A Phase 4 interventional study of Empagliflozin (Jardiance®) and Insulin Glargine (Lantus®) in Type2 Diabetes Mellitus, sponsored by University Hospital Tuebingen. Withdrawn at 2 sites in Germany. Open to participants aged 40 Years to 70 Years. Per ClinicalTrials.gov, last updated 2024-05-16.
Sponsored by University Hospital Tuebingen · Phase 4, Interventional, and Treatment
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.
Subjects must fulfill all of the following criteria before inclusion in the study:
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:
Women of childbearing potential unless women who meet the following criteria:
Dose/frequency: 10 mg once daily for 12 weeks Route of administration: oral
Drug: Empagliflozin (Jardiance®)
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
Drug: Insulin Glargine (Lantus®)
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)
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 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.
Time frame: 12 weeks
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
Time frame: 12 weeks
Change in skeletal muscle lipid peroxidation
Change in skeletal muscle lipid peroxidation between baseline and EoT
Time frame: 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
Time frame: 12 weeks
• Difference in DNA methylation pattern
• Difference in DNA methylation pattern between the treatment groups at EoT
Time frame: 12 weeks
Change in plasma FFA levels
Change in plasma FFA levels between baseline and end of trial
Time frame: 12 weeks
Plan to share: No
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University Hospital Tuebingen