supplementary data - diabetes...

SUPPLEMENTARY DATA

©2012 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc11-1928/-/DC1

Inclusion criteria • Informed consent obtained before any trial-related activities • Participants diagnosed with type 2 diabetes, insulin naïve and treated with metformin as monotherapy for ≥3 months

prior to screening, at a stable dose of ≥1500 mg/day or metformin (≥1500 mg/day) and a sulfonylurea (less than or equal to ½ of the maximum approved dose according to local label), both at a stable dose for ≥3 months prior to screening. Previous short-term insulin treatment in connection with inter-current illness was allowed, at the discretion of the investigator

• Glycated hemoglobin (A1C) levels of 7.0–10.0% (both inclusive) for participants on metformin monotherapy, A1C levels of 7.0–8.5% (both inclusive) for participants on metformin in combination with a sulfonylurea

• Age 18–80 years, both inclusive (or as allowed according to local guidelines) • Able and willing to perform self-monitoring of plasma glucose according to the protocol, to keep a diabetes diary and

willing to use a pen-injector device and the FlexPen® device if necessary Exclusion criteria • Previous treatment with insulin (with exception noted above) • Treatment with glucose-lowering agent(s) other than those stated in the inclusion criteria for a period of 3 months prior

to screening • Impaired liver function, defined as alanine aminotransferase (ALAT) ≥2.5 times upper normal limit (one re-test analyzed

at the central laboratory within 1 week was permitted with the result of the last sample being the conclusive) • Impaired renal function defined as serum-creatinine ≥133 μmol/l for males and ≥124 µmol/l for females, or as allowed

according to local contraindications for metformin or sulfonylurea use (one re-test analyzed at the central laboratory within 1 week was permitted with the result of the last sample being the conclusive)

• History of chronic pancreatitis or idiopathic acute pancreatitis • Known history of unstable angina, acute coronary event, other significant cardiac event (including history of arrhythmias

or conduction delays on ECG), or cerebral stroke within the past 6 months • Heart failure: New York Heart Association class IV • Known proliferative retinopathy or maculopathy requiring acute treatment as judged by the investigator • Uncontrolled treated or untreated hypertension (systolic blood pressure ≥180 mmHg and/or diastolic blood pressure

≥110 mmHg) • Cancer (except basal cell skin cancer or squamous cell skin cancer) or any clinically significant disorder, except for

conditions associated with type 2 diabetes history, which in the investigator’s opinion could interfere with the results of the trial

• Recurrent major hypoglycemia or hypoglycemic unawareness as judged by the investigator • Known or suspected allergy to trial product(s) or related products • Use of any drug (except for those stated in the inclusion criteria), which in the investigator’s opinion could interfere with

the glucose level (e.g., systemic corticosteroids) • Receipt of any other investigational drug within 3 months prior to screening into this trial • Any contraindications to metformin or insulin detemir according to local labels • Surgery scheduled during the trial period (excluding minor surgical procedures performed under local anesthesia, as

judged by the investigator) • Previous participation in the run-in period of this trial • Known or suspected abuse of alcohol or narcotics • Females of child-bearing potential who were pregnant, breast-feeding or intended to become pregnant or were not using

adequate contraceptive methods (adequate contraceptive measures as required by local law or practice) • Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation. Applicable for

Germany and Spain only: Participants with medical history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma if total thyroidectomy was not performed or could not be ensured (i.e., posterior capsule of the thyroid gland not removed)

Randomization At the screening visit, investigators assigned participants to the lowest available number from the range of numbers allocated to the site by the telephone- (Interactive Voice Response System) or web-based randomization system (Interactive Web Response System) prepared by Novo Nordisk A/S. The participant number had six digits (XXXYYY), where XXX referred to the site number and YYY represented the participant number at that site. At the randomization visit (Visit 4), eligible participants were allocated to one of the two randomized treatment groups: insulin detemir + liraglutide 1.8 mg + metformin or liraglutide 1.8 mg + metformin in a 1:1 manner. Randomization of participants was stratified by previous treatment with either metformin or a combination of metformin and a sulfonylurea. Stratification was performed by entering the

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participant’s previous treatment when obtaining the randomization number. At each site, each consecutive patient had an equal chance to be randomized into one of the two treatment arms, hence it expected that at each site, on average, a balance between patients intensified with insulin detemir vs. those in the control arm was maintained. Insulin detemir titration At randomization, the start dose of insulin was 10 U. The insulin detemir dose could be adjusted by the investigator at site visits and telephone contacts, based upon the participant’s self-measured fasting plasma glucose measurements (SMPG) fasting measurements on 3 days in the week prior to dose adjustment) according to the algorithm below:

Average plasma glucose value (mmol/l) in a fasting state used for titration

Change in dose (units)

4.1–6.0 (target) No adjustment

6.1–8.0 +2

8.1–9.0 +4

9.1–10.0 +6

>10.0 +8

If a participant had only measured plasma glucose in a fasting state on 2 of the 3 requested days, titration of insulin dose was to be based on the average of these values. If only one measurement was available, this was used to assess the need for insulin dose adjustment at the discretion of the investigator. Furthermore, the algorithm (above) was only to be used if there had been no major hypoglycemic episodes and/or plasma glucose values <4.0 mmol/l without obvious explanations between two consecutive contacts. If low plasma glucose values occurred without any obvious explanation, reduction of insulin detemir dose was to be performed according to the schedule below.

Plasma glucose value (mmol/l) in fasting state Dose change

One or more values <3.1 without obvious explanation

Reduce by 4 units (if dose >50 units, a dose reduction of 10% is

suggested)

One or more values between 3.1 and 4.0 without obvious explanation

Reduce by 2 units (if dose >50 units, a dose reduction of 5% is

suggested)

The titration target during the treatment period was a fasting SMPG of 4.0–6.0 mmol/l. Titration was optimized by means of weekly teleconferences between investigators and study participants and also by a local titration monitoring committee overseeing the titration guidance recommended by investigators. Protocol amendments There were 2 global and 16 local substantial amendments to the final protocol, version 1, dated September 30, 2008. Most of the substantial amendments were prepared locally and included updates in key staff, number of participating sites and a change in local investigator agreement. Substantial amendments with impact on trial activities and subject information are listed below: • Global substantial amendment dated 10-Jul-2009

This amendment was introduced to include a withdrawal criterion concerning pancreatitis (to avoid drug exposure if a subject was diagnosed with acute pancreatitis), to clarify reporting procedures with respect to medical events of special interest, including pancreatitis, and to clarify the visit schedule for subjects receiving intensification of treatment with insulin detemir during the extension period. Furthermore, the section on statistical considerations was updated (the handling of 52-week data was clarified) and the role of the local titration consultants was included in Appendix C to the protocol. Attachment 1 describing the key staff involved in the trial was updated. • Global substantial amendment dated 10-Sep-2009

This amendment was introduced to accommodate a request from the Food and Drug Administration. The pre-clinical section of the liraglutide summary in Section 3.1.3 of the protocol (Appendix 16.1.1) was updated with the preclinical subcutaneous

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tumors observed in rodents: ‘dorsal skin sarcomas at the injection site were significantly increased in male mice at the highest dose of 3 mg/kg/day’. The tumors were located in the area of the micro-chip implant and the injection site area. Repeated subcutaneous injections of non-genotoxic compounds and solutions as well as implantation of solid material such as micro-chips in the subcutis are known to cause development of skin sarcomas in rodents. (Greaves P. Integumentary system in Histopathology of Preclinical Toxicity studies. Edn 3, 38. 2007. Amsterdam; Academic Press.) The NOAEL for skin sarcomas was 1.0 mg/kg, providing a human safety ratio of 13. The observed increase in skin sarcomas in high-dose male mice is of unknown relevance for human safety. There have been no reports of skin sarcomas in the clinical development program’. This information was also added to the Informed Consent Form. Furthermore, a correction was made to the trial flow charts clarifying that informed consent was required for subjects before starting an intensification of treatment. • Local substantial amendment (Germany) dated 03-Feb-2009

