Short summary

The concept of the trial individually tailored treatment of type 2 diabetic patients is to improve diabetic regulation and reduce complications and at the same time reduce side-effects and polypharmacy, thereby improving patient compliance and quality of life in a cost-effective manor.

This new concept for treatment of T2D consist of three inter-supportive elements: 1) Individualized antidiabetic and antihypertensive treatment based on suspected pathophysiology for T2D and hemodynamic status in each patient, respectively. 2) General practitioner (GP) centred treatment supervised by specialists in T2D and hypertension using latest techniques for individual patient phenotyping. 3) Patient empowerment using modern technology (internet, mobile phones and apps) to engage patients in improving their lifestyle on their own terms.

Rationale

During the last decades improved treatment of type 2 diabetes mellitus (T2D) has postponed macro- and especially microvascular complications, but morbidity and mortality is still high in T2D. Recent traditional add-on-trials has failed to reduce this, possibly due to large variations in individual treatment responses, which are not handled on an individual level, undermining the patients trust in the doctor and decreasing treatment adherence.

Therefore, we propose a new concept for treatment of T2D consisting of three inter-supportive elements: 1) Individualized antidiabetic and antihypertensive treatment based on suspected pathophysiology for T2D and hemodynamic status in each patient, respectively. 2) General practitioner (GP) centred treatment supervised by specialists in T2D and hypertension using latest techniques for individual patient phenotyping. 3) Patient empowerment using modern technology (internet, mobile phones and apps) to engage patients in improving their lifestyle on their own terms.

Today, patients with T2D are treated according to algorithms based on the "treat-to-target" approach and polypharmacy, as described in the general clinical guidelines of T2D. The results obtained with polypharmacy and the "treat-to-target" approach aiming at near-normalization of HbA1c (often under 47.6 mmol/mol) ) have failed, as shown in three recent studies: The ACCORD, VADT and ADVANCE studies. The concept has been a uniform treatment strategy and goal setting, irrespective of concomitant illness and diabetic traits. Further the "treat-to-target" approach, often resulting in polypharmacy, has been shown to result in low patient compliance.

Older studies had less restrictive goals of the anti-diabetic treatment. The UKPDS showed that more intensive initial control of newly diagnosed T2D, in comparison with lifestyle intervention alone, did reduce complications, both micro- and macrovascular. The effect was more pronounced 10 years after intervention had cessed, where HbA1c levels had become identical, indicating that initial control is important.

Later trials, as ACCORD and ADVANCE, have tried to establish if further reduction in blood glucose is beneficial. Data after termination of intervention is available, but long-term follow up is not. Target HbA1c in these trials was 48.6 and 47.5 mmol/mol after intensive intervention, compared to 56.3 and 57.4 mmol/mol in the control groups, respectively. ACCORD showed an increased all-cause mortality following intensive intervention and this trend persisted also after treatment was eased in the intensive group. Even though target HbA1c does not differ in the 2 trials only the ADVANCE trial showed a significant reduction in a composite endpoint of micro- and macrovascular events. Evaluation of micro- and macrovascular endpoints independently did not show significant differences in either of the studies.

Initial HbA1c was different in the two trials - 67.2 vs. 58.5 mmol/mol in ACCORD and ADVANCE respectively. Post-hoc analysis of the incidents of hypoglycaemia in the ACCORD study has suggested that high initial level of HbA1c was associated with increased risk of hypoglycaemia and that those with the least decline in HbA1c during the study also had the highest risk of hypoglycaemia. This indicates that poor responders to treatment are at increased risk of hypoglycaemia, especially in a context where the treatment is being intensified! Post-hoc analysis of subgroup effect on mortality has identified baseline HbA1c above 69.4 mmol/mol, aspirin and neuropathy as significant determinants of the increased mortality in the intensive vs. the control group. Insulin treatment or anti-hypertensive drugs did not have an effect on the increased mortality seen.

The discrepancy between the ACCORD study and ADVANCE in outcome could, in light of the post-hoc analysis, be hypothesized to be, in part, linked to the difference in baseline HbA1c.

