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Empagliflozin Effect on Glucose Toxicity

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ClinicalTrials.gov Identifier: NCT03437330
Recruitment Status : Not yet recruiting
First Posted : February 19, 2018
Last Update Posted : February 19, 2018
Sponsor:
Information provided by (Responsible Party):
GWT-TUD GmbH

Brief Summary:
Empagliflozin effect on glucose toxicity in type 2 diabetes patients - a randomized, open-label, controlled, parallel group, exploratory study

Condition or disease Intervention/treatment Phase
Type2 Diabetes Mellitus Drug: Empagliflozin (Jardiance®) Phase 4

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Empagliflozin Effect on Glucose Toxicity in Type 2 Diabetes Patients - a Randomized, Open-label, Controlled, Parallel Group, Exploratory Study
Estimated Study Start Date : March 1, 2018
Estimated Primary Completion Date : September 1, 2018
Estimated Study Completion Date : March 31, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Empagliflozin (Jardiance®)
Dose/frequency: 25 mg once daily for 12 weeks Route of administration: oral
Drug: Empagliflozin (Jardiance®)
Empagliflozin Dose/frequency: 25 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)
Other Name: Insulin Glargine (Lantus®)

Active Comparator: Insulin Glargine (Lantus®)

Thus, insulin glargine doses should be adapted as follows:

FBG 6-7 mmol/L: +2 IU FBG 7-8 mmol/L: +4 IU FBG > 8 mmol/L: +6 IU

Drug: Empagliflozin (Jardiance®)
Empagliflozin Dose/frequency: 25 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)
Other Name: Insulin Glargine (Lantus®)




Primary Outcome Measures :
  1. Change in skeletal muscle H202 concentration between baseline and end of treatment (EoT) [ Time Frame: 12 weeks ]
    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 :
  1. Secondary objectives of the study are to evaluate the effect of empagliflozin and insulin glargine on glucose toxicity in skeletal muscle by investigating [ Time Frame: 12 weeks ]
    Change in skeletal muscle mitochondrial function (O2consumption) between baseline and EoT

  2. Change in skeletal muscle lipid peroxidation [ Time Frame: 12 weeks ]
    Change in skeletal muscle lipid peroxidation between baseline and EoT

  3. Change in 24-hour urinary excretion rate of 8-iso PGF2a [ Time Frame: 12 weeks ]
    Change in 24-hour urinary excretion rate of 8-iso PGF2a between baseline and EoT

  4. • Difference in DNA methylation pattern [ Time Frame: 12 weeks ]
    • Difference in DNA methylation pattern between the treatment groups at EoT



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Ages Eligible for Study:   40 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
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

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 (> 180/100 mmHg in three subsequent measurements - mean value)
  • eGFR < 60 ml/min/1.73 m2
  • Macroalbuminuria defined as ≥ 300 mg albumin / 24h urine
  • Triglyceride > 8.5 mmol/l
  • 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 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

Responsible Party: GWT-TUD GmbH
ClinicalTrials.gov Identifier: NCT03437330     History of Changes
Other Study ID Numbers: 12685
First Posted: February 19, 2018    Key Record Dates
Last Update Posted: February 19, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Empagliflozin
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Insulin, Globin Zinc
Insulin
Insulin Glargine
Hypoglycemic Agents
Physiological Effects of Drugs