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| Name | Class |
|---|---|
| Region Västmanland | OTHER |
| Region Skane | OTHER |
| Chalmers University of Technology | OTHER |
| Värmland County Council, Sweden |
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Background:
Bilberries from Sweden, rich in polyphenols, have shown cholesterol-lowering effects in small studies, and the cholesterol-lowering properties of oats, with abundant beta-glucans and potentially bioactive phytochemicals, are well established. Both may provide cardiometabolic benefits for patients with manifest chronic cardiometabolic disease, such as type 2 diabets mellitus (T2DM) and myocardial infarction (MI). However, large studies of adequate statistical power and appropriate duration are needed to confirm clinically relevant treatment effects. No previous study has evaluated the potential additive or synergistic effects of bilberry combined with oats on cardiometabolic risk factors.
Design:
This is a double-blind, randomized, placebo-controlled clinical trial. Our primary objective is to assess cardioprotective effects of diet supplementation with dried bilberry and with bioprocessed oat bran, with a secondary explorative objective of assessing their combination, compared with a neutral isocaloric reference supplement, for patients diagnosed with T2DM and/or MI. Patients will be randomized 1:1:1:1 to a three-month intervention. The primary endpoint is the difference in LDL cholesterol change between the intervention groups after three months. The major secondary endpoint is exercise capacity at three months. Other secondary endpoints include plasma concentrations of biochemical markers of inflammation, glycaemia, and gut microbiota composition after three months.
Implications:
Secondary prevention after cardiometabolic disease, including T2DM and MI, has improved during the last decades but diabetes complications, readmissions and cadiovascular related deaths following these conditions remain large health care challenges. Controlling hyperlipidemia, hyperglycaemia, hypertension and inflammation is critical to preventing (new) cardiovascular events, but novel pharmacological treatments for these conditions are expensive and associated with negative side effects. If bilberry and/or oat, in addition to standard medical therapy, can lower LDL cholesterol and inflammation more than standard therapy alone, this could be a cost-effective and safe dietary strategy for secondary prevention in high-risk patients or risk prevention in subjects with T2DM.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Bilberry | Experimental | Dietary supplement with bilberry shakes 2 times daily for 3 months (containing in total 40g of dried bilberry powder equalling 480 g of fresh berries per day). Product development in collaboration with Glucanova AB. |
|
| Reference/Placebo | Placebo Comparator | Dietary supplement with reference shakes 2 times daily for 3 months (containing no active bilberry or no active oats, but with similar texture and taste as both bilberry and oat). Product development in collaboration with Glucanova AB. |
|
| Bioprocessed oat bran | Experimental | Dietary supplement with bioprocessed oat bran shakes 2 times daily for 3 months (containing beta glucans from the Glucanova® technology, invented by Glucanova AB).Product development in collaboration with Glucanova AB. |
|
| Combination of oat and bilberry | Experimental | Dietary supplement with a combination of bioprocessed oat bran and dried bilberry (shakes) 2 times daily for 3 months. Product development in collaboration with Glucanova AB. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bilberry | Dietary Supplement | The dietary intervention will continued for three months. After randomization, participants will be given bilberry shakes (active), liquid oat shakes (active), a combination shake with bilberry and oats, or reference shakes (placebo product containing no active bilberry or active oats but with similar taste and texture as both oat and bilberry), for intake two times a day (t.i.d). The formula for the shakes to be used in the intervention will be finalized during the initial project period. |
| Measure | Description | Time Frame |
|---|---|---|
| Plasma levels of LDL cholesterol | The effect of intervention on difference between the groups of LDL cholesterol after three months | Three months |
| Measure | Description | Time Frame |
|---|---|---|
| Plasma lipid profile | The effect of intervention on differences between the groups of fasting lipid profile including HDL, triglycerides, total cholesterol, small-dense LDL cholesterol, apo A, apo B, Lp(a) and oxidized LDL. | Three months |
| Symptom-limited bicycle ergometer test |
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Inclusion criteria
Exclusion criteria
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| Name | Affiliation | Role |
|---|---|---|
| Ole Frobert, Prof | Department of Cardiology, Örebro Univerity Hospital, 701 85 Örebro, Sweden | Study Director |
| Cecilia Bergh, PhD | Clinical Epidemiology and Biostatistics, School of medical Sciences, örebro University, Sweden | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Steno Diabetes center | Aarhus | Denmark | ||||
