Multifactorial Treatment of Cardiovascular Risk in Diabetic Patients: Identification of Treatment Non-Responders
Condition: Diabetes Mellitus, Type II
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Observational

Summary: 
      The aim of the study is to develop a model that allows early identification of type-2
      diabetic patients who will face progressive atherosclerosis despite intensive,
      multifactorial, target oriented treatment
    

Detailed description: 
      Background: Patients with type-2 diabetes face a substantially elevated risk for
      cardiovascular and cerebrovascular disease. This risk is based on traditional and
      non-traditional cardiovascular risk factors. It is, thus, partially mediated by modifiable
      conditions for instance blood pressure, cholesterol, or hyperglycemia. Indeed, controlled
      prospective intervention studies highlighted that individual lowering of those risk factors
      resulted in a reduction of vascular events such as acute coronary syndromes or stroke. The
      STENO-2 trial convincingly proved that multifactorial risk intervention, targeting all those
      risk factors substantially slowed the progression of atherosclerosis. As a result an even
      greater than 50 % reduction of vascular risk in patients with type-2 diabetes was observed.
      Thus, state of the art treatment for type-2 diabetic patients is multifactorial risk
      intervention targeting glucose control, lipids, blood pressure, platelets and the
      rennin-angiotensin-system.

      Rationale: Risk normalisation for type-2 diabetic patients was not reached in the STENO-2
      trial. In addition, it is, up to now, not possible to predict at early treatment stages who
      was to suffer progressive atherosclerosis and a future event despite intensive treatment of
      risk factors. Such early identification of treatment non-responders could enable to further
      intensify treatment or to develop new treatment strategies.

      Aim: To develop a model that allows early identification of type-2 diabetic patients who will
      face progressive atherosclerosis despite intensive, multifactorial, target oriented
      treatment.

      Experimental approach: To pursue the above mentioned aim, it will be investigated if, in
      patients with an indication to multifactorial risk intervention, either baseline
      characteristics or treatment responses after 3 months of intensified, multifactorial risk
      intervention can be used to predict progressive atherosclerosis during the study period of 2
      years. To construct the model, traditional and non-traditional vascular risk factors will be
      evaluated.

      Traditional vascular risk factors:

      Traditional vascular risk factors may be grouped according to whether they may be modified or
      not. The major modifiable risk factors are hypertension, lipids, and hyperglycemia. All of
      them can be treated by lifestyle modification and pharmacologically. Smoking behaviour,
      sedentary lifestyle, nutrition and weight on the other hand may be influenced by lifestyle
      advice. Classic risk models such as the Framingham algorithm or the Prospective
      Cardiovascular Munster Study (PROCAM) model are based on traditional risk factors for risk
      estimation. They are, however, of limited applicability for diabetic patients due to the
      small number of such patients included and the lack of diabetes-specific variables in the
      model. From UK Prospective Diabetes Study (UKPDS) data a risk model for type-2 diabetes has
      been developed that describes future vascular risk based on such traditional risk factors
      including glycemic control and duration of diabetes. It is the only risk engine developed for
      a diabetic population. This model, however, does not take into account lipid lowering
      treatment in general, nor treatment responses to intensified intervention, nor novel vascular
      risk factors.

      Novel, non-traditional vascular risk factors:

      Endothelial dysfunction as well as inflammatory activity, reduced endothelial progenitor
      cells, and increased endothelial microparticles can be seen as more integral vascular risk
      factors or indicators, representing the combined influence of different traditional risk
      factors as well as specific vascular susceptibility. As such, they have been shown to be
      influenced by hyperglycemia, blood pressure or cholesterol. Specific treatment of those risk
      factors results in improvement of endothelial dysfunction, reduction of inflammatory
      activity, and increased number of endothelial progenitor cells.

      Very recently, data from the Hoorn-study indicated that indeed about 43% of the excess
      vascular risk observed in diabetic patients is based on endothelial dysfunction and
      inflammatory activity. These data further point to the importance of non-traditional risk
      factors in the development of atherosclerosis and vascular events.

      Progression of carotid artery intima media thickness (IMT) as a vascular endpoint:

      The intima-media-thickness of the carotid arteries (IMT) is closely related to
      atherosclerotic burden in the coronary arteries and the risk for acute vascular events. It
      progressively increases over time, driven by age and cardiovascular risk factors. A high
      progression rate of IMT is indicative for future vascular events and treatment of risk
      factors reduces progression of IMT. Consequently, progression of IMT is a highly valid
      surrogate endpoint for progression of atherosclerosis and future vascular events.

      Risk factors tested: Traditional risk factors:

      Age, Gender, smoking behaviour, family history for coronary artery disease (CAD) or stroke,
      physical activity, lipids (total cholesterol, LDL-C, HDL-C, Triglycerides (TG), ApoA1,
      Apolipoprotein B (ApoB), Apo(a)), office blood pressure, serum creatinine, albuminuria, left
      ventricular hypertrophy (ECG)

      Diabetes specific risk factors:

      Duration of diabetes, HbA1c, fasting insulin, fasting proinsulin, fasting glycemia,
      Homeostasis Model Assessment (HOMA), glucose tolerance, BMI, waist circumference

      Non-traditional risk factors:

      Carotid artery IMT, prevalence and extend of carotid plaque, pulse wave velocity, vascular
      stiffness, ankle-brachial-index, endothelial function, inflammatory activity (both according
      to the Hoorn Study methods), endothelial progenitor cells, endothelial microparticles,
      plasminogen-activator-inhibitor-1 (PAI-1), tissue factor (TF).

      Indication for multifactorial risk intervention: Based on the present knowledge type-2
      diabetic patients are high risk subjects for the development of vascular disease and events.
      The excess risk, depending on the population studied is in the range of 2-6 fold. For that
      reason, every patient with type-2 diabetes per se has an indication for multifactorial risk
      intervention.

      Intervention: Target oriented treatment of risk factors according to current treatment
      guidelines. Pharmacological therapy will be either newly installed or changed according the
      outline below.

      All patients will receive comprehensive lifestyle counseling, personalized nutrition, and
      exercise advice.

      After 3 months all modifiable or potentially variable risk factors will be evaluated again.

      18 months after inclusion into the study carotid artery IMT will be measured again.

      Outcome variables: The progression of IMT from baseline to 18 months will be the primary
      (dependent) outcome variable for the development of the model.

      Modeling process: All risk factor variables to be tested for the model will be tested in
      univariate regression analyses with the progression of IMT as dependent variable. All
      variables with a p value below 0.200 will further be included into a multivariate regression
      analysis using a stepwise inclusion process.

      Potential benefit: Early identification of type-2 diabetic patients who, despite intensified
      multifactorial risk intervention, face progressive atherosclerosis. Such patients, as a
      consequence could receive more individualized treatment by means of even more intensive
      intervention or application of different treatment strategies. As a result improved
      prevention of vascular events in type-2 diabetic patients could be finally reached.
    

Intervention name(s): Intensified Treatment of risk factors
Intervention type(s): Other
Intervention description(s): Patients received a target oriented, intensified treatment of risk factors according to current national treatment guidelines
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        120 Type-2 diabetic patients with no history of vascular events and need for therapy
        intensification.
      
Biospecimen description: 
      plasma, serum
    
Keywords: diabetes mellitus type II, therapy non-responders