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

Acromegaly Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02152124
• Other study ID #: EC/2013/857
• Secondary ID: WI182140
• Status: Completed
• Start date: June 1, 2014
• Est. completion date: August 31, 2017

Study information

• Verified date: December 2022
• Source: University Hospital, Ghent
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: August 31, 2017
• Est. primary completion date: August 31, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Acromegaly

Locations

Country	Name	City	State
Belgium	Ghent University Hospital, Department of Endocrinology, 9K12IE	Ghent

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Ghent	Pfizer

Country where clinical trial is conducted

Belgium, 

References & 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Resting energy expenditure	Resting energy expenditure determined using indirect calorimetry	At enrollment in group 1-4
Other	Weight		At enrollment in group 1-4
Other	Standing height		At enrollment in group 1-4
Other	Waist and hip circumference		At enrollment in group 1-4
Other	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
Other	Weight change		before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5
Other	Change in standing height		before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5
Other	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
Primary	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
Primary	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	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
Secondary	fasting and postprandial insulin	Insulin levels during standard mixed-meal test (cfr.supra)	At enrollment in groups 1-4
Secondary	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
Secondary	fasting adipokine levels	Fasting serum levels of leptin, adiponectin and interleukin 6 (IL-6)	At enrollment in group 1-4
Secondary	fasting lipid levels	Fasting serum levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol	At enrollment in groups 1-4
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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