parallel randomized trial

PIONEER 2

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

Type 2 diabetes (adults)NCT02863328S000251

Design

Randomized: 822
Start year: 2016
Treatment: 52 weeks, follow-up 57 weeks
Countries: Argentina, Brazil, Croatia, Greece, Hungary, Italy, Poland, Russia, Serbia, Spain, Thailand, USA
Sponsor: Novo Nordisk A/S (industry)
Eligibility: type 2 diabetes on metformin; HbA1c 7.0 to 10.5 percent; eGFR 60 or more

Conduct and analysis

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

Arms

Arm	Treatment	Background	Randomized	Analyzed	Completed treatment
A1	Semaglutide 14 mg oral once daily (original tablet) Oral semaglutide 14 mg	metformin; lifestyle: not reported	412	411	339
A2	Empagliflozin Empagliflozin 25 mg	metformin; lifestyle: not reported	410	410	365

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	Empagliflozin A2	Whole trial ALL
age: 45 to less than 65	n			512
age: 65 or older	n			215
age: less than 45	n			94
age	mean (years)	57	58
age	sd (years)	10	10
asian	n	28	21
black	n	26	33
bmi: 25 to less than 30	n			241
bmi: 30 to less than 35	n			265
bmi: 35 or more	n			262
bmi: less than 25	n			52
bmi	mean (kg/m2)	32.9	32.8
bmi	sd (kg/m2)	6.3	5.9
diabetes duration: 10 or more	n			200
diabetes duration: 5 to less than 10	n			274
diabetes duration: less than 5	n			347
diabetes duration	mean (years)	7.2	7.7
diabetes duration	sd (years)	5.8	6.3
egfr	mean (mL/min/1.73 m2)	96	95
egfr	sd (mL/min/1.73 m2)	15	15
female	n	205	201
hba1c: 8 or less	n			457
hba1c: more than 8 to 9	n			211
hba1c: more than 9	n			153
hba1c	mean (percent)	8.1	8.1
hba1c	sd (percent)	0.9	0.9
hispanic	n	91	108
other race american indian alaska native	n	0	0
other race native hawaiian pacific islander	n	0	0
other race other	n	2	3
white	n	355	353