| Odense University Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33971938 | Derived | Bergh C, Landberg R, Andersson K, Heyman-Linden L, Rascon A, Magnuson A, Khalili P, Karegren A, Nilsson J, Pirazzi C, Erlinge D, Frobert O. Effects of Bilberry and Oat intake on lipids, inflammation and exercise capacity after Acute Myocardial Infarction (BIOAMI): study protocol for a randomized, double-blind, placebo-controlled trial. Trials. 2021 May 10;22(1):338. doi: 10.1186/s13063-021-05287-5. |
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| ID | Term |
|---|---|
| D009203 | Myocardial Infarction |
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| C073305 | Vaccinium myrtillus extract |
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| OTHER_GOV |
| Vastra Gotaland Region | OTHER_GOV |
| Aarhus University Hospital | OTHER |
| Odense University Hospital | OTHER |
| Falu Hospital | OTHER |
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|
| Placebo | Dietary Supplement | The dietary intervention will be continued for three months. After randomization, participants will be given bilberry shakes (active), liquid oat shakes (active), a combination shake with bilberry and oats, or reference shakes (placebo product containing no active bilberry or active oats but with similar taste and texture), for intake two times a day (t.i.d). The formula for the shakes to be used in the intervention will be finalized during the initial project period. |
|
| Bioprocessed oat bran | Dietary Supplement | The dietary intervention will be continued for three months. After randomization, participants will be given bilberry shakes (active), liquid oat shakes (active), a combination shake with bilberry and oats, or reference shakes (placebo product containing no active bilberry or active oats but with similar taste and texture), for intake two times a day (t.i.d). The formula for the shakes to be used in the intervention will be finalized during the initial project period. |
|
| Combination bilberry/oats | Dietary Supplement | The dietary intervention will be continued for three months. After randomization, participants will be given bilberry shakes (active), liquid oat shakes (active), a combination shake with bilberry and oats, or reference shakes (placebo product containing no active bilberry or active oats but with similar taste and texture), for intake two times a day (t.i.d). The formula for the shakes to be used in the intervention will be finalized during the initial project period. |
|
The effect of intervention on exercise capacity (measured as maximal workload in Watts and as estimated maximal oxygen uptake (VO2 max)) |
| Three months |
| Dynamic unilateral heel-lft and unilateral shoulder flexion tests | The effect of intervention on muscle endurance | Three months |
| Self-reported physical activity level | The effect of intervention on the Frändin/Grimby activity scale (6 levels of physical activity, min:1 (low activity) max:6 (heavy activity)) and the Haskell physical activity scale ("For how many days were you physically active during the last week for at least 20 minutes?", min:0 max:7) | Three months |
| Plasma Cardiac Troponin Concentration | Change in plasma cardiac troponin (high-sensitivity cardiac troponin T or I) concentration from baseline to 3 months to assess myocardial injury. The effect of intervention on Troponin levels, Unit of Measure: ng/L | Three months |
| Plasma NT-proBNP Concentration | Change in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration from baseline to 3 months to assess cardiac stress, pg/mL | Three months |
| Plasma hs-CRP Concentration | Change in plasma high-sensitivity C-reactive protein (hs-CRP) concentration from baseline to 3 months to assess systemic inflammation. Unit of Measure: mg/L | Three months |
| Plasma IL-6 Concentration | Change in plasma interleukin-6 (IL-6) concentration from baseline to 3 months to assess inflammatory response. Unit of Measure: pg/mL | Three months |
| Glycosylated Hemoglobin (HbA1c) | Change in glycosylated hemoglobin (HbA1c) from baseline to 3 months to assess glycemic control. Unit of Measure: % | Three months |
| Fasting Plasma Insulin Concentration | Change in fasting plasma insulin concentration from baseline to 3 months to assess insulin sensitivity and metabolic status. Unit of Measure: µIU/mL (micro-international units per milliliter) | Three months |
| Fasting Plasma C-Peptide Concentration | Change in fasting plasma C-peptide concentration from baseline to 3 months to assess endogenous insulin secretion and beta-cell function. Unit of Measure: ng/mL | Three months |
| Serum Creatinine Concentration | Change in serum creatinine concentration from baseline to 3 months to assess renal function. Unit of Measure: mg/dL | Three months |
| Fasting Plasma Glucose Concentration | Change in fasting plasma glucose concentration from baseline to 3 months to assess glycemic control. Unit of Measure: mg/dL Unit of Measure: mg/dL | Three months |
| Serum Cystatin C Concentration | Change in serum cystatin C concentration from baseline to 3 months to assess renal function and estimate glomerular filtration independent of muscle mass. Unit of Measure: mg/L Unit of Measure: mg/dL Unit of Measure: mg/dL | Three months |
