Growth Hormone, IGF-1 and Medical Treatment in Acromegaly: Are There Effects on Gut Hormone Physiology and Postprandial Substrate Metabolism?

NCT02152124 | Completed

• 2 other identifiers: EC/2013/857WI182140
• Study Type: observational
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

Acromegaly is a rare hormonal disorder leading to increased morbidity and mortality. In the vast majority of cases, a pituitary somatotroph cell adenoma causes excess growth hormone (GH) secretion, leading to hepatic insulin-like-growth factor 1 (IGF-1) hypersecretion. Both the disease as well as its treatment with long-acting somatostatin analogs (LA-SMSA) and/or pegvisomant affect glucose and lipid metabolism, possibly contributing to increased cardiovascular risk. In this pilot study, the investigators want to explore insulin sensitivity, postprandial gut hormone response, lipid handling and adipocytokine profile in the following 4 groups:

• controlled acromegalic patients on LA-SMSA (group 1)
• controlled acromegalic patients on combination treatment of LA-SMSA and pegvisomant (group 2)
• acromegalic patients without need for medical therapy after surgery (group 3)
• healthy control subjects (group 4) Furthermore, a longitudinal exploration will be performed in uncontrolled acromegalic patients (i.e. patients with serum IGF-1 levels above age-specific thresholds and/or symptoms due to active acromegaly (excessive sweating , arthralgia)) on LA-SMSA monotherapy (group 5). In this group, insulin sensitivity, postprandial gut hormone response, lipid handling and adipocytokine profile will be explored before introducing pegvisomant and three months after normalisation of IGF-1 levels. The investigators hypothesize that lipid and glucose handling will be less efficient in the controlled acromegalic patients on LA-SMSA than in controlled patients on combination therapy or after surgery, and that there will be no difference in substrate metabolism between healthy controls and controlled acromegalic patients on combination treatment or after surgery. Further, they hypothesize that introducing pegvisomant in uncontrolled acromegalic patients will improve their postprandial lipid and glucose handling.

Conditions

Acromegaly

Keywords

Acromegaly; Acromegaly treatment; Long-acting somatostatin analogs; Pegvisomant; Insulin sensitivity; Gut hormones; Lipid metabolism; Adipokines

Outcome Measures

Primary Outcomes (2)

• change in insulin sensitivity

  Glucose disposal rate during last half hour of hyperinsulinemic-euglycemic clamp procedure, corrected for lean body mass (in µmol/min/kgLBM)

  before start of pegvisomant and 3 months after normalisation of IGF-1 after start of pegvisomant in group 5

• insulin sensitivity

  Glucose disposal rate during last half hour of hyperinsulinemic-euglycemic clamp procedure, corrected for lean body mass (in µmol/min/kgLBM)

  At enrollment in groups 1-4

Secondary Outcomes (10)

• fasting and postprandial glucose

  At enrollment in groups 1-4

• fasting and postprandial insulin

  At enrollment in groups 1-4

• fasting and postprandial gut hormone levels

  At enrollment in groups 1-4

• fasting adipokine levels

  At enrollment in group 1-4

• fasting lipid levels

  At enrollment in groups 1-4

Other Outcomes (8)

• Resting energy expenditure

  At enrollment in group 1-4

• Weight

  At enrollment in group 1-4

• Standing height

  At enrollment in group 1-4

Study Arms (5)

Controlled on LA-SMSA

Patients with controlled acromegaly on long-acting somatostatin analogs

Controlled on LA-SMSA and pegvisomant

Patients with controlled acromegaly on long-acting somatostatin analogs and pegvisomant

Controlled after surgery

Controlled acromegaly patients without need for medical therapy after surgery

Healhy controls

Healthy volunteers

Uncontrolled on LA-SMSA

Patients with uncontrolled acromegaly (i.e. with serum IGF-1 levels above age-specific thresholds and/or symptoms due to active acromegaly (e.g. excessive sweating, arthralgia)) on LA-SMSA monotherapy in maximal dosage

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Groups 1-3 and 5: outpatient clinic attendants Group 4: recruted from community (by placard)

You may qualify if:

• Diagnosis of acromegaly over 1 year ago, no changes in treatment schedule since at least 6 months (groups 1-3 and 5) OR healthy volunteer without diagnosis of acromegaly (group 4)
• Patient is willing to participate and has signed the informed consent
• Age \> 18 years and \< 80 years
• Body Mass Index 18-40 kg/m²

You may not qualify if:

• Biochemistry: liver function tests \> 3x ULN; HbA1C \> 58 mmol/mol
• All untreated endocrine disorders including uncontrolled diabetes mellitus type 2 (i.e. HbA1C \> 58 mmol/mol)
• Bariatric surgery; malabsorptive syndromes; hepatic or renal failure
• Current medication use: insulin, metformin, sulfonylurea, fibrates, incretin mimetics, dopamine agonists (for all but insulin, participation is allowed after a 2- week wash-out period)
• Abuse of alcohol or drugs
• Weight changes \> 10% of body weight during preceding 12 months

Sponsors & Collaborators

• University Hospital, Ghent: lead
• Pfizer: collaborator

Study Sites (1)

Ghent University Hospital, Department of Endocrinology, 9K12IE

Ghent, 9000, Belgium

Location

Related Publications (16)

• Baldelli R, Battista C, Leonetti F, Ghiggi MR, Ribaudo MC, Paoloni A, D'Amico E, Ferretti E, Baratta R, Liuzzi A, Trischitta V, Tamburrano G. Glucose homeostasis in acromegaly: effects of long-acting somatostatin analogues treatment. Clin Endocrinol (Oxf). 2003 Oct;59(4):492-9. doi: 10.1046/j.1365-2265.2003.01876.x.

  PMID: 14510913 BACKGROUND

• Barkan AL, Burman P, Clemmons DR, Drake WM, Gagel RF, Harris PE, Trainer PJ, van der Lely AJ, Vance ML. Glucose homeostasis and safety in patients with acromegaly converted from long-acting octreotide to pegvisomant. J Clin Endocrinol Metab. 2005 Oct;90(10):5684-91. doi: 10.1210/jc.2005-0331. Epub 2005 Aug 2.

  PMID: 16076947 BACKGROUND

• Berg C, Petersenn S, Lahner H, Herrmann BL, Buchfelder M, Droste M, Stalla GK, Strasburger CJ, Roggenbuck U, Lehmann N, Moebus S, Jockel KH, Mohlenkamp S, Erbel R, Saller B, Mann K; Investigative Group of the Heinz Nixdorf Recall Study and the German Pegvisomant Observational Study Board and Investigators. Cardiovascular risk factors in patients with uncontrolled and long-term acromegaly: comparison with matched data from the general population and the effect of disease control. J Clin Endocrinol Metab. 2010 Aug;95(8):3648-56. doi: 10.1210/jc.2009-2570. Epub 2010 May 12.

  PMID: 20463098 BACKGROUND

• Colao A, Pivonello R, Auriemma RS, De Martino MC, Bidlingmaier M, Briganti F, Tortora F, Burman P, Kourides IA, Strasburger CJ, Lombardi G. Efficacy of 12-month treatment with the GH receptor antagonist pegvisomant in patients with acromegaly resistant to long-term, high-dose somatostatin analog treatment: effect on IGF-I levels, tumor mass, hypertension and glucose tolerance. Eur J Endocrinol. 2006 Mar;154(3):467-77. doi: 10.1530/eje.1.02112.

  PMID: 16498061 BACKGROUND

• De Marinis L, Bianchi A, Fusco A, Cimino V, Mormando M, Tilaro L, Mazziotti G, Pontecorvi A, Giustina A. Long-term effects of the combination of pegvisomant with somatostatin analogs (SSA) on glucose homeostasis in non-diabetic patients with active acromegaly partially resistant to SSA. Pituitary. 2007;10(3):227-32. doi: 10.1007/s11102-007-0037-7.

  PMID: 17484056 BACKGROUND

• Freda PU, Reyes CM, Conwell IM, Sundeen RE, Wardlaw SL. Serum ghrelin levels in acromegaly: effects of surgical and long-acting octreotide therapy. J Clin Endocrinol Metab. 2003 May;88(5):2037-44. doi: 10.1210/jc.2002-021683.

  PMID: 12727951 BACKGROUND

• Kim SK, Suh S, Lee JI, Hur KY, Chung JH, Lee MK, Min YK, Kim JH, Kim JH, Kim KW. The ability of beta-cells to compensate for insulin resistance is restored with a reduction in excess growth hormone in Korean acromegalic patients. J Korean Med Sci. 2012 Feb;27(2):177-83. doi: 10.3346/jkms.2012.27.2.177. Epub 2012 Jan 27.

  PMID: 22323865 BACKGROUND

• Kozakowski J, Rabijewski M, Zgliczynski W. [Lowered ghrelin levels in acromegaly-normalization after treatment]. Endokrynol Pol. 2005 Nov-Dec;56(6):862-70. Polish.

  PMID: 16821203 BACKGROUND

• Mazziotti G, Floriani I, Bonadonna S, Torri V, Chanson P, Giustina A. Effects of somatostatin analogs on glucose homeostasis: a metaanalysis of acromegaly studies. J Clin Endocrinol Metab. 2009 May;94(5):1500-8. doi: 10.1210/jc.2008-2332. Epub 2009 Feb 10.

  PMID: 19208728 BACKGROUND

• Moller N, Jorgensen JO. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev. 2009 Apr;30(2):152-77. doi: 10.1210/er.2008-0027. Epub 2009 Feb 24.

  PMID: 19240267 BACKGROUND

• Moller L, Norrelund H, Jessen N, Flyvbjerg A, Pedersen SB, Gaylinn BD, Liu J, Thorner MO, Moller N, Lunde Jorgensen JO. Impact of growth hormone receptor blockade on substrate metabolism during fasting in healthy subjects. J Clin Endocrinol Metab. 2009 Nov;94(11):4524-32. doi: 10.1210/jc.2009-0381. Epub 2009 Oct 9.

  PMID: 19820031 BACKGROUND

• Neggers SJ, Kopchick JJ, Jorgensen JO, van der Lely AJ. Hypothesis: Extra-hepatic acromegaly: a new paradigm? Eur J Endocrinol. 2011 Jan;164(1):11-6. doi: 10.1530/EJE-10-0969. Epub 2010 Nov 2.

  PMID: 21045065 BACKGROUND

• Peracchi M, Porretti S, Gebbia C, Pagliari C, Bucciarelli P, Epaminonda P, Manenti S, Arosio M. Increased glucose-dependent insulinotropic polypeptide (GIP) secretion in acromegaly. Eur J Endocrinol. 2001 Jul;145(1):R1-4. doi: 10.1530/eje.0.145r001.

  PMID: 11415859 BACKGROUND

• Pierluissi J, de Pierluissi RM. Effect of glucose-dependent insulinotropic polypeptide (GIP) on insulin response to glucose in acromegalics. Acta Cient Venez. 1995;46(2):89-96.

  PMID: 9279024 BACKGROUND

• Plockinger U, Holst JJ, Messerschmidt D, Hopfenmuller W, Quabbe HJ. Octreotide suppresses the incretin glucagon-like peptide (7-36) amide in patients with acromegaly or clinically nonfunctioning pituitary tumors and in healthy subjects. Eur J Endocrinol. 1999 Jun;140(6):538-44. doi: 10.1530/eje.0.1400538.

  PMID: 10377503 BACKGROUND

• Velasquez-Mieyer PA, Umpierrez GE, Lustig RH, Cashion AK, Cowan PA, Christensen M, Spencer KA, Burghen GA. Race affects insulin and GLP-1 secretion and response to a long-acting somatostatin analogue in obese adults. Int J Obes Relat Metab Disord. 2004 Feb;28(2):330-3. doi: 10.1038/sj.ijo.0802561.

  PMID: 14708034 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Serum

MeSH Terms

Conditions

Acromegaly; Insulin Resistance

Condition Hierarchy (Ancestors)

Bone Diseases, Endocrine; Bone Diseases; Musculoskeletal Diseases; Hyperpituitarism; Pituitary Diseases; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Guy T'Sjoen, MD, PhD

  University Hospital, Ghent

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2014
• First Posted: June 2, 2014
• Study Start: June 1, 2014
• Primary Completion: August 31, 2017
• Study Completion: August 31, 2017
• Last Updated: December 29, 2022

Record last verified: 2022-12

Locations

BE (1)