parallel randomized trial

PIONEER 4

Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus

Type 2 diabetes (adults)NCT02863419S000133

Design

Randomized: 711
Start year: 2016
Treatment: 52 weeks, follow-up 57 weeks
Countries: Croatia, Czech Republic, Germany, Hungary, Japan, Latvia, Poland, Slovakia, South Africa, Ukraine, United Arab Emirates, USA (100 sites)
Sponsor: Novo Nordisk A/S (industry)
Eligibility: Age 18 or older; T2D on metformin with or without SGLT2i; HbA1c 7.0 to 9.5 percent; eGFR 60 or more

Conduct and analysis

Blinding: double blind
Sequence generation: other adequate
Allocation concealment: central
Outcome adjudication: yes
Primary estimand: treatment policy
Analysis population: full analysis
Missing data: pattern mixture model with multiple imputation

Arms

Arm	Treatment	Background	Randomized	Analyzed	Completed treatment
A1	Semaglutide 14 mg oral once daily (original tablet) Oral semaglutide 14 mg	metformin with or without SGLT2 inhibitor; lifestyle: not reported	285	285	241
A2	Liraglutide 1.8 mg subcutaneous once daily Subcutaneous liraglutide 1.8 mg	metformin with or without SGLT2 inhibitor; lifestyle: not reported	284	284	248
A3	Placebo Placebo	metformin with or without SGLT2 inhibitor; lifestyle: not reported	142	142	125

Baseline characteristics

As printed in the trial reports or registry, per arm or for the whole trial.

Characteristic	Statistic	Semaglutide 14 mg oral once daily (original tablet) A1	Liraglutide 1.8 mg subcutaneous once daily A2	Placebo A3
age	mean (years)	56	56	57
age	sd (years)	10	10	10
asian	n	39	36	19
asian	percent	14	13	13
black	n	12	9	8
black	percent	4	3	6
bmi	mean (kg/m2)	32.5	33.4	32.9
bmi	sd (kg/m2)	5.9	6.7	6.1
diabetes duration	mean (years)	7.8	7.3	7.8
diabetes duration	sd (years)	5.7	5.3	5.5
egfr	mean (mL/min/1.73 m2)	96	96	95
egfr	sd (mL/min/1.73 m2)	15	15	15
female	n	138	135	68
female	percent	48	48	48
hba1c	mean (percent)	8.0	8.0	7.9
hba1c	sd (percent)	0.7	0.7	0.7
hispanic	n	17	18	5
hispanic	percent	6	6	4
other race other	n	3	10	4
other race other	percent	1	4	3
sglt2i use	n	74	73	36
sglt2i use	percent	26	26	25
waist	mean (cm)	108.3	109.1	108.0
waist	sd (cm)	14.3	15.1	13.6
weight	mean (kg)	92.9	95.5	93.2
weight	sd (kg)	20.6	21.9	20.0
white	n	208	212	99
white	percent	73	75	70

Analyses this trial contributes to

Results

282 adjudicated result lines, grouped by outcome. Open an outcome to see its values.

