parallel randomized trial

SURPASS-2

A Phase 3, Randomized, Open-Label Trial Comparing Efficacy and Safety of Tirzepatide Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Patients With Type 2 Diabetes

Type 2 diabetes (adults)NCT03987919S000095

Design

Randomized: 1,879
Start year: 2019
Treatment: 40 weeks, follow-up 44 weeks
Countries: Argentina, Australia, Brazil, Canada, Israel, Mexico, United Kingdom, United States (128 sites)
Sponsor: Eli Lilly and Company (industry)
Eligibility: age 18 or older, HbA1c 7.0 to 10.5 percent, BMI 25 or more, metformin 1500 mg/day or more, eGFR 45 or more

Conduct and analysis

Blinding: single blind
Sequence generation: not reported
Allocation concealment: not reported
Outcome adjudication: yes
Primary estimand: treatment policy
Analysis population: modified itt
Missing data: multiple imputation (retrieved dropouts)

Arms

Arm	Treatment	Background	Randomized	Analyzed	Completed treatment
A1	Tirzepatide 5 mg subcutaneous once weekly Tirzepatide 5 mg	metformin at least 1500 mg per day; lifestyle: not reported	471	470	431
A2	Tirzepatide 10 mg subcutaneous once weekly Tirzepatide 10 mg	metformin at least 1500 mg per day; lifestyle: not reported	469	469	411
A3	Tirzepatide 15 mg subcutaneous once weekly Tirzepatide 15 mg	metformin at least 1500 mg per day; lifestyle: not reported	470	469	408
A4	Semaglutide 1.0 mg subcutaneous once weekly Semaglutide 1 mg	metformin at least 1500 mg per day; lifestyle: not reported	469	468	428

Baseline characteristics

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

Characteristic	Statistic	Tirzepatide 5 mg subcutaneous once weekly A1	Tirzepatide 10 mg subcutaneous once weekly A2	Tirzepatide 15 mg subcutaneous once weekly A3	Semaglutide 1.0 mg subcutaneous once weekly A4	Whole trial ALL
age	mean (years)	56.3	57.2	55.9	56.9
age	sd (years)	10.0	10.5	10.4	10.8
asian	n	6	11	5	3
asian	percent	1.3	2.3	1.1	0.6
black	n	28	21	15	15
black	percent	6.0	4.5	3.2	3.2
bmi: 27 or more	n	415	417	416	422
bmi: 27 or more	percent	88.3	88.9	88.5	90.0
bmi: 30 to less than 35	n	168	155	156	157
bmi: 30 to less than 35	percent	35.7	33.0	33.2	33.5
bmi: 35 or more	n	162	181	179	168
bmi: 35 or more	percent	34.5	38.6	38.1	35.8
bmi: less than 27	n	55	52	54	47
bmi: less than 27	percent	11.7	11.1	11.5	10.0
bmi: less than 30	n	140	133	135	144
bmi: less than 30	percent	29.8	28.4	28.7	30.7
bmi	mean (kg/m2)	33.8	34.3	34.5	34.2
bmi	sd (kg/m2)	6.85	6.60	7.11	7.15
diabetes duration	mean (years)	9.1	8.4	8.7	8.3
diabetes duration	sd (years)	7.16	5.90	6.85	5.80
egfr: 60 or more	n	451	454	459	450
egfr: 60 or more	percent	96.0	96.8	97.7	95.9
egfr: less than 60	n	19	15	11	19
egfr: less than 60	percent	4.0	3.2	2.3	4.1
egfr	mean (mL/min/1.73 m2)	96.6	95.5	96.3	95.6
egfr	sd (mL/min/1.73 m2)	17.51	16.62	16.92	17.25
established cvd	percent					8
female	n	265	231	256	244
female	percent	56.4	49.3	54.5	52.0
hba1c: 8.5 or less	n	293	294	303	302
hba1c: 8.5 or less	percent	62.3	62.7	64.5	64.4
hba1c: more than 8.5	n	177	175	167	167
hba1c: more than 8.5	percent	37.7	37.3	35.5	35.6
hba1c	mean (percent)	8.32	8.30	8.26	8.25
hba1c	sd (percent)	1.08	1.02	1.00	1.01
hispanic	n	325	322	334	336
hispanic	percent	69.1	68.7	71.1	71.6
metformin use	n	470	469	470	469
metformin use	percent	100.0	100.0	100.0	100.0
other race american indian alaska native	n	53	53	57	45
other race american indian alaska native	percent	11.3	11.3	12.1	9.6
other race multiple	n	1	8	0	3
other race native hawaiian pacific islander	n	0	0	1	2
sbp	mean (mmHg)	130.53	131.47	130.45	129.96
sbp	sd (mmHg)	14.11	13.77	14.32	12.99
uacr: 30 to 300	n	111	87	85	90
uacr: 30 to 300	percent	23.6	18.6	18.1	19.2
uacr: less than 30	n	340	353	357	364
uacr: less than 30	percent	72.3	75.3	76.0	77.6
uacr: more than 300	n	18	29	27	15
uacr: more than 300	percent	3.8	6.2	5.7	3.2
waist	mean (cm)	108.06	110.55	109.55	109.04
waist	sd (cm)	14.81	16.05	15.60	14.90
weight	mean (kg)	92.5	94.8	93.8	93.7
weight	sd (kg)	21.76	22.71	21.83	21.12
white	n	382	376	392	401
white	percent	81.3	80.2	83.4	85.5

