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

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.

Study Overview

• Status: Completed
• Conditions: Acromegaly

• Study Type: Observational
• Enrollment (Actual): 21

Contacts and Locations

Study Locations

• Belgium
  • Ghent, Belgium, 9000
    • Ghent University Hospital, Department of Endocrinology, 9K12IE

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

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

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
fasting and postprandial glucose	Serum glucose levels during mixed-meal test (before and 10, 30, 60, 120, 180, 240, 300 minutes after ingestion of standard mixed-meal (bread, margarine, cheese and milk) providing a caloric content of 1000 kCal whereby 45% of the energy comes from fat, 36% from carbohydrates and 19% from proteins)	At enrollment in groups 1-4
fasting and postprandial insulin	Insulin levels during standard mixed-meal test (cfr.supra)	At enrollment in groups 1-4
fasting and postprandial gut hormone levels	Serum levels of gastric inhibitory polypeptide (GIP), ghrelin, peptide YY, pancreatic polypeptide, glucagon-like peptide 1 (GLP-1), oxyntomodulin and cholecystokinin before start during standard mixed-meal test (cfr.supra)	At enrollment in groups 1-4
fasting adipokine levels	Fasting serum levels of leptin, adiponectin and interleukin 6 (IL-6)	At enrollment in group 1-4
fasting lipid levels	Fasting serum levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol	At enrollment in groups 1-4
change in fasting and postprandial glucose	Serum glucose levels during mixed-meal test (before and 10, 30, 60, 120, 180, 240, 300 minutes after ingestion of standard mixed-meal (bread, margarine, cheese and milk) providing a caloric content of 1000 kCal whereby 45% of the energy comes from fat, 36% from carbohydrates and 19% from proteins)	before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5
change in fasting and postprandial insulin levels	Insulin levels during standard mixed-meal test (cfr.supra)	before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5
change in fasting and postprandial gut hormone levels	Serum levels of gastric inhibitory polypeptide (GIP), ghrelin, peptide YY, pancreatic polypeptide, glucagon-like peptide 1 (GLP-1), oxyntomodulin and cholecystokinin before start during standard mixed-meal test (cfr.supra)	before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5
change in fasting adipokine levels	Fasting serum levels of leptin, adiponectin and interleukin 6 (IL-6)	before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5
change in fasting lipid levels	Fasting serum levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol	before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resting energy expenditure	Resting energy expenditure determined using indirect calorimetry	At enrollment in group 1-4
Weight		At enrollment in group 1-4
Standing height		At enrollment in group 1-4
Waist and hip circumference		At enrollment in group 1-4
Change in resting energy expenditure	Resting energy expenditure determined using indirect calorimetry	before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5
Weight change		before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5
Change in standing height		before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5
Change in waist and hip circumference		before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5

Collaborators and Investigators

• Sponsor: University Hospital, Ghent
• Collaborators: Pfizer

Publications and helpful links

General Publications

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

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2014
• Primary Completion (Actual): August 31, 2017
• Study Completion (Actual): August 31, 2017

Study Registration Dates

• First Submitted: May 21, 2014
• First Submitted That Met QC Criteria: May 28, 2014
• First Posted (Estimate): June 2, 2014

Study Record Updates

• Last Update Posted (Estimate): December 29, 2022
• Last Update Submitted That Met QC Criteria: December 28, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Acromegaly; Adipokines; Insulin sensitivity; Pegvisomant; Lipid metabolism; Gut hormones; Acromegaly treatment; Long-acting somatostatin analogs
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Musculoskeletal Diseases; Hypothalamic Diseases; Bone Diseases; Bone Diseases, Endocrine; Hyperpituitarism; Pituitary Diseases; Acromegaly
• Other Study ID Numbers: EC/2013/857; WI182140 (Other Grant/Funding Number: Pfizer)