Short summary

The worldwide continuous increase in the incidence of type 2 diabetes mellitus calls for a more effective approach to risk stratification. There is only sparse information regarding the atherosclerotic burden and cardiovascular biomarkers in the early stages of type 2 diabetes mellitus. The aim of this study is to evaluate the occurrence of early-stage subclinical atherosclerosis in asymptomatic patients with newly diagnosed type 2 diabetes mellitus compared with healthy participants.

Rationale

The major cause of morbidity and mortality in this population is attributed to cardiovascular disease, which has led to more restrictive algorithms regarding treatment of known risk factors such as hypercholesterolemia and hypertension.

As coronary artery disease (CAD) is much more frequent and the outcome after revascularization is poorer in diabetic patients, early identification of CAD may be a reasonable approach to improve prognosis in these patients. However, the true prevalence of CAD in asymptomatic patients with type 2 diabetes mellitus is unknown.

Cardiac Computed Tomography Angiography (CCTA) has the capability non-invasively to identify luminal coronary lesions and in addition to visualize atherosclerotic manifestations of the coronary arterial wall, including characterization of coronary plaque-morphology at an early stage of disease. Moreover, CCTA may give information of plaque vulnerability.

In the literature, there seems to be consensus for a high coronary calcium score in diabetic patients, which has a strong association with mortality, but only few papers have dealt with coronary plaque morphology in asymptomatic diabetic patients. There is only sparse information regarding the atherosclerotic burden and cardiovascular biomarkers in the early stages of type 2 diabetes mellitus. The vast majority of studies have concerned diabetes populations with more than 5 years average diabetes age or high-risk subgroups, who at inclusion already had atherosclerotic disease manifestations.

Therefore, the aim of this study is to evaluate the occurrence of early-stage subclinical atherosclerosis in asymptomatic patients with newly diagnosed type 2 diabetes mellitus with special emphasis on coronary plaque characteristics by CCTA compared with healthy participants. Ultrasound of the carotids will supplement the morphological evaluation of the atherosclerotic burden. These findings will be compared to the functional status of various peripheral arterial segments (Pulse-wave-velocity and ankle-brachial-index) and biomarkers in the cross-sectional part of this study.

In a 5-year follow-up study we intend to describe relationships between these selected measures for general atherosclerotic involvement and the progression of especially the coronary atherosclerotic burden by the described contemporary techniques.

The objective of this study is to:

• Compare the prevalence and complexity of coronary plaques in patients with newly discovered T2DM with a healthy control group matched for age and gender, as evaluated by CCTA.

• Describe the relationship between morphological, functional and biochemical estimates of arteriosclerosis in newly diagnosed T2DM.

• Characterize the progression of coronary plaques in patients with newly discovered T2DM in a 5-year follow-up study.

Description of the cohort

A prospective cohort follow-up study. The inclusion phase will run for 2 years and the follow-up phase is 5 years from inclusion.

The DD2-plaque study (diabetic patient's cohort):

Recruitment in this cohort will take place in 2 ways:

1. From the 'Danish centers for strategic research in type 2 diabetes' (DD2)
   
2. Direct through general practitioners or from outpatient clinics in The Region of Southern Denmark.

We expect to be able to include 100 asymptomatic patients with newly diagnosed T2DM.

Inclusion criteria:

• Newly diagnosed (< 1 year) diabetes patients clinically classified as T2DM patients.
• Age 18 +

Exclusion criteria:

• Renal insufficiency (GFR < 45 or se-creatinine >140 mikromol/l).
• BMI > 35.
• Atrial fibrillation
  
• Patients with a history of prior atherothrombotic disease or events

The DD2-plaque study (control patients cohort):

The Danish Risk Score Study (DanRisk) was performed at four centers (Odense, Vejle, Svendborg and Esbjerg) in Southern Denmark from 2009 to 2010 based on 1,825 randomly selected subjects from the general population, aged 50 or 60 years, using the Danish government database. A total of (in Esbjerg) 209 participants without symptoms of cardiovascular disease or diabetes and without any kind of medicine were included. This group constitutes the population, which is scheduled for a follow-up in spring 2015. The protocol was approved by the Regional Scientific Ethical Committee for Southern Denmark (S-20080140). Persons from this cohort will be included as the age - and sex matched control group. A contrast CCTA will be performed and will supplement the below listed examinations:

• Medical conditions i.e. cardiovascular disease, medication, smoking habits and family history.
• Physical examination including measurement of height, weight, waist circumference and calculation of body mass index.
• Blood pressure and blood sampling.
• All patients will undergo: ECG, carotid ultrasound, CACS, ankle brachial index, urin albumin creatinine ratio and evaluation by HeartScore.

Data and biological material

The proxy statement.

Participants will fill in a questionnaire concerning:

• Cardiovascular and diabetes hereditary
• Medication
• Alcohol and drugs consumption
• Smoking habits (current, prior and never smokers)
• Family history (cardiac events or strokes for women < 65 years of age and men < 55 years of age in first generation relatives)
• Medical history

Physical examination will include measurement of:

• Height, weight, BMI.
• Waist/hip ratio
• ECG

Brachial blood pressure will be measured by oscillometric technics during 24 hours using TM-2430 (A&D CO., LTD, Saitama, Japan) or BDM Mobil-O-Graph® NG Classic (IEM GmbH, Stolberg, Germany).

Blood samples: 1 container with green lid, 4 containers with blue lid and 1 container with pink lid. 10 ml of morning midstream urine will be sampled.

All patients will undergo:

• Carotid intima media thickness (IMT) will be measured by B-mode ultrasound (Model IE33, Koninklijke Philips Electronics N.V, Eindhoven, The Netherlands) using a linear array transducer, L11-3 with a frequency up to 11 MHz.
• Pulse wave velocity: Using sphygmocor (ArtCor, Sydney, Australia).
• Coronary atherosclerosis is evaluated by measurement of calcium in the coronary arteries and by evalution of coronary plaques using contrast enhanced cardic CT. CACS will be estimated by the Agatston score while the evaluation of coronary plaques will be performed by a dedicated plaque-analysis tool, Auto-Plaque.
• Ankle brachial index.
• Albumin creatinine ratio. 
• Automated blood pressure and pulse wave analysis: Blood pressure is measured by oscillometric technics by the Mobil-o-graph PWA (IEM GmbH, Stolberg, Germany).

Collaborating researchers and departments

Department of Cardiology, Hospital of Southwest Denmark

• Clinical Associate Professor Niels Peter Rønnow Sand, MD, PhD
• Ramshanker Ramanathan, MD

Department of Cardiology, Odense University Hospital

• Kristian øvrehus, MD, PhD
• Axel Diederichsen, MD, PhD

Department of Cardiology, Skejby University Hospital

• Associate Professor Bjarne Linde Nørgaard, MD, PhD

Department of Endocrinology, Hospital of Southwest Denmark

• Chief Physician Jeppe Gram, MD, PhD

Department of Endocrinology, Odense University Hospital

• Professor Michael Hecht Olsen, MD, DMSc
• Jacob Volmer Stidsen, MD

Department of Clinical Biochemistry, Hospital of Southwest Denmark

• Professor Jørgen Gram, MD, DMSc

Department of Radiology, Hospital of South West Denmark

• Martin Weber Kusk, RT, MMDI

Institute of Regional Health Research, University of Southern Denmark, Odense

• Statistician Rene Holst

Department of Internal Medicine, Hillerød Hospital

• Ida Solborg Bjerrum, MD