Addition of Liraglutide to Patients With Type 2 Diabetes Treated With Multiple Daily Insulin Injections
Addition of Liraglutide to Patients With Type 2 Diabetes Treated With Multiple Daily Insulin Injections
Liraglutide, a GLP-1-analogue has been shown to be an effective treatment option in patients
 on oral anti-diabetes therapy with beneficial effects on both glycaemic control and weight.
 However, to date there are no clinical trials of liraglutide added to insulin therapy, a
 population of patients generally having worse glycaemic control and weight gain. In clinical
 guidelines, use of multiple daily insulin injections (MDI) is usually the final therapeutic
 option for type 2 diabetic patients.

 The primary study aim is to evaluate whether the addition of liraglutide, compared to
 placebo, reduces the HbA1c level for overweight and obese type 2 diabetes patients with
 inadequate glycaemic control treated with multiple daily insulin injections (MDI). MDI is
 defined as treatment with any basal insulin combined with separate meal time insulin
 injections before the main meals, i.e. an insulin regimen with premixed insulin is not
 considered as MDI.

 The planned study duration is 24 weeks and includes 120 patients at 15 centers in Sweden.
Background

 Patients with type 2 diabetes are generally treated with metformin and diet as first-line
 therapy (1). In Sweden sulphonylureas are generally recommended as the next treatment option
 due to their low cost and evidence for reducing diabetes complications (2). The next line of
 therapy includes adding basal or premixed insulin. As a final step multiple daily insulin
 injections with basal and prandial insulin have become the standard if glycaemic control does
 not meet targets. Obesity is another co-morbid condition in this population (3). The United
 Kingdom Prospective Diabetes Study (UKPDS) published 1998, the seminal trial demonstrating
 the importance of glycaemic control in type 2 diabetes, illustrated that insulin therapy
 (mostly basal insulin alone) is accompanied by significant weight gain in patients with type
 2 diabetes (4). MDI generally results in even greater weight gain. Today there are few
 treatment options in patients with type 2 diabetes on MDI with poor glycaemic control.

 In patients with basal, intermediate or premixed insulin, addition of sitagliptin has shown
 further reduction in HbA1c of 0.6 percentage units (6 mmol/mol) with no change in weight (5).
 However, the effect in patients with the most severe disease, namely those requiring MDI, was
 not evaluated. In combination with metformin or sulphonylurea, adding the GLP-1-analogue
 liraglutide, compared with adding sitagliptin, has shown greater reductions in HbA1c and
 significant weight reductions (6). In an uncontrolled study in clinical practice, the
 addition of exanatide (n=22) or liraglutide (n=43) to patients on insulin therapy, the
 majority using MDI, was associated with a mean reduction in HbA1c by 1.0 percentage units (10
 mmol/mol), reduction in weight of 7.1 kg and, simultaneously, a mean reduction in insulin
 dose by 37 units (7). At baseline patients were generally obese (mean BMI 36kg/m2), had poor
 glycaemic control, mean HbA1c of 8.9% (74 mmol/mol) and insulin doses of 92 units. The number
 of hypoglycaemic events was low, treatment satisfaction was high and patients rated
 hypoglycaemic episodes to be fewer than with insulin therapy alone. From these results it
 seems that there may be a beneficial effect associated with liraglutide when added to type 2
 diabetic patients on MDI; however, this requires confirmation in a randomised clinical trial.
 This question is of particular concern since currently there are no treatment options for
 reducing weight and insulin doses while simultaneously improving glycaemic control for this
 patient group having most advanced disease. Further, many clinicians today use a therapeutic
 strategy consisting of MDI as a final treatment option, but many patients do still not reach
 target HbA1c and some even continue to have very poor glycaemic control (7). Therefore, the
 aim of this study is to study the effect on HbA1c when adding liraglutide to MDI in
 overweight and obese patients with impaired glycaemic control.

 The proposed study is a randomised double-blind trial for 24 weeks including patients with
 type 2 diabetes and poor glycaemic control despite being treated with MDI for at least 6
 months.