A meta-analysis found no effect of intensive hyperglycaemic treatment on over-all or cardiovascular death, and the authors speculated that the effect on myocardial infarction and microalbuminuria might be counterbalanced by an increased risk of hypoglycaemia

The participants in all the mentioned trials have not been randomly chosen from the T2D population, but a set of inclusion and exclusion criteria has been applied. Some trials excluding and other including patient with complications. The design also had different features; comparing fixed drug formulations to placebo or diet, where other trials have had wide restrictions on the drugs used. This implies that treatment strategies need to be evaluated in real world with no or limited inclusion and exclusion criteria.

Our concept is that T2D is a heterogeneous disease affecting patients of all ages and patients with several confounding diseases especially hypertension. We believe that the T2D population can be categorized into distinct subgroups requiring specific therapy. Therefore, we have developed an interim trial, as part of the DD2 project, comparing individually tailored treatment with the current "treat-to-target" approach.

The concept of individually tailored treatment described above will improve diabetic regulation and complications and at the same time reduce side-effects and reduce polypharmacy, thereby improving patient compliance and quality of life in a cost-effective manor.

The primary endpoint is the incidence of a composite of micro- and macro-vascular events, cancer, hospitalization for hypoglycaemia and over-all death over a 10 year period. Secondary endpoints are the reduction in number of pharmacological agents used, improvement in quality of life and cost effectiveness. Furthermore, we will investigate the association at baseline and over time between metabolic and hemodynamic phenotypes and subclinical cardiovascular damage

Description of the cohort

Inclusion criteria:

The participation in the DD2-project is a mandatory condition for both GP clinics and patients prior to participating in this ITT trial. Thus, patient must have type 2 diabetes diagnosed after 1.1.2009. and the GP clinic need to sign up for both DD2 and ITT. Prior final enrolment in this trial patient also needs, following thorough information, to give a signed written informed consent.

The exclusion criteria for this trial are defined as:

• Type 1 diabetes. If patients at baseline investigations have age<30 years AND C-peptid<300pmol/l AND GAD-ab titer> 20 IU/ml they are also considered as having type 1 diabetes.
• Life expectancy below 2 years
• Participation in any other clinical trial
• Women who are or plan to become pregnant within 1 year after examination judged on questions during the detailed trial information. If pregnancy occurs or is planned after inclusion the patient should not be excluded but treated according to national guidelines during pregnancy and lactation.

Data and biological material

An extensive collection of data, blood and urine samples is performed in the trial. For a detailed description please look at the updated protocol at the project website www.dd2.nu

In brief data sampling is conducted at baseline and after 2, 4 and 10 years of follow-up and in the in between periods by sub-sequent data-linking to the national healthcare registers and databases. At all patient will under go extensive non-invasive examinations. The measurements will include:

• Automated office blood pressure
• Questions on cardiovascular hereditary, former gestational diabetes or pancreatitis and prednisolon treatment within the last 3 month of debut. (baseline only)
• Thoracic impedans measurements
• Adverse events
• Waist to hip ratio (2 and 4 years only)
• Medication (aided by data from the Danish Diabetes Database (DDD))
• Medical history at baseline (aided by data from LPR)
• A blood and a spot urine sample is taken after 24 hours pause of long-acting anti-diabetics if possible.
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The following examinations will be done in a subset of patients where a separate informed consent is obtained at the phenotype evaluation visit. Visits will be scheduled by default at year 0, 2 and 4.

• Home based or ambulatory 24 hours blood pressure
• Retinal photo
• ECG for assessment of ventricular hypertrophy
• Intima media thickness of the carotid artery along with assessment of plaque presence
• Measurement of calcification of the coronary, aortic, iliac and femoral arteries by CT
• Blood borne and urine markers of cardiovascular disease

Prior the screening the written informed content is signed. This will enable the trial to retrieve personalised data via the registers for use in the treatment.

Collaborating researchers and departments

Department of Endocrinology, Odense University Hospital

Department of Endocrinology, Hospital of South West Denmark, Esbjerg

Department of Nuclear Medicine, Odense University Hospital

Department of Medicine, Endokrinology, Holbæk Hospital Næstved

Lægecenter, Omøvej 7, Næstved