HbA1c change (29 lines; O01)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
26	A1 vs A3	md	-1.1 percent		-1.2 to -0.9		treatment policy; full analysis; R0015836:Results
26	A1	change	-1.4 percent	0.9		285	hypothetical; full analysis; registry:outcomes
26	A1	change	-1.2 percent	0.1		285	treatment policy; full analysis; R0015836:Results
26	A1	change	-1.2 percent	0.9		285	treatment policy; full analysis; registry:outcomes
26	A1 vs A2	md	-0.1 percent		-0.3 to 0.0		treatment policy; full analysis; R0015836:Results
26	A1 vs A3	md	-1.2 percent		-1.4 to -1.0		hypothetical; full analysis; R0015836:Results
26	A1	change	-1.3 percent			238	hypothetical; full analysis; R0015836:Figure 2B
26	A1 vs A2	md	-0.2 percent		-0.3 to -0.1		hypothetical; full analysis; R0015836:Results
26	A2	change	-1.1 percent	0.9		284	treatment policy; full analysis; registry:outcomes
26	A2	change	-1.2 percent	0.9		284	hypothetical; full analysis; registry:outcomes
26	A2	change	-1.1 percent			245	hypothetical; full analysis; R0015836:Figure 2B
26	A2	change	-1.1 percent	0.1		284	treatment policy; full analysis; R0015836:Results
26	A3	change	-0.2 percent	0.1		142	treatment policy; full analysis; R0015836:Results
26	A3	change	-0.1 percent			112	hypothetical; full analysis; R0015836:Figure 2B
26	A3	change	-0.1 percent	0.7		142	hypothetical; full analysis; registry:outcomes
26	A3	change	-0.1 percent	0.7		142	treatment policy; full analysis; registry:outcomes
52	A1	change	-1.2 percent			220	hypothetical; full analysis; R0015836:Figure 2B
52	A1 vs A2	md	-0.3 percent		-0.4 to -0.1		hypothetical; full analysis; R0015836:Figure 2B
52	A1 vs A3	md	-1.4 percent		-1.6 to -1.2		hypothetical; full analysis; R0015836:Figure 2B
52	A1	change	-1.2 percent			285	treatment policy; full analysis; R0015836:Figure 2B
52	A1	change	-1.2 percent	1.0		275	treatment policy; other; registry:outcomes
52	A1 vs A2	md	-0.3 percent		-0.5 to -0.1		treatment policy; full analysis; R0015836:Results
52	A1 vs A3	md	-1.0 percent		-1.2 to -0.8		treatment policy; full analysis; R0015836:Results
52	A2	change	-0.9 percent			230	hypothetical; full analysis; R0015836:Figure 2B
52	A2	change	-0.9 percent			284	treatment policy; full analysis; R0015836:Figure 2B
52	A2	change	-0.9 percent	1.0		269	treatment policy; other; registry:outcomes
52	A3	change	-0.2 percent			142	treatment policy; full analysis; R0015836:Figure 2B
52	A3	change	-0.1 percent	0.9		133	treatment policy; other; registry:outcomes
52	A3	change	0.2 percent			82	hypothetical; full analysis; R0015836:Figure 2B

Body weight change in kilograms (diabetes) (29 lines; O02)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
26	A1 vs A3	md	-3.8 kg		-4.7 to -3.0		treatment policy; full analysis; R0015836:Results
26	A1	change	-4.4 kg	4.4		285	treatment policy; full analysis; registry:outcomes
26	A1 vs A2	md	-1.2 kg		-1.9 to -0.6		treatment policy; full analysis; R0015836:Results
26	A1	change	-4.7 kg			238	hypothetical; full analysis; R0015836:Figure 3B
26	A1	change	-4.7 kg	4.3		285	hypothetical; full analysis; registry:outcomes
26	A1 vs A2	md	-1.5 kg		-2.2 to -0.9		hypothetical; full analysis; R0015836:Results
26	A1 vs A3	md	-4.0 kg		-4.8 to -3.2		hypothetical; full analysis; R0015836:Results
26	A1	change	-4.4 kg	0.2		285	treatment policy; full analysis; R0015836:Results
26	A2	change	-3.2 kg	3.7		284	treatment policy; full analysis; registry:outcomes
26	A2	change	-3.2 kg			244	hypothetical; full analysis; R0015836:Figure 3B
26	A2	change	-3.3 kg	3.7		284	hypothetical; full analysis; registry:outcomes
26	A2	change	-3.1 kg	0.2		284	treatment policy; full analysis; R0015836:Results
26	A3	change	-0.7 kg	3.1		142	hypothetical; full analysis; registry:outcomes
26	A3	change	-0.7 kg			112	hypothetical; full analysis; R0015836:Figure 3B
26	A3	change	-0.6 kg	3.1		142	treatment policy; full analysis; registry:outcomes
26	A3	change	-0.5 kg	0.3		142	treatment policy; full analysis; R0015836:Results
52	A1 vs A3	md	-3.8 kg		-4.8 to -2.7		hypothetical; full analysis; R0015836:Figure 3B
52	A1	change	-4.3 kg			285	treatment policy; full analysis; R0015836:Figure 3B
52	A1 vs A2	md	-1.3 kg		-2.1 to -0.5		treatment policy; full analysis; R0015836:Figure 3B
52	A1	change	-4.4 kg	5.5		275	treatment policy; other; registry:outcomes
52	A1 vs A3	md	-3.3 kg		-4.3 to -2.4		treatment policy; full analysis; R0015836:Figure 3B
52	A1	change	-5.0 kg			223	hypothetical; full analysis; R0015836:Figure 3B
52	A1 vs A2	md	-1.8 kg		-2.6 to -1.0		hypothetical; full analysis; R0015836:Figure 3B
52	A2	change	-3.0 kg			284	treatment policy; full analysis; R0015836:Figure 3B
52	A2	change	-3.1 kg			230	hypothetical; full analysis; R0015836:Figure 3B
52	A2	change	-3.1 kg	4.4		269	treatment policy; other; registry:outcomes
52	A3	change	-1.2 kg			83	hypothetical; full analysis; R0015836:Figure 3B
52	A3	change	-1.0 kg	3.8		133	treatment policy; other; registry:outcomes
52	A3	change	-1.0 kg			142	treatment policy; full analysis; R0015836:Figure 3B

HbA1c below 7 percent (26 lines; O03)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
26	A1 vs A2	or	1.45	0.98 to 2.13		hypothetical; full analysis; R0015836:Figure 2C
26	A1 vs A3	or	19.80	10.82 to 36.24		hypothetical; full analysis; R0015836:Figure 2C
26	A1	responders	67.6		278	treatment policy; full analysis; R0015836:Figure 2C
26	A1 vs A2	or	1.31	0.91 to 1.89		treatment policy; full analysis; R0015836:Figure 2C
26	A1	responders			188 / 285	treatment policy; full analysis; registry:outcomes
26	A1 vs A3	or	17.10	9.50 to 30.77		treatment policy; full analysis; R0015836:Figure 2C
26	A1	responders	72.3		238	hypothetical; full analysis; R0015836:Figure 2C
26	A2	responders	61.8		272	treatment policy; full analysis; R0015836:Figure 2C
26	A2	responders	65.3		245	hypothetical; full analysis; R0015836:Figure 2C
26	A2	responders			168 / 284	treatment policy; full analysis; registry:outcomes
26	A3	responders	14.2		134	treatment policy; full analysis; R0015836:Figure 2C
26	A3	responders	16.1		112	hypothetical; full analysis; R0015836:Figure 2C
26	A3	responders			19 / 142	treatment policy; full analysis; registry:outcomes
52	A1 vs A2	or	1.38	0.93 to 2.04		hypothetical; full analysis; R0015836:Figure 2C
52	A1 vs A3	or	18.45	9.63 to 35.35		hypothetical; full analysis; R0015836:Figure 2C
52	A1	responders	68.6		220	hypothetical; full analysis; R0015836:Figure 2C
52	A1	responders	60.7		275	treatment policy; full analysis; R0015836:Figure 2C
52	A1	responders			167 / 285	treatment policy; full analysis; registry:outcomes
52	A1 vs A2	or	1.33	0.93 to 1.91		treatment policy; full analysis; R0015836:Figure 2C
52	A1 vs A3	or	11.36	6.40 to 20.19		treatment policy; full analysis; R0015836:Figure 2C
52	A2	responders	55.0		269	treatment policy; full analysis; R0015836:Figure 2C
52	A2	responders			148 / 284	treatment policy; full analysis; registry:outcomes
52	A2	responders	62.6		230	hypothetical; full analysis; R0015836:Figure 2C
52	A3	responders	18.3		82	hypothetical; full analysis; R0015836:Figure 2C
52	A3	responders			20 / 142	treatment policy; full analysis; registry:outcomes
52	A3	responders	15.0		133	treatment policy; full analysis; R0015836:Figure 2C

Level 2 or 3 hypoglycemia (participants) (3 lines; O04)

Arm	Statistic	Events / N	Detail
A1	events	2 / 285	while on treatment; safety; R0015836:Table 3
A2	events	7 / 284	while on treatment; safety; R0015836:Table 3
A3	events	3 / 142	while on treatment; safety; R0015836:Table 3

Level 2 or 3 hypoglycemia (episode rate) (3 lines; O04B)

Arm	Statistic	Events / N	Detail
A1	rate	285	while on treatment; safety; registry:outcomes
A2	rate	284	while on treatment; safety; registry:outcomes
A3	rate	142	while on treatment; safety; registry:outcomes