 The aim is to study the effect on HbA1c when adding liraglutide to MDI in overweight or obese
 patients with impaired glycaemic control.

 Study drug preparation

 Novo Nordisk will provide study medication and treatment codes. Apoteket AB, Sweden, will
 handle study treatment logistics.

 Site monitoring

 Gothia Forum, Gothenburg, Sweden

 Data management

 Gothia Forum will provide the eCRF system to be used in the study. Data Management (including
 the randomisation system) and statistical analysis will be performed by Statistiska
 Konsultgruppen, Gothenburg, Sweden.

 Lab and continuous glucose monitoring

 All laboratory tests will be measured at the Research Centre for Laboratory Medicine at
 Karolinska University Hospital, Stockholm, Sweden.

 The DexCom G4 CGM device will be used for 21 days (7 days during the run-in period, 7 days
 during week 12 ± 7 days and 7 days during the last 2 weeks of the trial) for blinded
 monitoring of glucose values.

 Risk-benefit assessment

 Previously published observations from clinical practice (7) have shown that patients treated
 with multiple daily insulin injections (MDI) with concomitant addition of liraglutide
 (off-label) decreases the HbA1c by approximately 10 mmol/mo (1 percentage unit), reduces the
 weight by 7 kg and decreases the insulin dose with 37 units (7). These patients were prior to
 treatment overweight (BMI around 36), had HbA1c on average 74 mmol /mol and insulin doses
 were at 92 units. Patients also rated hypoglycaemias to be fewer when insulin was combined
 with liraglutide than when used alone. In general, patients reported an improved quality of
 life.

 There is always a risk of hypoglycaemia during insulin therapy irrespective of any additional
 glucose-lowering therapy. However, previous findings from clinical practice (7) and that the
 effect of GLP-1 on insulin release is only observed under hyperglycaemic conditions (8)
 indicate that liraglutide does probably not lead to major increased risks of hypoglycaemias.
 Since, liraglutide has been associated with a reduction in body weight in previous clinical
 trials (8) it is likely that such an effect exists also in individuals treated with insulin.

 In summary, the risk of side effects or adverse reactions with the combination of insulin and
 liraglutide is probably small in relation to the improved hyperglycaemic control and weight
 reduction that may exist when adding liraglutide in type 2 diabetic patients with basal and
 prandial insulin.

 Rational

 Multiple daily insulin injections (MDI) are regarded as the most advanced treatment regimen
 in patients with type 2 diabetes. At study start all patients have been treated with MDI for
 at least 6 months but are still suffering from poor glycaemic control. The patients included
 are also overweight or obese. It is therefore of importance to evaluate whether this patient
 group have a beneficial effect, on the glycaemic control and weight reduction, by adding
 liraglutide, since liraglutide has shown such beneficial effects in combination with oral
 glucose lowering drugs.

 Moreover, beneficial effects by liraglutide have been observed when used off-label in
 combination with insulin in clinical practice (7).

 Design

 This is a double-blind, placebo-controlled clinical trial with parallel-group design. The
 study involves 120 patients at 15 health centres in Sweden and includes 10 visits over 26
 weeks.

 Treatments

 The study drug will be liraglutide which includes 3 different dosages: 0.6 mg, 1.2 mg and 1.8
 mg. Liraglutide will be titrated to 1.8 mg by increasing the dose every week. Since subjects
 will have inappropriate glycaemic control (greater than or equal to 7.5%=58 mmol/mol HbA1c)
 no general reduction in insulin doses will be made, but if glucose curves during the run-in
 period show clearly lower mean glucose levels than those corresponding to HbA1c 7.5%=58
 mmol/mol or are well-controlled before certain meals, insulin adjustments will temporarily be
 considered during the titration phase of liraglutide/placebo.

 Liraglutide will be available at a concentration of 6.0 mg/ml and supplied in a 3 ml
 disposable pen-injector. Placebo is supplied in an identical disposable pen-injector.

 Randomization

 After a run-in period of maximally 60 days, patients will be randomised to receive either 0.6
 mg liraglutide or 0.6 mg placebo. Novo Nordisk will provide (coded) medication pens and the
 associated code-list. No study personnel other than a designated data manager responsible for
 setting-up randomisation will have access to the complete code-list until the study blind is
 broken. Apoteket AB/farmaci will handle study treatment logistics.

 Minimisation (optimal allocation) using a centralised web system (handled by Statistiska
 Konsultgruppen) will be used for randomisation. At randomisation each subject will be
 assigned a randomisation code that (blindly) represents the treatment (liraglutide or
 placebo) that the patient is randomised to. The patient will also be assigned a unique and
 anonymous Subject ID.

 Breaking blind

 The study is double-blinded. The randomisation codes will not be broken until last subject's
 last visit and when all study data are collected, the study database is cleaned and declared
 locked. Apoteket AB/farmaci will be responsible for keeping the complete randomisation list.

 The code for a particular subject may be broken in a medical emergency situation.
 Apoteket/farmaci is equipped with 24 hour emergency telephone service in case of need for
 breaking blind in an individual patient.

 Telephone number:

 Weekdays 08.30-16.00: 040-33 26 74. Any other time: 040-331000 - ask for emergency telephone
 service.

 The subject should be withdrawn from the study in case of a code break but be included in the
 safety population in the statistical analyses.

 Duration

 The expected duration of subject participation is approximately 32 weeks (maximally 60 days
 run-in, and 24 weeks follow-up after randomisation).

 Study population

 The study will include 120 patients at 15 centres in Sweden. Patients requiring MDI and who
 are on no other diabetes drugs except metformin will be recruited and included in the study
 after receiving oral and written information about the study and given informed consent and
 fulfilling all the inclusion criteria and none of the exclusion criteria. The study
 population will be identified among diabetic outpatient clinics at hospitals and will be
 recruited on a community-wide basis and in communication with primary care physicians.

 The written information will include objects and purpose of the study, risks and benefits,
 and a detailed description of the events during the study. The patient will have the
 opportunity to ask additional questions at the first clinic visit The patients will be
 randomised 1:1 to liraglutide or placebo Randomisation codes will be assigned strictly
 sequentially as subjects are eligible for randomisation. If a subject discontinues
 participation in the study, his/her enrolment/subject number cannot be reused. Drop-outs
 (expected to be ~5%) will not be replaced.

 Study Stop Criteria

 The Sponsor/Investigator may decide to stop the trial or part of the trial at any time for
 medical reasons. Furthermore, the manufacturers of the study drugs may revoke their products,
 which may lead to the entire study may be interrupted.

 If a trial is prematurely terminated or suspended, the Investigator should promptly inform
 the patients and ensure appropriate therapy and follow-up. Furthermore, the Investigator
 should promptly inform the Ethics committee and provide a detailed written explanation. The
 regulatory authority should be informed according to national regulations.

 Drop-outs

 Patients who drop-out from the study or receive rescue therapy shall be requested for
 follow-up on an additional visit. HbA1c, FPG, C-peptide, pro-insulin, amylase, lipase, liver
 transaminases, creatinine, calcitonin, fasting blood lipids, adiponectin, sensitive CRP,
 apolipoproteins, weight, blood pressure, insulin dose, waist-hip ratio, abdominal sagittal
 diameter, concomitant medications and treatment satisfaction shall be checked. Blood samples
 for biobank will be taken. Insulin doses and other medications recorded. If drop-out exists
 the reason shall be recorded. Regarding rescue therapy the variables above shall be checked
 if possible before rescue therapy is given.

 Investigational product and treatment of subjects

 The trial product will be dispensed to each subject as required according to treatment group.
 The centralized web randomisation system will allocate trial product Dispensing Unit Number
 (DUN) to the subject at the randomisation visit. The correct DUN must be dispensed to the
 subject.

 The Investigator must ensure availability of proper storage conditions and record and
 evaluate the temperature (at least every working day). Storage facilities should be checked
 frequently. A log to document the temperature must be kept.

 The study is planned for 24 weeks and in addition a run-in period of maximally 60 days.
 Capillary glucose values will be measured before each meal and 1.5-2 hours after meals at 2
 days during the 60-day run-in period, 2 days per week during the first 3 weeks of the trial
 and 2 days during the last 2 weeks of the trial. Capillary glucose curves performed during
 the run-in period and the last two weeks of the study will always be measured after the week
 with CGM to not disturb the interpretation of CGM data. The Contour XT SMBG meter (Bayer)
 shall be used for capillary glucose measurements during the study. The SMBG meter shall be
 checked at eash visit before initiating CGM, i.e. during the run-in period, week 12 (+- 7
 days) and week 23-24. Calibration will be performed according to the manufacturer's
 standards. The SMBG meter shall be introduced at visit 4. During 7 days of the run-in period,
 7 days of week 12 ± 7 days and 7 days of the 2 last weeks in the study, CGM with DexCom 4G
 will be used. CGM should be taken for 7 days, but a minimum of 5 days is acceptable. If a
 shorter period exists, a new sensor shall be set to get data for a total of 7 days (A total
 period of 5 days is acceptable). Investigators will recommend patients measure 3-4 glucose
 values per day before meals and at bedtime daily according to clinical guidelines for
 potentially adjusting insulin doses, diet or physical activity.

 Liraglutide/placebo will be administered at 0.6 mg the first week, 1.2 mg the second week and
 1.8 mg the third week and onward. Dose increase periods can be extended based on subject's
 tolerance to the trial product. If the subject does not tolerate 1.8 mg liraglutide/placebo
 due to side effects, the dose shall be reduced to 1.2 mg liraglutide/placebo.
 Correspondingly, if 1.2 mg liraglutide/placebo is not tolerated 0.6 mg liraglutide/placebo
 shall be used.

 Since subjects will have inappropriate glycaemic control (greater than or equal to 7.5%=58
 mmol/mol in HbA1c) no general reduction in insulin doses will be made. However, glucose
 profiles during the run-in period shall be judged by the clinician. In the following cases
 the clinician will consider to take the following actions when liraglutide is added:

 A) If the patient has a mean glucose level lower than 8.5 mmol/l the clinician should
 consider reducing the total insulin dose by 10%-20% when adding liraglutide 0.6 mg B) If
 glucose levels before a certain meal are well-controlled (less than 7 mmol/l) the clinician
 should consider reducing the meal-time insulin dose administered at the previous meal by
 10%-20% when adding liraglutide 0.6 mg. If daytime hypoglycaemia has occurred a larger than
 20% reduction in the insulin dose at the previous meal shall be considered when adding
 liraglutide 0.6 mg.

 C) If fasting glucose is 5.0-7.0 mmol/l the basal insulin shall be reduced by 20%-30% when
 adding liraglutide 0.6 mg.

 D) If fasting glucose is less than 5 mmol/l or nocturnal hypoglycaemia has occurred during
 the run-in period basal insulin shall be reduced by 20%-40%. Novel evaluations with glucose
 measurements during 4-5 days shall be performed to confirm that FPG is greater than 5 mmol/l
 and no new nocturnal hypoglycaemia exists before adding liraglutide. A novel evaluation
 according to point A)-D) shall then be performed from the new glucose values when adding
 liraglutide.

 When increasing liraglutide from 0.6 mg to 1.2 mg as well as from 1.2 mg to 1.8 mg the
 corresponding actions as points A-D above shall be considered based on glucose values and
 hypoglycaemias during the previous week.

 After titrating liraglutide/placebo to 1.8 mg in patients where insulin doses at any stage
 have been reduced, the insulin doses will be increased until the original doses are reached.
 However, the titration will be stopped, i.e., the insulin doses will not be titrated to the
 original doses, if glucose levels at any stage in the phase of increasing doses are already
 on target. For example, if the mean glucose level before a certain meal is less than 7 mmol/l
 after adding liraglutide/placebo 1.8 mg, the insulin dose before the previous meal will not
 be increased although the dose has been reduced. Correspondingly, if mean FPG is less than
 7.0 mmol/l the basal insulin dose will not be increased although it has been reduced.

 The total insulin dose shall not be titrated higher than the original total insulin dose at
 any point during the study, except if rescue therapy is required. The diabetes educator or
 physician will have regular telephone contact with the patient during the initial period when
 liraglutide is titrated and for possibly adjusting insulin doses. At the 6, 12 and 18 week
 follow-up visits and other contacts with the patient, e.g. telephone contacts, the insulin
 doses can be increased in patients with a lower insulin dose than the original insulin dose
 before randomisation so long as glucose levels then not are on target (less than 7.0 mmol/l
 fasting or before meal). However, the insulin doses shall not be increased higher than the
 original doses, except if rescue therapy is undertaken In daily activity, the patient will
 continue to adjust meal-time insulin doses in the same way as previously performed in
 clinical practice.

 Rescue Criteria

 If the fasting self-measured plasma glucose (fasting SMPG) values taken on three separate
 days or if any of the FPG samples analysed by the central laboratory exceeds the limit of
 15.5 mmol/l from baseline to week 12 or 13.5 mmol/l from week 12 to week 24, the subject
 should be called for an unscheduled visit as soon as possible. The next scheduled visit
 should not be awaited. A confirmatory FPG should be obtained and analysed by the central
 laboratory. If this FPG exceeds the above described values, and no treatable intercurrent
 cause for the hyperglycaemia has been diagnosed (e.g. compliance to liraglutide/placebo,
 missing of insulin dose in the evening, infection), the subject should receive rescue
 therapy.

 Rescue therapy is defined as an increase of the total insulin dose above the original total
 insulin dose (i.e. total insulin dose at baseline, at randomisation).

 It should be noticed that rescue therapy is NOT given if the total insulin dose was initially
 reduced in the trial and the total insulin dose is increased by the physician due to FPG
 above thresholds but not higher than the total original insulin dose. Rescue therapy will not
 exist either if a patient increases the total insulin dose at any point in time above the
 total original insulin dose by, e.g., self-adjustments of meal-time insulin doses in daily
 activity.

 Other medication, which is considered necessary for the subject's safety and well-being, may
 be given at the discretion of the investigator. Medications prescribed before study entry
 should preferably remain unchanged during the study period unless changes are made for safety
 reasons.

 Procedures for Monitoring Subject Compliance

 Compliance and adherence to protocol will be checked at each contact with the patient.

 Subject compliance will be assessed by DMG monitoring accountability. The unused amount of
 trial product will be assessed against the dispensed amount and, in case of discrepancies,
 the subjects must be asked about compliance.

 The individual delegated by the Investigator must keep track of all received, used, partly
 used and unused trial products and, if possible, all empty packaging. This shall be properly
 documented. Used, partly used and unused trial products and empty packaging must be stored
 separately from non-allocated trial products. Used, partly used and unused trial products
 must be stored until the monitor has performed drug accountability.

 Destruction of trial products will be performed in accordance with local legislation and
 recorded on a destruction form.

 Liraglutide/Placebo

 Not in use: The liraglutide/placebo pen-injector must be stored in a refrigerator at a
 temperature between +2°C and +8°C. Keep away from the cooling element. Do not freeze and do
 not use if it has been frozen.

 In use: After first opening the liraglutide/placebo pen-injector can be stored for one month
 at temperatures below +30°C or in a refrigerator between +2°C and +8°C.

 The liraglutide/placebo pen-injector must be protected from all sources of light, and the pen
 cap should be kept on when the pen is not in use. The liraglutide/placebo should not be used
 if it does not appear clear and colorless.

 In case of incorrect storage the Investigator or site staff must contact Novo Nordisk without
 delay. Trial product(s) must be set on-hold and not dispensed to subjects until notified by
 Novo Nordisk.

 The individual delegated by the Investigator must keep track of all received, used, partly
 used and unused trial products and, if possible, all empty packaging, by using the drug
 accountability module in the centralised web system. No trial product should be dispensed to
 any person not enrolled in the trial.

 Returned trial product(s) (used, partly used or unused and if possible, empty packaging
 material) must be stored separately from non-allocated trial product(s). Destruction of trial
 products will be done according to local laws and will be recorded on a destruction form,
 which must be signed by the individual responsible for destruction.

 Standardised procedures for administration of questionnaires

 The questionnaires will be filled in at the study site. The patients should be allowed to sit
 alone in a reasonable quiet environment to answer the questions. It will be emphasized that
 patients complete the questionnaires prior to clinical measurements and before meeting a
 doctor. Questionnaires should be answered by the patient herself alone, however, the
 nurse/assistant will be informed about helping the patients to complete the questionnaires if
 necessary, however without influencing the patients' responses. Ensure the patient
 confidentiality. Study nurse/assistant should check the questionnaires for completeness. The
 principal investigator will assure that appropriate training relevant to the study is given

 Trial Procedures

 Run-in period

 The purpose of the run-in period is to check glucose values as a basis for possible insulin
 adjustments and to perform CGM before randomisation. Blinded CGM will be performed during 1
 week of the 60-day run-in period. Capillary glucose values before meals and 1.5 hours after
 meals will be measured during at least 2 days, after the CGM-period. Treatment satisfaction
 (DTSQs) will be checked, preferentially before initiating CGM, since CGM may influence
 treatment satisfaction.

 Randomization visit

 Glucose profiles and hypoglycaemias during the run-in period will be checked to judge whether
 insulin reductions shall be performed (See section 8.2 Titration Algorithm).

 At the randomisation visit the following variables will be measured before randomisation and
 blood samples will be sent to the Research Centre for Laboratory Medicine at Karolinska
 University Hospital. All blood samples are recommended to be fasting to facilitate logistics
 since several tests require fasting conditions.

 -  Systolic and diastolic blood pressure after at least 5 minutes rest in sitting position
 with appropriate cuff-size

 -  HbA1c and fasting glucose

 -  Amylase, lipase, creatinine, liver transaminases

 -  Fasting Blood Lipids (Triglycerides, Total-, HDL- and LDL-Cholesterol), fasting
 apolipoproteins

 -  Weight

 -  Waist-hip ratio and abdominal sagittal diameter

 -  Type of insulin and doses of insulin and metformin

 -  AE, SAE and hypoglycaemia

 -  Adiponectin, sensitive CRP

 -  GAD-antibodies, calcitonin, amylase, lipase

 -  Fasting C-peptide and fasting pro-insulin

 -  Biobank samples

 -  Type of insulin, doses of insulin and doses of metformin recorded.

 -  Other types of medications recorded

 -  A morning urin sample of Albuminuria/Creatinine ratio will be measured with local
 laboratory analysis either at inclusion/exclusion visit or at randomisation visit.

 Web randomisation will be performed with minimisation (optimal allocation) to liraglutide or
 placebo in 1:1 proportion.

 Telephone contacts

 The diabetes educator or the physician will have telephone contact with the patient as
 follows:

 -  The day after starting liraglutide/placebo

 -  One of the 2 days before increasing liraglutide/placebo to 1.2 mg

 -  The day after the increase to 1.2 mg

 -  One of the two days before increasing liraglutide/placebo to 1.8 mg

 -  The day after increasing liraglutide to 1.8 mg

 -  One week after the increase of liraglutide/placebo to 1.8 mg

 More frequent telephone contacts during the initial weeks or later in the study will be made
 depending on the decision of the diabetic educator or physician if needed for the individual
 patient.

 At each telephone contact, insulin adjustments will be considered according to specified
 algorithms, i.e.:

 -  if hypoglycaemia exists

 -  If glucose values are well-controlled before titrating liraglutide/placebo

 In patients where insulin doses are reduced at any stage during the titration of liraglutide,
 regular telephone contacts every 3-4 day after titrating liraglutide/placebo to 1.8 mg shall
 be performed. Insulin doses will then be increased until the original insulin doses are
 reached. The increase of insulin doses will be stopped at a lower level earlier before
 original doses are reached if glucose levels already are on target.

