Supplemental Data

Table 1 Comparison of estimated means and treatment differences for appetite and nausea ratings (assessed by visual analog scales following the breakfast meal) after 5 weeks of treatment.

Parameter / Liraglutide
1.8 mg
n=30 / Liraglutide
3.0 mg
n=30 / Placebo
n=30 / Treatment difference (D) for
1liraglutide 1.8 mg vs placebo
2liraglutide 3.0 mg vs placebo
3liraglutide 3.0 mg vs 1.8 mg / P value
Appetite
Overall appetite score (mm)
Fasting rating / 47 / 44 / 43
1D: 4 (3; 11) / 0.23
2D: 2 (5; 8) / 0.64
3D: -3 (-9; 4) / 0.44
Mean rating AUC15-300min/285min / 68 / 68 / 56
1D: 12 (6; 18) / 0.0004
2D: 12 (6; 18) / 0.0003
3D: 0.2 (-6; 6) / 0.94
Maximum rating / 91 / 92 / 81
1D: 10 (4; 16) / 0.001
2D: 11 (5; 16) / 0.0005
3D: 1 (-5; 7) / 0.80
15-min postprandial rating / 88 / 88 / 77
1D: 11 (6; 17) / 0.0002
2D: 11 (6; 17) / 0.0002
3D: 0 (-6; 6) / 0.98
Satiety (mm)
Fasting rating / 40 / 38 / 38
1D: 2 (7; 12) / 0.61
2D: -0 (10; 9) / 0.92
3D: -3 (-12; 6) / 0.54
Mean rating AUC15-300min/285min / 66 / 66 / 55
1D: 11 (4; 18) / 0.002
2D: 11 (4; 18) / 0.002
3D: -0.3 (-7; 6) / 0.94
Maximum rating / 90 / 91 / 81
1D: 10 (4; 16) / 0.0021
2D: 11 (5; 17) / 0.0009
3D: 1 (-5; 7) / 0.78
15-min postprandial rating / 88 / 87 / 73
1D: 15 (8; 22) / <0.0001
2D: 14 (7; 21) / 0.0001
3D: -1 (-8; 6) / 0.84
Fullness (mm)
Fasting rating / 35 / 35 / 30
1D: 5 (-5; 15) / 0.31
2D: 5 (-5; 15 / 0.33
3D: -0 (-10; 10) / 0.97
Mean rating AUC15-300min/285min / 64 / 66 / 52
1D: 12 (5; 19) / 0.001
2D: 15 (8; 22) / 0.0001
3D: 3 (-4; 10) / 0.42
Maximum rating / 90 / 92 / 79
1D: 12 (5; 19) / 0.0009
2D: 13 (6; 20) / 0.0003
3D: 1 (-6; 8) / 0.73
15-min postprandial rating / 87 / 87 / 71
1D: 16 (7; 25) / 0.0006
2D: 16 (7; 25) / 0.0005
3D: 0 (-9; 9) / 0.97
(100-hunger) (mm)
Fasting rating / 62 / 58 / 59
1D: 3 (-9; 15) / 0.57
2D: -1 (-13; 11) / 0.92
3D: -4 (-16; 8) / 0.50
Mean rating AUC15-300min/285min / 75 / 72 / 63
1D: 11 (4; 18) / 0.002
2D: 9 (2; 16) / 0.01
3D: -2 (-9; 4) / 0.51
Maximum rating / 96 / 96 / 94
1D: 2 (-2; 6) / 0.40
2D: 2 (-2; 6) / 0.29
3D: 0 (-4; 4) / 0.83
15-min postprandial rating / 91 / 94 / 91
1D: 0 (-5; 6) / 0.89
2D: 3 (-2; 9) / 0.24
3D: 3 (-3; 8) / 0.30
(100-prospective food consumption) (mm)
Fasting rating / 51 / 45 / 45
1D: 5 (-3; 14) / 0.19
2D: 0 (-8; 8) / 0.97
3D: -5 (-13; 3) / 0.19
Mean rating AUC15-300min/285min / 66 / 67 / 54
1D: 13 (6; 19) / 0.0002
2D: 13 (7; 20) / 0.0001
3D: 0.7 (-6; 7) / 0.82
Maximum rating / 92 / 90 / 80
1D: 12 (6; 18) / 0.0004
2D: 10 (4; 17) / 0.002
3D: -2 (-8; 5) / 0.59
15-min postprandial rating / 87 / 84 / 72
1D: 15 (5; 24) / 0.003
2D: 12 (3; 22) / 0.01
3D: -2 (-12; 7) / 0.64
Nausea (mm)
Fasting rating / 5 / 11 / 4
1D: 1 (-6; 7) / 0.81
2D: 7 (1; 14) / 0.02
3D: 7 (0; 13) / 0.04
Mean rating AUC15-300min/285min / 13 / 16 / 12
1D: 2 (-6; 9) / 0.66
2D: 5 (-2; 12) / 0.18
3D: 3 (-4; 10) / 0.35
Maximum rating / 28 / 34 / 26
1D: 2 (-12; 16) / 0.72
2D: 8 (-5; 22) / 0.23
3D: 6 (-8; 20) / 0.39
15-min postprandial rating / 18 / 22 / 13
1D: 4 (-7; 16) / 0.46
2D: 9 (-3; 21) / 0.14
3D: 4 (-7; 16) / 0.46

