Effects of Bilberry and Oat Intake After Type 2 Diabetes and/or MI (BioDiaMI)

Effects of Bilberry and Oat Intake on Plasma Lipid Profile, Inflammation, and Exercise Capacity in Patients With Type 2 Diabetes and/or Myocardial Infarction (BioDiaMI): a Randomized, Double-blind, Placebo-controlled Trial

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 Overview

• Status: Active, not recruiting
• Conditions: Myocardial Infarction
• Intervention / Treatment: Dietary supplement: Bilberry; Dietary supplement: Placebo; Dietary supplement: Bioprocessed oat bran; Dietary supplement: Combination bilberry/oats

• Study Type: Interventional
• Enrollment (Estimated): 900
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark
    • Steno Diabetes Center
  • Odense, Denmark
    • Odense University Hospital
• Sweden
  • Falun, Sweden
    • Falu Lasarett
  • Gothenburg, Sweden
    • Sahlgrenska Universitetssjukhuset
  • Karlstad, Sweden
    • Karlstad general hospital
  • Lund, Sweden, 221 00
    • Department of Cardiology, Skånes universitetssjukhus
  • Västerås, Sweden, 721 89
    • Cardiology Clinic, Västmanlands sjukhus
  • Örebro, Sweden, 701 85
    • Department of Cardiology, Örebro University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

• Confirmed T2DM diagnosis (any treatment modality accepted) and/or within 3 years post STEMI or NSTEMI
• Completed coronary angiography/PCI
• Male and female subjects ≥18 years
• Allocated to atorvastatin at a daily dose of 80 mg (only eligible for patients enrolled up to 7 days post MI and not for T2D subjects)
• Written informed consent

Exclusion criteria

• Emergency coronary artery bypass grafting
• <18 years of age
• LDL cholesterol <2.0 mmol/L
• Daily intake or the intent to initiate daily intake of bilberry in any form or daily intake of >15 g of oatmeal or equivalent
• Food allergy/intolerance to gluten, bilberries or legumes
• Previous randomization in the BioDiaMI trial
• Inability to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bilberry; 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.	Dietary supplement: Bilberry; 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.
Placebo Comparator: Reference/Placebo; 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.	Dietary supplement: Placebo; 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.
Experimental: Bioprocessed oat bran; 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.	Dietary supplement: Bioprocessed oat bran; 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.
Experimental: Combination of oat and bilberry; 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.	Dietary supplement: Combination bilberry/oats; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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	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
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
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
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

Collaborators and Investigators

• Sponsor: Ole Frobert, MD, PhD
• Collaborators: Odense University Hospital; Aarhus University Hospital; Vastra Gotaland Region; Värmland County Council, Sweden; Chalmers University of Technology; Region Skane; Falu Hospital; Region Västmanland
• Investigators: Study Director: Ole Frobert, Prof, Department of Cardiology, Örebro Univerity Hospital, 701 85 Örebro, Sweden; Principal Investigator: Cecilia Bergh, PhD, Clinical Epidemiology and Biostatistics, School of medical Sciences, örebro University, Sweden

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2021
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: August 2, 2018
• First Submitted That Met QC Criteria: August 2, 2018
• First Posted (Actual): August 8, 2018

Study Record Updates

• Last Update Posted (Actual): March 23, 2026
• Last Update Submitted That Met QC Criteria: March 18, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: exercise capacity; type 2 diabetes mellitus; acute myocardial infarction; anthocyanin; cholesterol; diet therapy; bilberry bush; beta glucans
• Additional Relevant MeSH Terms: Endocrine System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Infarction; Necrosis; Myocardial Ischemia; Ischemia; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Myocardial Infarction; Vaccinium myrtillus extract
• Other Study ID Numbers: BioDiaMI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No