 Clinical Visits

 Clinical visits will be performed at weeks 6, 12, 18 and 24. Visit at Week 6, 12 and 18

 At the 6 weeks follow-up visit (± 7 days), 12 weeks follow-up visit (± 7 days) and 18 weeks
 (± 7 days) follow-up visit the following variables will be measured:

 -  Systolic and diastolic blood pressure after at least 5 minutes rest in sitting position
 with appropriate cuff-size

 -  HbA1c, Fasting plasma glucose sent to central laboratory

 -  Weight

 -  Type of insulin and doses of insulin and doses of metformin

 -  AE, SAE and hypoglycaemia

 -  Changes to concomitant medication

 -  Trial product dispensing

 -  At week 12: blood lipids, lipase, amylase, liver transaminases, creatinine, calcitonin
 and biobank samples sent to central laboratory. Waist-hip ratio and abdominal sagittal
 diameter shall be measured.

 Week 12 ± 7 days

 -  Blinded CGM will be performed during 1 week.

 -  Treatment satisfaction (DTSQs) will be evaluated, preferentially before CGM since CGM
 may influence the treatment satisfaction.

 Two last weeks (week 23-24)

 -  Blinded CGM will be performed during 7 days. Capillary glucose values measured before
 and 1.5 hours after meals during 2 days.

 -  Treatment satisfaction (DTSQs and DTSQc) will be performed, preferentially before CGM
 since CGM may influence treatment satisfaction.

 Week 24

 At the final 24 weeks follow-up visit (± 7 days) the following variables will be measured
 (all blood samples sent to central laboratory):

 -  Physical investigation

 -  Systolic and diastolic blood pressure after at least 5 minutes rest in sitting position

 -  HbA1c and fasting plasma glucose

 -  Fasting blood lipids (Triglycerides, Total-, HDL- and LDL-Cholesterol) and
 apolipoproteins

 -  Weight

 -  Waist-hip ratio and abdominal sagittal diameter

 -  Sensitive CRP, adiponectin, liver transaminases, creatinine, calcitonin, lipase and
 amylase

 -  Type of insulin and doses of insulin and metformin

 -  AE, SAE and hypoglycaemia

 -  Changes to concomitant medication

 -  Fasting C-peptide and fasting pro-insulin

 -  Biobank samples

 -  A morning urin sample of Albuminuria/Creatinine ratio will be measured with local
 laboratory analysis.

 Hypoglycaemias

 Hypoglycaemias will be defined according to the general guidelines from the American Diabetes
 Association of definitions of hypoglycaemias in study settings (9). Hypoglycaemias will be
 divided into documented symptomatic hypoglycaemias, documented asymptomatic hypoglycaemias
 and severe hypoglycaemias. Patients will be counselled of typical symptoms of hypoglycaemia
 and given a diabetes diary for recordings of glucose values, signs of hypoglycaemias and
 recovery from symptoms after intake of carbohydrates. The frequency of hypoglycaemia with
 glucose values below 3.0 mmol/l and 4.0 mmol/l will both be used as endpoints. Severe
 hypoglycaemias will also be recorded in the diabetes diary. If a severe hypoglycaemia appears
 the responsible physician for the patient should be informed as soon as possible. The
 following parameters of hypoglycaemia will be recorded in accordance with guidelines for
 study design of the American Diabetes Association:

 -  Number of documented symptomatic hypoglycaemias (PG less than 4.0 mmol/l).

 -  Number of documented asymptomatic hypoglycaemia (PG less than 4.0 mmol/l).

 -  The number of symptomatic and asymptomatic documented hypoglycaemia with PG less than
 3.0 mmol/l will also be recorded.

 -  Number of glucose values recorded by CGM below 3.0 mmol/l and 4.0 mmol/l respectively.

 -  Number of severe hypoglycaemias.

