The effect of bile acid binding with colesevelam on postprandial glucose concentrations in patients after RYGB and cholecystectomy : a meal test study

Rationale:
Postprandial hyperinsulinemic hypoglycaemia often occurs after bariatric
surgery and is called PBH.
We previously found that 48% of patients after RYGB developed a hypoglycemic
event in a mixed meal test (MMT). In these patients bile acid (BA)
concentrations were much higher compared to those without hypoglycemia.
Furthermore, more patients with hypoglycemia had undergone a cholecystectomy
(CCx). The role of postprandial bile acids in PBH has up till now not been
elucidated

Objective:
Primary : To compare the difference in glucose nadir during the MMT on and off
pre-treatment with colesevelam in RYGB-CCx patients with a hypoglycaemia
(RYGB-CCx-hypo) in the first MMT
Secondary:To evaluate the difference in number of RYGB-CCx-hypo patients
developing a hypoglycemia (glucose < 3.0 mmol/L) during the MMT on and off
pretreatment with colesevelam
To compare differences during the MMT on and off pre-treatment with colesevelam
in glucose AUC at different time intervals : 0-60, 60-120, 60-180, bile acids,
bile acid subclasses, GLP-1, PPY, and insulin, both as peaks and as AUC0-60 min
.
To compare differences during the MMT on and off treatment with colesevelam in
glucose kinetics (absorption rate, distribution) using stable isotope dilution
of glucose
To compare differences during the MMT on and off treatment with colesevelam in
level of satiety, hunger score and dumping complaints
Study design: prospective, non-blinded, intervention
Study population:
Patients between 20 and 60 years who underwent RYGB surgery 2 years or more
before and have a history of CCx
Intervention : colesevelam tablets 625mg , 3,750 mg dissolved in water
Main study parameters/endpoints:
Glucose nadir during the MMT
Number of patients developing hypoglycemia during the MMT
Glucose disposal rate and endogenous glucose production during the MMT measured
with stable isotope dilution
Changes in bile acids and subclasses during the MMT
Changes in insulin, GLP-1, PYY, FGF19 during the MMT
Nature and extent of the burden and risks associated with participation,
benefit and group relatedness:
Patients have to visit the outpatient clinic 2 times max, in fasting condition.
Via an indwelling catheter blood samples will be drawn 11 times to a total
amount of 242 mL
The meal can induce dumping complaints and can induce a low blood sugar, which
will be monitored and treated if necessary.

Patients 2-3 years after RYGB with a previous cholecystectomy will start this
study with a MMT. After full explanation of the study and written informed
consent patients will be admitted in the outpatient clinic between 8 and 9 pm
after an overnight fast of at least 10 hours. An indwelling catheter will be
placed in an antecubital vein for blood withdrawal. After the first sample is
drawn, they will be asked to consume in 10 minutes a liquid mixed meal,
consisting of 200mL Ensure® Plus to which 50 mL 2,5% D-[6,6,-2H]-glucose tracer
(:1,25 gram) is added, in total volume of 250 mL
Blood samples will be withdrawn, blood pressure and pulse will be measured,
satiety, hunger and dumping scores will be documented at various time points
until 180 minutes.
Those patients who develop a hypoglycemic event (glucose < 3.0 mmol/L) during
the MMT will repeate the MMT between 7 and 14 days with pretreatment with
colesevelam 3750mg dissolved in 25 ml water once dosed shortly before the MMT.

Colesevelam tablet 625 mg (Cholestagel®) 3750 mg once dosed dissolved in water

1. during the MMT a hypoglycemic event can occur. Patients are under constant
observation and an intravenous access is available for administration of
glucose in case of clinical signs of neuroglycopenia.
2. insertion of a cannula for venous access can fail leading to a small
hematoma.
3. Colesevelam can cause side effects, mainly gastro-intestinal (constipation,
nasea, sometimes diarrhea) which can be simply treated by stopping the drug.
4. Colesevelam can reduce the absorption of other drugs. Therefore patients who
use drugs could possibly be interfered with by colesevelam are excluded. Also
patients will be reminded to contact the investigator when new drugs are
prescribed to them during the study