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

Study Overview
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Brief Summary
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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.

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

Conditions
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Dumping Syndrome, Hypoglycemia, Reactive

Intervention / Treatment
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* Drug: Empagliflozin 25 MG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized, double-blind, placebo-controlled, crossover trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin first, Placebo second<br>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<br>* Treatment naive patients with bariatric bypass surgery will be given oral empagliflozin 25mg once daily for 20 days<br>Drug: Placebo<br>* Treatment naive patients with bariatric bypass surgery will be given oral placebo once daily for 20 days<br>|
| Placebo Comparator: Placebo first, Empagliflozin second<br>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<br>* Treatment naive patients with bariatric bypass surgery will be given oral empagliflozin 25mg once daily for 20 days<br>Drug: Placebo<br>* Treatment naive patients with bariatric bypass surgery will be given oral placebo once daily for 20 days<br>|

What is the study measuring?
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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. |