This amendment was introduced following a recommendation by the German Health Authority (BfArM) to include an additional exclusion criterion regarding subjects with a medical history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma. Furthermore, the section on thyroid gland disorders in the medical events of special interest section was updated with concrete terms for further evaluation of increases in calcitonin during the course of the trial. A procedural deviation was made in Germany explaining the wrong amendment numbering. • Local substantial amendment (Spain) dated 27-Feb-2009

This amendment was introduced following a recommendation by the Spanish Health Authorities (AEMPs) to include an additional exclusion criterion regarding subjects with a medical history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma. The section on thyroid gland disorders in the medical events of special interest section was updated with concrete terms for further evaluation of increases in calcitonin during the course of the trial. Furthermore, an additional withdrawal criterion based on A1c was added to Section 6.5 of the protocol and a more detailed description of acute pancreatitis cases was added to the Subject Information Sheet, both of which were made based on recommendations from the Spanish Health Authorities. Lastly, attachment II to the Spanish protocol was updated with respect to participating sites and key staff. • Local substantial amendment (France) dated 27-Mar-2009

This amendment was introduced following a recommendation by the French Health Authorities to include a mandatory follow-up visit with an endocrinologist for patients in French sites with a calcitonin post baseline value of more than two times the upper normal limit and an increase of more than 50% from the baseline value. • Local substantial amendment (Spain) dated 17-Apr-2009

This amendment was introduced following a recommendation by the Reference Ethics Committee of Spain to modify the wording of the withdrawal criterion based on A1c in Section 6.5 of the protocol. Instead of ‘….withdrawal of the patient is recommended based on the discretion of the investigator’ the new wording was ‘…the patient will be withdrawn’. Furthermore, an inconsistency in the protocol was corrected and Attachment II to the protocol was updated with details of key staff. • Local substantial amendment (Germany) dated 15-Jul-2009

This amendment was introduced to update the protocol wording on thyroid gland disorders, medical events of special interest, following the global amendment 11, where changes to this text were made. This update was made to reflect the recommendation made by the German Health Authorities, already mentioned and changed in a previous local substantial amendment (Germany) Supplementary Table 1. Change in A1C values during run-in (week –12 to week 0)

Mean (SD) Median Range

Observational group (metformin + liraglutide 1.8 mg) –1.34 (0.70) –1.20 –3.80; 0.00

Randomized control group (metformin + liraglutide 1.8 mg) –0.66 (0.82) –0.60 –3.30; 1.80

Randomized treatment group (metformin + liraglutide 1.8 mg + insulin detemir)

–0.60 (0.83) –0.50 –3.20; 1.80

Data are for the full analysis set with no imputation

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Supplementary Table 2. Summary of hypoglycemic episodes, excluding outlier: safety analysis set

Randomized treatment group Metformin + liraglutide 1.8 mg + insulin detemir

Randomized control group Metformin + liraglutide

1.8 mg

Observational group Metformin + liraglutide

1.8 mg

Early withdrawals Metformin + liraglutide

1.8 mg

N (%) E R N (%) E R N (%) E R N (%) E R

Run-in period (week –12 to 0)

Safety analysis set 163 158 499 166

Exposure liraglutide (participant-years)

39 38 118 17

Major 0 (0.0) 0 0.000 0 (0.0) 0 0.000 0 (0.0) 0 0.000 1 (0.6) 1 0.057

Minor 7 (4.3) 8 0.205 0 (0.0) 0 0.000 31 (6.2) 45 0.380 1 (0.6) 1 0.057

Symptoms only 4 (2.5) 5 0.128 1 (0.6) 1 0.027 27 (5.4) 36 0.304 1 (0.6) 1 0.057

Randomized period (week 0 to week 26)

Safety analysis set 163 158 499 N/A

Exposure liraglutide (participant-years)

77 69 241 N/A

Exposure detemir (participant-years)