Systolic blood pressure change (26 lines; O05)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
26	A1 vs A2	md	-0 mmHg		-2 to 2		treatment policy; safety; R0015836:Supplement Table S9
26	A1 vs A3	md	-2 mmHg		-4 to 1		treatment policy; safety; R0015836:Supplement Table S9
26	A1	change	-4 mmHg				while on treatment; safety; R0015836:Supplement Table S9
26	A1	change	-4 mmHg			285	treatment policy; safety; R0015836:Supplement Table S9
26	A1	change	-4 mmHg	13		285	while on treatment; safety; registry:outcomes
26	A1 vs A2	md	-0 mmHg		-2 to 2		while on treatment; safety; R0015836:Supplement Table S9
26	A1 vs A3	md	-2 mmHg		-4 to 1		while on treatment; safety; R0015836:Supplement Table S9
26	A2	change	-4 mmHg				while on treatment; safety; R0015836:Supplement Table S9
26	A2	change	-3 mmHg			284	treatment policy; safety; R0015836:Supplement Table S9
26	A2	change	-4 mmHg	13		284	while on treatment; safety; registry:outcomes
26	A3	change	-2 mmHg				while on treatment; safety; R0015836:Supplement Table S9
26	A3	change	-2 mmHg	13		142	while on treatment; safety; registry:outcomes
26	A3	change	-2 mmHg			142	treatment policy; safety; R0015836:Supplement Table S9
52	A1 vs A3	md	-3 mmHg		-6 to -1		treatment policy; safety; R0015836:Supplement Table S9
52	A1	change	-3 mmHg			285	treatment policy; safety; R0015836:Supplement Table S9
52	A1 vs A2	md	-1 mmHg		-3 to 2		treatment policy; safety; R0015836:Supplement Table S9
52	A1	change	-3 mmHg				while on treatment; safety; R0015836:Supplement Table S9
52	A1	change	-3 mmHg	14		285	while on treatment; safety; registry:outcomes
52	A1 vs A2	md	-0 mmHg		-3 to 2		while on treatment; safety; R0015836:Supplement Table S9
52	A1 vs A3	md	-3 mmHg		-6 to -1		while on treatment; safety; R0015836:Supplement Table S9
52	A2	change	-3 mmHg				while on treatment; safety; R0015836:Supplement Table S9
52	A2	change	-3 mmHg	13		284	while on treatment; safety; registry:outcomes
52	A2	change	-2 mmHg			284	treatment policy; safety; R0015836:Supplement Table S9
52	A3	change	-0 mmHg				while on treatment; safety; R0015836:Supplement Table S9
52	A3	change	0 mmHg			142	treatment policy; safety; R0015836:Supplement Table S9
52	A3	change	-0 mmHg	13		142	while on treatment; safety; registry:outcomes