 Patients shall be informed regarding the symptoms of hypoglycaemia and requested to
 immediately perform a finger stick glucose measurement if symptoms occur that may be related
 to hypoglycaemia, but to avoid delay in treating these symptoms.

 Full analysis set (ITT-population) The full analysis set (ITT-population) consists of all
 randomised patients who received at least one dose of study medication and has at least one
 follow-up measurement.

 Primary Efficacy Analysis Primary efficacy analysis will be change in HbA1c from baseline to
 24 weeks follow-up between the two treatment groups using analysis of covariance (ANCOVA)
 with HbA1c at baseline as covariate on the full analysis set (ITT-population), two-sided test
 on significance level 0.05. If HbA1c from 24 weeks follow-up is missing the last observation
 carry forward (LOCF) principle from 6, 12 and 18 weeks will be applied. All measurements
 obtained after rescue therapy should be excluded in all efficacy analyses.
Inclusion Criteria:

 -  Informed consent obtained before trial-related activities (i.e., any activity that
 would not have been performed during routine patient management)

 -  Type 2 diabetes

 -  Adult patients over 18 years of age and less than or equal to 80 years of age

 -  HbA1c greater than or equal to 7.5% (NGSP standard=DCCT standard)=58 mmol/mol (IFCC
 standard) and less than or equal to 11.5%=102 mmol/mol

 -  Treated with MDI for at least the last 6 months

 -  Treated with/without metformin as only diabetes therapy apart from insulin

 -  Fasting C-peptide of 0.10 nmol/l or greater (ref. 0.25-1.0 nmol/l)

 -  BMI greater than 27,5 kg/m2 and less than 45 kg/m2

 Exclusion Criteria:

 -  Type 1 diabetes

 -  Fasting glucose less than 6.0 mmol/l or greater than 15.0 mmol/l

 -  Unstable cardiovascular disease, NYHA Class II or greater heart failure , new symptoms
 of cardiovascular disease)

 -  Proliferative diabetic retinopathy or clinically significant macula oedema. Retinal
 photograph should not be older than 3 years.

 -  Systemic glucocorticoid treatment during the last 3 months, however, patients using
 systemic corticoid treatment only for substitution of cortisol deficiency (physiologic
 doses) such as Addisons Disease, do not need to be excluded

 -  Acute coronary syndrome, stroke, coronary artery intervention or myocardial infarction
 during the previous 6 months

 -  Creatinine greater than 150 micromol/l

 -  Liver transaminases greater than double of the normal reference interval

 -  Treatment with other oral antidiabetic agents than metformin during the previous 3
 months

 -  Treatment with GLP-1 receptor agonists within 90 days of screening

 -  Severe psychiatric disorder (untreated severe depression, schizophrenia, dementia or
 severe alcohol or drug abuse)

 -  Frequent non-severe hypoglycaemia (greater than 2 times per week) or any severe
 hypoglycaemia during the previous month.

 -  Hypoglycaemic unawareness

 -  Current cancer or diagnosis of cancer in the previous 5 years (except basal cell skin
 cancer or squamous cell skin cancer).

 -  Personal history of non-familial thyroid carcinoma or multiple endocrine neoplasia
 syndrome type 2 (MEN2)

 -  Screening calcitonin values greater than 14.6 pmol/l.

 -  Females of childbearing potential who are pregnant, breast-feeding or intend to become
 pregnant or are not using adequate contraceptive methods (adequate contraceptive
 measures as required by local law or practice; accepted methods: oral contraceptive
 pills, depo provera contraceptive injections, implanted contraceptive, transdermal
 patch, intrauterine device, vasectomized partner, or abstinence.)

 -  Blood pressure greater than 160/100 mmHg

 -  Need for continuous use of paracetamol. During the 3 periods of 7 days with CGM,
 paracetamol cannot be used. Alternative pain killers can be substituted if plausible
 because paracetamol is the only medication influencing CGM results.

 -  History of chronic or acute pancreatitis

 -  Inflammatory Bowel Disease

 -  Participation in another study