Results

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

HbA1c change (47 lines; O01)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
26	A1 vs A2	md	-0.5 percent		-0.7 to -0.4		hypothetical; full analysis; registry:outcomes
26	A1	change	-1.5 percent	1.1		411	hypothetical; full analysis; registry:outcomes
26	A1	change	-1.3 percent	1.1		411	treatment policy; full analysis; registry:outcomes
26	A1 vs A2	md	-0.4 percent		-0.6 to -0.3		treatment policy; full analysis; R0018256:Supplement Figure S5A
26	A2	change	-0.9 percent	0.9		410	hypothetical; full analysis; registry:outcomes
26	A2	change	-0.9 percent	0.9		410	treatment policy; full analysis; registry:outcomes
52	A1	change	-1.3 percent			50	hypothetical; full analysis; age:less_than_45; R0021795:Figure 1A
52	A1	change	-1.3 percent	1.2		384	treatment policy; other; registry:outcomes
52	A1	change	-1.3 percent			256	hypothetical; full analysis; age:45_to_less_than_65; R0021795:Figure 1A
52	A1	change	-1.4 percent			105	hypothetical; full analysis; age:65_or_older; R0021795:Figure 1A
52	A1	change	-1.3 percent			124	hypothetical; full analysis; bmi:25_to_less_than_30; R0021795:Supplement Figure S11A
52	A1	change	-1.3 percent			126	hypothetical; full analysis; bmi:30_to_less_than_35; R0021795:Supplement Figure S11A
52	A1	change	-1.4 percent			131	hypothetical; full analysis; bmi:35_or_more; R0021795:Supplement Figure S11A
52	A1	change	-1.1 percent			29	hypothetical; full analysis; bmi:less_than_25; R0021795:Supplement Figure S11A
52	A1	change	-1.1 percent			88	hypothetical; full analysis; diabetes_duration:10_or_more; R0021795:Figure 2A
52	A1	change	-1.4 percent			144	hypothetical; full analysis; diabetes_duration:5_to_less_than_10; R0021795:Figure 2A
52	A1	change	-1.3 percent			179	hypothetical; full analysis; diabetes_duration:less_than_5; R0021795:Figure 2A
52	A1	change	-1.4 percent			91	hypothetical; full analysis; ethnicity:hispanic_latino; R0021795:Supplement Figure S4A
52	A1	change	-1.3 percent			320	hypothetical; full analysis; ethnicity:not_hispanic_latino; R0021795:Supplement Figure S4A
52	A1	change	-0.9 percent			228	hypothetical; full analysis; hba1c:8_or_less; R0021795:Figure 3A
52	A1	change	-1.7 percent			106	hypothetical; full analysis; hba1c:more_than_8_to_9; R0021795:Figure 3A
52	A1	change	-1.7 percent			77	hypothetical; full analysis; hba1c:more_than_9; R0021795:Figure 3A
52	A1	change	-1.8 percent			28	hypothetical; full analysis; race:asian; R0021795:Supplement Figure S3A
52	A1 vs A2	md	-0.7 percent		-1.3 to -0.2		hypothetical; other; race:asian; R0008864:Table
52	A1	change	-1.3 percent			26	hypothetical; full analysis; race:black; R0021795:Supplement Figure S3A
52	A1 vs A2	md	-0.8 percent		-1.3 to -0.3		hypothetical; other; race:black; R0008864:Table
52	A1	change	-1.3 percent			355	hypothetical; full analysis; race:white; R0021795:Supplement Figure S3A
52	A1 vs A2	md	-0.5 percent		-0.6 to -0.3		hypothetical; other; race:white; R0008864:Table
52	A2	change	-0.8 percent			168	hypothetical; full analysis; diabetes_duration:less_than_5; R0021795:Figure 2A
52	A2	change	-0.9 percent			108	hypothetical; full analysis; ethnicity:hispanic_latino; R0021795:Supplement Figure S4A
52	A2	change	-0.6 percent			112	hypothetical; full analysis; diabetes_duration:10_or_more; R0021795:Figure 2A
52	A2	change	-0.9 percent			130	hypothetical; full analysis; diabetes_duration:5_to_less_than_10; R0021795:Figure 2A
52	A2	change	-0.8 percent			353	hypothetical; full analysis; race:white; R0021795:Supplement Figure S3A
52	A2	change	-1.1 percent			21	hypothetical; full analysis; race:asian; R0021795:Supplement Figure S3A
52	A2	change	-0.8 percent			302	hypothetical; full analysis; ethnicity:not_hispanic_latino; R0021795:Supplement Figure S4A
52	A2	change	-0.8 percent			256	hypothetical; full analysis; age:45_to_less_than_65; R0021795:Figure 1A
52	A2	change	-0.8 percent			110	hypothetical; full analysis; age:65_or_older; R0021795:Figure 1A
52	A2	change	-0.5 percent			44	hypothetical; full analysis; age:less_than_45; R0021795:Figure 1A
52	A2	change	-0.5 percent			229	hypothetical; full analysis; hba1c:8_or_less; R0021795:Figure 3A
52	A2	change	-0.6 percent			117	hypothetical; full analysis; bmi:25_to_less_than_30; R0021795:Supplement Figure S11A
52	A2	change	-0.5 percent			33	hypothetical; full analysis; race:black; R0021795:Supplement Figure S3A
52	A2	change	-0.8 percent			139	hypothetical; full analysis; bmi:30_to_less_than_35; R0021795:Supplement Figure S11A
52	A2	change	-1.0 percent			105	hypothetical; full analysis; hba1c:more_than_8_to_9; R0021795:Figure 3A
52	A2	change	-1.0 percent			131	hypothetical; full analysis; bmi:35_or_more; R0021795:Supplement Figure S11A
52	A2	change	-0.9 percent	1.0		382	treatment policy; other; registry:outcomes
52	A2	change	-0.4 percent			23	hypothetical; full analysis; bmi:less_than_25; R0021795:Supplement Figure S11A
52	A2	change	-1.4 percent				hypothetical; full analysis; hba1c:more_than_9; R0021795:Figure 3A

Body weight change in kilograms (diabetes) (44 lines; O02)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
26	A1	change	-4.3 kg	4.4		411	hypothetical; full analysis; registry:outcomes
26	A1	change	-3.9 kg	4.4		411	treatment policy; full analysis; registry:outcomes
26	A1 vs A2	md	-0.1 kg		-0.7 to 0.5		treatment policy; full analysis; R0018256:Supplement Figure S5B
26	A1 vs A2	md	-0.4 kg		-1.0 to 0.1		hypothetical; full analysis; registry:outcomes
26	A2	change	-3.8 kg	3.8		410	treatment policy; full analysis; registry:outcomes
26	A2	change	-3.9 kg	3.8		410	hypothetical; full analysis; registry:outcomes
52	A1	change	-3.8 kg			126	hypothetical; full analysis; bmi:30_to_less_than_35; R0021795:Supplement Figure S11B
52	A1	change	-4.5 kg			179	hypothetical; full analysis; diabetes_duration:less_than_5; R0021795:Figure 2B
52	A1	change	-4.5 kg			50	hypothetical; full analysis; age:less_than_45; R0021795:Figure 1B
52	A1	change	-5.1 kg			91	hypothetical; full analysis; ethnicity:hispanic_latino; R0021795:Supplement Figure S4B
52	A1	change	-6.4 kg			131	hypothetical; full analysis; bmi:35_or_more; R0021795:Supplement Figure S11B
52	A1	change	-4.6 kg			320	hypothetical; full analysis; ethnicity:not_hispanic_latino; R0021795:Supplement Figure S4B
52	A1	change	-4.7 kg			105	hypothetical; full analysis; age:65_or_older; R0021795:Figure 1B
52	A1	change	-5.1 kg			228	hypothetical; full analysis; hba1c:8_or_less; R0021795:Figure 3B
52	A1	change	-2.7 kg			29	hypothetical; full analysis; bmi:less_than_25; R0021795:Supplement Figure S11B
52	A1	change	-5.2 kg			106	hypothetical; full analysis; hba1c:more_than_8_to_9; R0021795:Figure 3B
52	A1	change	-4.3 kg			124	hypothetical; full analysis; bmi:25_to_less_than_30; R0021795:Supplement Figure S11B
52	A1	change	-2.7 kg			77	hypothetical; full analysis; hba1c:more_than_9; R0021795:Figure 3B
52	A1	change	-4.0 kg	5.5		386	treatment policy; other; registry:outcomes
52	A1	change	-6.2 kg			28	hypothetical; full analysis; race:asian; R0021795:Supplement Figure S3B
52	A1	change	-4.9 kg			88	hypothetical; full analysis; diabetes_duration:10_or_more; R0021795:Figure 2B
52	A1	change	-3.8 kg			26	hypothetical; full analysis; race:black; R0021795:Supplement Figure S3B
52	A1	change	-4.7 kg			256	hypothetical; full analysis; age:45_to_less_than_65; R0021795:Figure 1B
52	A1	change	-4.6 kg			355	hypothetical; full analysis; race:white; R0021795:Supplement Figure S3B
52	A1	change	-4.9 kg			144	hypothetical; full analysis; diabetes_duration:5_to_less_than_10; R0021795:Figure 2B
52	A2	change	-2.9 kg				hypothetical; full analysis; hba1c:more_than_9; R0021795:Figure 3B
52	A2	change	-3.7 kg	4.3		383	treatment policy; other; registry:outcomes
52	A2	change	-3.9 kg			256	hypothetical; full analysis; age:45_to_less_than_65; R0021795:Figure 1B
52	A2	change	-4.0 kg			110	hypothetical; full analysis; age:65_or_older; R0021795:Figure 1B
52	A2	change	-2.8 kg			44	hypothetical; full analysis; age:less_than_45; R0021795:Figure 1B
52	A2	change	-3.2 kg			117	hypothetical; full analysis; bmi:25_to_less_than_30; R0021795:Supplement Figure S11B
52	A2	change	-3.6 kg			139	hypothetical; full analysis; bmi:30_to_less_than_35; R0021795:Supplement Figure S11B
52	A2	change	-4.7 kg			131	hypothetical; full analysis; bmi:35_or_more; R0021795:Supplement Figure S11B
52	A2	change	-2.3 kg			23	hypothetical; full analysis; bmi:less_than_25; R0021795:Supplement Figure S11B
52	A2	change	-4.1 kg			112	hypothetical; full analysis; diabetes_duration:10_or_more; R0021795:Figure 2B
52	A2	change	-4.3 kg			130	hypothetical; full analysis; diabetes_duration:5_to_less_than_10; R0021795:Figure 2B
52	A2	change	-3.3 kg			168	hypothetical; full analysis; diabetes_duration:less_than_5; R0021795:Figure 2B
52	A2	change	-4.4 kg			108	hypothetical; full analysis; ethnicity:hispanic_latino; R0021795:Supplement Figure S4B
52	A2	change	-3.6 kg			302	hypothetical; full analysis; ethnicity:not_hispanic_latino; R0021795:Supplement Figure S4B
52	A2	change	-3.8 kg			229	hypothetical; full analysis; hba1c:8_or_less; R0021795:Figure 3B
52	A2	change	-4.5 kg			105	hypothetical; full analysis; hba1c:more_than_8_to_9; R0021795:Figure 3B
52	A2	change	-3.2 kg			21	hypothetical; full analysis; race:asian; R0021795:Supplement Figure S3B
52	A2	change	-2.7 kg			33	hypothetical; full analysis; race:black; R0021795:Supplement Figure S3B
52	A2	change	-3.9 kg			353	hypothetical; full analysis; race:white; R0021795:Supplement Figure S3B

