Departments of Medicine and Neurological Surgery, Pituitary Center, Oregon Health & Science University, Portland, Oregon; ¹⁵Neuroendocrinology Research Center/Endocrinology Section, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; ¹⁶Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Turin, Italy; ¹⁷University of Cambridge & Addenbrooke's Hospital, Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; ¹⁸Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California; ¹⁹The Garvan Institute of Medical Research and St. Vincent's Hospital, Sydney, Australia; ²⁰Department of Medicine, Division of Endocrinology, Metabolism and Lipids, and Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia; ²¹Departments of Medicine and Neurosurgery, Stanford University School of Medicine, Stanford, California; ²²Yeditepe University, Faculty of Medicine, Istanbul, Turkey; ²³Edison Biotechnology Institute and Department of Biomedical Sciences, Ohio University, Athens, Ohio; ²⁴2nd Department of Medicine, 3rd Faculty of Medicine of the Charles University and University Hospital Kralovske Vinohrady, Prague, Czech Republic; ²⁵Erasmus Medical Center, Rotterdam, The Netherlands; ²⁶Department of Neurosurgery, San Raffaele University Health Institute Milan, Milan, Italy; ²⁷Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria; ²⁸Department of Medicine, Padua University Hospital, Padua, Italy; ²⁹Department of Medicine, CIBERER, Universidad Autónoma de Madrid, Madrid, Spain; ³⁰Endocrinology Unit, Humanitas University and Humanitas Clinical and Research Center, Rozzano, Milan, Italy; ³¹Division of Medicine, National Autonomous University of Mexico, Experimental Endocrinology Unit, Centro Médico Nacional, Siglo XXI, IMSS, Mexico City, Mexico; ³²Pituitary Center Rotterdam, Endocrinology Section, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; ³³ENDOC Center for Endocrine Tumors, Hamburg, Germany; ³⁴Endocrinology Service, CIBER and CIBERES Germans Trias i Pujol Research Institute and Hospital, Autonomous University of Barcelona, Badalona, Spain; ³⁵Division of Endocrinology, Diabetes, and Metabolism and Pituitary Center, Johns Hopkins School of Medicine, Baltimore, Maryland; ³⁶Endocrine Institute, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel; ³⁷Department of Medicine for Endocrinology, Diabetes and Nutritional Medicine, Charité Universitätsmedizin, Berlin, Germany; ³⁸Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens, Greece; ³⁹Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, United Kingdom; and ⁴⁰Section of Endocrinology & Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy

Correspondence and Reprint Requests
Shlomo Melmed, MD, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Room 2015, Los Angeles, CA, 90048.

Author Contributions
A.G. and S.M. served as Program Coordinators of the 12th Acromegaly Consensus Conference. N.B., M.D.B., F.E.C., D.C., M.F., C.S., P.M., J.W., and A.V.D.L. served as Steering Committee Members. All authors researched data for the Conference. A.G. and S.M. wrote the initial manuscript and all authors reviewed and/or edited the manuscript before submission.

Disclosure Summary
B.M.K.B., M.B., M.D.B., V.B., D.C., M.F., A.G., A.I., A.L., M.M., S.N., S.P., C.S., I.S., R.S., and A.V.D.L. have received consulting fees from Pfizer. B.M.K.B., D.F., M.F., A.G., M.R.G., A.P..H, A.L., M.L., G.M., M.M., S.M., S.P., C.S., I.S., and M.C.Z. have received consulting fees from Novartis. D.C., D.F., M.F., A.G., A.L., M.L., G.M., S.N., S.P., and C.S. have received consulting fees from Ipsen. D.C., M.F., A.G., L.K., S.M., and C.S. have received consulting fees from Chiasma. D.C. and S.N. have received consulting fees from Crinetics. M.F. and S.M. have received consulting fees from Ionis and Ono. M.G. has received consulting fees from AstraZeneca. D.F. has received consulting fees from Bristol-Myers Squibb. M.L. has received consulting fees from Eli Lilly. S.M. has received consulting fees from Midatech. A.P.H. and R.S. have received consulting fees from Novo Nordisk. M.C.Z. has received consulting fees from Sanofi. A.P.H. has received consulting fees from Strongbridge. A.B., B.M.K.B., M.B., M.D.B., D.F., M.F., M.R.G., A.I., L.K., and R.S. have received fees for contracted research from Novartis. M.B., M.D.B., F.F.C., D.F., M.F., M.R.G., and R.S. have received fees for contracted research from Ipsen. F.F.C., M.F., A.I., P.M., S.M., and R.S. have received fees for contracted research from Pfizer. M.B., M.F., A.I., and M.P.D. have received fees for contracted research from Chiasma. M.B., K.H., and R.S. have received fees for contracted research from Novo Nordisk. M.B. and R.S. have received fees for contracted research from Strongbridge. M.B. has received fees for contracted research from HRA Pharma. M.F. has received fees for contracted research from Ionis and Ono. R.S. has received fees for contracted research from Opko Biologics. K.H. has received fees for contracted research from Versartis. C.B., M.B., M.D.B., M.G., K.H., A.L., M.M., and M.P.D. have served as members of the speakers bureau for Ipsen. C.B., M.B., M.D.B., M.G., K.H., A.L., M.M., and M.P.D. have served as members of the speakers bureau for Novartis. C.B., M.B., F.F.C., M.G., and A.L. have served as members of the speakers bureau for Pfizer. M.K. has received lecture fees from Merck, Eli Lilly, and Shire. M.R.G. has received lecture fees from Novartis. A.V.D.L. has an ownership interest in Millendo Therapeutics. A.B., N.B., A.C., S.F., E.G., F.K., J.K., S.L., P.M., A.P., S.T., and J.W. have nothing to declare.