Short summary

The Steno INTEN-CT trial aims to evaluate a combined strategy of improved CVD risk stratification by use of cardiac CT (coronary artery calcification, CAC) and adjustment of multifactorial CVD treatment based on CAC score. We hypothesize that i) intensified medical treatment lower CVD event rates in high-risk patients (CAC  100), and ii) that less intensive multifactorial treatment is safe in very low-risk patients (CAC = 0).

Rationale

Type 2 diabetes mellitus (T2DM) confers an elevated risk of cardiovascular disease (CVD) 1. The risk is, however unevenly distributed within the group of T2DM patients and current methods to estimate CVD risk are highly inaccurate2-4. This challenges the clinical decision of primary CVD prophylaxis in T2DM as one approach does not fit all. Primary CVD prophylaxis is further complicated by the emergence of two new drug classes, each with proven cardiovascular protection in patients with T2DM and manifest CVD or, to a lesser degree, presence of cardiovascular risk factors 5-12. We present the design and rationale for the randomized Steno INTEN-CT trial. The trial aims to evaluate a CVD prevention strategy with coronary calcification score (CAC) as a decisive tool to risk stratify patients with T2DM and based on this information to intensify or de-intensify multifactorial treatment.

HYPOTHESIS AND AIMS The overall research objective is to evaluate the possible cardiovascular benefit of a multifactorial treatment strategy based on a CAC score. Our two co-primary aims are - Co-primary aim 1: to compare the effect of intensified multifactorial treatment versus standard treatment on rates of a composite cardiovascular endpoint (cardiovascular mortality, non-fatal stroke, non-fatal myocardial infarction and hospitalization for heart failure) in patients identified with high cardiovascular risk as indicated by a CAC score ≥100. We hypothesize that intensified multifactorial treatment is superior to standard treatment in patients with CAC score ≥100.

- Co-primary aim 2: to compare the effect of de-intensified multifactorial treatment versus standard treatment on rates of the same composite cardiovascular endpoint in patients identified with low cardiovascular risk as indicated by a CAC score of zero. We hypothesize that downgraded multifactorial treatment is non-inferior to standard treatment in patients with CAC score of zero. Secondarily we aim to - compare harms (patient-reported outcomes) in the CAC-based treatment group and the control group. - compare sex differences in cardiovascular outcomes and harms between the two study arms. - compare costs and outcomes between the two groups after study completion. - quantify and compare the diagnostic tests and therapeutic interventions between the intervention groups and control groups during the study period. - evaluate the adherence and efficacy of the therapeutic interventions in the intervention groups and the control groups during the study period. - evaluate the association of CAC score and coronary CT angiography derived measures of coronary atherosclerosis burden, respectively, and CVD prognosis and treatment effects in patients with T2DM. - explore the association between CAC score, coronary CT angiography derived measures of coronary atherosclerosis burden. - explore the association between CAC score, biochemical markers of inflammation and atherosclerosis in relation to CVD prognosis in patients with T2DM.

Description of the cohort

We will include men and women with T2DM in Denmark. Inclusion criteria: - New or former diagnosis of T2DM according to WHO13. - Age between 55-69 years (men) and 60-74 years (women). Exclusion criteria: - Previous history of CVD (previous myocardial infarction or coronary intervention [Percutaneous coronary intervention or by-pass], heart failure, stroke or peripheral artery disease [ABI<0.9 and symptoms or surgical intervention] as documented by the patient or the patient medical record). - Contraindications or allergies to both Forxiga and Ozempic. - Signs of critical cardiac disease at screening: >50% stenosis of left main coronary artery (CT angiography) or left ventricular ejection fraction below 40% (if echocardiography is performed). If a CT angiography is not available, a CAC>1000 on the non-contrast cardiac CT will be considered equal to critical cardiac disease. - Expected life duration < 1 year for any reason.

Data and biological material

Primary outcome: Combined cardiovascular outcome obtained through National Health registries and adjudicated in patient journal.

We collect blood, urine, CT scans and questionnaires.

Collaborating researchers and departments

Steno Diabetes Center Aarhus

• Per Løgstrup Poulsen
• Kristian Løkke Funck

Steno Diabetes Center Nordjylland

• Peter Vestergaard

Steno Diabetes Center Copenhagen

• Peter Rossing

Steno Diabetes Center Odense

• Kurt Højlund

Steno Diabetes Center Sjælland

• Michael Hecht