The Effect of Empagliflozin and Metformin on Oxidative Capacity and Microvascular Reactivity of Skeletal Muscle in Patients With Type 2 Diabetes Mellitus

NCT07771010 | Recruiting Phase 4

• 1 other identifier: 0120-32/2024-2711-3
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Diabetes Type 2

Keywords

type 2 diabetes mellitus; Empagliflozin; Metformin; Skeletal muscle oxidative capacity; Near-infrared spectroscopy; Microvascular reactivity

Outcome Measures

Primary Outcomes (1)

• 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.

  Baseline, Day 14, Month 1, Month 3, and Month 6

Secondary Outcomes (13)

• Change in skeletal muscle microvascular reactivity

  Baseline, Day 14, Month 1, Month 3, and Month 6

• Change in body fat mass

  Baseline, Month 3, and Month 6

• Change in lean body mass

  Baseline, Month 3, and Month 6

• Change in body fat percentage

  Baseline, Month 3, and Month 6

• Change in appendicular lean mass index

  Baseline, Month 3, and Month 6

Study Arms (3)

Empagliflozin

ACTIVE COMPARATOR

Participants with newly diagnosed type 2 diabetes will receive empagliflozin monotherapy for 6 months.

Drug: Empagliflozin (Jardiance®)

Metformin

ACTIVE COMPARATOR

Participants with newly diagnosed type 2 diabetes will receive metformin monotherapy for 6 months.

Drug: Metformin

Empagliflozin + Metformin

ACTIVE COMPARATOR

Participants with newly diagnosed type 2 diabetes will receive combination therapy with empagliflozin and metformin for 6 months.

Combination Product: Synjardy® 12.5mg/1000mg film-coated tablets

Interventions

Empagliflozin (Jardiance®) DRUG

Empagliflozin 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.

Empagliflozin

Metformin DRUG

Metformin 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.

Metformin

Synjardy® 12.5mg/1000mg film-coated tablets COMBINATION_PRODUCT

Fixed-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.

Empagliflozin + Metformin

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Currently managed at a diabetes outpatient clinic
• No known chronic diabetes-related complications
• No prior antidiabetic pharmacological treatment, with the exception of sulfonylureas

You may not qualify if:

• 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
• Heart failure, NYHA class II or higher
• Chronic kidney disease, stage 3 or higher
• Poorly controlled chronic medical conditions (e.g., arterial hypertension, hypothyroidism)
• Recurrent urinary tract infections
• Active malignancy currently undergoing oncologic treatment
• Life expectancy less than 3 months
• Symptomatic hyperglycemia with fasting plasma glucose above 18 mmol/L, HbA1c ≥ 10%
• Unwillingness to provide informed consent

Sponsors & Collaborators

• University Medical Centre Ljubljana: lead
• University of Ljubljana, Faculty of Medicine: collaborator

Study Sites (1)

UMC Ljubljana

Ljubljana, 1000, Slovenia

RECRUITING

Related Publications (5)

• Erickson ML, Ryan TE, Backus D, McCully KK. Endurance neuromuscular electrical stimulation training improves skeletal muscle oxidative capacity in individuals with motor-complete spinal cord injury. Muscle Nerve. 2017 May;55(5):669-675. doi: 10.1002/mus.25393. Epub 2017 Jan 11.

  PMID: 27576602 BACKGROUND

• Ryan TE, Brophy P, Lin CT, Hickner RC, Neufer PD. Assessment of in vivo skeletal muscle mitochondrial respiratory capacity in humans by near-infrared spectroscopy: a comparison with in situ measurements. J Physiol. 2014 Aug 1;592(15):3231-41. doi: 10.1113/jphysiol.2014.274456. Epub 2014 Jun 20.

  PMID: 24951618 BACKGROUND

• Ryan TE, Southern WM, Reynolds MA, McCully KK. A cross-validation of near-infrared spectroscopy measurements of skeletal muscle oxidative capacity with phosphorus magnetic resonance spectroscopy. J Appl Physiol (1985). 2013 Dec;115(12):1757-66. doi: 10.1152/japplphysiol.00835.2013. Epub 2013 Oct 17.

  PMID: 24136110 BACKGROUND

• Brizendine JT, Ryan TE, Larson RD, McCully KK. Skeletal muscle metabolism in endurance athletes with near-infrared spectroscopy. Med Sci Sports Exerc. 2013 May;45(5):869-75. doi: 10.1249/MSS.0b013e31827e0eb6.

  PMID: 23247709 BACKGROUND

• Hagstromer M, Oja P, Sjostrom M. The International Physical Activity Questionnaire (IPAQ): a study of concurrent and construct validity. Public Health Nutr. 2006 Sep;9(6):755-62. doi: 10.1079/phn2005898.

  PMID: 16925881 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

empagliflozin; Metformin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Central Study Contacts

Eva Podbregar Kolar, MD

CONTACT

+38640762768; evapodbregar@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Model Details: This is a parallel-group, three-arm interventional study. Participants with newly diagnosed type 2 diabetes will be randomized via a computer-generated sequence in a 1:1:1 ratio to one of three treatment arms: (1) empagliflozin monotherapy, (2) metformin monotherapy, or (3) combination therapy with empagliflozin and metformin. Each participant will remain in their assigned treatment arm for the full study duration (baseline through Month 6 follow-up). Outcomes will be compared across the three groups at matched timepoints (Day 14, Month 1, Month 3, Month 6) to evaluate the differential and combined effects of the two drug classes on skeletal muscle oxidative capacity and microvascular reactivity.

Study Record Dates

• First Submitted: July 20, 2026
• First Posted: August 18, 2026
• Study Start: April 16, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): July 31, 2028
• Last Updated: August 18, 2026

Record last verified: 2026-08

Locations

SL (1)