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

Study Overview

• Status: Completed
• Conditions: Type2 Diabetes Mellitus
• Intervention / Treatment: Drug: Glimepiride; Drug: Empagliflozin

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 03722
    • Yonsei University College of Medicine, Department of Internal Medicine, Division of Endocrinology, Severance Hospital, Diabetes Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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:

  1. History of myocardial infarction
  2. Evidence of multi-vessel coronary artery disease
  3. Evidence of single-vessel coronary artery disease with a positive non-invasive stress test for ischemia or history of hospitalization for unstable angina
  4. History of stroke
  5. Evidence of occlusive peripheral artery disease
  6. Evidence of carotid atherosclerosis
  7. 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Glimepiride; Glimepiride (anti-diabetic drug) as a comparison group	Drug: Glimepiride; 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.; Other Names: Amaryl
Experimental: Empagliflozin; Empagliflozin (anti-diabetic drug) as a study group	Drug: Empagliflozin; Empagliflozin as a drug of experimental will be administered to improve blood sugar in patients with poorly controlled blood sugar.; Other Names: Jardiance

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Yonsei University

Publications and helpful links

General Publications

• Kim ER, Kim SR, Cho W, Lee SG, Kim SH, Kim JH, Choi E, Kim JH, Yu JW, Lee BW, Kang ES, Cha BS, Lee MS, Cho JW, Jeon JY, Lee YH. Short Term Isocaloric Ketogenic Diet Modulates NLRP3 Inflammasome Via B-hydroxybutyrate and Fibroblast Growth Factor 21. Front Immunol. 2022 Apr 28;13:843520. doi: 10.3389/fimmu.2022.843520. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2016
• Primary Completion (Actual): July 1, 2017
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: November 11, 2016
• First Submitted That Met QC Criteria: November 15, 2016
• First Posted (Estimate): November 16, 2016

Study Record Updates

• Last Update Posted (Actual): August 27, 2020
• Last Update Submitted That Met QC Criteria: August 24, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Immunosuppressive Agents; Immunologic Factors; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin; Glimepiride
• Other Study ID Numbers: 4-2016-0795

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED