Effect of Sodium Glucose Co-transporter 2 Inhibitor on Inflammatory Cytokine in Type 2 Diabetes

Study Overview
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Brief Summary
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Single-center, prospective, active-controlled, open, randomized, 2 arm parallel, interventional, exploratory pilot Type 2 diabetic patients with high cardiovascular risks who have inadequate glycaemic control with metformin-based oral hypoglycemic agents will be prescribed glimepiride (comparison group) or empagliflozin (study group) for 60 days (plus or minus 32 days) as add-on therapy Changes in IL-1beta secretion, serum beta-hydroxybutyrate concentration, and NLRP3 inflammasome activity from baseline to final timepoint will be assessed.

Detailed Description
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First among cardiovascular (CV) end point trials of glucose-lowering agents, the EMPA-REG OUTCOME trial-using 10 or 25 mg/day SGLT2 inhibitor empagliflozin against placebo in 7,020 patients with T2DM who were at increased CV risk-reported a 14% reduction in major CV events and marked relative risk reductions in CV mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) over a median time period of 2.6 years. Though these results have raised the possibility that mechanisms other than those observed in the trial-modest improvement in glycemic control, small decrease in body weight, and persistent reductions in blood pressure and uric acid level-may be at play, it's not clearly known yet. The inflammatory nature of atherosclerosis is well established. We hypothesized that empagliflozin might have an inhibitory effect on inflammasome activity in macrophages, thus contribute to cardioprotective effects in diabetes. Single-center, prospective, active-controlled, open, randomized, 2 arm parallel, interventional, exploratory pilot Type 2 diabetic patients with high cardiovascular risks who have inadequate glycaemic control with metformin-based oral hypoglycemic agents will be prescribed glimepiride (comparison group) or empagliflozin (study group) for 60 days (plus or minus 32 days) as add-on therapy Changes in IL-1beta secretion, serum beta-hydroxybutyrate concentration, and NLRP3 inflammasome activity from baseline to final timepoint will be assessed Healthy volunteers : effect of 3 day-ketogenic diet on changes in cytokines, metabolites (IL-1beta, beta-hydroxybutyrate , etc) and inflammasome activity in macrophages

Conditions
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Type2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Glimepiride
* Drug: Empagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥19 years inadequate glycaemic control : HbA1c ≥6.5% or fasting glucose >120 mg/dl or random glucose >180 mg/dl High risk of cardiovascular events defined as the presence of ≥1 of the following: History of myocardial infarction Evidence of multi-vessel coronary artery disease Evidence of single-vessel coronary artery disease with a positive non-invasive stress test for ischemia or history of hospitalization for unstable angina History of stroke Evidence of occlusive peripheral artery disease Evidence of carotid atherosclerosis Metabolic syndrome Healthy volunteers Exclusion Criteria: Type 1 diabetes Organ transplantation Pregnant women eGFR <45 Cortisol or growth hormone deficiency, pituitary diseases Gastric surgery Hematologic disorders Active cancers

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Glimepiride<br>Glimepiride (anti-diabetic drug) as a comparison group | Drug: Glimepiride<br>* In accordance with the standard treatment guidelines of diabetes, glimepiride as a drug of active comparator will be administered to improve blood sugar in patients with poorly controlled blood sugar.<br>* Other names: Amaryl;|
| Experimental: Empagliflozin<br>Empagliflozin (anti-diabetic drug) as a study group | Drug: Empagliflozin<br>* Empagliflozin as a drug of experimental will be administered to improve blood sugar in patients with poorly controlled blood sugar.<br>* Other names: Jardiance;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes in the secretion of IL-1 beta from peripheral blood mononuclear cells | The effect of empagliflozin on the secretion of IL-1beta from peripheral blood mononuclear cells | Day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the secretion of TNF-alpha from peripheral blood mononuclear cells, before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days | 
| Changes in serum concentrations of beta-hydroxybutyrate, before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days | 
| Changes in body weight (kg), before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days | 
| Changes in serum concentrations of insulin (µU/mL), before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days | 
| Changes in serum concentrations of glucagon (pg/mL), before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days | 
| Changes in serum concentrations of free fatty acid (μEq/L), before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days | 
| Changes in serum glycated albumin (%), before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days | 
| Changes in serum concentrations of glucose (mg/dL), before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days | 
| Changes in serum concentrations of uric acid (mg/dL), before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days | 
| Changes in serum concentrations of liver enzymes (aspartate aminotransferase and alanine aminotransferase (IU/L)), before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days | 
| Changes in serum lipids (total cholesterol, triglyceride, HDL cholesterol, and LDL cholesterol (mg/dL)), before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days | 
| Changes in serum concentrations of creatinine (mg/dL), before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days | 
| Changes in spot urine concentrations of glucose (mg/dL) and creatinine (mg/dL) (those will be combined to report spot urine glucose-to-creatinine ratio in mg/mg), before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days | 
| Changes in mRNA expression level (PCR, fold) of IL-1beta, TNF-alpha, and NLRP3 in peripheral blood mononuclear cells, before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days | 
| Changes in protein expression pattern (western blot, relative to control) of IL-1beta, TNF-alpha, and NLRP3 in peripheral blood mononuclear cells, before and after the administration of empagliflozin or glimepiride |  | Day 60 plus or minus 32 days |