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

NCT05057819 | Completed Phase 4

• 1 other identifier: DEEP-Empa
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

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.

Conditions

Dumping Syndrome; Hypoglycemia, Reactive

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• Mean amplitude of glucose excursion (MAGE) based on CGM glucose

  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

  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

  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

  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

  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).

Other Outcomes (8)

• Measures of beta-cell function using the oral minimal model method calculated using 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

  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

  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).

Study Arms (2)

Empagliflozin first, Placebo second

EXPERIMENTAL

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; Drug: Placebo

Placebo first, Empagliflozin second

PLACEBO COMPARATOR

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; Drug: Placebo

Interventions

Empagliflozin 25 MG DRUG

Treatment naive patients with bariatric bypass surgery will be given oral empagliflozin 25mg once daily for 20 days

Empagliflozin first, Placebo second; Placebo first, Empagliflozin second

Placebo DRUG

Treatment naive patients with bariatric bypass surgery will be given oral placebo once daily for 20 days

Empagliflozin first, Placebo second; Placebo first, Empagliflozin second

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead

Study Sites (1)

Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern

Bern, Canton of Bern, 3010, Switzerland

Location

Related Publications (2)

• Ferreira A, Schonenberger KA, Potoczna N, Vogt A, Gerber PA, Zehetner J, Giachino D, Nett P, Gawinecka J, Cossu L, Fuster DG, Dalla Man C, Facchinetti A, Melmer A, Nakas CT, Hepprich M, Donath MY, Herzig D, Bally L. Randomized, Double-Blind, Placebo-Controlled Crossover Trial of Once Daily Empagliflozin 25 mg for the Treatment of Postprandial Hypoglycemia After Roux-en-Y Gastric Bypass. Diabetes Technol Ther. 2023 Jul;25(7):467-475. doi: 10.1089/dia.2023.0036. Epub 2023 Jun 5.

  PMID: 37093196 DERIVED

• 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.

  PMID: 36123073 DERIVED

MeSH Terms

Conditions

Dumping Syndrome; Hypoglycemia

Interventions

empagliflozin

Condition Hierarchy (Ancestors)

Postgastrectomy Syndromes; Stomach Diseases; Gastrointestinal Diseases; Digestive System Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Lia Bally, MD/PhD

  Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized, double-blind, placebo-controlled, crossover trial

Study Record Dates

• First Submitted: September 16, 2021
• First Posted: September 27, 2021
• Study Start: December 1, 2021
• Primary Completion: August 11, 2022
• Study Completion: August 11, 2022
• Last Updated: March 14, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR, ANALYTIC CODE
• Time Frame: After study completion, 10 years
• Access Criteria: After written inquiry and approval by the principal investigator

Locations

CH (1)