parallel randomized trial

SURPASS-6

A Randomized, Phase 3, Open-label Trial Comparing the Effect of the Addition of Tirzepatide Once Weekly Versus Insulin Lispro (U100) Three Times Daily in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine (U100) With or Without Metformin (SURPASS-6)

Type 2 diabetes (adults)NCT04537923S000108

Design

Randomized: 1,428
Start year: 2020
Treatment: 52 weeks, follow-up 56 weeks
Countries: Argentina, Belgium, Brazil, Czech Republic, Germany, Greece, Hungary, Italy, Mexico, Romania, Russia, Slovakia, Spain, Turkey, United States (135 sites)
Sponsor: Eli Lilly and Company (industry)
Eligibility: adults 18 or older; HbA1c 7.5 to 11 percent; BMI 23 to 45; basal insulin at least 30 U/day with or without up to 2 oral drugs

Conduct and analysis

Blinding: open label
Sequence generation: computer
Allocation concealment: central
Outcome adjudication: not reported
Primary estimand: treatment policy
Analysis population: full analysis
Missing data: multiple imputation (retrieved dropouts)

Arms

Arm	Treatment	Background	Randomized	Analyzed	Completed treatment
A1	Tirzepatide 5 mg subcutaneous once weekly Tirzepatide 5 mg	insulin glargine U100 titrated to fasting glucose 100 to 125 mg/dL, reduced 30 percent at randomization, with or without metformin; lifestyle: standard	243	242	224
A2	Tirzepatide 10 mg subcutaneous once weekly Tirzepatide 10 mg	insulin glargine U100 titrated to fasting glucose 100 to 125 mg/dL, reduced 30 percent at randomization, with or without metformin; lifestyle: standard	238	238	218
A3	Tirzepatide 15 mg subcutaneous once weekly Tirzepatide 15 mg	insulin glargine U100 titrated to fasting glucose 100 to 125 mg/dL, reduced 30 percent at randomization, with or without metformin; lifestyle: standard	236	236	206
A4	Insulin lispro (prandial) Insulin lispro three times daily	insulin glargine U100 titrated to fasting glucose 100 to 125 mg/dL, reduced 30 percent at randomization, with or without metformin; lifestyle: standard	711	708	620
A5	Pooled Tirzepatide pooled 5, 10 and 15 mg	lifestyle: standard		716

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	Insulin lispro (prandial) A4	Whole trial ALL
age	mean (years)	58.0	59.6	58.2	59.0
age	sd (years)	10.2	9.4	9.6	9.7
asian	n	2	0	2	4
asian	percent	0.8		0.8	0.6
black	n	11	9	11	26
black	percent	4.5	3.8	4.7	3.7
bmi: 27 or more	n	221	211	209	637
bmi: 27 or more	percent	91.3	88.7	88.6	90.0
bmi: 30 or more	n	106	72	87	261
bmi: 30 or more	percent	43.8	30.3	36.9	36.9
bmi: 35 or more	n	77	88	76	217
bmi: 35 or more	percent	31.8	37.0	32.2	30.6
bmi: less than 27	n	21	27	27	71
bmi: less than 27	percent	8.7	11.3	11.4	10.0
bmi: less than 30	n	59	78	73	230
bmi: less than 30	percent	24.4	32.8	30.9	32.5
bmi	mean (kg/m2)	33.5	33.4	33.0	33.0
bmi	sd (kg/m2)	5.3	5.5	5.3	5.2
diabetes duration	mean (years)	13.4	13.9	13.4	14.0
diabetes duration	sd (years)	6.9	7.3	7.6	7.4
egfr: less than 60	n	27	14	24	65
egfr: less than 60	percent	11.1	5.9	10.2	9.2
egfr	mean (mL/min/1.73 m2)	89.0	89.5	89.3	88.8
egfr	sd (mL/min/1.73 m2)	20.7	18.0	19.9	18.8
female	n	144	149	133	396
female	percent	59.3	62.6	56.4	55.9
hba1c: more than 8.5	n	146	133	132	407
hba1c: more than 8.5	percent	60.1	55.9	55.9	57.5
hba1c	mean (percent)	8.89	8.78	8.74	8.80
hba1c	sd (percent)	0.97	0.98	1.01	0.96
hispanic	n	148	142	149	443
hispanic	percent	60.9	59.7	63.1	62.6
insulin dose	median (U/kg/day)	0.51	0.54	0.52	0.53
insulin dose	q1 (U/kg/day)	0.41	0.41	0.41	0.42
insulin dose	q3 (U/kg/day)	0.66	0.69	0.69	0.68
metformin use	n	202	195	201	606
metformin use	percent	83.1	81.9	85.2	85.6
other race american indian alaska native	n	0	0	1	2
other race american indian alaska native	percent			0.4	0.3
other race multiple	n	0	5	2	8
other race multiple	percent		2.1	0.8	1.1
other race native hawaiian pacific islander	n	0	0	0	0
sbp	mean (mmHg)					136
uacr	mean (g/kg)	28.9	24.4	23.7	27.2
uacr	se (g/kg)	2.97	2.54	2.46	1.65
weight	mean (kg)	91.7	89.1	91.2	90.3
weight	sd (kg)	17.9	18.8	18.7	17.7
white	n	230	224	220	668
white	percent	94.7	94.1	93.2	94.4

Analyses this trial contributes to

Results

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

HbA1c change (24 lines; O01)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
52	A1 vs A4	md	-0.79 percent		-1.01 to -0.56		treatment policy; full analysis; R0009666:Table 2
52	A1	change	-1.92 percent		-2.1 to -1.8	242	treatment policy; full analysis; R0009666:Table 2
52	A1	change	-2.05 percent	0.08		241	hypothetical; modified itt; R0009666:Supplement eTable 9
52	A1 vs A4	md	-0.89 percent		-1.08 to -0.70		hypothetical; modified itt; R0009666:Supplement eTable 9
52	A2	change	-2.27 percent	0.08		234	hypothetical; modified itt; R0009666:Supplement eTable 9
52	A2 vs A4	md	-1.11 percent		-1.30 to -0.92		hypothetical; modified itt; R0009666:Supplement eTable 9
52	A2	change	-2.15 percent		-2.3 to -2.0	238	treatment policy; full analysis; R0009666:Table 2
52	A2 vs A4	md	-1.01 percent		-1.26 to -0.77		treatment policy; full analysis; R0009666:Table 2
52	A3	change	-2.46 percent	0.08		233	hypothetical; modified itt; R0009666:Supplement eTable 9
52	A3	change	-2.27 percent		-2.4 to -2.1	236	treatment policy; full analysis; R0009666:Table 2
52	A3 vs A4	md	-1.13 percent		-1.37 to -0.90		treatment policy; full analysis; R0009666:Table 2
52	A3 vs A4	md	-1.30 percent		-1.49 to -1.11		hypothetical; modified itt; R0009666:Supplement eTable 9
52	A4	change	-1.13 percent		-1.3 to -1.0	708	treatment policy; full analysis; R0009666:Table 2
52	A4	change	-0.62 percent	0.07			hypothetical; modified itt; hba1c:8.5_or_less; R0009666:Supplement eTable 10
52	A4	change	-1.16 percent	0.05		692	hypothetical; modified itt; R0009666:Supplement eTable 9
52	A4	change	-1.58 percent	0.07			hypothetical; modified itt; hba1c:more_than_8.5; R0009666:Supplement eTable 10
52	A5	change	-2.26 percent	0.05		708	hypothetical; modified itt; R0009666:Supplement eTable 9
52	A5	change	-2.11 percent		-2.2 to -2.0	716	treatment policy; full analysis; R0009666:Table 2
52	A5 vs A4	md	-0.98 percent		-1.17 to -0.79		treatment policy; full analysis; R0009666:Table 2
52	A5	change	-1.68 percent	0.06			hypothetical; modified itt; hba1c:8.5_or_less; R0009666:Supplement eTable 10
52	A5 vs A4	md	-1.06 percent		-1.24 to -0.89		hypothetical; modified itt; hba1c:8.5_or_less; R0009666:Supplement eTable 10
52	A5	change	-2.69 percent	0.07			hypothetical; modified itt; hba1c:more_than_8.5; R0009666:Supplement eTable 10
52	A5 vs A4	md	-1.12 percent		-1.30 to -0.93		hypothetical; modified itt; hba1c:more_than_8.5; R0009666:Supplement eTable 10
52	A5 vs A4	md	-1.10 percent		-1.24 to -0.97		hypothetical; modified itt; R0009666:Supplement eTable 9

Body weight change in kilograms (diabetes) (18 lines; O02)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
52	A1	change	-6.7 kg		-7.7 to -5.7	242	treatment policy; full analysis; R0009666:Table 2
52	A1 vs A4	md	-10.7 kg		-11.5 to -9.9		hypothetical; modified itt; R0009666:Supplement eTable 9
52	A1 vs A4	md	-9.9 kg		-11.4 to -8.4		treatment policy; full analysis; R0009666:Table 2
52	A1	change	-6.9 kg	0.37		241	hypothetical; modified itt; R0009666:Supplement eTable 9
52	A2 vs A4	md	-12.4 kg		-13.9 to -11.0		treatment policy; full analysis; R0009666:Table 2
52	A2	change	-9.9 kg	0.37		234	hypothetical; modified itt; R0009666:Supplement eTable 9
52	A2 vs A4	md	-13.7 kg		-14.5 to -12.9		hypothetical; modified itt; R0009666:Supplement eTable 9
52	A2	change	-9.2 kg		-10.2 to -8.3	238	treatment policy; full analysis; R0009666:Table 2
52	A3	change	-11.0 kg		-11.9 to -10.0	236	treatment policy; full analysis; R0009666:Table 2
52	A3 vs A4	md	-14.2 kg		-15.6 to -12.7		treatment policy; full analysis; R0009666:Table 2
52	A3 vs A4	md	-15.9 kg		-16.7 to -15.0		hypothetical; modified itt; R0009666:Supplement eTable 9
52	A3	change	-12.0 kg	0.38		233	hypothetical; modified itt; R0009666:Supplement eTable 9
52	A4	change	3.8 kg	0.22		694	hypothetical; modified itt; R0009666:Supplement eTable 9
52	A4	change	3.2 kg		2.1 to 4.2	708	treatment policy; full analysis; R0009666:Table 2
52	A5	change	-9.6 kg	0.21			hypothetical; modified itt; R0009666:Supplement eTable 9
52	A5 vs A4	md	-13.4 kg		-14.0 to -12.8		hypothetical; modified itt; R0009666:Supplement eTable 9
52	A5	change	-9.0 kg		-9.5 to -8.4	716	treatment policy; full analysis; R0009666:Table 2
52	A5 vs A4	md	-12.2 kg		-13.4 to -10.9		treatment policy; full analysis; R0009666:Table 2