77 N/A N/A N/A

Major 0 (0.0) 0 0.000 0 (0.0) 0 0.000 0 (0.0) 0 0.000 N/A

Minor 15 (9.2 ) 22 0.286 2 (1.3) 2 0.029 21 (4.2) 31 0.129 N/A

Symptoms only 11 (6.7) 19 0.247 6 (3.8) 9 0.130 18 (3.6) 26 0.108 N/A

N, number of participants having at least one hypoglycemic episode; %, proportion of participants exposed in the treatment period having an episode; E, number of episodes; R, episodes per participant year (liraglutide). N/A, not applicable. Data exclude one outlier, a participant treated with metformin and liraglutide (randomized control group) who had a history of hypoglycemia at screening and who reported minor and symptom-only hypoglycemic episodes on 25 separate occasions during screening, run-in, and the main trial period. A major hypoglycemic episode was reported in the early withdrawals group. The participant reported fainting 10 minutes after a meal (5 hours after a liraglutide injection). The blood glucose level was 5.2 mmol/l and the participant recovered immediately without carbohydrate administration.

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Supplementary Table 3. Number of new nausea events (incidence) starting each week after first liraglutide drug date: safety analysis set. (The proportions of participants experiencing nausea in each week of the study is shown in Online Appendix Fig. 1.) Randomized treatment group

Metformin + liraglutide 1.8 mg + insulin detemir


1.8 mg


1.8 mg

Early withdrawals Metformin + liraglutide

1.8 mg

Time after first liraglutide drug date (weeks)

N n (%) E N n (%) E N n (%) E N n (%) E

1 163 14 (8.6) 18 159 15 (9.4) 16 499 69 (13.8) 76 166 38 (22.9) 38

2 163 6 (3.7) 6 159 6 (3.8) 6 499 35 (7.0) 41 166 15 (9.0) 15

3 163 4 (2.5) 4 159 11 (6.9) 11 499 26 (5.2) 29 144 8 (5.6) 8

4 163 – 159 1 (0.6) 1 499 8 (1.6) 9 119 5 (4.2) 5

5 163 – 159 1 (0.6) 1 499 9 (1.8) 9 99 4 (4.0) 4

6–12 163 1 (0.6) 1 159 3 (1.9) 3 499 5 (1.0) 7 81 2 (2.5) 2

13 to end of trial 163 7 (4.3) 7 159 9 (5.7) 10 499 14 (2.8) 17 29 –

N, number of participants exposed. n, number of participants with nausea ; %, calculated by (n/N)*100; E, number of nausea events , hyphen (–), no observation.

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Supplementary Table 4. Pancreas and thyroid-related adverse event summaries Run-in (weeks –12 to 0)

One case of acute pancreatitis was reported on day 61 in a 61-year-old male who had prior history of alcoholic pancreatitis. Lipase level was markedly increased (12,215 U/l, normal range <400 U/l). The patient recovered from the event which was considered to be possibly related to trial drug by the investigator and was withdrawn from the trial. Concomitant medication included ramipril and simvastatin. One case of thyroid neoplasm occurred in a 53-year-old male who underwent further thyroid examination due to an increased calcitonin level at screening (23.53 ng/l). Thyroidectomy was performed, whereupon histology identified a 1-mm papillary micro-carcinoma. The patient recovered from the event, which was considered unlikely to be related to trial product.

Randomized period (weeks 0 to 26)

One case of chronic pancreatitis was reported on day 216 in association with biopsy-confirmed Helicobacter pylori-associated gastritis in a 54-year-old male randomized to the control group. During the episode, the participant had a CT scan, which indicated chronic pancreatitis. The amylase level was elevated (290 U/l, normal range <101 U/l). Previous amylase and lipase levels while on trial product were within the normal ranges, although values at first visit (before trial drug administration) were amylase 97 U/l (28–100 U/l) and lipase 147 U/l (13–60 U/l). According to the investigator, the chronic pancreatitis was discovered incidentally. The participant received the following concomitant medications: ramipril, simvastatin, allopurinol, amplodipine, aspirin, dicycloverine – some of which have previously been associated with pancreatitis. The patient was also suffering from gout and hyperlipidemia.

