Empagliflozin for the Treatment of Postprandial Hypoglycemia (EmpHy)

This randomized trial is to test whether a treatment with empagliflozin is superior to placebo in patients with postprandial hypoglycemia after bariatric surgery, that is if it improves health related quality of life (mentally or physically) or reduces the risk of hypoglycemic events.

Study Overview

• Status: Recruiting
• Conditions: Postprandial Hypoglycemia
• Intervention / Treatment: Drug: Empagliflozin (Jardiance®;; Other: Placebo Control Intervention

Detailed Description

Postprandial hypoglycemia is a debilitating medical complication after bariatric surgery for which no approved pharmacological treatment exists. The prevalence of hypoglycemia in bariatric patients ranges from 0.5 % severe episodes up to 56 % and its symptoms range from asymptomatic to deleterious. This hypoglycemic condition is characterized by a rapid increase of plasma glucose after carbohydrate ingestion followed by an exaggerated hyperinsulinemic response. Hypoglycemia itself may lead to increased hunger, carbohydrate ingestion and following weight regain.

In a placebo-controlled, randomized, double-blind, crossover study, the SGLT2-inhibitor empagliflozin statistically significantly reduced the number of symptomatic hypoglycemia (2 vs. 7 symptomatic hypoglycemic episodes; p=0.013) compared to placebo after a mixed meal test in 12 patients after Roux-en-Y gastric bypass. Empagliflozin reduced the postprandial rise in glycemia and decreased subsequent insulin secretion, underlining the postulated mechanism of action.

This randomized trial is to test whether a treatment with empagliflozin is superior to placebo in patients with postprandial hypoglycemia after bariatric surgery, that is if it improves health related quality of life (mentally or physically) or reduces the risk of hypoglycemic events.

• Study Type: Interventional
• Enrollment (Estimated): 62
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Marc Y Donath, Prof. Dr. med.; Phone Number: +41 61 265 25 25; Email: marc.donath@usb.ch
• Study Contact Backup: Name: Matthias Hepprich, Dr. med.; Phone Number: +41 61 328 60 77; Email: matthias.hepprich@usb.ch

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • Recruiting
    • University Hospital Basel, Division of Endocrinology, Diabetes and Metabolism
    • Contact: Marc Y Donath, Prof. Dr. med.; Phone Number: +41 61 265 25 25; Email: marc.donath@usb.ch
    • Principal Investigator: Marc Y Donath, Prof. Dr. med.
    • Sub-Investigator: Justus Fischer
    • Sub-Investigator: Matthias Hepprich, Dr. med.
    • Contact: Matthias Hepprich, Dr. med.; Phone Number: +41 61 328 60 77; Email: matthias.hepprich@usb.ch
  • Bern, Switzerland, 3010
    • Recruiting
    • University Hospital Berne and Center of Bariatric Surgery Berne
    • Contact: Lia Bally, Prof. Dr. med.; Email: lia.bally@insel.ch
    • Contact: David Herzig, Dr. med.; Email: david.herzig@extern.insel.ch
    • Principal Investigator: Lia Bally, Prof. Dr. med.
    • Sub-Investigator: David Herzig, Dr. med.
  • Olten, Switzerland
    • Recruiting
    • Cantonal Hospital Olten, Endocrine Outpatient Clinic
    • Contact: Gottfried Rudofsky, Prof. Dr. med.; Email: gottfried.rudofsky@spital.so.ch
    • Principal Investigator: Gottfried Rudofsky, Prof. Dr. med.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients after bariatric surgery (i.e. sleeve gastrectomy, Roux-en-Y gastric bypass, omega- loop bypass, biliopancreatic diversion) with documented hypoglycemia, i. e. < 3.0 mmol/l and at least 5 hypoglycemic episodes per week despite dietary modification
• For women with child-bearing potential, willingness to use contraceptive measures adequate to prevent pregnancy during the study
• Informed Consent as documented by signature

Exclusion Criteria:

• Any type of diabetes mellitus according to ADA criteria
• Intolerance to the study drug
• Signs of current infection
• Use of any drug therapy for postbariatric hypoglycemia apart from acarbose (all remaining drugs have to be discontinued four half-life times before screening phase)
• 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, AST/ALT > 2 × ULN, alkaline phosphatase > 2 × ULN, or total bilirubin [tBili] > 1.5 × ULN)
• Uncontrolled congestive heart failure
• Uncontrolled malignant disease
• Currently pregnant or breastfeeding
• Known or suspected non-compliance, drug or alcohol abuse
• Meeting the criteria for vulnerability (e.g. participants incapable of judgment or participants under tutelage)
• Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc.
• Participation in another clinical trial using investigational drugs in the last 30 days or planned participation in the next 60 days
• Previous enrolment into the current study,
• Enrolment of the investigator, his/her family members, employees and other dependent persons

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Empagliflozin; Standard dose of empagliflozin (Jardiance®; Boehringer Ingelheim GmbH), i. e. 10 mg. Empagliflozin is an orally available inhibitor of SGLT2 and approved for the treatment of type 2 diabetes mellitus and will be given per os once daily in the morning for 28 days.	Drug: Empagliflozin (Jardiance®; Each tablet contains the active substance of 10 mg empagliflozin as well as the adjuvant lactose-monohydrate and is taken orally once daily in the morning.
Placebo Comparator: Placebo; Placebo provided by Boehringer Ingelheim Switzerland. Per os once daily in the morning for 28 days.	Other: Placebo Control Intervention; Placebo will be provided by Boehringer Ingelheim. It is identical to the interventional product apart from the active compound.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Quality of life (mental health; as assessed by the SF-36 mental health component score; MCS)	Change in Quality of life (mental health; as assessed by the SF-36 mental health component. Each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. Scores represent the percentage of total possible score achieved.	at baseline, at day 29 and at day 60 (+/- 10 days) after baseline
Change in Quality of life (physical health; as assessed by the SF-36 mental physical component score; PCS)	Change in Quality of life (physical health; as assessed by the SF-36 mental physical component score; PCS). Each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. Scores represent the percentage of total possible score achieved.	at baseline, at day 29 and at day 60 (+/- 10 days) after baseline
Hypoglycemic events defined as glucose values below 3.0 mmol/l	Hypoglycemic events defined as glucose values below 3.0 mmol/l	at 28 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postprandial Symptoms of hypoglycemia defined as acute onset of typical symptoms according to Edinburgh Hypoglycemia Scale along with a decreasing blood glucose level.	Postprandial Symptoms of hypoglycemia defined as acute onset of typical symptoms according to Edinburgh Hypoglycemia Scale (7-point Likert scale (1 = not present, 7 = very intense)) along with a decreasing blood glucose level. The postprandial period is defined as 3 hours following meal intake.	at 28 days after randomization
Hypoglycemia unawareness (measured by modified Clarke Score)	Hypoglycemia unawareness (measured by modified Clarke Score). The Clarke method comprises eight questions characterizing the participant's exposure to episodes of moderate and severe hypoglycemia. It also examines the glycemic threshold for, and symptomatic responses to, hypoglycemia. A score of four or more implies impaired awareness of hypoglycemia.	at 28 days after randomization
Fear of hypoglycemia (measured on a scale of 0 to 10)	Fear of hypoglycemia (measured on a scale of 0 to 10)	at 28 days after randomization
Time below range (TBR): % of sensor glucose readings and time between 3.0 and 3.8 mmol/L)	Time below range (TBR): % of sensor glucose readings and time between 3.0 and 3.8 mmol/L)	at 28 days after randomization
Time in hypoglycemia: % of sensor glucose readings and time below 3.0 mmol/L	Time in hypoglycemia: % of sensor glucose readings and time below 3.0 mmol/L	at 28 days after randomization
Pattern of sensor glucose	Pattern of sensor glucose, defined as the slope of postprandial increase (calculated as the maximal rate of increase observed over 20min in the postprandial period) and decrease (calculated as the maximal rate of decrease over 20min in the postprandial period).	at 28 days after randomization
Glycemic variability	Glycemic variability (defined as the coefficient of variation (CV) of sensor glucose)	at 28 days after randomization
Mean amplitude of sensor glucose excursions (MAGE)	Mean amplitude of sensor glucose excursions (MAGE)	at 28 days after randomization
Total number of adverse events	Total number of adverse events	up to 60 days after randomization
Number of Serious adverse events	Number of Serious adverse events	up to 60 days after randomization

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Collaborators: Boehringer Ingelheim
• Investigators: Principal Investigator: Marc Y Donath, Prof. Dr. med., University Hospital Basel, Division of Endocrinology, Diabetes and Metabolism

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2022
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: September 1, 2021
• First Submitted That Met QC Criteria: September 1, 2021
• First Posted (Actual): September 5, 2021

Study Record Updates

• Last Update Posted (Actual): May 9, 2024
• Last Update Submitted That Met QC Criteria: May 8, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: bariatric surgery; Empagliflozin; insulin secretion; hyperinsulinemic response; SGLT2-inhibitor; postbariatric hypoglycemia
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hypoglycemia; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 2021-00078; kt21Donath

Drug and device information, study documents

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