The purpose of the study is to compare the effect of empagliflozin, metformin, and the combination of both on the oxidative capacity of skeletal muscle and its microvascular reactivity in individuals with newly diagnosed type 2 diabetes. As the primary outcome, the investigators selected the change in skeletal muscle oxidative capacity and posed the following scientific question: Does empagliflozin significantly improve the oxidative capacity of skeletal muscle? The study will enroll 54 individuals with type 2 diabetes in a prospective, randomized, interventional, open-label study. Participants will be randomized into 3 equally sized groups: 1) a group receiving empagliflozin; 2) a group receiving metformin; and 3) a group receiving a combination of both drugs (empagliflozin and metformin). The investigators will analyze the clinical variables of the subjects, near-infrared spectroscopy (NIRS) measurements over the flexor digitorum superficialis muscle of the non-dominant arm at rest, after submaximal muscular work, and during transient brachial artery occlusion at specified time intervals (14 days, 1 month, 3 months, 6 months), as well as body composition, physical performance, and glycemic control following the pharmacological intervention.
Male sex
Age 18-75 years
Newly diagnosed type 2 diabetes mellitus, confirmed no more than 2 years prior to enrollment
Body mass index (BMI) 25-35 kg/m²
Other forms of diabetes mellitus (i.e., not type 2)
Type 2 diabetes mellitus known for more than 2 years
Comorbidities known to independently affect skeletal muscle oxidative capacity, including: spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, cystic fibrosis, local joint immobility, or hemiplegia
Known mitochondrial disease
Parallel
Empagliflozin (Jardiance®)
DrugEmpagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor administered orally at a standard therapeutic dose for the treatment of type 2 diabetes mellitus. In this study, empagliflozin will be administered alone (Arm 1) or in combination with metformin (Arm 3) for 6 months, with skeletal muscle oxidative capacity and microvascular reactivity assessed at baseline and follow-up visits.
Metformin
DrugMetformin is a biguanide antihyperglycemic agent administered orally at a standard therapeutic dose for the treatment of type 2 diabetes mellitus. In this study, metformin will be administered alone (Arm 2) or in combination with empagliflozin (Arm 3) for 6 months, with skeletal muscle oxidative capacity and microvascular reactivity assessed at baseline and follow-up visits.
Synjardy® 12.5mg/1000mg film-coated tablets
Combination productFixed-dose combination product containing empagliflozin and metformin, administered orally at standard therapeutic doses for the treatment of type 2 diabetes mellitus. Used in the combination therapy arm (Arm 3) for 6 months, with skeletal muscle oxidative capacity and microvascular reactivity assessed at baseline and follow-up visits.
Change in skeletal muscle mitochondrial oxidative capacity
Skeletal muscle mitochondrial oxidative capacity will be assessed non-invasively using near-infrared spectroscopy (NIRS) over the flexor digitorum superficialis muscle of the non-dominant forearm. The recovery rate of tissue oxygen saturation (StO2) following submaximal muscular exercise and repeated brief arterial occlusions will be used as an index of mitochondrial oxidative capacity. This outcome will be compared across the three treatment arms to test the hypotheses that empagliflozin increases skeletal muscle oxidative capacity, that metformin does not alter oxidative capacity, and that combination therapy increases oxidative capacity to a lesser degree than empagliflozin monotherapy.
Change in skeletal muscle microvascular reactivity
Description: Microvascular reactivity will be assessed using NIRS by measuring peak tissue oxygen saturation (StO2) and StO2 recovery rate following release of a transient brachial artery occlusion. This outcome will be compared across the three treatment arms to test the hypothesis that microvascular reactivity increases to a greater extent in the empagliflozin group compared with the metformin and combination therapy groups.
Change in body fat mass
Body fat mass will be assessed using whole-body dual-energy X-ray absorptiometry (DXA).
Change in lean body mass
Lean body mass will be assessed using whole-body dual-energy X-ray absorptiometry (DXA).
Change in body fat percentage
Total body fat percentage will be assessed using whole-body DXA.
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University Medical Centre Ljubljana
Lead sponsor
University of Ljubljana, Faculty of Medicine
Collaborator