HbA1c below 7 percent (18 lines; O03)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
52	A1	responders	61.0		242	hypothetical; modified itt; R0009666:Supplement eTable 9
52	A1 vs A4	or	3.13	2.25 to 4.36		hypothetical; modified itt; R0009666:Supplement eTable 9
52	A1	responders	58		242	treatment policy; full analysis; R0009666:Table 2
52	A1 vs A4	or	2.8	2.0 to 3.9		treatment policy; full analysis; R0009666:Table 2
52	A2 vs A4	or	6.16	4.27 to 8.88		hypothetical; modified itt; R0009666:Supplement eTable 9
52	A2	responders	75.6		238	hypothetical; modified itt; R0009666:Supplement eTable 9
52	A2 vs A4	or	5.1	3.5 to 7.4		treatment policy; full analysis; R0009666:Table 2
52	A2	responders	72		238	treatment policy; full analysis; R0009666:Table 2
52	A3	responders	73		236	treatment policy; full analysis; R0009666:Table 2
52	A3 vs A4	or	5.2	3.6 to 7.5		treatment policy; full analysis; R0009666:Table 2
52	A3	responders	79.9		236	hypothetical; modified itt; R0009666:Supplement eTable 9
52	A3 vs A4	or	7.94	5.37 to 11.75		hypothetical; modified itt; R0009666:Supplement eTable 9
52	A4	responders	36.7		708	hypothetical; modified itt; R0009666:Supplement eTable 9
52	A4	responders	36		708	treatment policy; full analysis; R0009666:Table 2
52	A5 vs A4	or	5.35	4.14 to 6.91		hypothetical; modified itt; R0009666:Supplement eTable 9
52	A5	responders	72.1		716	hypothetical; modified itt; R0009666:Supplement eTable 9
52	A5	responders	68		716	treatment policy; full analysis; R0009666:Table 2
52	A5 vs A4	or	4.2	3.2 to 5.5		treatment policy; full analysis; R0009666:Table 2

Level 2 or 3 hypoglycemia (participants) (30 lines; O04)

Arm	Statistic	Events / N	Detail
A1	events	0 / 243	not stated; safety; R0009666:Supplement eTable 12
A1	events	29 / 243	hypothetical; safety; R0009666:Table 4
A1	events	0 / 243	hypothetical; safety; R0009666:Table 4
A1	events	0 / 243	hypothetical; safety; R0009666:Table 4
A1	events	86 / 243	hypothetical; safety; R0009666:Table 4
A1	events	0 / 243	not stated; safety; R0009666:Supplement eTable 12
A1	events	2 / 243	not stated; safety; registry:adverse_events
A1	events	0 / 243	not stated; safety; R0009666:Supplement eTable 12
A2	events	3 / 238	not stated; safety; R0009666:Supplement eTable 12
A2	events	2 / 238	hypothetical; safety; R0009666:Table 4
A2	events	0 / 238	not stated; safety; R0009666:Supplement eTable 12
A2	events	22 / 238	hypothetical; safety; R0009666:Table 4
A2	events	0 / 238	not stated; safety; R0009666:Supplement eTable 12
A2	events	3 / 238	hypothetical; safety; R0009666:Table 4
A2	events	89 / 238	hypothetical; safety; R0009666:Table 4
A3	events	88 / 236	hypothetical; safety; R0009666:Table 4
A3	events	0 / 236	hypothetical; safety; R0009666:Table 4
A3	events	0 / 236	hypothetical; safety; R0009666:Table 4
A3	events	25 / 236	hypothetical; safety; R0009666:Table 4
A3	events	0 / 236	not stated; safety; R0009666:Supplement eTable 12
A3	events	1 / 236	not stated; safety; registry:adverse_events
A3	events	0 / 236	not stated; safety; R0009666:Supplement eTable 12
A3	events	0 / 236	not stated; safety; R0009666:Supplement eTable 12
A4	events	2 / 708	not stated; safety; R0009666:Supplement eTable 12
A4	events	28 / 708	not stated; safety; R0009666:Supplement eTable 12
A4	events	2 / 708	not stated; safety; R0009666:Supplement eTable 12
A4	events	340 / 708	hypothetical; safety; R0009666:Table 4
A4	events	519 / 708	hypothetical; safety; R0009666:Table 4
A4	events	25 / 708	hypothetical; safety; R0009666:Table 4
A4	events	30 / 708	hypothetical; safety; R0009666:Table 4

