Clinical trial NCT02964572: Effect of Sodium Glucose Co-transporter 2 Inhibitor on Inflammatory Cytokine in Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type2 Diabetes Mellitus
Lead sponsor: Yonsei University
Sponsor class: OTHER
First posted: 2016-11-16
Enrollment: 61
Sex: ALL
Minimum age (years): 19
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: * 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: 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

Eligibility criteria: 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

Primary outcomes:
measure: changes in the secretion of IL-1 beta from peripheral blood mononuclear cells
timeFrame: Day 60
Secondary outcomes:
measure: Changes in the secretion of TNF-alpha from peripheral blood mononuclear cells, before and after the administration of empagliflozin or glimepiride
timeFrame: Day 60 plus or minus 32 days
measure: Changes in serum concentrations of beta-hydroxybutyrate, before and after the administration of empagliflozin or glimepiride
timeFrame: Day 60 plus or minus 32 days
measure: Changes in body weight (kg), before and after the administration of empagliflozin or glimepiride
timeFrame: Day 60 plus or minus 32 days
measure: Changes in serum concentrations of insulin (µU/mL), before and after the administration of empagliflozin or glimepiride
timeFrame: Day 60 plus or minus 32 days
measure: Changes in serum concentrations of glucagon (pg/mL), before and after the administration of empagliflozin or glimepiride
timeFrame: Day 60 plus or minus 32 days
measure: Changes in serum concentrations of free fatty acid (μEq/L), before and after the administration of empagliflozin or glimepiride
timeFrame: Day 60 plus or minus 32 days
measure: Changes in serum glycated albumin (%), before and after the administration of empagliflozin or glimepiride
timeFrame: Day 60 plus or minus 32 days
measure: Changes in serum concentrations of glucose (mg/dL), before and after the administration of empagliflozin or glimepiride
timeFrame: Day 60 plus or minus 32 days
measure: Changes in serum concentrations of uric acid (mg/dL), before and after the administration of empagliflozin or glimepiride
timeFrame: Day 60 plus or minus 32 days
measure: Changes in serum concentrations of liver enzymes (aspartate aminotransferase and alanine aminotransferase (IU/L)), before and after the administration of empagliflozin or glimepiride
timeFrame: Day 60 plus or minus 32 days
measure: Changes in serum lipids (total cholesterol, triglyceride, HDL cholesterol, and LDL cholesterol (mg/dL)), before and after the administration of empagliflozin or glimepiride
timeFrame: Day 60 plus or minus 32 days
measure: Changes in serum concentrations of creatinine (mg/dL), before and after the administration of empagliflozin or glimepiride
timeFrame: Day 60 plus or minus 32 days
measure: 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
timeFrame: Day 60 plus or minus 32 days
measure: 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
timeFrame: Day 60 plus or minus 32 days
measure: 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
timeFrame: Day 60 plus or minus 32 days
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Yonsei University College of Medicine, Department of Internal Medicine, Division of Endocrinology, Severance Hospital, Diabetes center
Study officials:
References:
citation: 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.