Clinical trial NCT02640118: The Impact of Lixisenatide on Postprandial Glucose Tolerance in Pancreatectomised Subjects
Official title: The Impact of Lixisenatide on Postprandial Glucose Tolerance in Pancreatectomised Subjects -a Delineation of Extrapancreatic Effects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes After Total Pancreatectomy
Lead sponsor: University Hospital, Gentofte, Copenhagen
Sponsor class: OTHER
Collaborators: name: MCM Vaccines B.V.
First posted: 2015-12-28
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Postprandial glucose (PPG) excursions are not only determined by insulin-mediated glucose disposal and endogenous glucose production (regulated by insulin and glucagon); also the rate of gastric emptying constitutes an important determinant of PPG levels 1. The short-acting glucagon-like peptide-1 (GLP-1) receptor agonist lixisenatide is used in the treatment of type 2 diabetes. It increases glucose-dependent insulin secretion, suppresses glucagon secretion and reduces gastric emptying of meals 2. These three mechanisms most likely constitute the weightiest mechanisms behind the potent impact of lixisenatide on exaggerated PPG excursions in patients with type 2 diabetes - which often are normalised during lixisenatide treatment 3. However, the separate impact of lixisenatide-induced reduction of gastric emptying (independently of the pancreatic effects) has been difficult to determine. Importantly, treatment with lixisenatide also decreases appetite and food intake and may, like native GLP-1, increase energy expenditure 4. So far an exact demarcation of the pancreatic and extrapancreatic effects of lixisenatide in humans remains to be established.

The present project serves to determine whether effects of lixisenatide on gastric emptying, appetite, food intake and resting energy expenditure are dependent on the endocrine pancreas.

The study is a randomised, placebo-controlled, double-blinded, cross-over study.

12 healthy persons and 12 pancreatectomized patients (i.e. patients who have had their pancreata removed due to pancreatic cancer or severe chronic pancreatitis) will be subjected to two experimental days on which they will undergo a liquid meal test followed by a fasting period and finished off with an ad libitum meal with lixisenatide and placebo, respectively.


Eligibility criteria: Inclusion criteria Pancreatectomised patients

* Caucasians above 18 years of age who have undergone total pancreatectomy
* Normal haemoglobin
* Informed consent Healthy subjects
* Normal fasting plasma glucose (FPG) and normal HbA1C (according to the World Health Organization (WHO) criteria)
* Normal haemoglobin
* Age above 18 years
* Informed consent

Exclusion criteria Pancreatectomised patients

* Inflammatory bowel disease
* Operation within the last 3 months
* Ongoing chemotherapy or chemotherapy within the last 3 months
* Ostomy
* Nephropathy (serum creatinine \>150 µM and/or albuminuria)
* Severe liver disease (serum alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) \>3×normal values)
* Pregnancy and/or breastfeeding
* Age above 80 years
* Any condition that the investigator feels would interfere with trial participation Healthy subjects
* Diabetes mellitus (DM)
* Prediabetes (impaired glucose tolerance and/or impaired FPG)
* First degree relatives with DM
* Inflammatory bowel disease
* Intestinal resection and/or ostomy
* Nephropathy (serum creatinine \>150 µM and/or albuminuria
* Liver disease (ALAT and/or serum ASAT \>2×normal values)
* Pregnancy and/or breastfeeding
* Age above 80 years
* Any condition that the investigator feels would interfere with trial participation

Primary outcomes:
measure: PPG excursions measured as incremental area under curve (iAUC)
timeFrame: -120,-45,-30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes
Secondary outcomes:
measure: differences in gastric emptying, measurement of s-paracetamol
timeFrame: -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes
measure: food intake and appetite
timeFrame: at time 0,30,60,90,120,150,180 minutes
measure: resting energy expenditure (REE)
timeFrame: -90,30,150 minutes
measure: p-glucose mmol/L
timeFrame: -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes
measure: p-C-peptide pmol/l
timeFrame: -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes
measure: glucagon, gastrin, cholecystokinin, GIP, GLP-1, oxyntomodulin
timeFrame: -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes
Other outcomes:
Locations:
Study officials:
affiliation: Center for Diabetes Research, Gentofte Hospital, Kildegaardsvej 28, 2900 Hellerup, Denmark
name: Filip K Knop, Assoc. Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Juel CTB, Lund A, Andersen MM, Hansen CP, Storkholm JH, Rehfeld JF, van Hall G, Hartmann B, Wewer Albrechtsen NJ, Holst JJ, Vilsboll T, Knop FK. The GLP-1 receptor agonist lixisenatide reduces postprandial glucose in patients with diabetes secondary to total pancreatectomy: a randomised, placebo-controlled, double-blinded crossover trial. Diabetologia. 2020 Jul;63(7):1285-1298. doi: 10.1007/s00125-020-05158-9. Epub 2020 May 11.