Percent body weight change (26 lines; O10)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
26	A1 vs A3	md	-4.3 percent		-5.2 to -3.4		treatment policy; full analysis; R0015836:Supplement Table S3
26	A1	percent change	-5.2 percent			238	hypothetical; full analysis; R0015836:Supplement Table S3
26	A1 vs A2	md	-1.8 percent		-2.5 to -1.1		hypothetical; full analysis; R0015836:Supplement Table S3
26	A1 vs A3	md	-4.5 percent		-5.4 to -3.6		hypothetical; full analysis; R0015836:Supplement Table S3
26	A1	percent change	-4.8 percent			285	treatment policy; full analysis; R0015836:Supplement Table S3
26	A1	percent change	-4.89 percent	4.95		285	treatment policy; full analysis; registry:outcomes
26	A1 vs A2	md	-1.5 percent		-2.2 to -0.7		treatment policy; full analysis; R0015836:Supplement Table S3
26	A2	percent change	-3.4 percent			244	hypothetical; full analysis; R0015836:Supplement Table S3
26	A2	percent change	-3.33 percent	3.78		284	treatment policy; full analysis; registry:outcomes
26	A2	percent change	-3.3 percent			284	treatment policy; full analysis; R0015836:Supplement Table S3
26	A3	percent change	-0.5 percent			142	treatment policy; full analysis; R0015836:Supplement Table S3
26	A3	percent change	-0.7 percent			112	hypothetical; full analysis; R0015836:Supplement Table S3
26	A3	percent change	-0.60 percent	3.34		142	treatment policy; full analysis; registry:outcomes
52	A1	percent change	-4.94 percent	6.37		285	treatment policy; full analysis; registry:outcomes
52	A1 vs A3	md	-3.9 percent		-5.0 to -2.8		treatment policy; full analysis; R0015836:Supplement Table S3
52	A1	percent change	-5.6 percent			223	hypothetical; full analysis; R0015836:Supplement Table S3
52	A1 vs A2	md	-2.2 percent		-3.1 to -1.3		hypothetical; full analysis; R0015836:Supplement Table S3
52	A1 vs A3	md	-4.4 percent		-5.6 to -3.3		hypothetical; full analysis; R0015836:Supplement Table S3
52	A1	percent change	-4.8 percent			285	treatment policy; full analysis; R0015836:Supplement Table S3
52	A1 vs A2	md	-1.6 percent		-2.5 to -0.7		treatment policy; full analysis; R0015836:Supplement Table S3
52	A2	percent change	-3.2 percent			284	treatment policy; full analysis; R0015836:Supplement Table S3
52	A2	percent change	-3.25 percent	4.33		284	treatment policy; full analysis; registry:outcomes
52	A2	percent change	-3.4 percent			230	hypothetical; full analysis; R0015836:Supplement Table S3
52	A3	percent change	-0.9 percent			142	treatment policy; full analysis; R0015836:Supplement Table S3
52	A3	percent change	-1.2 percent			83	hypothetical; full analysis; R0015836:Supplement Table S3
52	A3	percent change	-0.99 percent	4.12		142	treatment policy; full analysis; registry:outcomes

Weight loss of 5 percent or more (26 lines; O11A)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
26	A1 vs A3	or	9.40	4.71 to 18.77		treatment policy; full analysis; R0015836:Figure 3C
26	A1	responders	43.5		278	treatment policy; full analysis; R0015836:Figure 3C
26	A1	responders			121 / 285	treatment policy; full analysis; registry:outcomes
26	A1 vs A2	or	1.95	1.36 to 2.80		treatment policy; full analysis; R0015836:Figure 3C
26	A1 vs A2	or	2.22	1.54 to 3.20		hypothetical; full analysis; R0015836:Figure 3C
26	A1 vs A3	or	10.72	5.21 to 22.06		hypothetical; full analysis; R0015836:Figure 3C
26	A1	responders	46.2		238	hypothetical; full analysis; R0015836:Figure 3C
26	A2	responders			75 / 284	treatment policy; full analysis; registry:outcomes
26	A2	responders	28.3		244	hypothetical; full analysis; R0015836:Figure 3C
26	A2	responders	27.7		271	treatment policy; full analysis; R0015836:Figure 3C
26	A3	responders	7.5		134	treatment policy; full analysis; R0015836:Figure 3C
26	A3	responders	7.1		112	hypothetical; full analysis; R0015836:Figure 3C
26	A3	responders			10 / 142	treatment policy; full analysis; registry:outcomes
52	A1 vs A3	or	5.64	3.17 to 10.02		treatment policy; full analysis; R0015836:Figure 3C
52	A1	responders	49.3		223	hypothetical; full analysis; R0015836:Figure 3C
52	A1 vs A2	or	2.65	1.80 to 3.89		hypothetical; full analysis; R0015836:Figure 3C
52	A1 vs A3	or	6.34	3.33 to 12.07		hypothetical; full analysis; R0015836:Figure 3C
52	A1	responders	44.7		275	treatment policy; full analysis; R0015836:Figure 3C
52	A1	responders			123 / 285	treatment policy; full analysis; registry:outcomes
52	A1 vs A2	or	2.38	1.65 to 3.43		treatment policy; full analysis; R0015836:Figure 3C
52	A2	responders	26.1		230	hypothetical; full analysis; R0015836:Figure 3C
52	A2	responders			66 / 284	treatment policy; full analysis; registry:outcomes
52	A2	responders	24.5		269	treatment policy; full analysis; R0015836:Figure 3C
52	A3	responders	12.0		133	treatment policy; full analysis; R0015836:Figure 3C
52	A3	responders	12.0		83	hypothetical; full analysis; R0015836:Figure 3C
52	A3	responders			16 / 142	treatment policy; full analysis; registry:outcomes

Weight loss of 10 percent or more (20 lines; O11B)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
26	A1 vs A3	or	39.88	2.58 to 615.6		treatment policy; full analysis; R0015836:Table 2
26	A1	responders			36 / 238	hypothetical; full analysis; R0015836:Table 2
26	A1 vs A2	or	2.77	1.52 to 5.05		hypothetical; full analysis; R0015836:Table 2
26	A1 vs A3	or	42.92	2.85 to 646.3		hypothetical; full analysis; R0015836:Table 2
26	A1	responders			39 / 278	treatment policy; full analysis; R0015836:Table 2
26	A1 vs A2	or	2.45	1.35 to 4.44		treatment policy; full analysis; R0015836:Table 2
26	A2	responders			15 / 244	hypothetical; full analysis; R0015836:Table 2
26	A2	responders			16 / 271	treatment policy; full analysis; R0015836:Table 2
26	A3	responders			0 / 134	treatment policy; full analysis; R0015836:Table 2
26	A3	responders			0 / 112	hypothetical; full analysis; R0015836:Table 2
52	A1 vs A2	or	2.31	1.33 to 4.01		treatment policy; full analysis; R0015836:Table 2
52	A1	responders			41 / 223	hypothetical; full analysis; R0015836:Table 2
52	A1 vs A2	or	2.91	1.65 to 5.13		hypothetical; full analysis; R0015836:Table 2
52	A1 vs A3	or	8.39	2.79 to 25.26		hypothetical; full analysis; R0015836:Table 2
52	A1	responders			45 / 275	treatment policy; full analysis; R0015836:Table 2
52	A1 vs A3	or	5.74	2.14 to 15.36		treatment policy; full analysis; R0015836:Table 2
52	A2	responders			18 / 230	hypothetical; full analysis; R0015836:Table 2
52	A2	responders			20 / 269	treatment policy; full analysis; R0015836:Table 2
52	A3	responders			4 / 133	treatment policy; full analysis; R0015836:Table 2
52	A3	responders			3 / 83	hypothetical; full analysis; R0015836:Table 2

Acute kidney injury (3 lines; O121)

Arm	Statistic	Events / N	Detail
A1	events	0 / 285	treatment policy; safety; R0015836:Supplement Table S8
A2	events	1 / 284	treatment policy; safety; R0015836:Supplement Table S8
A3	events	0 / 142	treatment policy; safety; R0015836:Supplement Table S8

All cause mortality (3 lines; O20)

Arm	Statistic	Events / N	Detail
A1	events	3 / 285	treatment policy; safety; R0015836:Supplement Table S8
A2	events	4 / 284	treatment policy; safety; R0015836:Supplement Table S8
A3	events	1 / 142	treatment policy; safety; R0015836:Supplement Table S8

Four point MACE including unstable angina (3 lines; O21B)

Arm	Statistic	Events / N	Detail
A1	events	4 / 285	treatment policy; safety; R0015836:Supplement Table S8
A2	events	3 / 284	treatment policy; safety; R0015836:Supplement Table S8
A3	events	2 / 142	treatment policy; safety; R0015836:Supplement Table S8

Hospitalization for heart failure (3 lines; O23)

Arm	Statistic	Events / N	Detail
A1	events	0 / 285	while on treatment; safety; cardiac failure chronic; registry:adverse_events
A2	events	1 / 284	while on treatment; safety; cardiac failure chronic; registry:adverse_events
A3	events	0 / 142	while on treatment; safety; cardiac failure chronic; registry:adverse_events

Heart failure events (3 lines; O23B)

Arm	Statistic	Events / N	Detail
A1	events	0 / 285	treatment policy; safety; R0015836:Supplement Table S8
A2	events	1 / 284	treatment policy; safety; R0015836:Supplement Table S8
A3	events	0 / 142	treatment policy; safety; R0015836:Supplement Table S8

