The RISC Study

Relationship between Insulin Sensitivity and Cardiovascular disease: Status at 30 October 2008

The RISC (Relationship between Insulin Sensitivity and Cardiovascular disease) Study is being carried out in 19 European recruiting centres to examine whether insulin sensitivity (directly measured with the euglycaemic clamp technique) predicts cardiovascular disease (CVD) independently of other factors.

The study makes use of ultrasound scans of the carotid artery and takes the thickness of the intima-media layer in the artery wall (IMT) as an early marker of atherosclerosis. The study is being carried out across Europe and is the largest study to date to use the clamp technique to measure insulin sensitivity in healthy people.

RISC objectives

The primary objective of RISC is to establish whether insulin resistance predicts (in healthy people with no signs or symptoms of disease) the deterioration of CVD risk markers, diabetes, obesity, atherosclerosis, dyslipidaemia, and clinical CVD.

Secondary objectives are:1) to analyse genetic and environmental contributions to insulin resistance and CVD and 2) to develop and validate, against the clamp, a method for the assessment of insulin sensitivity based on the oral glucose tolerance test.

Baseline study

At the end of November 2004, the RISC study had recruited 1504 participants in 14 countries (Austria, Denmark, Finland, France, Germany, Greece, The Netherlands, Ireland, Italy, Sweden, Spain, Switzerland, United Kingdom and Serbia and Montenegro). Of these 1340 underwent the 'clamp' study and became part of the RISC population of which 1081 have completed the year 3 follow up.

The measures carried out in these volunteers included:

• Physical examination: blood pressure, ECG, height, weight, measures of body fat by bioimpedance
• Euglycaemic hyperinsulinaemic clamp: to measure insulin sensitivity (M/I value), with the addition of a glucose tracer (stable isotope) to measure glucose production (in about 1/3 of participants)
• Carotid artery ultrasound scan: and from these recordings measures of : - artery wall thickness (IMT), which indicates presence and extent of CVD - distensibility (stiffness) of the artery wall
• Ankle:arm arterial pressure: to detect peripheral artery disease using Doppler ultrasound
• Lipid measurements from a fasting blood sample
• Oral glucose tolerance test (to detect diabetes)
• Intravenous glucose test: to assess beta-cell function (at the end of the clamp study)
• DNA extracted from a blood sample: to test genes associated with insulin resistance and CVD
• Quantitative measure of physical activity with an Actigraph (accelerometer) movement monitor
• Qualitative assessment of physical activity: with the International Physical Activity questionnaire (IPAQ)
• Questionnaires on lifestyle (personal and family history, smoking, alcohol, peripheral artery disease and angina)

Characteristics of the RISC participants

• Age range: 30-60 years
• In general good health
• No symptoms of CVD
• Blood pressure less than 140/90 mm Hg
• Total cholesterol less than 7.8 mmol/l
• Triglycerides less than 4.6 mmol/l
• Plasma glucose (fasting and 2 h after oral glucose load) less than 7.0/11.1 mmol/l
• No treatment for diabetes, hypertension or lipid disorders.

Summary of work to date

Data has been collected on 1340 men and women who underwent the euglycaemic hyperinsulinaemic clamp (406 with additional measures of hepatic glucose production from the tracer studies) and carotid artery IMT measurement (as well as the other tests indicated above).

These participants form the core group that are being telephoned at yearly intervals and have been invited back for examinations after 3 years. Year 3 follow up examination data are now included for 1085 participants (30/10/2008). Follow up is now completed.

Publications are being produced with RISC data. Click here to see list of publications. A major symposium was held at the EASD in Amsterdam September 2007. Webcast can be accessed on Publications page. The RISC project is planned to continue at least until 2010.

Follow up and examinations at Year 3

RISC has competed the Year 3 follow up examinations. Participants have been contacted to invite them to undergo all the original tests except for the clamp and physical activity monitor. The participants are being telephoned at 4 years to update about health status and medication.

Preliminary findings

Abstracts and manuscripts have been prepared after preliminary examination of the data and these are listed on the publications page.

• Initial findings showed that the level of insulin sensitivity is not linked (cross-sectionally) to the thickness of the carotid artery (IMT), this makes folluw up measures even more important.

• Examination of the carotid artery ultrasound scan (by analysis of the pixels using specially designed software) confirmed that increased thickening of the IMT was not necessarily early atherosclerosis but is a part of aging in the normal population.

• Of interest was that although the participants in the RISC study are healthy, when their data were examined according to different criteria for the metabolic syndrome a high percentage were found to be within the limits of the syndrome and these were participants who showed high levels of insulin resistance (measured by the clamp).

• Physical activity has been measured with the Actigraph accelerometer and the IPAQ questionnaire in RISC (both validated methods). When preliminary data on 562 participants were examined for measures of physical activity and arterial distensibility (stiffness) those participants who had higher levels of vigorous physical activity (measured quantitatively by Actigraph) also had less stiff carotid arteries and the normal affect of aging on arterial distensibility was attenuated by vigorous activity.

The RISC Study is supported by EU FP5 contract: QLG1-CT-2001-01252 and by AstraZeneca. The EGIR group is supported by Merck-Serono.

Updated by Lucrecia Mota 26 March 2009