Level 2 or 3 hypoglycemia (episode rate) (19 lines; O04B)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1	rate	0.59		243	hypothetical; safety; R0009666:Table 4
A1 vs A4	rate ratio	0.13	0.04 to 0.46		hypothetical; safety; R0009666:Table 4
A1	rate	0		243	hypothetical; safety; R0009666:Table 4
A1	rate	2.6		243	hypothetical; safety; R0009666:Table 4
A1 vs A4	rate ratio	0.14	0.09 to 0.22		hypothetical; safety; R0009666:Table 4
A2 vs A4	rate ratio	0.14	0.09 to 0.23		hypothetical; safety; R0009666:Table 4
A2	rate	2.6		238	hypothetical; safety; R0009666:Table 4
A2	rate	0.41		238	hypothetical; safety; R0009666:Table 4
A2	rate	0.05		238	hypothetical; safety; R0009666:Table 4
A2 vs A4	rate ratio	0.29	0.07 to 1.18		hypothetical; safety; R0009666:Table 4
A2 vs A4	rate ratio	0.09	0.04 to 0.24		hypothetical; safety; R0009666:Table 4
A3 vs A4	rate ratio	0.05	0.03 to 0.09		hypothetical; safety; R0009666:Table 4
A3	rate	0		236	hypothetical; safety; R0009666:Table 4
A3	rate	2.3		236	hypothetical; safety; R0009666:Table 4
A3 vs A4	rate ratio	0.13	0.09 to 0.18		hypothetical; safety; R0009666:Table 4
A3	rate	0.23		236	hypothetical; safety; R0009666:Table 4
A4	rate	4.38		708	hypothetical; safety; R0009666:Table 4
A4	rate	18.4		708	hypothetical; safety; R0009666:Table 4
A4	rate	0.16		708	hypothetical; safety; R0009666:Table 4

Systolic blood pressure change (4 lines; O05)

Week	Arm	Statistic	Estimate	95% CI	Detail
52	A1	change	-7.4 mmHg	-8.9 to -5.9	not stated; safety; R0009666:Supplement eTable 7
52	A2	change	-9.0 mmHg	-10.6 to -7.4	not stated; safety; R0009666:Supplement eTable 7
52	A3	change	-5.9 mmHg	-7.5 to -4.3	not stated; safety; R0009666:Supplement eTable 7
52	A4	change	-0.4 mmHg	-1.3 to 0.5	not stated; safety; R0009666:Supplement eTable 7

Weight loss of 5 percent or more (14 lines; O11A)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
52	A1 vs A4	or	28.25	18.36 to 43.46		hypothetical; modified itt; registry:outcomes
52	A1	responders	64		242	hypothetical; modified itt; R0009666:Supplement eFigure 7D
52	A1	responders	62		242	treatment policy; full analysis; R0009666:Supplement eTable 7
52	A1 vs A4	or	15.8	9.8 to 25.6		treatment policy; full analysis; R0009666:Supplement eTable 7
52	A2 vs A4	or	58.90	36.76 to 94.39		hypothetical; modified itt; registry:outcomes
52	A2	responders	76		238	treatment policy; full analysis; R0009666:Supplement eTable 7
52	A2 vs A4	or	29.4	17.8 to 48.7		treatment policy; full analysis; R0009666:Supplement eTable 7
52	A2	responders	79		238	hypothetical; modified itt; R0009666:Supplement eFigure 7D
52	A3	responders	83		236	hypothetical; modified itt; R0009666:Supplement eFigure 7D
52	A3	responders	78		236	treatment policy; full analysis; R0009666:Supplement eTable 7
52	A3 vs A4	or	33.1	20.1 to 54.5		treatment policy; full analysis; R0009666:Supplement eTable 7
52	A3 vs A4	or	77.76	47.49 to 127.33		hypothetical; modified itt; registry:outcomes
52	A4	responders	6		708	hypothetical; modified itt; R0009666:Supplement eFigure 7D
52	A4	responders	10		708	treatment policy; full analysis; R0009666:Supplement eTable 7

Weight loss of 10 percent or more (8 lines; O11B)

Week	Arm	Statistic	Estimate	Events / N	Detail
52	A1	responders	33	242	hypothetical; modified itt; R0009666:Supplement eFigure 7D
52	A1	responders	32	242	treatment policy; full analysis; R0009666:Supplement eTable 7
52	A2	responders	49	238	treatment policy; full analysis; R0009666:Supplement eTable 7
52	A2	responders	52	238	hypothetical; modified itt; R0009666:Supplement eFigure 7D
52	A3	responders	61	236	hypothetical; modified itt; R0009666:Supplement eFigure 7D
52	A3	responders	57	236	treatment policy; full analysis; R0009666:Supplement eTable 7
52	A4	responders	2	708	hypothetical; modified itt; R0009666:Supplement eFigure 7D
52	A4	responders	5	708	treatment policy; full analysis; R0009666:Supplement eTable 7

Weight loss of 15 percent or more (3 lines; O11C)

Week	Arm	Statistic	Estimate	Events / N	Detail
52	A1	responders	14	242	hypothetical; modified itt; R0009666:Supplement eFigure 7D
52	A2	responders	30	238	hypothetical; modified itt; R0009666:Supplement eFigure 7D
52	A3	responders	41	236	hypothetical; modified itt; R0009666:Supplement eFigure 7D

Acute kidney injury (4 lines; O121)

Arm	Statistic	Events / N	Detail
A1	events	0 / 243	not stated; safety; R0009666:Supplement eTable 12
A2	events	1 / 238	not stated; safety; R0009666:Supplement eTable 12
A3	events	1 / 236	not stated; safety; R0009666:Supplement eTable 12
A4	events	0 / 708	not stated; safety; R0009666:Supplement eTable 12

All cause mortality (4 lines; O20)

Arm	Statistic	Events / N	Detail
A1	events	3 / 243	while on treatment; safety; R0009666:Table 3
A2	events	3 / 238	while on treatment; safety; R0009666:Table 3
A3	events	1 / 236	while on treatment; safety; R0009666:Table 3
A4	events	11 / 708	while on treatment; safety; R0009666:Table 3

Four point MACE including unstable angina (4 lines; O21B)

Arm	Statistic	Events / N	Detail
A1	events	5 / 243	while on treatment; safety; R0009666:Table 3
A2	events	7 / 238	while on treatment; safety; R0009666:Table 3
A3	events	3 / 236	while on treatment; safety; R0009666:Table 3
A4	events	12 / 708	while on treatment; safety; R0009666:Table 3

SF-36 physical component summary change (7 lines; O24A)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
52	A1 vs A4	md	1.5 points		0.5 to 2.6		hypothetical; modified itt; registry:outcomes
52	A1	change	1.0 points	0.46		222	hypothetical; modified itt; registry:outcomes
52	A2	change	1.7 points	0.46		217	hypothetical; modified itt; registry:outcomes
52	A2 vs A4	md	2.3 points		1.2 to 3.3		hypothetical; modified itt; registry:outcomes
52	A3	change	1.7 points	0.48		199	hypothetical; modified itt; registry:outcomes
52	A3 vs A4	md	2.2 points		1.2 to 3.3		hypothetical; modified itt; registry:outcomes
52	A4	change	-0.6 points	0.28		599	hypothetical; modified itt; registry:outcomes

Serious adverse events (8 lines; O25)

Arm	Statistic	Events / N	Detail
A1	events	20 / 243	not stated; safety; registry:adverse_events
A1	events	15 / 243	while on treatment; safety; R0009666:Table 3
A2	events	16 / 238	not stated; safety; registry:adverse_events
A2	events	14 / 238	while on treatment; safety; R0009666:Table 3
A3	events	15 / 236	while on treatment; safety; R0009666:Table 3
A3	events	17 / 236	not stated; safety; registry:adverse_events
A4	events	77 / 708	while on treatment; safety; R0009666:Table 3
A4	events	81 / 708	not stated; safety; registry:adverse_events

Discontinuation due to adverse events (68 lines; O26)

Arm	Statistic	Events / N	Detail
A1	events	5 / 243	while on treatment; safety; R0009666:Table 3
A1	events	0 / 243	while on treatment; safety; lung neoplasm malignant; R0009666:Table 3
A1	events	8 / 243	not stated; randomized; R0009666:Supplement eTable 6
A1	events	10 / 243	while on treatment; safety; R0009666:Table 3
A1	events	0 / 243	while on treatment; safety; acute coronary syndrome; R0009666:Table 3
A1	events	0 / 243	while on treatment; safety; acute kidney injury; R0009666:Table 3
A1	events	0 / 243	while on treatment; safety; covid-19; R0009666:Table 3
A1	events	2 / 243	not stated; randomized; registry:flow
A1	events	1 / 243	while on treatment; safety; death; R0009666:Table 3
A1	events	0 / 243	while on treatment; safety; decreased appetite; R0009666:Table 3
A1	events	2 / 243	while on treatment; safety; diarrhea; R0009666:Table 3
A1	events	0 / 243	while on treatment; safety; dyspepsia; R0009666:Table 3
A1	events	0 / 243	while on treatment; safety; gastritis; R0009666:Table 3
A1	events	3 / 243	while on treatment; safety; nausea; R0009666:Table 3
A1	events	0 / 243	while on treatment; safety; pancreatic enzymes increased; R0009666:Table 3
A1	events	0 / 243	while on treatment; safety; vomiting; R0009666:Table 3
A1	events	0 / 243	while on treatment; safety; weight decreased; R0009666:Table 3
A2	events	10 / 238	not stated; randomized; R0009666:Supplement eTable 6
A2	events	1 / 238	while on treatment; safety; dyspepsia; R0009666:Table 3
A2	events	11 / 238	while on treatment; safety; R0009666:Table 3
A2	events	0 / 238	while on treatment; safety; acute coronary syndrome; R0009666:Table 3
A2	events	1 / 238	while on treatment; safety; acute kidney injury; R0009666:Table 3
A2	events	0 / 238	while on treatment; safety; covid-19; R0009666:Table 3
A2	events	0 / 238	while on treatment; safety; death; R0009666:Table 3
A2	events	1 / 238	not stated; randomized; registry:flow
A2	events	1 / 238	while on treatment; safety; decreased appetite; R0009666:Table 3
A2	events	0 / 238	while on treatment; safety; diarrhea; R0009666:Table 3
A2	events	1 / 238	while on treatment; safety; gastritis; R0009666:Table 3
A2	events	0 / 238	while on treatment; safety; lung neoplasm malignant; R0009666:Table 3
A2	events	1 / 238	while on treatment; safety; nausea; R0009666:Table 3
A2	events	1 / 238	while on treatment; safety; pancreatic enzymes increased; R0009666:Table 3
A2	events	4 / 238	while on treatment; safety; R0009666:Table 3
A2	events	0 / 238	while on treatment; safety; vomiting; R0009666:Table 3
A2	events	0 / 238	while on treatment; safety; weight decreased; R0009666:Table 3
A3	events	6 / 236	while on treatment; safety; nausea; R0009666:Table 3
A3	events	21 / 236	not stated; randomized; R0009666:Supplement eTable 6
A3	events	22 / 236	while on treatment; safety; R0009666:Table 3
A3	events	1 / 236	while on treatment; safety; acute coronary syndrome; R0009666:Table 3
A3	events	0 / 236	while on treatment; safety; acute kidney injury; R0009666:Table 3
A3	events	0 / 236	while on treatment; safety; covid-19; R0009666:Table 3
A3	events	0 / 236	while on treatment; safety; death; R0009666:Table 3
A3	events	1 / 236	while on treatment; safety; decreased appetite; R0009666:Table 3
A3	events	0 / 236	while on treatment; safety; diarrhea; R0009666:Table 3
A3	events	1 / 236	while on treatment; safety; dyspepsia; R0009666:Table 3
A3	events	1 / 236	while on treatment; safety; gastritis; R0009666:Table 3
A3	events	0 / 236	while on treatment; safety; lung neoplasm malignant; R0009666:Table 3
A3	events	2 / 236	while on treatment; safety; pancreatic enzymes increased; R0009666:Table 3
A3	events	5 / 236	while on treatment; safety; vomiting; R0009666:Table 3
A3	events	2 / 236	while on treatment; safety; weight decreased; R0009666:Table 3
A3	events	2 / 236	not stated; randomized; registry:flow
A3	events	3 / 236	while on treatment; safety; R0009666:Table 3
A4	events	1 / 708	while on treatment; safety; death; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; diarrhea; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; dyspepsia; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; gastritis; R0009666:Table 3
A4	events	2 / 708	while on treatment; safety; lung neoplasm malignant; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; nausea; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; pancreatic enzymes increased; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; vomiting; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; weight decreased; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; acute kidney injury; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; acute coronary syndrome; R0009666:Table 3
A4	events	6 / 711	not stated; randomized; R0009666:Supplement eTable 6
A4	events	15 / 708	while on treatment; safety; R0009666:Table 3
A4	events	3 / 708	while on treatment; safety; covid-19; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; decreased appetite; R0009666:Table 3
A4	events	4 / 711	not stated; randomized; registry:flow
A4	events	17 / 708	while on treatment; safety; R0009666:Table 3