Supplementary Table 5. ANCOVA of change in A1C (%) – no imputation – full analysis set (additional analysis)

The estimates are from an ANCOVA model with treatment, country and previous OAD as fixed effect and baseline value as a covariat

Comparison of change from baseline after 26 weeks of treatment

Treatment/comparison Estimates Testing

Least square means N LS Mean SE

Randomized treatment group (metformin + liraglutide 1.8 mg + insulin detemir) 141 -0.53 (0.07)

Randomized control group (metformin + liraglutide 1.8 mg) 125 -0.06 (0.07)

Estimated treatment difference LS Mean 95% CI P-value

Randomized treatment group (metformin + liraglutide 1.8 mg + insulin detemir) - Randomized control group (metformin + liraglutide 1.8 mg)

-0.47 [-0.64;-0.30] <0.0001

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Supplementary Table 6. Repeated measurements analysis of A1C (%) – no imputation – full analysis set (additional analysis)

Comparison of A1C levels after 12 and 26 weeks of randomized treatment

Treatment/comparisons Estimates Testing

Week 0 Least square means Randomized control group (metformin + liraglutide 1.8 mg) Randomized treatment group (metformin + liraglutide 1.8 mg + insulin detemir)

N

157 162

Least square mean 7.62 7.61

SE

(0.05) (0.05)


N

148 159

Least square mean

7.57 7.13

SE

(0.05) (0.05)

Estimated treatment difference Least square mean 95% CI P-value


-0.43

[-0.55 ; -0.31]

<0.0001


N

129 146

Least square mean

7.59 7.10

SE

(0.05) (0.05)

Estimated treatment difference Least square mean 95% CI P-value


-0.49

[-0.62 ; -0.36]

<0.0001

The estimates are from a repeated measurement model with country, previous OAD, treatment, time, treatment by time as fixed effects and baseline A1C level as a covariate, subject as random effect and a compound symmetric covariance structure.

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Supplementary Table 7. Changes in lipid profiles from run-in start (week –12) to week 26 Randomized treatment group

(metformin + liraglutide 1.8 mg + insulin detemir)

Randomized control group (metformin + liraglutide 1.8 mg)

Observational group (metformin + liraglutide 1.8 mg)

Total cholesterol (mmol/L) -0.09 (0.82) -0.19 (0.79) -0.07 (0.79) LDL cholesterol (mmol/L) -0.11 (0.67) -0.22 (0.62) -0.11 (0.67) VLDL cholesterol (mmol/L) -0.05 (0.56) -0.01 (0.45) -0.00 (0.43) HDL cholesterol (mmol/L) 0.06 (0.16) 0.03 (0.18) 0.05 (0.16) Triglycerides (mmol/L) -0.50 (1.77) -0.33 (1.10) -0.36 (1.34) Free fatty acids (mmol/L) -0.20 (0.32) -0.03 (0.23) -0.10 (0.25)

Data are mean (SD) for the full analysis set with no imputation. LDL, low-density lipoprotein; HDL, high-density lipoprotein; VLDL, very low-density lipoprotein. Supplementary Table 8. Serious treatment-emergent adverse events (SAEs) by preferred term

Run-in (weeks -12 to 0)*


Cystocele (1)

Randomized control group Metformin + liraglutide 1.8 mg

Lipase increased (1), osteoarthritis (1), removal of foreign body (1)

Observational group Metformin + liraglutide 1.8 mg

Benign prostatic hyperplasia (1), thrombocytopenic purpura (1), coronary artery disease (1), supraventricular tachycardia (1), anal fistula (1), pneumonia (2), post lumbar puncture syndrome (1), tendon rupture (1), upper limb fracture (1), intervertebral disc protrusion (1), osteoarthritis (1), periarthritis (1), epistaxis (1)

Randomized period (weeks 0 to 26)


Ankle fracture (1), head injury (1) joint injury (1), abdominal pain (1), sarcoidosis (1), Clostridium difficile colitis (1), osteoarthritis (1), convulsion (1), depression (1), nephrolithiasis (1), bronchopulmonary disease (1), peripheral ischemia (1), thrombosis (1)

Randomized control group Metformin + liraglutide 1.8 mg

Pancreatitis chronic (1)†, abscess soft tissue (1), Helicobacter gastritis (1), post procedural infection (1), benign intracranial hypertension (1), peripheral arterial occlusive disease (1), angina pectoris (1), metastases to central nervous system (1)

Observational group Metformin + liraglutide 1.8 mg

Fall (2), femur fracture (1), ligament rupture (1), traumatic fracture (1), traumatic intracranial hemorrhage (1), abdominal hernia obstructive (1), intestinal infarction (1), abdominal wall abscess (1), viral infection (1), arthritis (1), bursitis (1), intervertebral disc degeneration (1), intervertebral disc protrusion (1), polymyalgia rheumatica (1), cerebrovascular accident (1), syncope (1), transient ischemic attack (1), nephrolithiasis (1), urinary retention (1), nasal septum deviation (1), coronary artery disease (2), supraventricular tachycardia (1), macular ischemia (1), macular oedema (1), chest pain (1), breast cancer (1), renal cancer (1), struma nodosa and C-cell hyperplasia (1), uterine leiomyoma (1), eczema (1)

*All participants received the same treatment during run-in (ie, liraglutide in addition to metformin at pre-trial levels) but the presentation of AEs is in accordance with treatment allocation during the randomized trial period; †See Online Appendix Table 4 for details.

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Supplementary Table 9. Additional safety assessments over the entire 38-week study (week –12 to 26) for all treatment groups

• Safety laboratory assessments over the entire 38-week study

– Over time, mean calcitonin levels remained at the lower end of the normal range, approximately 1.0–1.5 pg/ml for females (normal range: <5 pg/ml) and 3.75–4.75 pg/ml for males (normal range: <8.4 pg/ml).

– Using a repeated measurement analysis for calcitonin with censored observations, no significant treatment differences were observed for calcitonin between the randomized insulin detemir and randomized control groups at week 12 (1.05 pg/ml vs. 0.97 pg/ml, respectively; p=0.2616) or week 26 (1.15 pg/ml vs. 1.12 pg/ml, respectively; p=0.6907).

– No clinically relevant changes or differences between groups in urinalysis

– In all groups, there seemed to be a slight increase in median lipase levels within the normal range from week -12 to week 26 and no obvious treatment differences were observed. When entering the trial and before trial drug treatment, 186/977 (19%) had a lipase level above ULN, and 21/977 (2.1%) of participants had a lipase level >3×ULN, whereas 16/885 (1.8%) had lipase above 3× ULN at week 26 (or at early withdrawal). None of these participants reported gastrointestinal adverse events at week 26.

• Thyroid-related adverse event frequencies were comparable across groups (1.2%, 1.9% and 2.4% of participants in the randomized insulin detemir, randomized control, and observational groups, respectively).

• All groups had a mean increase in heart rate (3.6–3.9 beats/min) over the 38-week trial.

• Over 38 weeks, there were no clinically relevant differences in physical examination or ECG.

ULN, upper limit of normal.

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Supplementary Table 10. Adverse events (AEs) during entire 38-week period with an incidence ≥5% in any treatment by preferred term, and summary of serious adverse events (SAEs).



1.8 mg


1.8 mg

Early withdrawals Metformin +

liraglutide 1.8 mg

N (%) E N (%) E N (%) E N (%) E

Safety analysis set 163 159 499 166

All AEs 125 (76.7) 631 121 (76.1) 559 402 (80.6) 1765 122 (73.5) 383

All SAEs 9 (5.5) 14 8 (5.0) 11 39 (7.8) 49 5 (3.0) 5

Nausea 28 (17.2) 36 37 (23.3) 48 127 (25.5) 188 66 (39.8) 72

Vomiting 15 (9.2) 23 16 (10.1) 16 46 (9.2) 97 33 (19.9) 42

Diarrhea 27 (16.6) 37 24 (15.1) 27 60 (12.0) 88 21 (12.7) 25

Dyspepsia 10 (6.1) 11 7 (4.4) 9 37 (7.4) 45 11 (6.6) 11

Abdominal pain upper 6 (3.7) 7 4 (2.5) 5 11 (2.2) 14 9 (5.4) 14

Constipation 8 (4.9) 9 8 (5.0) 8 19 (3.8) 24 4 (2.4) 4

Nasopharyngitis 24 (14.7) 31 33 (20.8) 44 55 (11.0) 66 2 (1.2) 2

Upper respiratory tract infection 8 (4.9) 8 8 (5.0) 13 20 (4.0) 22

Lipase increased 24 (14.7) 24 14 (8.8) 15 34 (6.8) 35 6 (3.6) 7

Headache 18 (11.0) 32 21 (13.2) 37 61 (12.2) 105 13 (7.8) 22

Fatigue 11 (6.7) 11 9 (5.7) 10 12 (2.4) 13 6 (3.6) 8

Asthenia 4 (2.5) 4 6 (1.2) 6 11 (6.6) 13

Oropharyngeal pain 5 (3.1) 5 8 (5.0) 8 13 (2.6) 15 2 (1.2) 2

Decreased appetite 13 (8.0) 13 8 (5.0) 8 49 (9.8) 50 17 (10.2) 17

N, number of participants with adverse event (AE); %, proportion of participants in analysis set having adverse events; E, number of adverse events.

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Supplementary Table 11. Change in systolic blood pressure values at run-in start (week –12) to week 26 Mean (SD) Median Range

Observational group (metformin + liraglutide 1.8 mg) -3.33 (14.96) -2.00 -57.00; 48.00

Randomized control group (metformin + liraglutide 1.8 mg) -3.13 (15.13) -2.50 -50.5; 37.50

Randomized treatment group (metformin + liraglutide 1.8 mg + insulin detemir) -1.64 (17.54) -4.50 -55.0; 39.50

Data are for the full analysis set with no imputation. Supplementary Table 12. Change in heart rate at run-in start (week –12) to week 26

Mean (SD) Median Range

Observational group (metformin + liraglutide 1.8 mg) +3.64 (9.42) -4.00 -27.0; 40.00

Randomized control group (metformin + liraglutide 1.8 mg) +3.62 (8.81) -4.00 -19.00; 28.00

Randomized treatment group (metformin + liraglutide 1.8 mg + insulin detemir) +3.87 (8.68) -4.00 -17.00; 28.00

