Individually Tailored Treatment of Type 2 Diabetes (ITT)

The design is a prospective controlled open-label multicenter intervention study. General practitioners in region of southern Denmark are responsible for the treatment, while central visits for additional data sampling are located at Odense University hospital, Holbaek Hospital, Naestved Hospital, and hospital of south west Denmark, Esbjerg.

The inclusion phase will run for 2 years. The follow-up phase is 10 years from inclusion.

Registries will be employed in both the characterization of patients and in the sampling of end-points. Concomitant medication will be sampled from the National Prescription Database. Concomitant illness and identification of endpoints will be sampled from the Registry of Patients, Registry on Cause of Death, the Danish Registry on Regular Dialysis and transplantation, the Danish general practice database, The National Indicator project, Statistics Denmark, The National Indicator Project, The Danish Cancer Registry, the DD2-database and local databases.

Treatment The control group will be treated according to national guidelines. The intervention group will be treated according to individual assessment. Several approaches will be employed to achieve individualization.

• Identification of pathophysiological traits in order to chose the correct medication targeting hyperglycaemia. Identification of pathophysiological traits, through genetic testing, GAD antibodies and C-peptid level, will individualize the treatment of hyperglycaemia according to the following groups: MODY (maturity onset diabetes of the young), LADA (latent autoimmune diabetes of adults), steroid-induced diabetes, insulinopenic diabetes, secondary diabetes and patients with insulin resistance. Specific treatment algorithms will be applied in each group.
• Individualized targets for all patients with regard to hyperglycaemia. The target will be chosen on the basis of age, motivation, skills, risk of hypoglycaemic events, therapy resistance, initial hba1c and concomitant illness. As these factors change the target can be adjusted accordingly.
• Hemodynamic characterization by impedance cardiography will be used in order to individualize anti-hypertensive medication.
• Individualized targets for all patients with regard to hypertension. The target will be chosen on the basis of concomitant risk factors.

Further individualization will be achieved by discontinuing drugs which have not proven to be effective within a three-month period or have proven to have side-effects.

Treatment algorithms for the intervention group.

Hyperglycemia

• MODY (characterized by genetic test): Glimepiride or repaglinide for type 1 and 3. 1) diet, 2) basal insulin for type 2. Basal insulin for type 5
• LADA (GAD positive> 30UI/ml): basal bolus insulin-regime. Metformin if BMI > 25
• Secondary diabetes (HOMA-beta < 78.45 % AND history of pancreatitis or similar): basal bolus insulin regime
• Steroid induced diabetes: 1) meal time insulin 2) metformin 3) basal insulin if fasting blood glucose is above 7
• Insulinopenic type 2 diabetes (HOMA2-beta<78.45 % AND HOMA2-S>105.5%): 1) metformin 2) insulin, basal 3) meal time insulin
• Classical type 2 diabetes (HOMA2-beta<78.45% AND HOMA2-S<105.5%): 1) metformin 2) GLP-1 analogues* 3) basal insulin 4) meal time insulin.
• Hyperinsulinemic type 2 diabetes (HOMA2-beta>78.45% AND HOMA2-S<105.5%)

In patients with BMI>35 kg/m2 both gastric bypass and pharmacological treatment can be considered equally. In patients with BMI<35 kg/m2 only pharmacological treatment is an option:

1. In patients with BMI>35 kg/m2 gastric bypass should be considered according to the current national criteria and the preference of the patient.
2. 1) metformin 2) GLP-1 analogues* 3) Glitazones (pioglitazone is currently registered) 4) insulin, basal 5) meal time insulin If marked oedema develops in relation to institution of glitazones the treatment should be terminated. If patients have osteoporosis, glitazones should generally not be used.

If patients have heart failure glitazones should not be used.

*In cases were patients are reluctant to inject themselves or have economical objections, DD4-inhibitors can be chosen.

Premixed insulins can be used instead of basal insulin or instead of basal insulin+mealtime insulin whenever deemed relevant by the treating physician

Hypertension Hemodynamic characterization by impedance cardiography will be used in order to individualize anti-hypertensive medication. By impedance measures of vascular resistance, intravascular volemia and inotropy will be obtained.

All patients will be treated with ACE inhibitors. Secondary medication will in general be achieved by the following algorithm:

High vascular resistance:

1. Use ACE-inhibitor or add a calcium-channel blocker (CCB) to an existing ACE-inhibitor.
2. In case the resistance are increased by more than 100% and neither ACE-inhibitor or CCB is given, consecutive add both according to blood pressure. If hypervolemia is present address this before CCB is introduced.
3. If intravascular volume is normal and blood pressure is high after ACE-inhibitor; use CCB - also when resistance is normal

High intravascular volume:

1) Use hydrochlorthiazide 12.5mg combined with ACE inhibitor in one pill if possible. Else use bendroflumethiazide 2.5mg. If the patient is already receiving diuretics, spironolactone is used. Start with 25mg, maximum dose is 50mg. If kalium is above 4.3 or impaired kidney function is present start with 12.5mg. Control of kalium is paramount.

High inotropy

1) High inotropy might change with the institution of other drugs. Introduce CCB first and secondly thiazide if the patient is normovolemic. In reverse order if the patient is hypervolemic and with normal vascular resistance. Therefore high inotropy should only be treated with carvedilol if 1) the patient is receiving ACE inhibitor, thiazide and CCB and the impedance measure of high inotropy is made after ACE-inhibitor, thiazide and CCB is started.

Lifestyle A dietician will be employed to make written material regarding the diet. A Cookbook will be made available online, together with accompanying grocery lists. The diet will be done according to a composition of 20% protein, 40% fat and 40% carbohydrate to improve glycemic control. The extra percentage of fat, compared to current recommendations should come from polyunsaturated fat.

To facilitate exercise an accelerometer will be handed out and an individual goal of exercise will be set. A novel interface of the accelerometer will be used to monitor the exercise done and thereby enable the patient and the physician to evaluate the effort. Interval walking will be the general focus of the exercise guidance, if the patient does not have other individual exercise preferences. Individual goals of the exercise effort will be set and software will modify the goals according to current fitness.

Goal setting in the intervention group Treatment of hyperglycaemia should be made according to the following goals

• Optimal control of HbA1c < 6.5 % (48 mmol/mol)
• Acceptable control of hba1c < 7.5 % (58 mmol/mol)
• Free of symptoms, with the best possible Hb1ac within this restraint

The general practitioner is free to choose which goal is applicable, according to the above mentioned criteria. In patients with neuropathy or former cardiovascular disease extra vigilance should be taken if optimal control is chosen. If the patient develops a severe hypoglycaemic event, repeated measures of blood glucose below 4.0 mmol/l or is therapy resistant, the goal should be reassessed.

Treatment of hypertension should be made according to the following goals

1. BT < 135/85 in patients with microalbuminuria, increased creatinine or established cardiovascular disease
2. BT < 140/90 in patients without complications

First visit at primary physician In the control group this will be scheduled as deemed necessary by the physician In the intervention group this should be scheduled to be located after the baseline visit at the central hospital, in order to achieve collection of all relevant data for individualization.

Periodic visits at primary physician These are to take place every 3 month. At these visits treatment will be instituted according to the specified algorithms. If the goals are not met, intervals of 1 month are recommended in the intervention group.

Once a year the following will be collected for the study:

• Smoking habits, blood pressure, cholesterol levels, weight, HbA1c, Urine albumin-creatinine ratio, creatinine Visits for measurements of organ damage The initial visit will be scheduled within 4 weeks of the screening visit. Longitudinal measurements will be done after 2 and 4 years. The measurements will include
• 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 arteries by heart CT (only year 0 and 4)
• Blood borne and urine markers of cardiovascular disease
• Automated office blood pressure (used to direct treatment)
• Ambulatory 24 hours blood pressure
• Questionnaire on quality of life, (at baseline: cardiovascular hereditary, former gestational diabetes or pancreatitis and prednisolon treatment within the last 3 month of debut)
• Thoracic impedans measurements
• Adverse events (side effects)
• medication
• Waist to hip ratio
• Fundus photo

These visits will be organized centrally. In a subset of patient echocardiography and pulse wave velocity will be performed.

Visits for measurements of thoracic impedans The measurement will be done after 0, 2, 4 (also after 1 year in the intervention group) years throughout the follow-up period and will be organized centrally.

Time schedule Oct 2013: Inclusion of patients Oct 2015: inclusion ends Oct 2019: analysis of surrogate markers of cardiovascular disease Oct 2025: sampling and analysis of endpoints

Cooperation between primary care and project coordinators Daily management and coordination will be handled by investigators at the 3 central hospitals. Data-sampling at central visits will be their responsibility. The central investigators will have an advisory role in the treatment of the patient. Initial pathophysiological characterization will be managed centrally and the results will be forwarded to the primary physician. The coordinating investigator will be responsible for gathering of data from registries.

The daily treatment of the patients will be managed by the primary physician according to the algorithms. Recruitment will also be done by the primary physician. Serious adverse events will be reported centrally by the GP.

TAP will be employed to do conduct the investigations at the central visits.

Concomitant illness and identification of endpoints will be sampled from the Registry of Patients, Registry on Cause of Death, the Danish Registry on Regular Dialysis and transplantation, The Danish general practice database, The National Indicator project, The Danish Cancer Registry, the DD2-database and local databases at time of analysis.

Concomitant illness will be established at the baseline visit through patient interview, aided by records from the Registry of Patients.

Endpoints will also be sampled real time as part of the sampling of SAEs.

Statistical considerations An incident rate of 2.5% per year of macro- and microvascular complications, of 1.5% for cancer and approximate 1% of over-all mortality is expected. Hypoglycaemic event rate is expected to be less than 0.4%. The expected incident rate of the composite endpoint is 5%, a power of 80% and a type I error of 0.05. A benefit of 20% with intervention is expected. Loss to follow-up: the database approach will limit this to a minimum. For a cumulated event rate of 5% during 10 years the estimated sample size is 1123 patients per group.

Ethical considerations The patient physical and mental integrity will be safeguarded. The participants will be protected by the law on personal data and the Danish health legislation act. The study will be conducted in compliance with the principles set forth in the declaration of Helsinki and the guidelines for god clinical practise (GCP). The Study will be conducted in compliance with this protocol as well as according to national legislation. The study will be approved by the regional committee on medical health ethics, the Danish data protection agency and the Danish Health and Medicines Authority. The study will be submitted at ClinicalTrial.gov.