Health related quality of life total score (any instrument) (14 lines; O24C)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
26	A1 vs A2	md	-0.04 points		-0.88 to 0.80		treatment policy; full analysis; R0015836:Supplement Figure S4A
26	A1 vs A2	md	-0.48 points		-1.24 to 0.27		hypothetical; full analysis; R0015836:Supplement Figure S4B
26	A1 vs A3	md	1.66 points		0.70 to 2.61		hypothetical; full analysis; R0015836:Supplement Figure S4B
26	A1	change	3.59 points	6.12		285	not stated; full analysis; registry:outcomes
26	A1 vs A3	md	2.57 points		1.50 to 3.64		treatment policy; full analysis; R0015836:Supplement Figure S4A
26	A2	change	3.44 points	6.51		284	not stated; full analysis; registry:outcomes
26	A3	change	1.24 points	6.71		142	not stated; full analysis; registry:outcomes
52	A1 vs A3	md	2.03 points		0.85 to 3.22		hypothetical; full analysis; R0015836:Supplement Figure S4B
52	A1 vs A2	md	-0.14 points		-1.03 to 0.76		hypothetical; full analysis; R0015836:Supplement Figure S4B
52	A1	change	3.41 points	6.81		285	not stated; full analysis; registry:outcomes
52	A1 vs A2	md	-0.05 points		-0.94 to 0.84		treatment policy; full analysis; R0015836:Supplement Figure S4A
52	A1 vs A3	md	2.20 points		1.11 to 3.29		treatment policy; full analysis; R0015836:Supplement Figure S4A
52	A2	change	3.11 points	6.93		284	not stated; full analysis; registry:outcomes
52	A3	change	1.23 points	6.96		142	not stated; full analysis; registry:outcomes

Serious adverse events (3 lines; O25)

Arm	Statistic	Events / N	Detail
A1	events	31 / 285	while on treatment; safety; R0015836:Table 3
A2	events	22 / 284	while on treatment; safety; R0015836:Table 3
A3	events	15 / 142	while on treatment; safety; R0015836:Table 3

Discontinuation due to adverse events (3 lines; O26)

Arm	Statistic	Events / N	Detail
A1	events	31 / 285	while on treatment; safety; R0015836:Table 3
A2	events	26 / 284	while on treatment; safety; R0015836:Table 3
A3	events	5 / 142	while on treatment; safety; R0015836:Table 3

Nausea (7 lines; O27A)

Arm	Statistic	Events / N	Detail
A1	events	56 / 285	while on treatment; safety; R0015836:Table 3
A1	events	55 / 285	while on treatment; safety; registry:adverse_events
A1	events	1 / 285	while on treatment; safety; registry:adverse_events
A2	events	51 / 284	while on treatment; safety; R0015836:Table 3
A2	events	0 / 284	while on treatment; safety; registry:adverse_events
A3	events	5 / 142	while on treatment; safety; R0015836:Table 3
A3	events	0 / 142	while on treatment; safety; registry:adverse_events

Vomiting (7 lines; O27B)

Arm	Statistic	Events / N	Detail
A1	events	25 / 285	while on treatment; safety; R0015836:Table 3
A1	events	24 / 285	while on treatment; safety; registry:adverse_events
A1	events	1 / 285	while on treatment; safety; registry:adverse_events
A2	events	13 / 284	while on treatment; safety; R0015836:Table 3
A2	events	0 / 284	while on treatment; safety; registry:adverse_events
A3	events	3 / 142	while on treatment; safety; R0015836:Table 3
A3	events	0 / 142	while on treatment; safety; registry:adverse_events

Diarrhea (3 lines; O27C)

Arm	Statistic	Events / N	Detail
A1	events	43 / 285	while on treatment; safety; R0015836:Table 3
A2	events	31 / 284	while on treatment; safety; R0015836:Table 3
A3	events	11 / 142	while on treatment; safety; R0015836:Table 3

Constipation (3 lines; O27D)

Arm	Statistic	Events / N	Detail
A1	events	22 / 285	while on treatment; safety; R0015836:Table 3
A2	events	11 / 284	while on treatment; safety; R0015836:Table 3
A3	events	4 / 142	while on treatment; safety; R0015836:Table 3

Discontinuation due to gastrointestinal adverse events (3 lines; O27E)

Arm	Statistic	Events / N	Detail
A1	events	22 / 285	while on treatment; safety; R0015836:Table 3
A2	events	17 / 284	while on treatment; safety; R0015836:Table 3
A3	events	3 / 142	while on treatment; safety; R0015836:Table 3