| Untargeted plasma metabolome | Untargeted plasma metabolomics will be employed to exploratively assess alterations in endogenous and exposome-related metabolites and to identify metabolites that may differ with treatment. | Three months |
| Fecal samples of gut microbiota composition | These exploratory analyses of will allow to investigate the extent to which gut microbiota composition and activity differs between responders and non-responders to the interventions. | Three months |
| Left ventricular systolic function | The effect of intervention on left ventricular function. Baseline left ventricular systolic function, expressed as global ejection fraction in percent according to the biplane Simpson method, will be evaluated by echocardiography by the discharging physician. The procedure will be repeated after three months by an experienced echocardiography technician blinded to results of the initial examinations | Three months |
| Resting heart rate | The effect of intervention on resting heart rate | Three months |
| Systolic and diastolic blood pressure | The effect of intervention on blood pressure (mmHg) | Three months |
| Urine albumin-creatinine ratio | Urine albumin-creatinine ratio will be measured for for T2DM only | Three months |
| Continuous glucose monitoring with Continuous Glucose Monitors (CGM) - FreeStyle model 2 | Continuous glucose monitoring (in a subset of T2DM only, n=100 in total) | Three months |
| Body composition with multi-frequency bioimpedance | The effect of intervention on body composition measured with multi-frequency bioimpedance (for T2DM only) | Three months |
| Diabetic retinal changes | The effect of intervention on diabetic retinal changes (eye fundus examination) (in a subset of T2DM only, n=100 in total) | Three months |
| Platelet aggregation (Primary hemostasis) | Ex vivo platelet aggregation in whole blood measured with impedance aggregometry (Multiplate®, Roche, Switzerland) after stimulation with adenosine diphosphate (ADP), arachidonic acid and thrombin-related activation peptide (TRAP-6). Unit of measure: Aggregation units x min. (in a subset of T2DM only, n=100 in total) | Three months |
| P-selectin levels (Primary hemostasis) | Plasma concentration of P-selectin measured with commercial ELISA (CD62P Quantikine, Biotechne, Dublin, Ireland). Unit of measure: ng/mL. (in a subset of T2DM only, n=100 in total) | Three months |
| Ex vivo thrombin generation (Secondary hemostasis) | Ex vivo thrombin generation (endogenous thrombin potential) in platelet-poor plasma measured using Calibrated Automated Thrombogram (BV Thrombinoscope, Maastricht, the Netherlands) after stimulation with tissue factor. Unit of measure: nM x min. (in a subset of T2DM only, n=100 in total) | Three months |
| Prothrombin fragment 1+2 (Secondary hemostasis) | Plasma concentration of prothrombin fragment 1+2, measured with commercial ELISA (EnzygnostTM, Siemens Healthineers, Ballerup, Denmark). Unit of measure: pmol/L. (in a subset of T2DM only, n=100 in total) | Three months |
| Fibrinolysis speed | Ex vivo fibrinolytic capacity (fibrinolysis speed) in whole blood measured with in-house modified rotational thromboelastometry after stimulation with tissue factor and tissue plasminogen activator. Unit of measure: mm/min. (in a subset of T2DM only, n=100 in total) | Three months |
| Fibrinolytic capacity | Ex vivo fibrinolytic capacity (time from peak fibrin to 50% lysis) in platelet-poor plasma measured with in-house turbidimetric fibrin formation and lysis assay. Unit of measure: seconds. (in a subset of T2DM only, n=100 in total) | Three months |
| Fibrinolytic markers | Plasma concentrations of plasminogen activity, tissue plasminogen activator (unit of measure: ng/mL) and plasminogen activator inhibitor-1 (unit of measure: ng/mL) measured with ELISA (Technozym®, Technoclone, Vienna, Austria). (in a subset of T2DM only, n=100 in total) | Three months |
| Endothelial activation | Plasma concentrations of syndecan-1 (unit of measure: ng/mL) and thrombomodulin (unit of measure: ng/mL) measured with commercial ELISA kits (CD138 kit and CD141 kit, Diaclone, Medix Biochemica, Espoo, Finland). (in a subset of T2DM only, n=100 in total) | Three months |
| Inflammation | The effect of intervention on inflammatory markers (Olink panel) (in a subset of T2DM only, n=100 in total) | Three months |
| Oxidative stress | The effect of intervention on 8-Oxo-2'-deoxyguanosine levels (in a subset of T2DM only, n=100 in total) | Three months |
| Odense |
| Denmark |
| Falu lasarett | Falun | Sweden |
| Sahlgrenska Universitetssjukhuset | Gothenburg | Sweden |
| Karlstad general hospital | Karlstad | Sweden |
| Department of Cardiology, Skånes universitetssjukhus | Lund | 221 00 | Sweden |
| Department of Cardiology, Örebro University Hospital | Örebro | 701 85 | Sweden |
| Cardiology Clinic, Västmanlands sjukhus | Västerås | 721 89 | Sweden |
| D007238 |
| Infarction |
| D007511 | Ischemia |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009336 | Necrosis |
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |