Theobromine, Vascular Function and Intestinal apoA-I Production

NCT02209025 | Completed

• 1 other identifier: NL46131.068.13/METC 13-3-065
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

Rationale: Despite successful efforts to lower atherogenic serum low-density lipoprotein (LDL) cholesterol concentrations, a substantial residual cardiovascular risk remains. An additive strategy to further lower this residual risk may be via raising high-density lipoprotein (HDL) concentrations, and in particular those of its major protein constituent apolipoprotein A-I (apoA-I). Based on several studies, theobromine may be a promising candidate in this respect. Recently, theobromine was shown to increase serum HDL cholesterol (HDL-C) concentrations by 0.16 mmol/L or 10% and apoA-I levels with 8%. The question is whether this increase in HDL-C and apoA-I concentrations observed translates into an improved functionality of the blood vessels. Effects of theobromine on vascular function have never been evaluated in a placebo controlled human intervention study. Objective: The primary objective is to evaluate the long-term effects of theobromine on vascular function in healthy subjects with a slightly lowered HDL-C in the fasting and the postprandial state. The second primary objective is to evaluate the long-term effects of theobromine on intestinal apoA-I mRNA and protein expression levels in healthy subjects with a slightly lowered HDL-C in the fasting and the postprandial state. Secondary objectives are to study the long-term effects of theobromine on (1) fasting serum HDL-C concentrations, (2) cholesterol efflux capacity and (3) postprandial lipid and glucose metabolism. Study design: A randomized, double-blind, placebo controlled cross-over design. The total study duration will be 12 weeks, consisting of a 4 week experimental period, a 4 week wash-out, and a 4 week control period. At the end of the experimental and control periods, a postprandial test will take place. Study population: Forty-eight healthy men aged 45-70 years and women aged 50-70 years, with slightly lowered HDL-C concentrations (men \<1.3 mmol/L and women \<1.5 mmol/L). Intervention: During the experimental period, subjects will consume daily at breakfast an drink containing 500 mg theobromine. During the placebo period, the subjects will consume daily at breakfast the same drink without theobromine. During the wash-out period, they will not consume any of the drinks. Main study parameters/endpoints: Measurements will be performed at the end of both 4-week intervention periods. The effects of theobromine will be calculated as the absolute differences between values obtained at the end of each period. The primary endpoint is the change in vascular function defined as % change in flow-mediated dilation (FMD) after intake of a daily stressor, a milkshake providing all the three different macronutrients. The second primary endpoint is the change in apoA-I mRNA and protein expression on the end of each period 5 hours after intake of the milkshake.

Conditions

Cardiovascular Disease

Keywords

Atherosclerosis; Cholesterol; Cholesterol, HDL; Apolipoprotein A-I; Theobromine

Outcome Measures

Primary Outcomes (2)

• Flow mediated dilation

  FMD measurements after 4 weeks of intake. Fasting and postprandial measurements

  4 weeks

• Intestinal apoA-I production

  Intestinal biopsies after 4 weeks of intake to see changes in apoA-I gene expression

  After 4 weeks of intake

Secondary Outcomes (5)

• HDL cholesterol

  4 weeks

• Vascular measurements

  After 4 weeks

• serum lipid metabolism

  4 weeks

• glucose metabolism

  4 weeks

• (apo)lipoprotein metabolism

  4 weeks

Study Arms (2)

Placebo drink

PLACEBO COMPARATOR

A drink with the same components as the theobromine drink except for the theobromine

Dietary Supplement: Placebo drink

Theobromine

EXPERIMENTAL

500mg theobromine in a drink

Dietary Supplement: Theobromine

Interventions

Theobromine DIETARY_SUPPLEMENT

Theobromine a compound for cocoa

Theobromine

Placebo drink DIETARY_SUPPLEMENT

Placebo drink

Eligibility Criteria

• Age: 45 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men aged between 45 and 70 years,
• Women aged between 50 and 70 years,
• Serum HDL-C \<1.3 mmol/L (men),
• Serum HDL-C \<1.5 mmol/L (women),
• Serum total cholesterol \<8.0 mmol/L,
• Plasma glucose \<7.0 mmol/L,
• BMI between 25 - 35 kg/m2,
• Non-smoking,

You may not qualify if:

• Unstable body weight (weight gain or loss \>3 kg in the past 3 months),
• Any medical condition requiring treatment and/or medication use,
• Indication for treatment with cholesterol-lowering drugs according to the Dutch Cholesterol Consensus (30),
• Use of medication or a medically-prescribed diet known to affect serum lipid or glucose metabolism. The use of paracetamol is allowed.
• Active cardiovascular disease (for instance congestive heart failure) or recent (\<6 months) event, such as acute myocardial infarction or cerebro-vascular accident.
• Gastrointestinal diseases (like celiac disease, inflammatory bowel disease, irritable bowel disease and food allergies) or a history of any gastrointestinal disorders or complaints.
• Not willing to stop the consumption of vitamin supplements or fish oil capsules 2 weeks before the start of the study,
• Men: consumption of \>21 glasses of alcohol-containing drinks per week.
• Women: consumption of \>14 glasses of alcohol-containing drinks per week.
• Abuse of drugs,
• Extensive exercise,
• Not willing to abstain from caffeine containing painkillers two weeks prior to the study and the duration of the study,
• Not willing to abstain from theobromine rich products from two weeks prior to the study and the duration of the study:
• o Chocolate containing products (see Appendix A).
• Not willing to abstain from energy drinks from two weeks prior to the study and the duration of the study, because of the high caffeine content.

Sponsors & Collaborators

• Maastricht University Medical Center: lead
• Unilever R&D: collaborator
• DSM Nutritional Products, Inc.: collaborator

Study Sites (1)

Maastricht University Hospital

Maastricht, 6200 MD, Netherlands

Location

Related Publications (2)

• Smolders L, Mensink RP, van den Driessche JJ, Joris PJ, Plat J. Theobromine consumption does not improve fasting and postprandial vascular function in overweight and obese subjects. Eur J Nutr. 2019 Apr;58(3):981-987. doi: 10.1007/s00394-018-1612-6. Epub 2018 Jan 12.

  PMID: 29330660 DERIVED

• Smolders L, Mensink RP, Boekschoten MV, de Ridder RJJ, Plat J. Theobromine does not affect postprandial lipid metabolism and duodenal gene expression, but has unfavorable effects on postprandial glucose and insulin responses in humans. Clin Nutr. 2018 Apr;37(2):719-727. doi: 10.1016/j.clnu.2017.06.007. Epub 2017 Jun 10.

  PMID: 28645636 DERIVED

MeSH Terms

Conditions

Cardiovascular Diseases; Atherosclerosis

Interventions

Theobromine

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• J Plat, Prof

  Maastricht University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 4, 2014
• First Posted: August 5, 2014
• Study Start: June 1, 2014
• Primary Completion: September 1, 2015
• Study Completion: September 1, 2015
• Last Updated: September 7, 2015

Record last verified: 2014-08

Locations

NL (1)