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Sponsor- Investigator decision
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This study is to analyze whether the SGLT2-inhibitor empagliflozin or the IL-1 receptor antagonist anakinra may improve postprandial hypoglycemia in subjects with prediabetes.
Subjects with prediabetes may develop postprandial hypoglycemia. This is probably due to a dysfunction of the insulin producing β-cell characterized by a delayed and exaggerated insulin secretion leading to an initial peak in glycaemia followed by a rapid fall and eventually resulting in hypoglycemia. The latter occurring typically within 1 to 3 hours after food intake.
In patients with gastric bypass surgery and postprandial hypoglycemia the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra reduced postprandial insulin release and prevented hypoglycemia. This study is to analyze whether a similar therapeutic approach using empagliflozin and anakinra may also improve postprandial hypoglycemia in subjects with prediabetes.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group 1 (anakinra; placebo; empagliflozin) | Other | Group 1: study day 1: anakinra; study day2: placebo; study day 3: empagliflozin |
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| Group 2 (placebo; anakinra; empagliflozin) | Other | study day 1: placebo; study day2: anakinra; study day 3: empagliflozin |
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| Group 3 (empagliflozin; placebo; anakinra) | Other | study day 1: empagliflozin; study day2: placebo; study day 3: anakinra |
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| Group 4 (empagliflozin; anakinra; placebo) | Other | study day 1: empagliflozin; study day2: anakinra; study day 3: placebo |
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| Group 5 (placebo; empagliflozin; anakinra) |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| empagliflozin | Drug | Empagliflozin (Jardiance®; Boehringer Ingelheim (Schweiz) GmbH) is a highly selective, reversible inhibitor of the sodium glucose co-transporter 2 (SGLT2). Treatment consists of a single oral tablet of 25 mg of empagliflozin (Jardiance®) two hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes). |
| Measure | Description | Time Frame |
|---|---|---|
| Number of symptomatic hypoglycemia | Incidence of symptomatic hypoglycemia following a standardized mixed-meal test defined by appearance of typical symptoms, blood glucose level below 3.0 mmol/l and relief of symptoms when the glucose level is raised (Whipple's triad). | up to 3 hours after ingestion of the liquid mixed-meal |
| Measure | Description | Time Frame |
|---|---|---|
| Severity of symptoms of hypoglycemia according to the Edinburgh Hypoglycemia Scale | The Edinburgh Hypoglycemia Scale is a classification of the 11 most common symptoms of hypoglycemia. Subjective intensity-grading:
| up to 3 hours after ingestion of the liquid mixed-meal |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Marc Y. Donath, Prof. Dr. med. | Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel | Principal Investigator |
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Placebo controlled, double-blind, randomized, cross-over proof-of-concept study. Subjects will be randomized to either group 1-6 (ratio 1:1, in blocks of 4 participants).
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Participants, investigators and study nurses will be blinded to the study drug.
study day 1: placebo; study day2: empagliflozin; study day 3: anakinra |
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| Group 6 (anakinra; empagliflozin; placebo) | Other | study day 1:anakinra; study day2: empagliflozin; study day 3: placebo |
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| anakinra | Drug | Anakinra (Kineret®; r-metHuIL-1ra, Swedish Orphan Biovitrum AB) is a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra) in a 100 mg/0.67ml solution for SC injection. Treatment consists of a single subcutaneous injection of 100 mg Anakinra (Kineret®) three hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes). |
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| saline subcutaneous (s.c.) (placebo) | Other | Placebo for anakinra is 0.67 ml of sterile 0.9 % saline solution s. c. Treatment consists of a single subcutaneous injection of matched placebo (0.67 ml of 0.9 % saline) three hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes). |
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| tablet per oral (p.o.) (placebo) | Other | Placebo for empagliflozin is Winthrop P® (Zentiva, Frankfurt/Main) lactose tablet. Treatment consists of a single oral tablet of matched placebo two hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes). |
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| Nadir plasma glucose (mmol/l) | Nadir plasma glucose (mmol/l) | up to 3 hours after ingestion of the liquid mixed-meal |
| Change in proinsulin to insulin ratio in serum | Change in proinsulin to insulin ratio in serum | at baseline and 60 min after ingestion of the mixed meal |
| Change in inflammatory state | Change in inflammatory laboratory parameters (Interleukin (IL)1ß, IL6, Tumor necrosis factor (TNF) α, IL-10, IL-1Ra) in supernatants of Lipopolysaccharide (LPS)-stimulated and unstimulated peripheral blood mononuclear cells (PBMC) | at baseline and 60 min after ingestion of the mixed meal |
| Change in RNA sequencing (RNAseq) in peripheral PBMC | Change in RNAseq in peripheral PBMC | at baseline and 60 min after ingestion of the mixed meal |
| ID | Term |
|---|---|
| D007003 | Hypoglycemia |
| D011236 | Prediabetic State |
| C565100 | Diabetes Mellitus, Insulin-Dependent, 2 |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D003920 | Diabetes Mellitus |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| C570240 | empagliflozin |
| D053590 | Interleukin 1 Receptor Antagonist Protein |
| ID | Term |
|---|---|
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011506 | Proteins |
| D001685 | Biological Factors |
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