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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
900
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.
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 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 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.
Steno Diabetes center
Aarhus, Denmark
Odense University Hospital
Odense, Denmark
Falu lasarett
Falun, Sweden
Sahlgrenska Universitetssjukhuset
Gothenburg, Sweden
Karlstad general hospital
Karlstad, Sweden
Department of Cardiology, Skånes universitetssjukhus
Lund, Sweden
Department of Cardiology, Örebro University Hospital
Örebro, Sweden
Cardiology Clinic, Västmanlands sjukhus
Västerås, Sweden
Plasma levels of LDL cholesterol
The effect of intervention on difference between the groups of LDL cholesterol after three months
Time frame: Three months
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.
Time frame: Three months
Symptom-limited bicycle ergometer test
The effect of intervention on exercise capacity (measured as maximal workload in Watts and as estimated maximal oxygen uptake (VO2 max))
Time frame: Three months
Dynamic unilateral heel-lft and unilateral shoulder flexion tests
The effect of intervention on muscle endurance
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Three months
Glycosylated Hemoglobin (HbA1c)
Change in glycosylated hemoglobin (HbA1c) from baseline to 3 months to assess glycemic control. Unit of Measure: %
Time frame: 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)
Time frame: 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
Time frame: Three months
Serum Creatinine Concentration
Change in serum creatinine concentration from baseline to 3 months to assess renal function. Unit of Measure: mg/dL
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: Three months
Resting heart rate
The effect of intervention on resting heart rate
Time frame: Three months
Systolic and diastolic blood pressure
The effect of intervention on blood pressure (mmHg)
Time frame: Three months
Urine albumin-creatinine ratio
Urine albumin-creatinine ratio will be measured for for T2DM only
Time frame: 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)
Time frame: Three months
Body composition with multi-frequency bioimpedance
The effect of intervention on body composition measured with multi-frequency bioimpedance (for T2DM only)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: Three months
Inflammation
The effect of intervention on inflammatory markers (Olink panel) (in a subset of T2DM only, n=100 in total)
Time frame: Three months
Oxidative stress
The effect of intervention on 8-Oxo-2'-deoxyguanosine levels (in a subset of T2DM only, n=100 in total)
Time frame: Three months
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