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Empagliflozin Effect on Glucose Toxicity

Primary Purpose

Type2 Diabetes Mellitus

Status
Active
Phase
Phase 4
Locations
Germany
Study Type
Interventional
Intervention
Empagliflozin (Jardiance®)
Insulin Glargine (Lantus®)
Sponsored by
University Hospital Tuebingen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Type2 Diabetes Mellitus

Eligibility Criteria

40 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Subjects must fulfill all of the following criteria before inclusion in the study:

  • The informed consent form must be signed before any study specific tests or procedures are done
  • Male or female patients aged between 40 and 70 years (including) at the first screening visit
  • Patients diagnosed with T2DM
  • HbA1c between 7-9% (including)
  • Stable treatment with antidiabetic drugs over the last 4 weeks

  • Accepted background medication:

    • Metformin up to 2000 mg per day and/or
    • DPP-IV inhibitors:

Linagliptin up to 5 mg per day Sitagliptin up to 100 mg per day Vildagliptin up to 100 mg per day Saxagliptin up to 5 mg per day

  • Body mass index (BMI) between 25 and 40 kg/m2 (including)
  • Ability to understand and follow study-related instructions
  • No clinical relevant abnormalities during ECG and cardiac examinations

Exclusion Criteria:

Subjects are to be excluded from the study if they display any of the following criteria:

  • Unstable Angina pectoris, myocardial infarction or stroke within 1 year before inclusion in the study
  • History of atrial fibrillation
  • Uncontrolled arterial hypertension (> 160/100 mmHg in three subsequent measurements - mean value)
  • eGFR < 60 ml/min/1.73 m2
  • Macroalbuminuria defined as ≥ 300 mg albumin / 24h urine
  • Triglyceride > 250 mg/dl
  • Genetic muscle disease
  • Known coagulation disorder
  • Treatment with anti-platelet therapy and anticoagulation which cannot be paused for medical reasons
  • Treatment with anticoagulants within 7 days prior to the muscle biopsy
  • Contraindications according to the local SmPC of Lantus® or Jardiance® (see Appendix 1)
  • History of hypersensitivity to any of the study drugs or their ingredients or to drugs with similar structure or to the local anesthetic scandicaine or lidocaine
  • Addiction or other diseases that preclude the patient from appropriately assessing the nature and scope as well as possible consequences of the clinical study
  • Pregnant or breast-feeding women

  • Women of childbearing potential unless women who meet the following criteria:

    • Post-menopausal (12 months natural amenorrhea or 6 months amenorrhea with serum follicle-stimulating hormone [FSH] > 40 U/mL)
    • Postoperatively (six weeks after bilateral ovariectomy with or without hysterectomy)
    • Regular and correct use of a contraceptive method with error rate <1% per year such as implants, depot injections, oral contraceptives or intrauterine devices
    • Sexual abstinence
    • Vasectomy of the partner
  • Males must agree not to father a child and to refrain from donating semen or sperm while participating in the study and for 90 days following discontinuation from this study

Sites / Locations

  • University Hospital
  • German Diabetes Center, Leibniz-Center for Diabetes Research at the Heinrich-Heine-University Duesseldorf

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Empagliflozin (Jardiance®)

Insulin Glargine (Lantus®)

Arm Description

Dose/frequency: 10 mg once daily for 12 weeks Route of administration: oral

Thus, insulin glargine doses should be adapted as follows: FBG 6-7 mmol/L: +2 IU FBG 7-8 mmol/L: +3 IU FBG > 8 mmol/L: +5 IU

Outcomes

Primary Outcome Measures

Change in skeletal muscle H202 concentration between baseline and end of treatment (EoT)
The primary objective is to investigate the change in H2O2 concentration as a read out of reactive oxygen species (ROS) production in skeletal muscle biopsies from T2DM patients before and after treatment with empagliflozin or insulin glargine.

Secondary Outcome Measures

Secondary objectives of the study are to evaluate the effect of empagliflozin and insulin glargine on glucose toxicity in skeletal muscle by investigating
Change in skeletal muscle mitochondrial function (O2consumption) between baseline and EoT
Change in skeletal muscle lipid peroxidation
Change in skeletal muscle lipid peroxidation between baseline and EoT
Change in 24-hour urinary excretion rate of 8-iso PGF2a
Change in 24-hour urinary excretion rate of 8-iso PGF2a between baseline and EoT
• Difference in DNA methylation pattern
• Difference in DNA methylation pattern between the treatment groups at EoT
Change in plasma FFA levels
Change in plasma FFA levels between baseline and end of trial

Full Information

First Posted
December 21, 2017
Last Updated
August 24, 2022
Sponsor
University Hospital Tuebingen
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1. Study Identification

Unique Protocol Identification Number
NCT03437330
Brief Title
Empagliflozin Effect on Glucose Toxicity
Official Title
Empagliflozin Effect on Glucose Toxicity in Type 2 Diabetes Patients - a Randomized, Open-label, Controlled, Parallel Group, Exploratory Study
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 27, 2021 (Actual)
Primary Completion Date
February 2023 (Anticipated)
Study Completion Date
August 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital Tuebingen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Empagliflozin effect on glucose toxicity in type 2 diabetes patients - a randomized, open-label, controlled, parallel group, exploratory study
Detailed Description
The EMPA-REG outcome trial showed that empagliflozin on top of standard therapy for Type 2 diabetes mellitus (T2DM) resulted in superiority in terms of the primary composite cardiovascular endpoint (hazard ratio (1) = 0.86; 95% confidence interval [CI] 0.74-0.99; P value = 0.04), hospitalization for heart failure (-35%), cardiovascular mortality (-38%) and all-cause mortality (-32%, each p < 0.001) (2). This reduction in mortality is not fully explained by the reduction in HbA1c, body weight, waist circumference and blood pressure in the empagliflozin groups versus the placebo group. Differences in mode of action of empagliflozin compared to standard therapy might, thus, help to explain why empagliflozin was so efficient in reducing cardiovascular death. The aim of the present study is to provide evidence for a reduction of skeletal muscle H2O2 levels, and consequently improvement in mitochondrial function, and restored methylation pattern of key transcription factors in skeletal muscle from patients with T2DM when treated with empagliflozin versus insulin glargine as the prototypical medication favoring glucose uptake into tissues. It is hypothesized that empagliflozin compared to insulin specifically reduces H2O2 concentrations in skeletal muscle of patients with T2DM, because it leads to excretion of glucose and lower glucose uptake in skeletal muscle (22), while insulin shifts the major part of excess glucose into skeletal muscle cells.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type2 Diabetes Mellitus

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Empagliflozin (Jardiance®)
Arm Type
Experimental
Arm Description
Dose/frequency: 10 mg once daily for 12 weeks Route of administration: oral
Arm Title
Insulin Glargine (Lantus®)
Arm Type
Active Comparator
Arm Description
Thus, insulin glargine doses should be adapted as follows: FBG 6-7 mmol/L: +2 IU FBG 7-8 mmol/L: +3 IU FBG > 8 mmol/L: +5 IU
Intervention Type
Drug
Intervention Name(s)
Empagliflozin (Jardiance®)
Intervention Description
Empagliflozin Dose/frequency: 10 mg once daily for 12 weeks Route of administration: oral Reference group: Insulin glargine (Lantus®) Dose/frequency: see below FBG 6-7 mmol/L: +2 IU (stop when FBG is reduced by 0.5 mmol/L or documented hypoglycemia < 3.9 mmol/L occurs) FBG 7-8 mmol/L: +4 IU (stop when FBG is reduced by 1.0 mmol/L or documented hypoglycemia < 3.9 mmol/L occurs) FBG > 8 mmol/L: +6 IU (stop when FBG is reduced by 1.5 mmol/L or documented hypoglycemia < 3.9 mmol/L occurs)
Intervention Type
Drug
Intervention Name(s)
Insulin Glargine (Lantus®)
Intervention Description
insulin glargine shall be titrated according to the following scheme: If FBG 6-7 mmol/L: reduce fasting glucose by 0.5 mmol/L If FBG 7-8 mmol/L: reduce fasting glucose by 0.75 mmol/L If FBG 8-9 mmol/L: reduce fasting glucose by 1.0 mmol/L Thus, insulin glargine doses should be adapted as follows: FBG 6-7 mmol/L: +2 IU (stop when FBG is reduced by 0.5 mmol/L or documented hypoglycemia < 3.9 mmol/L occurs) FBG 7-8 mmol/L: +3IU (stop when FBG is reduced by 0.75 mmol/L or documented hypoglycemia < 3.9 mmol/L occurs) FBG > 8 mmol/L: +5 IU (stop when FBG is reduced by 1.0mmol/L or documented hypoglycemia < 3.9 mmol/L occurs)
Primary Outcome Measure Information:
Title
Change in skeletal muscle H202 concentration between baseline and end of treatment (EoT)
Description
The primary objective is to investigate the change in H2O2 concentration as a read out of reactive oxygen species (ROS) production in skeletal muscle biopsies from T2DM patients before and after treatment with empagliflozin or insulin glargine.
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Secondary objectives of the study are to evaluate the effect of empagliflozin and insulin glargine on glucose toxicity in skeletal muscle by investigating
Description
Change in skeletal muscle mitochondrial function (O2consumption) between baseline and EoT
Time Frame
12 weeks
Title
Change in skeletal muscle lipid peroxidation
Description
Change in skeletal muscle lipid peroxidation between baseline and EoT
Time Frame
12 weeks
Title
Change in 24-hour urinary excretion rate of 8-iso PGF2a
Description
Change in 24-hour urinary excretion rate of 8-iso PGF2a between baseline and EoT
Time Frame
12 weeks
Title
• Difference in DNA methylation pattern
Description
• Difference in DNA methylation pattern between the treatment groups at EoT
Time Frame
12 weeks
Title
Change in plasma FFA levels
Description
Change in plasma FFA levels between baseline and end of trial
Time Frame
12 weeks

10. Eligibility

Sex
All
Gender Based
Yes
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subjects must fulfill all of the following criteria before inclusion in the study: The informed consent form must be signed before any study specific tests or procedures are done Male or female patients aged between 40 and 70 years (including) at the first screening visit Patients diagnosed with T2DM HbA1c between 7-9% (including) Stable treatment with antidiabetic drugs over the last 4 weeks Accepted background medication: Metformin up to 2000 mg per day and/or DPP-IV inhibitors: Linagliptin up to 5 mg per day Sitagliptin up to 100 mg per day Vildagliptin up to 100 mg per day Saxagliptin up to 5 mg per day Body mass index (BMI) between 25 and 40 kg/m2 (including) Ability to understand and follow study-related instructions No clinical relevant abnormalities during ECG and cardiac examinations Exclusion Criteria: Subjects are to be excluded from the study if they display any of the following criteria: Unstable Angina pectoris, myocardial infarction or stroke within 1 year before inclusion in the study History of atrial fibrillation Uncontrolled arterial hypertension (> 160/100 mmHg in three subsequent measurements - mean value) eGFR < 60 ml/min/1.73 m2 Macroalbuminuria defined as ≥ 300 mg albumin / 24h urine Triglyceride > 250 mg/dl Genetic muscle disease Known coagulation disorder Treatment with anti-platelet therapy and anticoagulation which cannot be paused for medical reasons Treatment with anticoagulants within 7 days prior to the muscle biopsy Contraindications according to the local SmPC of Lantus® or Jardiance® (see Appendix 1) History of hypersensitivity to any of the study drugs or their ingredients or to drugs with similar structure or to the local anesthetic scandicaine or lidocaine Addiction or other diseases that preclude the patient from appropriately assessing the nature and scope as well as possible consequences of the clinical study Pregnant or breast-feeding women Women of childbearing potential unless women who meet the following criteria: Post-menopausal (12 months natural amenorrhea or 6 months amenorrhea with serum follicle-stimulating hormone [FSH] > 40 U/mL) Postoperatively (six weeks after bilateral ovariectomy with or without hysterectomy) Regular and correct use of a contraceptive method with error rate <1% per year such as implants, depot injections, oral contraceptives or intrauterine devices Sexual abstinence Vasectomy of the partner Males must agree not to father a child and to refrain from donating semen or sperm while participating in the study and for 90 days following discontinuation from this study
Facility Information:
Facility Name
University Hospital
City
Tuebingen
State/Province
Baden-Württemberg
ZIP/Postal Code
72076
Country
Germany
Facility Name
German Diabetes Center, Leibniz-Center for Diabetes Research at the Heinrich-Heine-University Duesseldorf
City
Duesseldorf
State/Province
North Rhine Westphalia
ZIP/Postal Code
40225
Country
Germany

12. IPD Sharing Statement

Plan to Share IPD
No

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Empagliflozin Effect on Glucose Toxicity

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