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Background: Metformin treatment has beneficial effects on both glucose and lipid metabolism. Whereas there is general agreement that the blood glucose lowering effect of metformin results from inhibition of hepatic gluconeogenesis, it is less clear exactly how the drug lowers blood triglyceride concentration. There are indications that it enhances hepatic free fatty acid (FFA) oxidation thus diminishing substrate for reesterification and resecretion as very-low-density-lipoprotein (VLDL) triglycerides (TG). However, the liver is not easily accessible for sampling in humans and data on the clinical effects of metformin in the liver are therefore lacking. This may change due to the increasing use of the positron emission tomography (PET) technique. Using PET isotopes (11C or 18F) coupled to either palmitate or a fatty acid analogue, it is possible to non-invasively measure hepatic fatty acid handling.
Aim: To determine how 3 months metformin treatment (1000 mg twice daily) affects hepatic lipid and glucose metabolism in patients with newly diagnosed type 2 diabetes.
Design: Randomized, placebo controlled, double-blind parallel study with patients receiving either metformin or placebo. A control group of BMI and age-matched non-diabetic individuals will receive metformin for 3 months.
Hypothesis: Metformin lowers VLDL-TG secretion and circulating triglycerides by increasing hepatic fatty acid oxidation
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Healthy controls | Other | Healthy controls receiving 1000 mg metformin twice daily for 3 months |
|
| Placebo | Placebo Comparator | Placebo |
|
| Metformin | Active Comparator | Metformin "Sandoz", 1000 mg twice daily for 3 months |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin | Drug | 1000 mg metformin twice daily in 3 months |
|
| Measure | Description | Time Frame |
|---|---|---|
| Hepatic Fatty Acid Oxidation | Hepatic fatty acid oxidation assessed by dynamic C11-palmitate PET | 90 days |
| Hepatic Fatty Acid Reesterification | Hepatic fatty acid reesterification assessed by C11-palmitate PET | 90 days |
| Hepatic Fatty Acid Uptake | Hepatic fatty acid uptake assessed by C11-palmitate PET | 90 days |
| VLDL-TG Secretion | Hepatic VLDL-TG secretion assessed by [1-14C] VLDL tracer | 90 days |
| Whole Body Glucose Rd | Whole body basal glucose metabolism assessed by [3-3H]glucose tracer kinetics | 90 days |
| Measure | Description | Time Frame |
|---|---|---|
| Fatty Acid Turnover | Fatty acid turnover assessed as whole body C11-palmitate turnover | 90 days |
| VLDL-TG Oxidation | VLDL-TG oxidation assessed by 14C carbon dioxide (CO2) in exhaled breath |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Lars C Gormsen, MD PhD | Aarhus University Hospital | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37776319 | Derived | Pedersen AKN, Gormsen LC, Nielsen S, Jessen N, Bjerre M. Metformin Improves the Prerequisites for FGF21 Signaling in Patients With Type 2 Diabetes. J Clin Endocrinol Metab. 2024 Jan 18;109(2):e552-e561. doi: 10.1210/clinem/dgad583. | |
| 30976851 | Derived | Gormsen LC, Sondergaard E, Christensen NL, Brosen K, Jessen N, Nielsen S. Metformin increases endogenous glucose production in non-diabetic individuals and individuals with recent-onset type 2 diabetes. Diabetologia. 2019 Jul;62(7):1251-1256. doi: 10.1007/s00125-019-4872-7. Epub 2019 Apr 11. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Healthy Controls | Healthy controls receiving 1000 mg metformin twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months |
| FG001 | Placebo | Placebo Placebo: 2 tablets twice daily in 3 months |
| FG002 | Metformin | Metformin "Teva", 1000 mg twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Healthy Controls | Healthy controls receiving 1000 mg metformin twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months |
| BG001 | Placebo | Placebo Placebo: 2 tablets twice daily in 3 months |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Hepatic Fatty Acid Oxidation | Hepatic fatty acid oxidation assessed by dynamic C11-palmitate PET | Posted | Mean | Standard Deviation | micromol/ml/min | 90 days |
|
During the 90 days trial
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Healthy Controls | Healthy controls receiving 1000 mg metformin twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal uncomfort | Gastrointestinal disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Lars C. Gormsen, Consultant | Department of Nuclear Medicine & PET Centre, Aarhus University Hospital | 004578456260 | lars.christian.gormsen@clin.au.dk |
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Feb 4, 2013 | Sep 24, 2019 | Prot_000.pdf |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D050171 | Dyslipidemias |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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| Placebo | Drug | 2 tablets twice daily in 3 months |
|
| 90 days |
| BG002 | Metformin | Metformin "Teva", 1000 mg twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| BMI | Mean | Standard Deviation | kg/m2 |
|
| HbA1C | Mean | Standard Deviation | mmol/mmol |
|
|
|
| Primary | Hepatic Fatty Acid Reesterification | Hepatic fatty acid reesterification assessed by C11-palmitate PET | Posted | Mean | Standard Deviation | micromol/ml/min | 90 days |
|
|
|
| Primary | Hepatic Fatty Acid Uptake | Hepatic fatty acid uptake assessed by C11-palmitate PET | Posted | Mean | Standard Deviation | micromol/ml/min | 90 days |
|
|
|
| Primary | VLDL-TG Secretion | Hepatic VLDL-TG secretion assessed by [1-14C] VLDL tracer | Posted | Mean | Standard Deviation | micromol/min | 90 days |
|
|
|
| Primary | Whole Body Glucose Rd | Whole body basal glucose metabolism assessed by [3-3H]glucose tracer kinetics | Posted | Mean | Standard Deviation | mg/kg/min | 90 days |
|
|
|
| Secondary | Fatty Acid Turnover | Fatty acid turnover assessed as whole body C11-palmitate turnover | Posted | Mean | Standard Deviation | micromol/min | 90 days |
|
|
|
| Secondary | VLDL-TG Oxidation | VLDL-TG oxidation assessed by 14C carbon dioxide (CO2) in exhaled breath | Posted | Mean | Standard Deviation | percentage of 14C-VLDL | 90 days |
|
|
|
| 0 |
| 12 |
| 0 |
| 12 |
| 1 |
| 12 |
| EG001 | Placebo | Placebo Placebo: 2 tablets twice daily in 3 months | 0 | 12 | 0 | 12 | 1 | 12 |
| EG002 | Metformin | Metformin "Teva", 1000 mg twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months | 0 | 12 | 0 | 12 | 0 | 12 |
| Fractured vertebral column | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
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| D004700 | Endocrine System Diseases |
| D052439 | Lipid Metabolism Disorders |