Clinical trial NCT05057819: Investigating the Impact of the SGLT2 Inhibitor Empagliflozin on Postprandial Hypoglycaemia After Gastric Bypass
Official title: Randomized, Double-blind, Placebo-controlled Crossover Trial Assessing the Impact of the SGLT2 Inhibitor Empagliflozin on Postprandial Hypoglycaemia After Gastric Bypass
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Dumping Syndrome
Hypoglycemia, Reactive
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
First posted: 2021-09-27
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized, double-blind, placebo-controlled, crossover trial
Primary purpose: TREATMENT

Brief summary: Bariatric surgery is an effective anti-obesity treatment providing durable weight loss and profound beneficial effects on glucose metabolism. However, bariatric surgery also comes with an increased risk for a late metabolic complication known as postbariatric hypoglycaemia (PBH). The condition presents with hypoglycaemic episodes 1-3 hours after meals and develops one to several years after bariatric surgery, mainly gastric bypass. PBH affects approximately 30% of patients without preexisting diabetes. For a subset of patients, hypoglycaemia-associated impairment of daily living and social functioning are commonly observed. The underlying mechanisms of PBH are multifactorial. It is considered that inadequately high insulin secretion caused by both accelerated glucose absorption from the gut and increased insulinotropic hormones such as GLP-1 are important pathophysiologic mechanisms. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor reduces glucose exposure by increasing urinary glucose excretion. In a pilot study, a single dose of 10mg of empagliflozin taken before a mixed meal reduced the risk of PBH by 74%. Both, postprandial glucose and insulin exposure were significantly lower with empagliflozin vs. placebo, which makes Empagliflozin a potential treatment for PBH. In this study, treatment naïve patients will be randomized to receive either oral empagliflozin 25 mg daily in the morning for 20 days, followed by 2-6 weeks wash out and 20 days placebo once daily in the morning, or the reverse sequence. Urine and blood analysis will be performed as detailed in the protocol.


Eligibility criteria: Inclusion Criteria:

* Informed Consent as documented by signature
* Age 18 years or older
* Gastric bypass surgery ≥1 year ago
* Biochemically confirmed postprandial hypoglycaemia (plasma or sensor glucose \<3.0mmol/l) within the past three months

Exclusion Criteria:

* Diabetes on anti-diabetic treatment (insulin and/or non-insulin agents)
* Genito-urinary infection, if not treated successfully
* Chronic kidney disease (defined as CKD-EPI eGFR \< 60 mL/min per 1.73 m2 body surface area)
* Pregnant and lactating women (urine pregnancy test to be performed for women of childbearing potential \[defined as women who are not surgically sterilized/ hysterectomized, and/ or who are postmenopausal for less than 12 months\]) or women of childbearing potential that refuse to use an effective contraceptive method \[birth control pill or intrauterine device (IUD)\]).
* Inability to understand and follow the protocol
* Known allergy to the study drug
* Participation in another interventional clinical trial overlapping with the current trial

Primary outcomes:
measure: Amplitude of change in plasma glucose (difference between peak and nadir plasma glucose concentration in mmol/L) during the mixed meal test.
timeFrame: The outcome will be assessed during the mixed-meal test on the day of the experimental visit at the end of each study period (day 20-24 of the respective study period).
Secondary outcomes:
measure: Mean amplitude of glucose excursion (MAGE) based on CGM glucose
timeFrame: The outcome will be calculated from day 1 to day 20 of intake of IMP/Placebo (i.e. aggregated measures of the outcome will be calculated for each period). The first 3 days of data of each period will be discarded.
measure: Mean coefficient of variability based on CGM glucose
timeFrame: The outcome will be calculated from day 1 to day 20 of intake of IMP/Placebo (i.e. aggregated measures of the outcome will be calculated for each period). The first 3 days of data of each period will be discarded.
measure: Peak plasma glucose during mixed meal test
timeFrame: The outcome will be assessed during the mixed-meal test on the day of the experimental visit at the end of each study period (day 20-24 of the respective study period).
measure: Percent time spent with CGM glucose >10.0mmol/L
timeFrame: The outcome will be calculated from day 1 to day 20 of intake of IMP/Placebo (i.e. aggregated measures of the outcome will be calculated for each period). The first 3 days of data of each period will be discarded.
measure: Proportion of participants experiencing hypoglycaemia (defined as plasma glucose<3.0mmol/L) during the mixed meal tolerance test
timeFrame: The outcome will be assessed during the mixed-meal test on the day of the experimental visit at the end of each study period (day 20-24 of the respective study period).
measure: Nadir plasma glucose during mixed meal test
timeFrame: The outcome will be assessed during the mixed-meal test on the day of the experimental visit at the end of each study period (day 20-24 of the respective study period).
measure: Percent time spent with CGM glucose <3.0mmol/L
timeFrame: The outcome will be calculated from day 1 to day 20 of intake of IMP/Placebo (i.e. aggregated measures of the outcome will be calculated for each period). The first 3 days of data of each period will be discarded.
measure: Percent time spent with CGM glucose <2.8mmol/L
timeFrame: The outcome will be calculated from day 1 to day 20 of intake of IMP/Placebo (i.e. aggregated measures of the outcome will be calculated for each period). The first 3 days of data of each period will be discarded.
measure: Frequency of postprandial symptoms based on a modified Edinburgh Hypoglycaemia
timeFrame: The outcome will be calculated from day 1 to day 20 of intake of IMP/Placebo.
Other outcomes:
measure: Measures of beta-cell function using the oral minimal model method calculated using data from the mixed-meal test
timeFrame: The outcome will be assessed during the mixed-meal test on the day of the experimental visit at the end of each study period (day 20-24 of the respective study period).
measure: Measures of insulin sensitivity using the oral minimal model method calculated using data from the mixed-meal test
timeFrame: The outcome will be assessed during the mixed-meal test on the day of the experimental visit at the end of each study period (day 20-24 of the respective study period).
measure: Measures of first-pass hepatic insulin extraction using the oral minimal model method calculated using data from the mixed-meal test
timeFrame: The outcome will be assessed during the mixed-meal test on the day of the experimental visit at the end of each study period (day 20-24 of the respective study period).
measure: Average daily meal frequency (meals>30g/24h and meals <30g/24h) assessed during the treatment periods
timeFrame: The outcome will be calculated from day 1 to day 20 of intake of IMP/Placebo.
measure: Total amount of daily excreted glucose (g/24h) measured in the 24h urine collection
timeFrame: The outcome will be assessed during the day before the experimental visit.
measure: Glucagon response during the mixed-meal test (incremental AUC from 0 to 120min following meal ingestion)
timeFrame: The outcome will be assessed during the mixed-meal test on the day of the experimental visit at the end of each study period (day 20-24 of the respective study period).
measure: Insulin response during the mixed-meal test (incremental AUC from 0 to 120min following meal ingestion)
timeFrame: The outcome will be assessed during the mixed-meal test on the day of the experimental visit at the end of each study period (day 20-24 of the respective study period).
measure: Ketone levels (3-beta-hydroxybutyrate) during the mixed-meal test
timeFrame: The outcome will be assessed during the mixed-meal test on the day of the experimental visit at the end of each study period (day 20-24 of the respective study period).
Locations:
city: Bern
country: Switzerland
facility: Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern
state: Canton Of Bern
Study officials:
affiliation: Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
name: Lia Bally, MD/PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ferreira A, Emara AFA, Herzig D, Melmer A, Vogt AP, Nakas CT, Facchinetti A, Dalla Man C, Bally L. Study protocol for a randomised, double-blind, placebo-controlled crossover trial assessing the impact of the SGLT2 inhibitor empagliflozin on postprandial hypoglycaemia after gastric bypass. BMJ Open. 2022 Sep 19;12(9):e060668. doi: 10.1136/bmjopen-2021-060668.