Postprandial Hypoglycemia in Patients After Bariatric Surgery With Empagliflozin and Anakinra - The Hypo-BEAR-Study (Hypo-BEAR)

The purpose of the study is to investigate whether hypoglycaemia observed after food intake in bariatric patients can be either influenced by an SGLT2 inhibitor, empagliflozin, or via inhibition of inflammation with an human interleukin-1 receptor antagonist (IL1-RA, anakinra).

Study Overview

• Status: Completed
• Conditions: Bariatric Surgery; Postprandial Hypoglycemia; Late Dumping Syndrome
• Intervention / Treatment: Other: oral placebo (winthrop tablet); Other: subcutaneous placebo (0.67 ml of 0.9% sodium chloride); Drug: Empagliflozin; Drug: Anakinra

Detailed Description

Postprandial hypoglycemia also referred as late-dumping after bariatric surgery can be clinically asymptomatic but also life-threatening. The exact mechanisms leading to postprandial hypoglycemia are not fully understood and therapeutic options are limited and often accompanied with reduced life-quality and weight gain.

In this study, prospective, randomly selected and double-blinded treatment is performed to investigate the effect on postprandial hypoglycemia. A total of 12 subjects participate in the study. After a screening date, three study dates will be performed. Participation in the study usually takes two weeks, but can also be extended to three weeks in individual cases. The University Hospital Basel will be the only test center in this study.

In order to check whether the increase in blood glucose after food intake and subsequent excessive reaction of the body followed by hypoglycaemia patients receive either anakinra as a subcutaneous injection 3h or empagliflozin as a tablet 2 h before a liquid standardized test meal. On one study day only subcutaneous and oral placebo control will be used.

At the beginning of each study date as well as at the time of the test meal several blood samples will be taken to evaluate blood glucose and blood glucose-influencing parameters (insulin / C-peptide, intestinal hormones, inflammatory parameters such as C-reactive protein, IL1beta and IL1-receptor agonist as well as macrophage and t-lymphocyte subpopulations) will be controlled. Questionnaires for dumping symptoms (Dumping Rating scale, Sigstad Score) and hypoglycemia testing with mini-mental test, stanford sleepiness scale and Edinburgh Hypoglycemia Scale will be performed repetitively.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland, 4056 Basel
    • University Hospital Basel, Department of Endocrinology, Diabetes and Metabolism

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:

• Patients after roux-y-gastric bypass or biliopancreatic diversion with documented hypoglycemia, i. e. ≤ 2.5 mmol/l and hypoglycaemic symptoms.
• For subjects with reproductive potential, willingness to use contraceptive measures adequate to prevent the subject or the subject's partner from becoming pregnant during the study

Exclusion Criteria:

• Signs of current infection
• Use of any investigational drug in the last four weeks prior to enrolment
• Use of any anti-diabetic drugs
• adrenal insufficiency and/or substitution with glucocorticoids
• Neutropenia (leukocyte count < 1.5 × 109/L or absolute neutrophil count (ANC) < 0.5 × 109/L)
• Anemia (hemoglobin < 11 g/dL for males, < 10 g/dL for females)
• Clinically significant kidney or liver disease (creatinine > 1.5 mg/dL, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2 × ULN, alkaline phosphatase > 2 × ULN, or total bilirubin [tBili] > 1.5 × ULN)
• Current immunosuppressive treatment or documented immunodeficiency
• Uncontrolled congestive heart failure
• Uncontrolled malignant disease
• Currently pregnant or breastfeeding
• known lactose intolerance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo-Placebo; subcutaneous placebo (0.67 ml of 0.9% sodium chloride) 3 hours before the test meal and an oral placebo (winthrop tablet) 2 hours before the test meal will be administered by an Independent nurse to the blinded patient	Other: oral placebo (winthrop tablet); subcutaneous placebo (0.67 ml of 0.9% sodium chloride) 3 hours before the test meal and an oral placebo (winthrop tablet) 2 hours before the test meal will be administered by an Independent nurse to the blinded patient; Other: subcutaneous placebo (0.67 ml of 0.9% sodium chloride); subcutaneous placebo (0.67 ml of 0.9% sodium chloride) will be administered in arm 'Placebo-Placebo' and arm 'drug: Empagliflozin'
Active Comparator: Investigational Drug A Empagliflozin; subcutaneous placebo (0.67 ml of 0.9% sodium chloride) 3 hours before the test meal and an 10mg of empagliflozin 2 hours before the test meal will be administered by an independent nurse to the blinded patient	Other: subcutaneous placebo (0.67 ml of 0.9% sodium chloride); subcutaneous placebo (0.67 ml of 0.9% sodium chloride) will be administered in arm 'Placebo-Placebo' and arm 'drug: Empagliflozin'; Drug: Empagliflozin; Glucose lowering effect of empagliflozin for reducing the counter-regulatory glucose-lowering response
Active Comparator: Investigational Drug B Anakinra; subcutaneous injection of 100mg anakinra 3 hours before the test meal and an oral placebo (winthrop tablet)before the test meal will be administered by an Independent nurse to the blinded patient	Other: oral placebo (winthrop tablet); subcutaneous placebo (0.67 ml of 0.9% sodium chloride) 3 hours before the test meal and an oral placebo (winthrop tablet) 2 hours before the test meal will be administered by an Independent nurse to the blinded patient; Drug: Anakinra; IL-1Beta blockage effect on insulin secretion and thereby influencing postprandial glucose level

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postprandial hypoglycemia in patients after bariatric surgery	To assess whether empagliflozin or anakinra compared to placebo reduce the severity of hypoglycemia (i.e. change of blood glucose level in mmol/l) following a mixed-meal in patients after bariatric surgery.	6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change of C-peptide	plasma level of c-peptide with anakinra or empagliflozin in comparison to placebo	6 hours
plasma level of IL-1Beta	plasma level of IL-1Beta with anakinra or empagliflozin in comparison to placebo	6 hours
plasma level of Glucagon-like Peptide1 (GLP1)	plasma level of GLP1 with anakinra or empagliflozin in comparison to placebo	6 hours
change of glucagon level	plasma level of glucagon with anakinra or empagliflozin in comparison to placebo	6 hours
changes in Edinburgh Hypoglycemia Scale	changes in Edinburgh Hypoglycemia Scale with anakinra or empagliflozin in comparison to placebo	6 hours
amount of glucose needed for restoring normoglycemia	amount (gramme) of glucose needed for restoring normoglycemia with anakinra or empagliflozin in comparison to placebo	6 hours
length of time needed for restoring normoglycemia	length of time (minutes) needed for restoring normoglycemia with anakinra or empagliflozin in comparison to placebo	6 hours

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Principal Investigator: Marc Donath, MD, Prof., University Hopsital Basel

Publications and helpful links

General Publications

• Hepprich M, Wiedemann SJ, Schelker BL, Trinh B, Starkle A, Geigges M, Loliger J, Boni-Schnetzler M, Rudofsky G, Donath MY. Postprandial Hypoglycemia in Patients after Gastric Bypass Surgery Is Mediated by Glucose-Induced IL-1beta. Cell Metab. 2020 Apr 7;31(4):699-709.e5. doi: 10.1016/j.cmet.2020.02.013. Epub 2020 Mar 19.

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2017
• Primary Completion (Actual): September 21, 2018
• Study Completion (Actual): September 21, 2018

Study Registration Dates

• First Submitted: May 30, 2017
• First Submitted That Met QC Criteria: June 26, 2017
• First Posted (Actual): June 27, 2017

Study Record Updates

• Last Update Posted (Actual): October 24, 2018
• Last Update Submitted That Met QC Criteria: October 22, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: bariatric surgery; anakinra; SGLT2 inhibitor; empagliflozin; postprandial hypoglycemia; late dumping syndrome; IL-1Beta; IL1
• 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; Antirheumatic Agents; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: EKNZ 2017-00689

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No