Investigating the Impact of the SGLT2 Inhibitor Empagliflozin on Postprandial Hypoglycaemia After Gastric Bypass

Randomized, Double-blind, Placebo-controlled Crossover Trial Assessing the Impact of the SGLT2 Inhibitor Empagliflozin on Postprandial Hypoglycaemia After Gastric Bypass

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.

Study Overview

• Status: Completed
• Conditions: Dumping Syndrome; Hypoglycemia, Reactive
• Intervention / Treatment: Drug: Empagliflozin 25 MG; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 4

Contacts and Locations

Study Locations

• Switzerland
  • Canton Of Bern
    • Bern, Canton Of Bern, Switzerland, 3010
      • Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Empagliflozin first, Placebo second; Oral empagliflozin 25 mg daily in the morning for 20 days, followed by oral placebo (daily in the morning) for 20 days after a wash-out period of 2-6 weeks	Drug: Empagliflozin 25 MG; Treatment naive patients with bariatric bypass surgery will be given oral empagliflozin 25mg once daily for 20 days; Drug: Placebo; Treatment naive patients with bariatric bypass surgery will be given oral placebo once daily for 20 days
Placebo Comparator: Placebo first, Empagliflozin second; Oral placebo (daily in the morning) for 20 days, followed by oral empagliflozin 25 mg daily in the morning for 20 days after a wash-out period of 2-6 weeks	Drug: Empagliflozin 25 MG; Treatment naive patients with bariatric bypass surgery will be given oral empagliflozin 25mg once daily for 20 days; Drug: Placebo; Treatment naive patients with bariatric bypass surgery will be given oral placebo once daily for 20 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amplitude of change in plasma glucose (difference between peak and nadir plasma glucose concentration in mmol/L) during the mixed meal test.	On day 20 of the intake of either empagliflozin or placebo, participants undergo a mixed meal test. During the test, the amplitude of plasma glucose (difference between peak and nadir plasma glucose concentration in mmol/L) will be measured.	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean amplitude of glucose excursion (MAGE) based on CGM glucose	During the intake of empagliflozin and placebo, participants will wear a continuous glucose monitoring device. After V1 and V2, CGM data will be extracted and analysed. MAGE will be calculated based on CGM data obtained during each observation period.	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.
Mean coefficient of variability based on CGM glucose	During the intake of empagliflozin and placebo, participants will wear a continuous glucose monitoring device. After V1 and V2, CGM data will be extracted and analysed. The mean coefficient of variability will be calculated based on CGM data obtained during each observation period.	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.
Peak plasma glucose during mixed meal test	On day 20 of the intake of either empagliflozin or placebo, participants undergo a mixed meal test. During the test, the peak of plasma glucose (in mmol/L) will be documented.	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).
Percent time spent with CGM glucose >10.0mmol/L	During the intake of empagliflozin and placebo, participants will wear a continuous glucose monitoring device. After V1 and V2, CGM data will be extracted and analysed. Percent time spent with CGM glucose >10.0mmol/L will be calculated based on CGM data obtained during each observation period.	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.
Proportion of participants experiencing hypoglycaemia (defined as plasma glucose<3.0mmol/L) during the mixed meal tolerance test	On day 20 of the intake of either empagliflozin or placebo, participants undergo a mixed meal test. During the test, the proportion of participants experiencing hypoglycaemia (defined as plasma glucose<3.0mmol/L) will be documented.	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).
Nadir plasma glucose during mixed meal test	On day 20 of the intake of either empagliflozin or placebo, participants undergo a mixed meal test. During the test, the nadir of plasma glucose (in mmol/L) will be documented.	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).
Percent time spent with CGM glucose <3.0mmol/L	During the intake of empagliflozin and placebo, participants will wear a continuous glucose monitoring device. After V1 and V2, CGM data will be extracted and analysed. Percent time spent with CGM glucose <3.0mmol/L will be calculated based on CGM data obtained during each observation period.	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.
Percent time spent with CGM glucose <2.8mmol/L	During the intake of empagliflozin and placebo, participants will wear a continuous glucose monitoring device. After V1 and V2, CGM data will be extracted and analysed. Percent time spent with CGM glucose <2.8mmol/L will be calculated based on CGM data obtained during each observation period.	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.
Frequency of postprandial symptoms based on a modified Edinburgh Hypoglycaemia	During the intake of empagliflozin and placebo, participants will report postprandial symptoms in an electronic event diary. The frequency of postprandial symptoms, based on a modified Edinburgh Hypoglycaemia Symptom Scale, will be documented.	The outcome will be calculated from day 1 to day 20 of intake of IMP/Placebo.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measures of beta-cell function using the oral minimal model method calculated using data from the mixed-meal test	On day 20 of the intake of either empagliflozin or placebo, participants undergo a mixed meal test. Measures of beta-cell function will be calculated using the oral minimal model method with data from the mixed-meal test.	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).
Measures of insulin sensitivity using the oral minimal model method calculated using data from the mixed-meal test	On day 20 of the intake of either empagliflozin or placebo, participants undergo a mixed meal test. Measures of insulin sensitivity will be calculated using the oral minimal model method with data from the mixed-meal test.	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).
Measures of first-pass hepatic insulin extraction using the oral minimal model method calculated using data from the mixed-meal test	On day 20 of the intake of either empagliflozin or placebo, participants undergo a mixed meal test. Measures of first-pass hepatic insulin extraction will be calculated using the oral minimal model method with data from the mixed-meal test.	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).
Average daily meal frequency (meals>30g/24h and meals <30g/24h) assessed during the treatment periods	During the intake of empagliflozin and placebo, participants will report meals in an electronic event diary. Average daily meal frequency per 24 hours will be calculated.	The outcome will be calculated from day 1 to day 20 of intake of IMP/Placebo.
Total amount of daily excreted glucose (g/24h) measured in the 24h urine collection	The participants will collect a 24-hours urine sample on the day before the mixed meal test. Total amount of daily excreted glucose (in grams per 24 hours) will be calculated.	The outcome will be assessed during the day before the experimental visit.
Glucagon response during the mixed-meal test (incremental AUC from 0 to 120min following meal ingestion)	On day 20 of the intake of either empagliflozin or placebo, participants undergo a mixed meal test. During the test, the plasma glucagon concentrations will be measured.	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).
Insulin response during the mixed-meal test (incremental AUC from 0 to 120min following meal ingestion)	On day 20 of the intake of either empagliflozin or placebo, participants undergo a mixed meal test. During the test, the plasma insulin concentrations will be measured.	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).
Ketone levels (3-beta-hydroxybutyrate) during the mixed-meal test	On day 20 of the intake of either empagliflozin or placebo, participants undergo a mixed meal test. During the test, ketone levels (3-beta-hydroxybutyrate) will be measured.	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).

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2021
• Primary Completion (Actual): August 11, 2022
• Study Completion (Actual): August 11, 2022

Study Registration Dates

• First Submitted: September 16, 2021
• First Submitted That Met QC Criteria: September 16, 2021
• First Posted (Actual): September 27, 2021

Study Record Updates

• Last Update Posted (Actual): March 14, 2023
• Last Update Submitted That Met QC Criteria: March 13, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Postoperative Complications; Gastrointestinal Diseases; Stomach Diseases; Postgastrectomy Syndromes; Hypoglycemia; Dumping Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: DEEP-Empa

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: After study completion, 10 years
• IPD Sharing Access Criteria: After written inquiry and approval by the principal investigator
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No