Data are estimated means. Treatment differences are estimated means (95% CIs). Overall appetite score was the average of the 4 scores (satiety + fullness + [100-prospective food consumption] + [100-hunger])/4. Comparisons between treatment groups were performed using the parametric linear mixed-effect model on the original outcome values. The model included effects of subject, period and treatment group (subject was included as a random effect).

TABLE 2. Comparison of estimated means and treatment differences for energy expenditure, substrate oxidation rates and weight measures after 5 weeks of treatment.

Parameter / Liraglutide
1.8 mg / Liraglutide
3.0 mg / Placebo / Treatment difference (D) for
1liraglutide 1.8 mg vs placebo
2liraglutide 3.0 mg vs placebo
3liraglutide 3.0 mg vs 1.8 mg / P value
Energy expenditure / n=26 / n=30 / n=29
Energy balance (%) / -4.63 / -3.74 / -2.76
1D: -1.87 (-3.58; -0.17) / 0.03
2D: -0.98 (-2.59; 0.64) / 0.23
3D: 0.90 (-0.75; 2.54) / 0.28
TEE (kJh-1) – original analysis / 478.3 / 468.8 / 492.9
1D: -14.6 (-26.7; -2.45) / 0.02
2D: -24.2 (-35.4; -12.9) / 0.0001
3D: -9.59 (-20.8; 1.66) / 0.09
TEE (kJh-1) – post hoc / 479.8 / 471.5 / 488.4
analysis / 1D: -8.63 (-22.3; 5.06) / 0.21
2D: -17.0 (-30.7; -3.19) / 0.02
3D: -8.33 (-19.5; 2.80) / 0.14
3-h EE during lowest SPA / 323.6 / 324.3 / 333.9
(kJh-1) / 1D: -10.3 (-20.2; -0.34) / 0.04
2D: -9.6 (-19.0; -0.12) / 0.05
3D: 0.71 (-8.6; 10.0) / 0.88
PAL / 1.48 / 1.45 / 1.48
1D: -0.00 (-0.04; 0.03) / 0.79
2D: -0.03 (-0.07; 0.00) / 0.06
3D: -0.03 (-0.06; 0.01) / 0.12
AIEE / 166.9 / 155.1 / 168.6
1D: -1.74 (-14.7; 11.24) / 0.79
2D: -13.5 (-25.7; -1.4) / 0.03
3D: -11.8 (-24.0; 0.42) / 0.06
Substrate oxidation rates
24-h RQ / n=26 / n=30 / n=29
0.86 / 0.88 / 0.88
1D: -0.02 (-0.03; -0.01) / <0.0001
2D: -0.01 (-0.02; 0.00) / 0.09
3D: 0.01 (0.00; 0.02) / 0.006
24-h fat oxidation (kJh-1) / n=26 / n=30 / n=29
– original analysis / 172.1 / 151.6 / 143.7
1D: 28.36 (12.50; 44.21) / 0.0008
2D: 7.92 (-6.95; 22.79) / 0.29
3D: -20.4 (-35.5; -5.42) / 0.009
24-h CHO oxidation (kJh-1) / n=26 / n=30 / n=29
– original analysis / 269.9 / 282.4 / 313.1
1D: -43.2 (-63.3; -23.2) / <0.0001
2D: -30.7 (-49.5; -11.9) / 0.002
3D: 12.52 (-6.45; 31.48) / 0.19
24-h protein oxidation (kJh-1) / n=28 / n=30 / n=30
– original analysis / 47.67 / 45.86 / 51.44
1D: -3.77 (-7.39; -0.15) / 0.04
2D: -5.58 (-9.14; -2.03) / 0.003
3D: -1.81 (-5.37; 1.75) / 0.31
24-h fat oxidation (%) / n=26 / n=30 / n=29
– post hoc analysis / 35.46 / 32.28 / 29.43
1D: 6.03 (2.86; 9.19) / 0.0003
2D: 2.85 (-0.09; 5.78) / 0.06
3D -3.18 (-6.16; -0.20) / 0.04
24-h CHO oxidation (%) / n=26 / n=30 / n=29
– post hoc analysis / 56.90 / 60.32 / 63.59
1D: -6.69 (-10.3; -3.04) / 0.0005
2D: -3.27 (-6.65; 0.10) / 0.06
3D: 3.42 (-0.00; 6.84) / 0.05
24-h protein oxidation (%) / n=26 / n=30 / n=29
– post hoc analysis / 9.94 / 9.72 / 10.14
1D: -0.20 (-1.01; 0.61) / 0.63
2D: -0.42 (-1.16; 0.32) / 0.26
3D: -0.22 (-0.97; 0.53) / 0.55
Weight measures / n=30 / n=32 / n=33
Body weight (kg) / 100.3 / 100.0 / 102.5
1D: -2.14 (-3.21; -1.07) / 0.0002
2D: -2.46 (-3.53; -1.38) / <0.0001
3D: -0.32 (-1.38; 0.74) / 0.55
BMI (kgm-2) / 33.54 / 33.41 / 34.27
1D: -0.72 (-1.09; -0.36) / 0.0003
2D: -0.86 (-1.22; -0.49) / <0.0001
3D: -0.14 (-0.49; 0.22) / 0.45