Results

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

HbA1c change (50 lines; O01)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
24	A1	change	-2.14 percent	0.043			hypothetical; modified itt; R0007660:Table 1
24	A2	change	-2.43 percent	0.043			hypothetical; modified itt; R0007660:Table 1
24	A3	change	-2.37 percent	0.043			hypothetical; modified itt; R0007660:Table 1
24	A4	change	-1.88 percent	0.043			hypothetical; modified itt; R0007660:Table 1
40	A1	change	-2.03 percent	0.086		140	hypothetical; modified itt; ethnicity:not_hispanic_or_latino; R0007214:Supplement Table S2
40	A1	change	-2.83 percent			167	treatment policy; modified itt; hba1c:more_than_8.5; R0013656:Supplement Figure S8
40	A1	change	-1.53 percent			284	treatment policy; modified itt; hba1c:8.5_or_less; R0013656:Supplement Figure S8
40	A1 vs A4	md	-0.15 percent		-0.30 to -0.01		treatment policy; modified itt; hba1c:8.5_or_less; R0013656:Supplement Figure S8
40	A1	change	-2.01 percent			470	treatment policy; modified itt; R0013656:Results
40	A1 vs A4	md	-0.15 percent		-0.28 to -0.03		treatment policy; modified itt; R0013656:Results
40	A1	change	-2.09 percent	0.047		461	hypothetical; modified itt; R0013656:Supplement Table S13
40	A1	final	6.19 percent				hypothetical; modified itt; R0013656:Figure 1B
40	A1	change	-2.11 percent	0.056		321	hypothetical; modified itt; ethnicity:hispanic_or_latino; R0007214:Supplement Table S2
40	A1 vs A4	md	-0.18 percent		-0.33 to -0.02		hypothetical; modified itt; ethnicity:hispanic_or_latino; R0007214:Supplement Table S2
40	A1 vs A4	md	-0.23 percent		-0.36 to -0.10		hypothetical; modified itt; R0013656:Supplement Table S13
40	A1 vs A4	md	-0.16 percent		-0.39 to 0.08		treatment policy; modified itt; hba1c:more_than_8.5; R0013656:Supplement Figure S8
40	A1 vs A4	md	-0.34 percent		-0.59 to -0.10		hypothetical; modified itt; ethnicity:not_hispanic_or_latino; R0007214:Supplement Table S2
40	A2	change	-2.24 percent			469	treatment policy; modified itt; R0013656:Results
40	A2 vs A4	md	-0.39 percent		-0.51 to -0.26		treatment policy; modified itt; R0013656:Results
40	A2	change	-2.37 percent	0.048		459	hypothetical; modified itt; R0013656:Supplement Table S13
40	A2	change	-2.46 percent	0.057		317	hypothetical; modified itt; ethnicity:hispanic_or_latino; R0007214:Supplement Table S2
40	A2	change	-1.73 percent			278	treatment policy; modified itt; hba1c:8.5_or_less; R0013656:Supplement Figure S8
40	A2 vs A4	md	-0.35 percent		-0.50 to -0.20		treatment policy; modified itt; hba1c:8.5_or_less; R0013656:Supplement Figure S8
40	A2 vs A4	md	-0.51 percent		-0.64 to -0.38		hypothetical; modified itt; R0013656:Supplement Table S13
40	A2	final	5.91 percent				hypothetical; modified itt; R0013656:Figure 1B
40	A2 vs A4	md	-0.45 percent		-0.69 to -0.21		hypothetical; modified itt; ethnicity:not_hispanic_or_latino; R0007214:Supplement Table S2
40	A2	change	-2.14 percent	0.086		142	hypothetical; modified itt; ethnicity:not_hispanic_or_latino; R0007214:Supplement Table S2
40	A2 vs A4	md	-0.46 percent		-0.70 to -0.23		treatment policy; modified itt; hba1c:more_than_8.5; R0013656:Supplement Figure S8
40	A2	change	-3.14 percent			167	treatment policy; modified itt; hba1c:more_than_8.5; R0013656:Supplement Figure S8
40	A2 vs A4	md	-0.53 percent		-0.68 to -0.37		hypothetical; modified itt; ethnicity:hispanic_or_latino; R0007214:Supplement Table S2
40	A3	change	-3.22 percent			161	treatment policy; modified itt; hba1c:more_than_8.5; R0013656:Supplement Figure S8
40	A3	change	-2.46 percent	0.048		464	hypothetical; modified itt; R0013656:Supplement Table S13
40	A3	final	5.82 percent				hypothetical; modified itt; R0013656:Figure 1B
40	A3 vs A4	md	-0.60 percent		-0.73 to -0.47		hypothetical; modified itt; R0013656:Supplement Table S13
40	A3	change	-2.30 percent			469	treatment policy; modified itt; R0013656:Results
40	A3 vs A4	md	-0.45 percent		-0.57 to -0.32		treatment policy; modified itt; R0013656:Results
40	A3	change	-2.47 percent	0.057		328	hypothetical; modified itt; ethnicity:hispanic_or_latino; R0007214:Supplement Table S2
40	A3 vs A4	md	-0.54 percent		-0.70 to -0.38		hypothetical; modified itt; ethnicity:hispanic_or_latino; R0007214:Supplement Table S2
40	A3	change	-2.43 percent	0.088		136	hypothetical; modified itt; ethnicity:not_hispanic_or_latino; R0007214:Supplement Table S2
40	A3 vs A4	md	-0.74 percent		-0.98 to -0.49		hypothetical; modified itt; ethnicity:not_hispanic_or_latino; R0007214:Supplement Table S2
40	A3	change	-1.78 percent			286	treatment policy; modified itt; hba1c:8.5_or_less; R0013656:Supplement Figure S8
40	A3 vs A4	md	-0.40 percent		-0.54 to -0.25		treatment policy; modified itt; hba1c:8.5_or_less; R0013656:Supplement Figure S8
40	A3 vs A4	md	-0.55 percent		-0.78 to -0.31		treatment policy; modified itt; hba1c:more_than_8.5; R0013656:Supplement Figure S8
40	A4	change	-1.93 percent	0.056		329	hypothetical; modified itt; ethnicity:hispanic_or_latino; R0007214:Supplement Table S2
40	A4	change	-1.86 percent			468	treatment policy; modified itt; R0013656:Results
40	A4	change	-1.69 percent	0.089		132	hypothetical; modified itt; ethnicity:not_hispanic_or_latino; R0007214:Supplement Table S2
40	A4	final	6.42 percent				hypothetical; modified itt; R0013656:Figure 1B
40	A4	change	-1.86 percent	0.048		461	hypothetical; modified itt; R0013656:Supplement Table S13
40	A4	change	-1.38 percent			287	treatment policy; modified itt; hba1c:8.5_or_less; R0013656:Supplement Figure S8
40	A4	change	-2.68 percent			156	treatment policy; modified itt; hba1c:more_than_8.5; R0013656:Supplement Figure S8

Body weight change in kilograms (diabetes) (32 lines; O02)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
24	A1	change	-6.8 kg	0.25			hypothetical; modified itt; R0007660:Table 1
24	A2	change	-8.8 kg	0.25			hypothetical; modified itt; R0007660:Table 1
24	A3	change	-9.7 kg	0.25			hypothetical; modified itt; R0007660:Table 1
24	A4	change	-5.3 kg	0.25			hypothetical; modified itt; R0007660:Table 1
40	A1 vs A4	md	-1.9 kg		-2.8 to -1.0		treatment policy; modified itt; R0013656:Results
40	A1	change	-7.8 kg	0.33		461	hypothetical; modified itt; R0013656:Supplement Table S13
40	A1 vs A4	md	-1.7 kg		-2.6 to -0.7		hypothetical; modified itt; R0013656:Supplement Table S13
40	A1	change	-7.6 kg			470	treatment policy; modified itt; R0013656:Results
40	A1	change	-6.9 kg	0.36		321	hypothetical; modified itt; ethnicity:hispanic_or_latino; R0007214:Supplement Table S3
40	A1 vs A4	md	-1.3 kg		-2.3 to -0.3		hypothetical; modified itt; ethnicity:hispanic_or_latino; R0007214:Supplement Table S3
40	A1	change	-9.9 kg	0.68		140	hypothetical; modified itt; ethnicity:not_hispanic_or_latino; R0007214:Supplement Table S3
40	A1 vs A4	md	-2.5 kg		-4.4 to -0.5		hypothetical; modified itt; ethnicity:not_hispanic_or_latino; R0007214:Supplement Table S3
40	A2	change	-10.3 kg	0.34		459	hypothetical; modified itt; R0013656:Supplement Table S13
40	A2	change	-9.3 kg			469	treatment policy; modified itt; R0013656:Results
40	A2 vs A4	md	-3.6 kg		-4.5 to -2.7		treatment policy; modified itt; R0013656:Results
40	A2	change	-9.7 kg	0.36		317	hypothetical; modified itt; ethnicity:hispanic_or_latino; R0007214:Supplement Table S3
40	A2 vs A4	md	-4.0 kg		-5.0 to -3.0		hypothetical; modified itt; ethnicity:hispanic_or_latino; R0007214:Supplement Table S3
40	A2	change	-11.6 kg	0.68		142	hypothetical; modified itt; ethnicity:not_hispanic_or_latino; R0007214:Supplement Table S3
40	A2 vs A4	md	-4.1 kg		-6.1 to -2.2		hypothetical; modified itt; ethnicity:not_hispanic_or_latino; R0007214:Supplement Table S3
40	A2 vs A4	md	-4.1 kg		-5.0 to -3.2		hypothetical; modified itt; R0013656:Supplement Table S13
40	A3	change	-10.5 kg	0.36		328	hypothetical; modified itt; ethnicity:hispanic_or_latino; R0007214:Supplement Table S3
40	A3 vs A4	md	-5.5 kg		-6.4 to -4.6		treatment policy; modified itt; R0013656:Results
40	A3	change	-11.2 kg			469	treatment policy; modified itt; R0013656:Results
40	A3 vs A4	md	-4.8 kg		-5.8 to -3.8		hypothetical; modified itt; ethnicity:hispanic_or_latino; R0007214:Supplement Table S3
40	A3 vs A4	md	-6.2 kg		-7.1 to -5.3		hypothetical; modified itt; R0013656:Supplement Table S13
40	A3	change	-17.1 kg	0.70		136	hypothetical; modified itt; ethnicity:not_hispanic_or_latino; R0007214:Supplement Table S3
40	A3 vs A4	md	-9.6 kg		-11.6 to -7.7		hypothetical; modified itt; ethnicity:not_hispanic_or_latino; R0007214:Supplement Table S3
40	A3	change	-12.4 kg	0.34		464	hypothetical; modified itt; R0013656:Supplement Table S13
40	A4	change	-6.2 kg	0.33		462	hypothetical; modified itt; R0013656:Supplement Table S13
40	A4	change	-7.5 kg	0.71		132	hypothetical; modified itt; ethnicity:not_hispanic_or_latino; R0007214:Supplement Table S3
40	A4	change	-5.6 kg	0.36		330	hypothetical; modified itt; ethnicity:hispanic_or_latino; R0007214:Supplement Table S3
40	A4	change	-5.7 kg			468	treatment policy; modified itt; R0013656:Results

HbA1c below 7 percent (12 lines; O03)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
24	A4	responders	93.0		468	hypothetical; modified itt; R0007660:Results
40	A1	responders	85.47		394 / 461	hypothetical; modified itt; R0013656:Supplement Table S13
40	A1 vs A4	or	1.54	1.06 to 2.23		hypothetical; modified itt; R0013656:Supplement Table S13
40	A1	responders	82		470	treatment policy; modified itt; R0013656:Figure 1C
40	A2	responders	86		469	treatment policy; modified itt; R0013656:Figure 1C
40	A2	responders	88.89		408 / 459	hypothetical; modified itt; R0013656:Supplement Table S13
40	A2 vs A4	or	2.14	1.44 to 3.17		hypothetical; modified itt; R0013656:Supplement Table S13
40	A3 vs A4	or	3.03	1.97 to 4.66		hypothetical; modified itt; R0013656:Supplement Table S13
40	A3	responders	92.24		428 / 464	hypothetical; modified itt; R0013656:Supplement Table S13
40	A3	responders	86		469	treatment policy; modified itt; R0013656:Figure 1C
40	A4	responders	79		468	treatment policy; modified itt; R0013656:Figure 1C
40	A4	responders	81.13		374 / 461	hypothetical; modified itt; R0013656:Supplement Table S13

Level 2 or 3 hypoglycemia (participants) (12 lines; O04)

Arm	Statistic	Events / N	Detail
A1	events	3 / 470	not stated; safety; R0013656:Table 2
A1	events	1 / 470	not stated; safety; R0013656:Table 2
A1	events	1 / 470	not stated; safety; R0013656:Supplement Table S7
A2	events	0 / 469	not stated; safety; R0013656:Supplement Table S7
A2	events	1 / 469	not stated; safety; R0013656:Table 2
A2	events	0 / 469	not stated; safety; R0013656:Table 2
A3	events	8 / 470	not stated; safety; R0013656:Table 2
A3	events	1 / 470	not stated; safety; R0013656:Table 2
A3	events	1 / 470	not stated; safety; R0013656:Supplement Table S7
A4	events	2 / 469	not stated; safety; R0013656:Table 2
A4	events	0 / 469	not stated; safety; R0013656:Supplement Table S7
A4	events	0 / 469	not stated; safety; R0013656:Table 2

Level 2 or 3 hypoglycemia (episode rate) (12 lines; O04B)

Arm	Statistic	Estimate	SE or SD	Events / N	Detail
A1	rate			470	not stated; safety; R0013656:Table 2
A1	rate			470	not stated; safety; R0013656:Table 2
A1	rate	0.0102	0.00423	470	not stated; modified itt; registry:outcomes
A2	rate			469	not stated; safety; R0013656:Table 2
A2	rate	0.0046	0.00488	469	not stated; modified itt; registry:outcomes
A2	rate			469	not stated; safety; R0013656:Table 2
A3	rate	0.0202	0.00840	470	not stated; modified itt; registry:outcomes
A3	rate			470	not stated; safety; R0013656:Table 2
A3	rate			470	not stated; safety; R0013656:Table 2
A4	rate	0.0046	0.00340	469	not stated; modified itt; registry:outcomes
A4	rate			469	not stated; safety; R0013656:Table 2
A4	rate			469	not stated; safety; R0013656:Table 2

Systolic blood pressure change (6 lines; O05)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
40	A1	change	-4.8 mmHg		449	not stated; safety; R0013656:Results
40	A2 vs A4	md	-1.8 mmHg	-3.4 to -0.1		not stated; safety; R0009496:Results
40	A2	change	-5.3 mmHg		444	not stated; safety; R0013656:Results
40	A3	change	-6.5 mmHg		447	not stated; safety; R0013656:Results
40	A3 vs A4	md	-3.0 mmHg	-4.6 to -1.3		not stated; safety; R0009496:Results
40	A4	change	-3.6 mmHg		445	not stated; safety; R0013656:Results

Percent body weight change (4 lines; O10)

Week	Arm	Statistic	Estimate	Detail
40	A1	percent change	-8.5 percent	hypothetical; modified itt; R0013656:Figure 2B
40	A2	percent change	-11.0 percent	hypothetical; modified itt; R0013656:Figure 2B
40	A3	percent change	-13.1 percent	hypothetical; modified itt; R0013656:Figure 2B
40	A4	percent change	-6.7 percent	hypothetical; modified itt; R0013656:Figure 2B

Weight loss of 5 percent or more (12 lines; O11A)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
24	A4	responders	51.5		468	hypothetical; modified itt; R0007660:Results
40	A1	responders	68.55		316 / 461	hypothetical; modified itt; R0013656:Supplement Table S5
40	A1 vs A4	or	1.58	1.20 to 2.08		hypothetical; modified itt; R0013656:Supplement Table S5
40	A1	responders	65		470	treatment policy; modified itt; R0013656:Figure 2C
40	A2 vs A4	or	3.49	2.57 to 4.75		hypothetical; modified itt; R0013656:Supplement Table S5
40	A2	responders	82.35		378 / 459	hypothetical; modified itt; R0013656:Supplement Table S5
40	A2	responders	76		469	treatment policy; modified itt; R0013656:Figure 2C
40	A3	responders	80		469	treatment policy; modified itt; R0013656:Figure 2C
40	A3	responders	86.21		400 / 464	hypothetical; modified itt; R0013656:Supplement Table S5
40	A3 vs A4	or	4.60	3.32 to 6.38		hypothetical; modified itt; R0013656:Supplement Table S5
40	A4	responders	54		468	treatment policy; modified itt; R0013656:Figure 2C
40	A4	responders	58.44		270 / 462	hypothetical; modified itt; R0013656:Supplement Table S5

Weight loss of 10 percent or more (11 lines; O11B)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
40	A1	responders	35.79		165 / 461	hypothetical; modified itt; R0013656:Supplement Table S5
40	A1 vs A4	or	1.68	1.26 to 2.25		hypothetical; modified itt; R0013656:Supplement Table S5
40	A1	responders	34		470	treatment policy; modified itt; R0013656:Figure 2C
40	A2	responders	52.94		243 / 459	hypothetical; modified itt; R0013656:Supplement Table S5
40	A2 vs A4	or	3.58	2.69 to 4.77		hypothetical; modified itt; R0013656:Supplement Table S5
40	A2	responders	47		469	treatment policy; modified itt; R0013656:Figure 2C
40	A3 vs A4	or	5.85	4.37 to 7.82		hypothetical; modified itt; R0013656:Supplement Table S5
40	A3	responders	64.87		301 / 464	hypothetical; modified itt; R0013656:Supplement Table S5
40	A3	responders	57		469	treatment policy; modified itt; R0013656:Figure 2C
40	A4	responders	25.32		117 / 462	hypothetical; modified itt; R0013656:Supplement Table S5
40	A4	responders	24		468	treatment policy; modified itt; R0013656:Figure 2C

Weight loss of 15 percent or more (11 lines; O11C)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
40	A1	responders	15.18		70 / 461	hypothetical; modified itt; R0013656:Supplement Table S5
40	A1	responders	15		470	treatment policy; modified itt; R0013656:Figure 2C
40	A1 vs A4	or	1.92	1.27 to 2.90		hypothetical; modified itt; R0013656:Supplement Table S5
40	A2 vs A4	or	4.27	2.90 to 6.29		hypothetical; modified itt; R0013656:Supplement Table S5
40	A2	responders	27.67		127 / 459	hypothetical; modified itt; R0013656:Supplement Table S5
40	A2	responders	24		469	treatment policy; modified itt; R0013656:Figure 2C
40	A3 vs A4	or	7.44	5.09 to 10.87		hypothetical; modified itt; R0013656:Supplement Table S5
40	A3	responders	39.87		185 / 464	hypothetical; modified itt; R0013656:Supplement Table S5
40	A3	responders	36		469	treatment policy; modified itt; R0013656:Figure 2C
40	A4	responders	8.66		40 / 462	hypothetical; modified itt; R0013656:Supplement Table S5
40	A4	responders	8		468	treatment policy; modified itt; R0013656:Figure 2C

Acute kidney injury (4 lines; O121)

Arm	Statistic	Events / N	Detail
A1	events	0 / 470	not stated; safety; registry:adverse_events
A2	events	0 / 469	not stated; safety; registry:adverse_events
A3	events	1 / 470	not stated; safety; registry:adverse_events
A4	events	0 / 469	not stated; safety; registry:adverse_events

All cause mortality (4 lines; O20)

Arm	Statistic	Events / N	Detail
A1	events	4 / 470	not stated; safety; R0013656:Table 2
A2	events	4 / 469	not stated; safety; R0013656:Table 2
A3	events	4 / 470	not stated; safety; R0013656:Table 2
A4	events	1 / 469	not stated; safety; R0013656:Table 2

Hospitalization for heart failure (4 lines; O23)

Arm	Statistic	Events / N	Detail
A1	events	1 / 470	not stated; safety; cardiac failure; registry:adverse_events
A2	events	0 / 469	not stated; safety; cardiac failure; registry:adverse_events
A3	events	0 / 470	not stated; safety; cardiac failure; registry:adverse_events
A4	events	0 / 469	not stated; safety; cardiac failure; registry:adverse_events

Physical functioning (any instrument) (14 lines; O24B)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
40	A1	change	5.7 points		422	hypothetical; modified itt; R0007531:Supplementary Table S3
40	A1	change	10.4 points		417	hypothetical; modified itt; R0007531:Supplement Table S3
40	A1 vs A4	md	0.3 points	-1.9 to 2.4		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A1 vs A4	md	2.6 points	0.2 to 5.0		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A2	change	6.6 points		403	hypothetical; modified itt; R0007531:Supplementary Table S3
40	A2	change	10.6 points		401	hypothetical; modified itt; R0007531:Supplement Table S3
40	A2 vs A4	md	1.2 points	-1.0 to 3.4		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A2 vs A4	md	2.8 points	0.4 to 5.2		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A3	change	7.9 points		400	hypothetical; modified itt; R0007531:Supplementary Table S3
40	A3	change	12.2 points			hypothetical; modified itt; R0007531:Supplement Table S3
40	A3 vs A4	md	2.6 points	0.4 to 4.7		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A3 vs A4	md	4.4 points	1.9 to 6.8		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A4	change	7.9 points		414	hypothetical; modified itt; R0007531:Supplement Table S3
40	A4	change	5.4 points		416	hypothetical; modified itt; R0007531:Supplementary Table S3

Health related quality of life total score (any instrument) (25 lines; O24C)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
40	A1	final	15.7 points	0.18		419	hypothetical; modified itt; registry:outcomes
40	A1	change	0.04 points			415	hypothetical; modified itt; R0007531:Supplementary Table S3
40	A1	change	9.2 points			417	hypothetical; modified itt; R0007531:Supplement Table S3
40	A1	final	15.7 points			419	hypothetical; modified itt; R0007531:Supplementary Table S3
40	A1 vs A4	md	-0.1 points		-0.6 to 0.4		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A1 vs A4	md	0.00 points		-0.02 to 0.02		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A1 vs A4	md	1.7 points		-0.2 to 3.6		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A2	change	0.04 points			401	hypothetical; modified itt; R0007531:Supplementary Table S3
40	A2	final	15.6 points			399	hypothetical; modified itt; R0007531:Supplementary Table S3
40	A2	final	15.6 points	0.19		399	hypothetical; modified itt; registry:outcomes
40	A2 vs A4	md	-0.3 points		-0.8 to 0.3		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A2 vs A4	md	0.01 points		-0.01 to 0.03		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A2 vs A4	md	2.0 points		0.0 to 3.9		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A2	change	9.4 points			401	hypothetical; modified itt; R0007531:Supplement Table S3
40	A3	change	10.6 points				hypothetical; modified itt; R0007531:Supplement Table S3
40	A3	final	16.1 points			398	hypothetical; modified itt; R0007531:Supplementary Table S3
40	A3	final	16.1 points	0.19		398	hypothetical; modified itt; registry:outcomes
40	A3 vs A4	md	0.3 points		-0.3 to 0.8		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A3 vs A4	md	0.00 points		-0.02 to 0.02		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A3 vs A4	md	3.1 points		1.2 to 5.1		hypothetical; modified itt; R0007531:Supplementary Table S3
40	A3	change	0.04 points			395	hypothetical; modified itt; R0007531:Supplementary Table S3
40	A4	change	0.04 points			413	hypothetical; modified itt; R0007531:Supplementary Table S3
40	A4	change	7.4 points			414	hypothetical; modified itt; R0007531:Supplement Table S3
40	A4	final	15.8 points			411	hypothetical; modified itt; R0007531:Supplementary Table S3
40	A4	final	15.8 points	0.19		412	hypothetical; modified itt; registry:outcomes

Serious adverse events (4 lines; O25)

Arm	Statistic	Events / N	Detail
A1	events	33 / 470	not stated; safety; R0013656:Table 2
A2	events	25 / 469	not stated; safety; R0013656:Table 2
A3	events	27 / 470	not stated; safety; R0013656:Table 2
A4	events	13 / 469	not stated; safety; R0013656:Table 2

Discontinuation due to adverse events (56 lines; O26)

Arm	Statistic	Events / N	Detail
A1	events	28 / 470	not stated; safety; R0013656:Table 2
A1	events	24 / 471	not stated; randomized; R0013656:Supplement Table S3
A1	events	2 / 470	not stated; safety; abdominal pain; R0013656:Table 2
A1	events	0 / 470	not stated; safety; constipation; R0013656:Table 2
A1	events	1 / 470	not stated; safety; covid-19 related pneumonia; R0013656:Table 2
A1	events	1 / 470	not stated; safety; decreased appetite; R0013656:Table 2
A1	events	1 / 470	not stated; safety; diarrhea; R0013656:Table 2
A1	events	2 / 470	not stated; safety; dyspepsia; R0013656:Table 2
A1	events	1 / 470	not stated; safety; elevated blood calcitonin level; R0013656:Table 2
A1	events	1 / 470	not stated; safety; fatigue; R0013656:Table 2
A1	events	0 / 470	not stated; safety; injection-site reaction; R0013656:Table 2
A1	events	6 / 470	not stated; safety; nausea; R0013656:Table 2
A1	events	1 / 471	not stated; randomized; registry:flow
A1	events	1 / 470	not stated; safety; vomiting; R0013656:Table 2
A2	events	40 / 469	not stated; safety; R0013656:Table 2
A2	events	36 / 469	not stated; randomized; R0013656:Supplement Table S3
A2	events	1 / 469	not stated; safety; abdominal pain; R0013656:Table 2
A2	events	2 / 469	not stated; safety; constipation; R0013656:Table 2
A2	events	1 / 469	not stated; safety; covid-19 related pneumonia; R0013656:Table 2
A2	events	2 / 469	not stated; safety; decreased appetite; R0013656:Table 2
A2	events	3 / 469	not stated; safety; diarrhea; R0013656:Table 2
A2	events	1 / 469	not stated; safety; dyspepsia; R0013656:Table 2
A2	events	1 / 469	not stated; safety; elevated blood calcitonin level; R0013656:Table 2
A2	events	1 / 469	not stated; safety; fatigue; R0013656:Table 2
A2	events	2 / 469	not stated; safety; injection-site reaction; R0013656:Table 2
A2	events	7 / 469	not stated; safety; nausea; R0013656:Table 2
A2	events	4 / 469	not stated; safety; vomiting; R0013656:Table 2
A2	events	4 / 469	not stated; randomized; registry:flow
A3	events	6 / 470	not stated; safety; diarrhea; R0013656:Table 2
A3	events	2 / 470	not stated; safety; dyspepsia; R0013656:Table 2
A3	events	1 / 470	not stated; safety; elevated blood calcitonin level; R0013656:Table 2
A3	events	1 / 470	not stated; safety; fatigue; R0013656:Table 2
A3	events	1 / 470	not stated; safety; injection-site reaction; R0013656:Table 2
A3	events	4 / 470	not stated; safety; nausea; R0013656:Table 2
A3	events	4 / 470	not stated; safety; vomiting; R0013656:Table 2
A3	events	2 / 470	not stated; safety; abdominal pain; R0013656:Table 2
A3	events	0 / 470	not stated; safety; constipation; R0013656:Table 2
A3	events	0 / 470	not stated; safety; covid-19 related pneumonia; R0013656:Table 2
A3	events	40 / 470	not stated; safety; R0013656:Table 2
A3	events	37 / 470	not stated; randomized; R0013656:Supplement Table S3
A3	events	1 / 470	not stated; randomized; registry:flow
A3	events	2 / 470	not stated; safety; decreased appetite; R0013656:Table 2
A4	events	0 / 469	not stated; safety; injection-site reaction; R0013656:Table 2
A4	events	19 / 469	not stated; safety; R0013656:Table 2
A4	events	18 / 469	not stated; randomized; R0013656:Supplement Table S3
A4	events	4 / 469	not stated; safety; abdominal pain; R0013656:Table 2
A4	events	1 / 469	not stated; safety; constipation; R0013656:Table 2
A4	events	1 / 469	not stated; safety; covid-19 related pneumonia; R0013656:Table 2
A4	events	0 / 469	not stated; safety; decreased appetite; R0013656:Table 2
A4	events	1 / 469	not stated; safety; diarrhea; R0013656:Table 2
A4	events	0 / 469	not stated; safety; dyspepsia; R0013656:Table 2
A4	events	0 / 469	not stated; safety; elevated blood calcitonin level; R0013656:Table 2
A4	events	1 / 469	not stated; safety; fatigue; R0013656:Table 2
A4	events	4 / 469	not stated; safety; nausea; R0013656:Table 2
A4	events	3 / 469	not stated; safety; vomiting; R0013656:Table 2
A4	events	3 / 469	not stated; randomized; registry:flow

Nausea (8 lines; O27A)

Arm	Statistic	Events / N	Detail
A1	events	82 / 470	not stated; safety; R0013656:Table 2
A1	events	0 / 470	not stated; safety; registry:adverse_events
A2	events	90 / 469	not stated; safety; R0013656:Table 2
A2	events	1 / 469	not stated; safety; registry:adverse_events
A3	events	104 / 470	not stated; safety; R0013656:Table 2
A3	events	0 / 470	not stated; safety; registry:adverse_events
A4	events	84 / 469	not stated; safety; R0013656:Table 2
A4	events	0 / 469	not stated; safety; registry:adverse_events

Vomiting (9 lines; O27B)

Arm	Statistic	Events / N	Detail
A1	events	27 / 470	not stated; safety; R0013656:Table 2
A1	events	0 / 470	not stated; safety; registry:adverse_events
A2	events	40 / 469	not stated; safety; R0013656:Table 2
A2	events	39 / 469	not stated; safety; registry:adverse_events
A2	events	1 / 469	not stated; safety; registry:adverse_events
A3	events	46 / 470	not stated; safety; R0013656:Table 2
A3	events	0 / 470	not stated; safety; registry:adverse_events
A4	events	0 / 469	not stated; safety; registry:adverse_events
A4	events	39 / 469	not stated; safety; R0013656:Table 2

Diarrhea (4 lines; O27C)

Arm	Statistic	Events / N	Detail
A1	events	62 / 470	not stated; safety; R0013656:Table 2
A2	events	77 / 469	not stated; safety; R0013656:Table 2
A3	events	65 / 470	not stated; safety; R0013656:Table 2
A4	events	54 / 469	not stated; safety; R0013656:Table 2

Constipation (9 lines; O27D)

Arm	Statistic	Events / N	Detail
A1	events	32 / 470	not stated; safety; R0013656:Table 2
A1	events	31 / 470	not stated; safety; registry:adverse_events
A1	events	1 / 470	not stated; safety; registry:adverse_events
A2	events	21 / 469	not stated; safety; R0013656:Table 2
A2	events	0 / 469	not stated; safety; registry:adverse_events
A3	events	21 / 470	not stated; safety; R0013656:Table 2
A3	events	0 / 470	not stated; safety; registry:adverse_events
A4	events	27 / 469	not stated; safety; R0013656:Table 2
A4	events	0 / 469	not stated; safety; registry:adverse_events

Discontinuation due to gastrointestinal adverse events (24 lines; O27E)

Arm	Statistic	Events / N	Detail
A1	events	2 / 470	not stated; safety; abdominal pain; R0013656:Table 2
A1	events	0 / 470	not stated; safety; constipation; R0013656:Table 2
A1	events	1 / 470	not stated; safety; diarrhea; R0013656:Table 2
A1	events	2 / 470	not stated; safety; dyspepsia; R0013656:Table 2
A1	events	6 / 470	not stated; safety; nausea; R0013656:Table 2
A1	events	1 / 470	not stated; safety; vomiting; R0013656:Table 2
A2	events	1 / 469	not stated; safety; abdominal pain; R0013656:Table 2
A2	events	2 / 469	not stated; safety; constipation; R0013656:Table 2
A2	events	3 / 469	not stated; safety; diarrhea; R0013656:Table 2
A2	events	1 / 469	not stated; safety; dyspepsia; R0013656:Table 2
A2	events	7 / 469	not stated; safety; nausea; R0013656:Table 2
A2	events	4 / 469	not stated; safety; vomiting; R0013656:Table 2
A3	events	2 / 470	not stated; safety; abdominal pain; R0013656:Table 2
A3	events	0 / 470	not stated; safety; constipation; R0013656:Table 2
A3	events	6 / 470	not stated; safety; diarrhea; R0013656:Table 2
A3	events	2 / 470	not stated; safety; dyspepsia; R0013656:Table 2
A3	events	4 / 470	not stated; safety; nausea; R0013656:Table 2
A3	events	4 / 470	not stated; safety; vomiting; R0013656:Table 2
A4	events	4 / 469	not stated; safety; abdominal pain; R0013656:Table 2
A4	events	1 / 469	not stated; safety; constipation; R0013656:Table 2
A4	events	1 / 469	not stated; safety; diarrhea; R0013656:Table 2
A4	events	0 / 469	not stated; safety; dyspepsia; R0013656:Table 2
A4	events	4 / 469	not stated; safety; nausea; R0013656:Table 2
A4	events	3 / 469	not stated; safety; vomiting; R0013656:Table 2

Gallbladder and biliary disease (12 lines; O28)

Arm	Statistic	Events / N	Detail
A1	events	1 / 470	not stated; safety; cholecystitis acute; R0013656:Supplement Table S7
A1	events	0 / 470	not stated; safety; cholecystitis infective; registry:adverse_events
A1	events	4 / 470	not stated; safety; cholelithiasis; R0013656:Table 2
A2	events	4 / 469	not stated; safety; cholelithiasis; R0013656:Table 2
A2	events	2 / 469	not stated; safety; cholecystitis acute; R0013656:Supplement Table S7
A2	events	1 / 469	not stated; safety; cholecystitis infective; registry:adverse_events
A3	events	4 / 470	not stated; safety; cholelithiasis; R0013656:Table 2
A3	events	0 / 470	not stated; safety; cholecystitis infective; registry:adverse_events
A3	events	2 / 470	not stated; safety; cholecystitis acute; R0013656:Supplement Table S7
A4	events	0 / 469	not stated; safety; cholecystitis infective; registry:adverse_events
A4	events	0 / 469	not stated; safety; cholecystitis acute; R0013656:Supplement Table S7
A4	events	2 / 469	not stated; safety; cholelithiasis; R0013656:Table 2

Acute pancreatitis (4 lines; O29)

Arm	Statistic	Events / N	Detail
A1	events	0 / 470	not stated; safety; pancreatitis; R0013656:Table 2
A2	events	2 / 469	not stated; safety; pancreatitis; R0013656:Table 2
A3	events	2 / 470	not stated; safety; pancreatitis; R0013656:Table 2
A4	events	3 / 469	not stated; safety; pancreatitis; R0013656:Table 2

Medullary thyroid carcinoma (4 lines; O32A)

Arm	Statistic	Events / N	Detail
A1	events	0 / 470	not stated; safety; R0013656:Results
A2	events	0 / 469	not stated; safety; R0013656:Results
A3	events	0 / 470	not stated; safety; R0013656:Results
A4	events	0 / 469	not stated; safety; R0013656:Results

Diabetic retinopathy complications (28 lines; O33)

Arm	Statistic	Events / N	Detail
A1	events	5 / 470	not stated; safety; R0013656:Supplement Table S12
A1	events	1 / 470	not stated; safety; diabetic hypertensive; R0013656:Supplement Table S12
A1	events	0 / 470	not stated; safety; diabetic retinopathy; R0013656:Table 2
A1	events	3 / 470	not stated; safety; macular edema; R0013656:Supplement Table S12
A1	events	0 / 470	not stated; safety; maculopathy; R0013656:Supplement Table S12
A1	events	1 / 470	not stated; safety; retinal vein occlusion; R0013656:Supplement Table S12
A1	events	1 / 470	not stated; safety; vision blurred; R0013656:Supplement Table S12
A2	events	0 / 469	not stated; safety; maculopathy; R0013656:Supplement Table S12
A2	events	3 / 469	not stated; safety; R0013656:Supplement Table S12
A2	events	0 / 469	not stated; safety; diabetic hypertensive; R0013656:Supplement Table S12
A2	events	2 / 469	not stated; safety; diabetic retinopathy; R0013656:Table 2
A2	events	2 / 469	not stated; safety; macular edema; R0013656:Supplement Table S12
A2	events	0 / 469	not stated; safety; retinal vein occlusion; R0013656:Supplement Table S12
A2	events	1 / 469	not stated; safety; vision blurred; R0013656:Supplement Table S12
A3	events	2 / 470	not stated; safety; R0013656:Supplement Table S12
A3	events	1 / 470	not stated; safety; diabetic hypertensive; R0013656:Supplement Table S12
A3	events	0 / 470	not stated; safety; diabetic retinopathy; R0013656:Table 2
A3	events	0 / 470	not stated; safety; macular edema; R0013656:Supplement Table S12
A3	events	0 / 470	not stated; safety; maculopathy; R0013656:Supplement Table S12
A3	events	0 / 470	not stated; safety; retinal vein occlusion; R0013656:Supplement Table S12
A3	events	1 / 470	not stated; safety; vision blurred; R0013656:Supplement Table S12
A4	events	2 / 469	not stated; safety; R0013656:Supplement Table S12
A4	events	0 / 469	not stated; safety; diabetic hypertensive; R0013656:Supplement Table S12
A4	events	0 / 469	not stated; safety; diabetic retinopathy; R0013656:Table 2
A4	events	0 / 469	not stated; safety; macular edema; R0013656:Supplement Table S12
A4	events	1 / 469	not stated; safety; maculopathy; R0013656:Supplement Table S12
A4	events	0 / 469	not stated; safety; retinal vein occlusion; R0013656:Supplement Table S12
A4	events	1 / 469	not stated; safety; vision blurred; R0013656:Supplement Table S12

Suicidal ideation or behavior (4 lines; O35A)

Arm	Statistic	Events / N	Detail
A1	events	0 / 470	not stated; safety; suicide attempt; registry:adverse_events
A2	events	0 / 469	not stated; safety; suicide attempt; registry:adverse_events
A3	events	1 / 470	not stated; safety; suicide attempt; registry:adverse_events
A4	events	0 / 469	not stated; safety; suicide attempt; registry:adverse_events

Death by suicide (4 lines; O35B)

Arm	Statistic	Events / N	Detail
A1	events	0 / 470	not stated; safety; R0013656:Supplement Table S10
A2	events	0 / 469	not stated; safety; R0013656:Supplement Table S10
A3	events	0 / 470	not stated; safety; R0013656:Supplement Table S10
A4	events	0 / 469	not stated; safety; R0013656:Supplement Table S10