HbA1c below 7 percent (4 lines; O03)

Week	Arm	Statistic	Events / N	Detail
26	A1	responders	262 / 411	treatment policy; full analysis; registry:outcomes
26	A2	responders	158 / 410	treatment policy; full analysis; registry:outcomes
52	A1	responders	254 / 411	treatment policy; full analysis; registry:outcomes
52	A2	responders	165 / 410	treatment policy; full analysis; registry:outcomes

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

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				7 / 410	while on treatment; safety; registry:outcomes
	A2	events				8 / 409	while on treatment; safety; registry:outcomes

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

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	rate					while on treatment; safety; registry:outcomes
	A2	rate					while on treatment; safety; registry:outcomes

Systolic blood pressure change (16 lines; O05)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
26	A1	change	-5 mmHg			410	treatment policy; safety; R0018256:Supplement Table S7
26	A1 vs A2	md	0 mmHg		-1 to 2		treatment policy; safety; R0018256:Supplement Table S7
26	A1 vs A2	md	0 mmHg		-1 to 2		while on treatment; safety; R0018256:Supplement Table S7
26	A1	change	-5 mmHg				while on treatment; safety; R0018256:Supplement Table S7
26	A1	change	-5 mmHg	15		410	while on treatment; safety; registry:outcomes
26	A2	change	-5 mmHg				while on treatment; safety; R0018256:Supplement Table S7
26	A2	change	-5 mmHg			409	treatment policy; safety; R0018256:Supplement Table S7
26	A2	change	-5 mmHg	14		409	while on treatment; safety; registry:outcomes
52	A1	change	-4 mmHg			410	treatment policy; safety; R0018256:Supplement Table S7
52	A1	change	-5 mmHg				while on treatment; safety; R0018256:Supplement Table S7
52	A1	change	-5 mmHg	13		410	while on treatment; safety; registry:outcomes
52	A1 vs A2	md	-1 mmHg		-2 to 1		while on treatment; safety; R0018256:Supplement Table S7
52	A1 vs A2	md	0 mmHg		-2 to 2		treatment policy; safety; R0018256:Supplement Table S7
52	A2	change	-4 mmHg			409	treatment policy; safety; R0018256:Supplement Table S7
52	A2	change	-4 mmHg				while on treatment; safety; R0018256:Supplement Table S7
52	A2	change	-4 mmHg	15		409	while on treatment; safety; registry:outcomes

Percent body weight change (16 lines; O10)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
26	A1	percent change	-4.34 percent	4.51		411	treatment policy; full analysis; registry:outcomes
26	A1	percent change	-4.7 percent				hypothetical; full analysis; R0018256:Supplement Table S3
26	A1 vs A2	md	-0.6 percent		-1.2 to 0.1		hypothetical; full analysis; R0018256:Supplement Table S3
26	A1	percent change	-4.2 percent			411	treatment policy; full analysis; R0018256:Supplement Table S3
26	A1 vs A2	md	-0.2 percent		-0.8 to 0.4		treatment policy; full analysis; R0018256:Supplement Table S3
26	A2	percent change	-4.1 percent			410	treatment policy; full analysis; R0018256:Supplement Table S3
26	A2	percent change	-4.14 percent	4.12		410	treatment policy; full analysis; registry:outcomes
26	A2	percent change	-4.1 percent				hypothetical; full analysis; R0018256:Supplement Table S3
52	A1	percent change	-4.2 percent			411	treatment policy; full analysis; R0018256:Supplement Table S3
52	A1	percent change	-5.2 percent				hypothetical; full analysis; R0018256:Supplement Table S3
52	A1 vs A2	md	-1.0 percent		-1.8 to -0.2		hypothetical; full analysis; R0018256:Supplement Table S3
52	A1	percent change	-4.38 percent	5.76		411	treatment policy; full analysis; registry:outcomes
52	A1 vs A2	md	-0.2 percent		-1.0 to 0.6		treatment policy; full analysis; R0018256:Supplement Table S3
52	A2	percent change	-4.1 percent				hypothetical; full analysis; R0018256:Supplement Table S3
52	A2	percent change	-4.0 percent			410	treatment policy; full analysis; R0018256:Supplement Table S3
52	A2	percent change	-4.09 percent	4.78		410	treatment policy; full analysis; registry:outcomes

Weight loss of 5 percent or more (4 lines; O11A)

Week	Arm	Statistic	Events / N	Detail
26	A1	responders	162 / 411	treatment policy; full analysis; registry:outcomes
26	A2	responders	143 / 410	treatment policy; full analysis; registry:outcomes
52	A1	responders	156 / 411	treatment policy; full analysis; registry:outcomes
52	A2	responders	150 / 410	treatment policy; full analysis; registry:outcomes

Weight loss of 10 percent or more (4 lines; O11B)

Week	Arm	Statistic	Events / N	Detail
26	A1	responders	49 / 411	treatment policy; full analysis; registry:outcomes
26	A2	responders	27 / 410	treatment policy; full analysis; registry:outcomes
52	A1	responders	58 / 411	treatment policy; full analysis; registry:outcomes
52	A2	responders	30 / 410	treatment policy; full analysis; registry:outcomes

Acute kidney injury (4 lines; O121)

Arm	Statistic	Events / N	Detail
A1	events	2 / 410	treatment policy; safety; R0018256:Supplement Table S6
A1	events	1 / 410	while on treatment; safety; registry:adverse_events
A2	events	1 / 409	while on treatment; safety; registry:adverse_events
A2	events	1 / 409	treatment policy; safety; R0018256:Supplement Table S6

All cause mortality (2 lines; O20)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 410	treatment policy; safety; R0018256:Supplement Table S6
	A2	events				1 / 409	treatment policy; safety; R0018256:Supplement Table S6

Hospitalization for heart failure (4 lines; O23)

Arm	Statistic	Events / N	Detail
A1	events	2 / 410	treatment policy; safety; R0018256:Supplement Table S6
A1	events	2 / 410	while on treatment; safety; cardiac failure chronic; registry:adverse_events
A2	events	1 / 409	treatment policy; safety; R0018256:Supplement Table S6
A2	events	1 / 409	while on treatment; safety; cardiac failure chronic; registry:adverse_events

SF-36 physical component summary change (8 lines; O24A)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
26	A1 vs A2	md	-0.50 points		-1.36 to 0.35		hypothetical; full analysis; R0018256:Supplement Figure S7A
26	A1	change	0.53 points	6.36		411	treatment policy; full analysis; registry:outcomes
26	A1 vs A2	md	-0.49 points		-1.32 to 0.35		treatment policy; full analysis; R0018256:Supplement Figure S7A
26	A2	change	1.21 points	6.39		410	treatment policy; full analysis; registry:outcomes
52	A1 vs A2	md	-0.51 points		-1.40 to 0.39		hypothetical; full analysis; R0018256:Supplement Figure S7A
52	A1	change	0.44 points	6.26		411	treatment policy; full analysis; registry:outcomes
52	A1 vs A2	md	-1.00 points		-1.88 to -0.12		treatment policy; full analysis; R0018256:Supplement Figure S7A
52	A2	change	1.36 points	6.50		410	treatment policy; full analysis; registry:outcomes

Physical functioning (any instrument) (8 lines; O24B)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
26	A1	change	0.87 points	7.35		411	treatment policy; full analysis; registry:outcomes
26	A1 vs A2	md	-0.11 points		-1.04 to 0.83		hypothetical; full analysis; R0018256:Supplement Figure S7A
26	A1 vs A2	md	-0.25 points		-1.19 to 0.68		treatment policy; full analysis; R0018256:Supplement Figure S7A
26	A2	change	0.99 points	7.11		410	treatment policy; full analysis; registry:outcomes
52	A1 vs A2	md	-0.18 points		-1.15 to 0.78		hypothetical; full analysis; R0018256:Supplement Figure S7A
52	A1	change	0.57 points	6.79		411	treatment policy; full analysis; registry:outcomes
52	A1 vs A2	md	-0.63 points		-1.55 to 0.30		treatment policy; full analysis; R0018256:Supplement Figure S7A
52	A2	change	0.84 points	7.32		410	treatment policy; full analysis; registry:outcomes

Serious adverse events (2 lines; O25)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				27 / 410	while on treatment; safety; registry:adverse_events
	A2	events				37 / 409	while on treatment; safety; registry:adverse_events

Discontinuation due to adverse events (2 lines; O26)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 412	not stated; randomized; R0018256:Supplement Figure S3
	A2	events				0 / 410	not stated; randomized; R0018256:Supplement Figure S3

Nausea (2 lines; O27A)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				81 / 410	while on treatment; safety; registry:adverse_events
	A2	events				10 / 409	while on treatment; safety; registry:adverse_events

Vomiting (2 lines; O27B)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				30 / 410	while on treatment; safety; registry:adverse_events
	A2	events				7 / 409	while on treatment; safety; registry:adverse_events

Diarrhea (2 lines; O27C)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				38 / 410	while on treatment; safety; registry:adverse_events
	A2	events				13 / 409	while on treatment; safety; registry:adverse_events

Discontinuation due to gastrointestinal adverse events (2 lines; O27E)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 412	not stated; randomized; R0018256:Supplement Figure S3
	A2	events				0 / 410	not stated; randomized; R0018256:Supplement Figure S3

Gallbladder and biliary disease (8 lines; O28)

Arm	Statistic	Events / N	Detail
A1	events	0 / 410	while on treatment; safety; cholecystitis acute; registry:adverse_events
A1	events	0 / 410	while on treatment; safety; cholangitis acute; registry:adverse_events
A1	events	2 / 410	while on treatment; safety; cholecystitis; registry:adverse_events
A1	events	1 / 410	while on treatment; safety; cholelithiasis; registry:adverse_events
A2	events	1 / 409	while on treatment; safety; cholecystitis acute; registry:adverse_events
A2	events	0 / 409	while on treatment; safety; cholecystitis; registry:adverse_events
A2	events	1 / 409	while on treatment; safety; cholangitis acute; registry:adverse_events
A2	events	1 / 409	while on treatment; safety; cholelithiasis; registry:adverse_events

Acute pancreatitis (6 lines; O29)

Arm	Statistic	Events / N	Detail
A1	events	1 / 410	treatment policy; safety; R0018256:Supplement Table S6
A1	events	0 / 410	while on treatment; safety; pancreatitis acute; registry:adverse_events
A1	events	1 / 410	while on treatment; safety; pancreatitis; registry:adverse_events
A2	events	1 / 409	treatment policy; safety; R0018256:Supplement Table S6
A2	events	1 / 409	while on treatment; safety; pancreatitis acute; registry:adverse_events
A2	events	0 / 409	while on treatment; safety; pancreatitis; registry:adverse_events

Medullary thyroid carcinoma (2 lines; O32A)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 410	treatment policy; safety; R0018256:Supplement Table S6
	A2	events				0 / 409	treatment policy; safety; R0018256:Supplement Table S6

Thyroid cancer (any) (2 lines; O32B)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 410	treatment policy; safety; R0018256:Supplement Table S6
	A2	events				0 / 409	treatment policy; safety; R0018256:Supplement Table S6

Diabetic retinopathy complications (8 lines; O33)

Arm	Statistic	Events / N	Detail
A1	events	14 / 410	treatment policy; safety; R0018256:Supplement Table S5
A1	events	13 / 410	treatment policy; safety; diabetic retinopathy; R0018256:Supplement Table S5
A1	events	0 / 410	treatment policy; safety; retinal hemorrhage; R0018256:Supplement Table S5
A1	events	1 / 410	treatment policy; safety; visual acuity reduced; R0018256:Supplement Table S5
A2	events	5 / 409	treatment policy; safety; R0018256:Supplement Table S5
A2	events	4 / 409	treatment policy; safety; diabetic retinopathy; R0018256:Supplement Table S5
A2	events	1 / 409	treatment policy; safety; retinal hemorrhage; R0018256:Supplement Table S5
A2	events	0 / 409	treatment policy; safety; visual acuity reduced; R0018256:Supplement Table S5

Death by suicide (1 lines; O35B)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 410	treatment policy; safety; R0018256:Supplement Table S6

Intestinal obstruction or ileus (2 lines; O37B)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				1 / 410	while on treatment; safety; small intestinal obstruction; registry:adverse_events
	A2	events				0 / 409	while on treatment; safety; small intestinal obstruction; registry:adverse_events

Pancreatic cancer (2 lines; O38)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 410	treatment policy; safety; R0018256:Supplement Table S6
	A2	events				0 / 409	treatment policy; safety; R0018256:Supplement Table S6

Any cancer (2 lines; O39)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				7 / 410	treatment policy; safety; R0018256:Supplement Table S6
	A2	events				2 / 409	treatment policy; safety; R0018256:Supplement Table S6