TEE, 24-hour total energy expenditure; SPA, spontaneous physical activity; PAL, physical activity level; AIEE, activity induced energy expenditure; RQ, respiratory quotient; CHO, carbohydrate; BMI, body mass index

Data are estimated means. Treatment differences are estimated means (95% CIs). Comparisons between treatment groups were performed using the parametric linear mixed effect model. The model included effects of subject, period and treatment group (subject was included as a random effect).

In the post hoc analysis for TEE, body weight after 5 weeks of treatment was added to the original linear mixed-effect model.

In the post hoc analyses for substrate oxidation rates, energy balance and gender were added as fixed effects to the original model. Substrate oxidation rates were expressed as either kJ/h or % of TEE.

TABLE 3. Adverse events with an incidence of >5% in any treatment group

Liraglutide 1.8 mg / Liraglutide 3.0 mg / Placebo
N / (%) / E / R / N / (%) / E / R / N / (%) / E / R
Safety analysis set / 30 / 32 / 32
Exposure (years) / 3.2 / 3.4 / 3.5
All adverse events / 27 / (90.0) / 117 / 36.1 / 30 / (93.8) / 86 / 25.1 / 24 / (75.0) / 54 / 15.6
Gastrointestinal disorders
Nausea / 11 / (36.7) / 18 / 5.6 / 9 / (28.1) / 13 / 3.8 / 3 / (9.4) / 4 / 1.2
Diarrhea / 6 / (20.0) / 6 / 1.9 / 9 / (28.1) / 13 / 3.8 / 3 / (9.4) / 3 / 0.9
Feces hard / 5 / (16.7) / 6 / 1.9 / 1 / (3.1) / 1 / 0.3
Gastroesophageal reflux disease / 4 / (13.3) / 12 / 3.7 / 5 / (15.6) / 6 / 1.8 / 4 / (12.5) / 4 / 1.2
Abdominal pain upper / 2 / (6.7) / 4 / 1.2 / 1 / (3.1) / 1 / 0.3 / 1 / (3.1) / 1 / 0.3
Constipation / 2 / (6.7) / 2 / 0.6 / 3 / (9.4) / 3 / 0.9 / 1 / (3.1) / 1 / 0.3
Eructation / 2 / (6.7) / 2 / 0.6 / 1 / (3.1) / 1 / 0.3
Infrequent bowel movements / 2 / (6.7) / 2 / 0.6
Vomiting / 2 / (6.7) / 2 / 0.6 / 4 / (12.5) / 4 / 1.2
Nervous system disorders
Headache / 15 / (50.0) / 19 / 5.9 / 9 / (28.1) / 11 / 3.2 / 10 / (31.3) / 11 / 3.2
Dizziness / 3 / (10.0) / 4 / 1.2 / 2 / (6.3) / 3 / 0.9 / 3 / (9.4) / 3 / 0.9
Metabolism and nutrition
Decreased appetite / 9 / (30.0) / 10 / 3.1 / 8 / (25.0) / 8 / 2.3 / 1 / (3.1) / 1 / 0.3
Infections and infestations
Influenza / 5 / (16.7) / 5 / 1.5 / 5 / (15.6) / 5 / 1.5 / 5 / (15.6) / 5 / 1.4
Nasopharyngitis / 2 / (6.7) / 2 / 0.6 / 1 / (3.1) / 1 / 0.3
General disorders and administration site conditions
Influenza-like illness / 2 / (6.7) / 2 / 0.6 / 2 / (6.3) / 2 / 0.6 / 1 / (3.1) / 1 / 0.3
Musculoskeletal and connective tissues disorders
Bursitis / 2 / (6.7) / 2 / 0.6

N, number of subjects with adverse event; %, proportion in analysis set having adverse events; E, Number of adverse events; R, event rate, exposure years

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