Data are for the full analysis set with no imputation

Supplementary Table 13. List of investigators

Belgium: C Mathieu, C Vercammen; Canada: I Blumer, K Bowering, DB Clayton, J Conway, I Gottesman, S Harris, V Woo; France: C Allesis, S Angeletti, A Avignon, F Ayon, M Benichou, C Boitard, B Catargi, G Charpentier, S Clavel, JP Courreges, X Debussche, B Delemer, P Fontaine, E Ghanassia, D Gouet, E Haddad, S Hadjadj, P Hassler, I Hochner, N Le Moullec, P Lecomte, R Mira, P Moulin, D Reynaud, P Vexiau; Germany: A Barakat, T Behnke, D Burchert, R Daikeler, M Dietlein, K Drynda, EM Fach, S Goelz, A Hamann, H Hammer, M Hanefeld, A Hinz, R Jordan, M Kaiser, A Klinge, W Kohn, R Lundershausen, S Maxeiner, F Merfort, K Milek, A Mölle, B Paschen, A Pohl, L Rose, J Sauter, K Schlecht, C Schramm, PM Schumm-Draeger, J Schwinn, A Segner, J Seufert, E Siegel, J Simon, J Steindorf, P Stübler, R Tosch-Sisting, S Vidal, M Weber, V Wenzl-Bauer, K Wilhelm; Italy: A Arcangeli, MG Baroni, M Boemi, M Bonomo, A Bossi, S Buscemi, S Caputo, A Ciavarella, L Corsi, E Dal Moro, E D'Amico, P Di Bartolo, G Fatati, S Gambardella, L Morviducci, E Orsi, F Paleari, M Parillo, G Pipicelli, L Puccio, M Pupillo, A Sforza, F Tomasi, A Venezia, G Vespasiani, D Zavaroni; Netherlands: I Agous, AB Arntzenius, R Bianchi, CB Brouwer, HW De Valk, JH DeVries, WL Feis, GAPM Hentenaar, K Hoogenberg, MCW Jebbink, S Kok, A Kooy, B Lokhorst, HGM Mevissen, PC Oldenburg-Ligtenberg, D Schweitzer, VEKM Van de Walle, GJM van Doesburg, AH Verhage, MGJ Willink; Spain: R Albero Gamboa, FJ Ampudia-Blasco, J Anglada Barcelo, M Brito Sanfiel, F Cañizo, R Domínguez, J Dominguez Escribano, J Escalada, E Faure Nogueras, J Gómez Cerezo, E González Sarmiento, J Izaguirre, E Jodar, I Llorente Gómez De Segura, C López Tinoco, A Lucas, A Merchante Alfaro, P Mezquita Raya, F Morales Pérez, T Muros de Fuentes, M Paja Fano, JA Paniagua González, E Pujol De La Llave, L Ramírez Muñoz, W Ricart, A Rovira, A Sánchez Rodríguez, JM Varela Aguilar; United Kingdom: P Abraham, J Andrews, S Atkin, S Bain, M Davies, C Dayan, M Gibson, R Harper, G Hitman, S Hunter, E Jude, A Kilvert, S Kumar, J Lindsay, A Mackie, S MacRury, D Matthews, J Mcknight, P Narendran, J O'Hare, S Ramtoola, A Robinson, D Rooney, D Russell-Jones, P Saravanan, WP Stephens, G Tan, B Vaidya, J Vora, D Whitelaw, J Wilding, P Wiles, P Winocour; United States: F Abreu, M Acampora, A Ahmed, H Bays, R Bergenstal, O Brusco, L Chaykin, R Cherlin, S Chilka, M Christina, L Chuck, J Cohen, A Comulada-Rivera, C Corder, D D’Alessio, L Dunn, A Dwarakanathan, M Feinglos, R Forbes, J Gilbert, S Greco, G Griffing, M Harris, R Harris, S Harris, K Hershon, J Hoekstra, P Hollander, J Hone, D Huffman, R Jain, A Kapoor, D Kayne, J Kennedy, P Levin, R Lipetz, B Lubin, M McCartney, L Meneghini, A Murillo, F Ovalle, E Perez, L Phillips, D Popov, M Ramos-Roman, L Ratcliff, R Ratner, J Reed, HW Rodbard, J Rosenstock, R Sachson, J Saponaro, C Scott, J-L Selam, J Stoever, S Sulman, J Testa, A Philis-Tsimikas, J Unger, R Vigersky, P Weissman, K Wheeler, B Wittmer, G Yeoman, B Zamora, F Zieve, T Zimmerman, J Zonszein.

SUPPLEMENTARY DATA


Supplementary Figure 1. Percentage of participants experiencing nausea in each week of the study: safety analysis set. One participant withdrawing before week 0 was included in the early withdrawals group but data were collected for that participant until he/she attended a discontinuation visit; the last discontinuation visit occurred 19 weeks after the end of the run-in period. Solid squares: randomized treatment group (metformin + liraglutide 1.8 mg + insulin detemir); open squares: randomized control group (metformin + liraglutide 1.8 mg); solid triangles: observational group (metformin + liraglutide 1.8 mg); open circles: early withdrawals (metformin + liraglutide 1.8 mg before randomization). Please see Online Appendix Table 3 for the number of nausea events starting in each week of the study.

Supplementary Figure 2. Proportion of participants reaching target of glycated hemoglobin (A1C) <7% (left) and ≤6.5% (middle) and proportion of participants reaching the composite endpoint of <7%, body weight change <0 kg and no hypoglycemic episodes (right) during the 26-week randomized period. Solid bars: randomized treatment group (metformin + liraglutide 1.8 mg + insulin detemir); open bars: randomized control group (metformin + liraglutide 1.8 mg). Missing data were imputed using the last observation carried forward method.

supplementary data - diabetes...

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