Description

BACKGROUND AND RATIONALE Type 2 diabetes mellitus (T2D) is a major and growing global health challenge, affecting an estimated 11.1% of the adult population worldwide. Despite substantial advances in treatment, cardiovascular disease (CVD) remains a leading cause of morbidity and mortality among people with T2D.

T2D is associated with chronic low-grade inflammation and multiple metabolic and vascular abnormalities that contribute to cardiovascular complications and myocardial remodeling. Consequently, people with T2D are at increased risk of developing both at atherosclerotic disease and heart failure, particularly heart failure with preserved ejection fraction (HFpEF).

HFpEF remains particularly challenging to diagnose, and previous studies have suggested a considerable burden of previously unrecognized HFpEF among people with T2D.

Recent major therapeutic advances including Sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1-RA) and non-steroidal mineralocorticoid receptor antagonists have transformed the prevention of cardiac and vascular complications, with proven benefits in HFpEF, cardiovascular outcomes and diabetic kidney disease.

Beyond cardiovascular protection, these therapies may also improve systemic inflammation, plaque volume in coronary arteries and cardiac function.

However, despite increasing theurapeutic options, the implementation of evidence-based therapies in clinical practice remains suboptimal. Current care models are often fragmented, with cardiology, endocrinology, nephrology, and primary care operating independently. This may lead to delayed treatment optimization, inconsistent implementation of guidelines and increased patient inconvenience and healthcare costs. More importantly, multimorbid patients, such as those with combined CVD and T2D, may be particularly vulnerable to these limitations.

The Cardio-Metabolic Clinic (CMC) was developed to address this implementation gap by combining comprehensive clinical assessment, structured guideline-based decision support, and access to multidisciplinary specialist expertise within an integrated care model.

Echo-CT-ProtecT-2D evaluates the cardiovascular effects of this approach through two parallel and independently evaluated studies conducted within the same randomized study population:

EchoProtecT-2D - Cardiac Function and Heart Failure Phenotyping Study, focusing on cardiac function, exercise hemodynamics, and heart failure phenotyping; and CT-ProtecT-2D - Coronary Inflammation and Atherosclerosis Study, focusing on coronary inflammation and atherosclerotic plaque characteristics.

HYPOTHESES

EchoProtecT-2D - Cardiac Function and Heart Failure Phenotyping Study

Primary Hypothesis - Left Ventricular Hemodynamics We hypothesize that optimized implementation of evidence-based multifactorial cardiometabolic treatment leads to greater improvement in left ventricular function compared with usual care, reflected primarily by a greater reduction in left ventricular filling pressure, assessed by resting E/e', from baseline to 12 months. We further hypothesize that the treatment effect may be greater among participants with HFpEF.

Heart Failure Phenotyping We hypothesize that a substantial proportion of participants with T2D and established cardiovascular disease have previously unrecognized heart failure, with HFpEF being the predominant phenotype.

Systemic Inflammation We hypothesize that optimized implementation of evidence-based multifactorial cardiometabolic treatment reduces systemic inflammation more effectively than usual care, reflected by greater reductions in IL-6 and other circulating inflammatory biomarkers.

Functional Capacity and Patient-Reported Outcomes We hypothesize that optimized implementation of evidence-based multifactorial cardiometabolic treatment improves functional exercise capacity, symptom burden, and health-related quality of life compared with usual care.

CT-ProtecT-2D - Coronary Inflammation and Atherosclerosis Study

Primary Hypothesis - Coronary Inflammation We hypothesize that optimized implementation of evidence-based multifactorial cardiometabolic treatment reduces coronary inflammation compared with usual care, reflected primarily by a greater reduction in global mean pericoronary adipose tissue (PCAT) attenuation from baseline to 12 months.

Coronary Atherosclerotic Plaque Burden We hypothesize that optimized implementation of evidence-based multifactorial cardiometabolic treatment reduces coronary atherosclerotic plaque burden compared with usual care.

Coronary Plaque Composition and High-Risk Features We hypothesize that optimized implementation of evidence-based multifactorial cardiometabolic treatment results in favorable changes in coronary plaque composition and CT-derived high-risk plaque characteristics compared with usual care.

METHODS Echo-CT-ProtecT-2D is a single-center, open-label, prospective, randomized controlled trial embedded within the ongoing ProtecT-2D trial (NCT06203860). The study will be conducted at the Cardiovascular Research Unit, Odense University Hospital, Svendborg, Denmark. Echo-CT-ProtecT-2D comprises two parallel substudies, EchoProtecT-2D and CT-ProtecT-2D, focusing on echocardiographic and coronary CT angiography-based assessments, respectively (CCTA). The two substudies have distinct scientific aims and independently evaluated primary endpoints while sharing the same study population, intervention, and organizational and logistical framework.

Participants are randomized in a 2:1 ratio to either the CMC intervention or usual care. Participants allocated to usual care continue treatment through their general practitioner and/or relevant hospital outpatient clinics.

Participants undergo comprehensive cardiovascular and metabolic assessment at baseline and follow-up. The study includes echocardiographic assessment of cardiac function at rest and during exercise, Coronary CT angiography, 6 minute walk testing to asses functional capacity, inflammatory biomarkers, patient reported symptoms, and questionnaire-assessment of health-related quality of life (QoL). Detailed cardiac phenotyping will additionally be used to explore the prevalence of previously unrecognized heart failure, particularly HFpEF.

INTERVENTION - The Cardio-metabolic Clinic (CMC) :

The CMC provides integrated, individualized, and multifactorial management of T2D and cardiovascular disease. A central component of the intervention is a REDCap-integrated clinical decision-support algorithm developed according to current clinical guidelines for T2D and CVD.

Individual patient characteristics, current treatment, comorbidities, and cardiovascular risk factors are entered into the system. Based on these data, the algorithm provides structured guideline-based treatment recommendations across ten prespecified clinical domains: dyslipidemia, hypertension, thrombosis prophylaxis, diabetes management, assessment of microvascular complications, consideration of SGLT2 inhibitors and/or GLP-1 receptor agonists, lifestyle modification, peripheral artery disease, HFpEF, and vaccinations.

The algorithm supports systematic identification of relevant treatment opportunities and facilitate implementation of evidence-based therapies while maintaining individualized clinical decision-making.

ORGANIZATION IN THE CMC:

The Cardio-metabolic Clinic is an integrated care model designed to be a resource-efficient scalable approach to improving implementation of evidence-based cardiometabolic treatment and is structured in three interconnected layers.

Frontline consultations are conducted by trained medical staff, either medical students or a resident doctor, who perform standardized clinical assessments and enter data into a REDCap-based electronic form with the abovementioned integrated decision-support algorithm.

Based on individual patient data the algorithm generates structured, guideline-based treatment recommendations to support systematic implementation of all therapies relevant to the patient in question.

The next layer consists of a supervising cardiologist to ensure clinical accuracy. When needed, complex issues can be discussed with a third layer, consisting of relevant specialists in endocrinology, nephrology and hepatology, ensuring access to multidisciplinary expertise when required.

This structure aims to combine standardized implementation of guideline-directed treatment with individualized multidisciplinary specialist care integrated within a single clinical setting.

HEART FAILURE PHENOTYPING:

EchoProtecT-2D will characterize the burden of previously unrecognized heart failure among participants without a prior heart failure diagnosis. Comprehensive echocardiographic assessment at rest and during exercise, together with clinical and functional assessments, will be used to examine hemodynamic changes and characterize heart failure stages and phenotypes, with particular emphasis on HFpEF.

LONG-TERM FOLLOW-UP All participants are scheduled for a 3-year follow-up visit as part of the parent ProtecT-2D trial. Therefore the EchoProtecT-2D may be extended to include repeat echocardiographic assessment at the 3-year follow-up.

If implemented, the long-term echocardiographic follow-up, corresponding outcomes, and statistical analyses will be prespecified in an updated study protocol and Statistical Analysis Plan prior to initiation of the 3-year echocardiographic assessments.

STATISTICAL ANALYSES The parallel studies; EchoProtecT-2D and CT-ProtecT-2D, address seperate scientific hypotheses and are evaluated independently within the overall Echo-CT-ProtecT-2D framework. Each study has a separate prespecified primary hypothesis, primary endpoint, and sample size calculation.

EchoProtecT-2D - Cardiac Function and Heart Failure Phenotyping Study Sample size estimation is based on the primary echocardiographic endpoint, E/e'. To detect a clinically relevant between-group difference of 15% in E/e' with 80% statistical power, a two-sided significance level of 0.05, and a 2:1 allocation ratio, a minimum of 111 evaluable participants is required.

Allowing for 10-15% of participants being non-evaluable due to dropout and/or insufficient echocardiographic image quality, and assuming an HFpEF prevalence of approximately 35%, approximately 375 participants will be included, thereby ensuring a sufficient number of evaluable participants for the prespecified HFpEF analysis.

The primary endpoint is the between-group difference in change in resting E/e' from baseline to 12 months.

CT-ProtecT-2D - Coronary Inflammation and Atherosclerosis Study

Sample size estimation is based on the primary CT-derived endpoint, global mean pericoronary adipose tissue (PCAT) attenuation. To detect a clinically relevant between-group difference of 7% in global mean PCAT attenuation with 90% statistical power, a two-sided significance level of 0.05, and a 2:1 allocation ratio, a total of 141 evaluable participants is required.

The primary endpoint is the between-group difference in change in global mean PCAT attenuation from baseline to 12 months.

Further Statistical Considerations The two primary hypotheses will be analyzed and interpreted independently, and conclusions regarding one study will not depend on the results of the other.

Secondary outcomes encompass both key secondary outcomes addressing the principal prespecified hypotheses and exploratory secondary outcomes providing additional mechanistic and phenotypic characterization.

Detailed statistical methods, including the hierarchy and statistical treatment of secondary outcomes, model specification, handling of missing data, multiplicity within each study, subgroup and interaction analyses, and sensitivity analyses, will be prespecified in a Statistical Analysis Plan (SAP) finalized prior to outcome analyses.