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poor recruitment
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Empagliflozin effect on glucose toxicity in type 2 diabetes patients - a randomized, open-label, controlled, parallel group, exploratory study
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Empagliflozin (Jardiance®) | Experimental | Dose/frequency: 10 mg once daily for 12 weeks Route of administration: oral |
|
| Insulin Glargine (Lantus®) | Active Comparator | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Empagliflozin (Jardiance®) | Drug | 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) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 12 weeks |
| Change in skeletal muscle lipid peroxidation |
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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:
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
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:
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
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital | Tübingen | Baden-Wurttemberg | 72076 | Germany | ||
| German Diabetes Center, Leibniz-Center for Diabetes Research at the Heinrich-Heine-University Duesseldorf |
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| ID | Term |
|---|---|
| C570240 | empagliflozin |
| D000069036 | Insulin Glargine |
| ID | Term |
|---|---|
| D049528 | Insulin, Long-Acting |
| D061385 | Insulins |
| D010187 | Pancreatic Hormones |
| D036361 | Peptide Hormones |
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|
| Insulin Glargine (Lantus®) | Drug | 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) |
|
Change in skeletal muscle lipid peroxidation between baseline and EoT |
| 12 weeks |
| 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 | 12 weeks |
| • Difference in DNA methylation pattern | • Difference in DNA methylation pattern between the treatment groups at EoT | 12 weeks |
| Change in plasma FFA levels | Change in plasma FFA levels between baseline and end of trial | 12 weeks |
| Düsseldorf |
| North Rhine-Westphalia |
| 40225 |
| Germany |
| D006728 |
| Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |