Clinical trial NCT02244164: Pathophysiological Study of the Increase in Pancreatic Volume in Type 2 Diabetes Treatments.
Official title: Pathophysiological Study of the Increase in Pancreatic Volume in Type 2 Diabetes Treatments.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Type 2 Diabetes
Incretinomimetics
Pancreas
Keywords: Type 2 Diabetes
Incretinomimetics
DPP-4 inhibitors
Pancreas
PanIN
RMN
Lipasemia
Lead sponsor: Erasme University Hospital
Sponsor class: OTHER
First posted: 2014-09-18
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Incretinomimetics and inhibitors of dipeptidyl peptidase-4 (DPP-4) are new treatments for diabetes. Previous retrospective studies have shown that these treatments induced an increase in pancreatic mass with potentially a risk for pancreatitis and development of precancerous lesions.

The aim of our study is to provide a better understanding of the pathophysiological mechanisms of increased volume and / or pancreatic exocrine secretion when exposed to certain treatment of type 2 diabetes.

Detailed description: The incretinomimetics and the inhibitors of dipeptidyl peptidase-4 (DPP-4) are new treatments for diabetes. The incretinomimetics are analogs of Glucagon Like Peptide 1 (GLP-1), secreted from endocrine L-cells of the colon and terminal ileum peptide. Serum GLP-1 increase rapidly after a meal. But its degradation is also fast. It acts on the hypothalamus by reducing appetite and food intake, on the stomach by delaying gastric emptying and the level of beta islet cells by inducing the synthesis and secretion of insulin (1). The incretinomimetics currently marketed in Belgium (March 2014) are exenatide (Byetta ®), liraglutide (Victoza ®), lixisenatide (Lyxumia ®) and very soon (April 2014) extended-release exenatide (Bydureon ®). The DPP-4 prevent the degradation of GLP-1. The DPP-4 currently marketed (March 2014) are sitagliptin (Januvia ®), vildagliptin (Galvus ®), saxagliptin (Onglyza ®) and (Trajenta ®) linagliptin.

In diabetic patients, these treatments allow a significant reduction in fasting plasma glucose and postprandial, with a low risk of hypoglycemia and no weight gain (and sometimes weight loss) (2).

Their place in the management of type 2 diabetes is considered or in combination with metformin, when diabetes is inadequately controlled despite maximal dose of the latter, or when patients are intolerant to metformin.

A study to evaluate the safety of 'incretinomimetics therapy "showed an increase in pancreatic weight of 40% (3). Indeed, in a cohort of 34 pancreatic organ donors from brain death, 20 patients were diabetic and 8 as incretin mimetics for over 1 year. An increase in pancreatic mass on average 40% was observed compared to diabetic patients without this treatment.

This study also demonstrated an increase in the mass of beta cells without restoring insulin function. The advanced for this mass increase without a significant increase of cell size is a hypothesis decreased apoptosis of beta cells.

Furthermore there is also an increase in the mass of cells producing α intraductulaire cell proliferation. This would be responsible for the onset of pancreatitis but also the appearance of endocrine microadenomas. The same study (3) also observed an increase in cell proliferation in the exocrine compartment of the pancreas (ductal and acinar cells) induced by incretinomimetic and an increased frequency of lesions potentially pre-cancerous PanIN 1 and 2 with this treatment.

Another study (4) by the same group of researchers showed that GLP-1 induced ductal cell growth in rats treated with high-dose exenatide for 12 weeks. It could therefore, by ductal obstruction induce pancreatitis.

All of these studies therefore warns about these new treatments potentially inducers of different pancreatic lesions.

The aim of our study is to provide a better understanding of the pathophysiological mechanisms of increased volume and / or pancreatic exocrine secretion when exposed to certain treatment of type 2 diabetes.

Eligibility criteria: Inclusion Criteria:

* Type 2 diabetes inadequately controlled or intolerant to metformin
* Obtaining informed consent
* Aged between 18 and 70 years
* BMI between 20 and 45 kg / m²

Exclusion Criteria:

* Contraindication to nuclear magnetic resonance (NMR):
* Carrying a metallic foreign body (pacemaker, valve, intraocular equipment, clips)
* Allergy to Gadolinium / Secretin
* Pregnancy or breastfeeding
* Contraindication to treatment with incretinomimetic:
* Hypersensitivity to the active substance or to any of the excipients
* Severe Gastroparesis
* Severe renal impairment
* History of Surgery (gastroduodenal, pancreatic or ileocecal)
* Presence or history of pancreatic disease
* Active alcoholism

Primary outcomes:
measure: Volumetric measurement of the pancreas
timeFrame: 1 year
Secondary outcomes:
measure: Quantitative response to secretin
timeFrame: 1 year
Other outcomes:
measure: Fasting glycemia
timeFrame: 1 year
measure: C-Peptide
timeFrame: 1 years
measure: HbA1c
timeFrame: 1 year
measure: Cholesterol
timeFrame: 1 year
measure: Calcium
timeFrame: 1 year
measure: Phosphorus
timeFrame: 1 year
measure: Urea
timeFrame: 1 year
measure: Creatininemia
timeFrame: 1 year
measure: Bilirubinemia
timeFrame: 1 year
measure: Alcaline phosphatase
timeFrame: 1 year
measure: Gamma GT
timeFrame: 1 year
measure: Alanine aminotransferase
timeFrame: 1 year
measure: Asparate aminotransferase
timeFrame: 1 year
measure: Lipasemia
timeFrame: 1 year
Locations:
city: Brussels
country: Belgium
facility: Gastroenterology Department Erasme Hospital
Study officials:
affiliation: Gastroenterology Department Erasme Hospital
name: Vincent Huberty, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006 Nov 11;368(9548):1696-705. doi: 10.1016/S0140-6736(06)69705-5.
citation: Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007 Jul 11;298(2):194-206. doi: 10.1001/jama.298.2.194.
citation: Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 2013 Jul;62(7):2595-604. doi: 10.2337/db12-1686. Epub 2013 Mar 22.
citation: Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care. 2013 Jul;36(7):2118-25. doi: 10.2337/dc12-2713. Epub 2013 May 3.