Gallbladder and biliary disease (6 lines; O28)

Arm	Statistic	Events / N	Detail
A1	events	0 / 285	while on treatment; safety; cholelithiasis; registry:adverse_events
A1	events	0 / 285	while on treatment; safety; cholecystitis; registry:adverse_events
A2	events	1 / 284	while on treatment; safety; cholecystitis; registry:adverse_events
A2	events	1 / 284	while on treatment; safety; cholelithiasis; registry:adverse_events
A3	events	0 / 142	while on treatment; safety; cholecystitis; registry:adverse_events
A3	events	0 / 142	while on treatment; safety; cholelithiasis; registry:adverse_events

Acute pancreatitis (3 lines; O29)

Arm	Statistic	Events / N	Detail
A1	events	0 / 285	treatment policy; safety; R0015836:Supplement Table S8
A2	events	1 / 284	treatment policy; safety; R0015836:Supplement Table S8
A3	events	1 / 142	treatment policy; safety; R0015836:Supplement Table S8

Thyroid cancer (any) (9 lines; O32B)

Arm	Statistic	Events / N	Detail
A1	events	0 / 285	while on treatment; safety; thyroid cancer metastatic; registry:adverse_events
A1	events	1 / 285	treatment policy; safety; papillary malignant thyroid neoplasms; R0015836:Supplement Table S8
A1	events	1 / 285	while on treatment; safety; papillary thyroid cancer; registry:adverse_events
A2	events	1 / 284	while on treatment; safety; thyroid cancer metastatic; registry:adverse_events
A2	events	1 / 284	treatment policy; safety; papillary malignant thyroid neoplasms; R0015836:Supplement Table S8
A2	events	0 / 284	while on treatment; safety; papillary thyroid cancer; registry:adverse_events
A3	events	0 / 142	treatment policy; safety; papillary malignant thyroid neoplasms; R0015836:Supplement Table S8
A3	events	0 / 142	while on treatment; safety; papillary thyroid cancer; registry:adverse_events
A3	events	0 / 142	while on treatment; safety; thyroid cancer metastatic; registry:adverse_events

Diabetic retinopathy complications (9 lines; O33)

Arm	Statistic	Events / N	Detail
A1	events	8 / 285	treatment policy; safety; R0015836:Supplement Table S7
A1	events	0 / 285	treatment policy; safety; diabetic retinal edema; R0015836:Supplement Table S7
A1	events	8 / 285	treatment policy; safety; diabetic retinopathy; R0015836:Supplement Table S7
A2	events	4 / 284	treatment policy; safety; R0015836:Supplement Table S7
A2	events	2 / 284	treatment policy; safety; diabetic retinal edema; R0015836:Supplement Table S7
A2	events	3 / 284	treatment policy; safety; diabetic retinopathy; R0015836:Supplement Table S7
A3	events	2 / 142	treatment policy; safety; R0015836:Supplement Table S7
A3	events	0 / 142	treatment policy; safety; diabetic retinal edema; R0015836:Supplement Table S7
A3	events	2 / 142	treatment policy; safety; diabetic retinopathy; R0015836:Supplement Table S7

Death by suicide (3 lines; O35B)

Arm	Statistic	Events / N	Detail
A1	events	0 / 285	treatment policy; safety; R0015836:Supplement Table S6
A2	events	0 / 284	treatment policy; safety; R0015836:Supplement Table S6
A3	events	0 / 142	treatment policy; safety; R0015836:Supplement Table S6

Pancreatic cancer (3 lines; O38)

Arm	Statistic	Events / N	Detail
A1	events	0 / 285	treatment policy; safety; R0015836:Supplement Table S8
A2	events	1 / 284	treatment policy; safety; R0015836:Supplement Table S8
A3	events	0 / 142	treatment policy; safety; R0015836:Supplement Table S8

Any cancer (3 lines; O39)

Arm	Statistic	Events / N	Detail
A1	events	3 / 285	treatment policy; safety; R0015836:Supplement Table S8
A2	events	3 / 284	treatment policy; safety; R0015836:Supplement Table S8
A3	events	0 / 142	treatment policy; safety; R0015836:Supplement Table S8