Nausea (4 lines; O27A)

Arm	Statistic	Events / N	Detail
A1	events	33 / 243	while on treatment; safety; R0009666:Table 3
A2	events	49 / 238	while on treatment; safety; R0009666:Table 3
A3	events	61 / 236	while on treatment; safety; R0009666:Table 3
A4	events	8 / 708	while on treatment; safety; R0009666:Table 3

Vomiting (4 lines; O27B)

Arm	Statistic	Events / N	Detail
A1	events	11 / 243	while on treatment; safety; R0009666:Table 3
A2	events	21 / 238	while on treatment; safety; R0009666:Table 3
A3	events	30 / 236	while on treatment; safety; R0009666:Table 3
A4	events	4 / 708	while on treatment; safety; R0009666:Table 3

Diarrhea (4 lines; O27C)

Arm	Statistic	Events / N	Detail
A1	events	29 / 243	while on treatment; safety; R0009666:Table 3
A2	events	36 / 238	while on treatment; safety; R0009666:Table 3
A3	events	26 / 236	while on treatment; safety; R0009666:Table 3
A4	events	17 / 708	while on treatment; safety; R0009666:Table 3

Constipation (4 lines; O27D)

Arm	Statistic	Events / N	Detail
A1	events	6 / 243	while on treatment; safety; R0009666:Table 3
A2	events	8 / 238	while on treatment; safety; R0009666:Table 3
A3	events	14 / 236	while on treatment; safety; R0009666:Table 3
A4	events	4 / 708	while on treatment; safety; R0009666:Table 3

Discontinuation due to gastrointestinal adverse events (20 lines; O27E)

Arm	Statistic	Events / N	Detail
A1	events	0 / 243	while on treatment; safety; vomiting; R0009666:Table 3
A1	events	2 / 243	while on treatment; safety; diarrhea; R0009666:Table 3
A1	events	0 / 243	while on treatment; safety; dyspepsia; R0009666:Table 3
A1	events	0 / 243	while on treatment; safety; gastritis; R0009666:Table 3
A1	events	3 / 243	while on treatment; safety; nausea; R0009666:Table 3
A2	events	0 / 238	while on treatment; safety; diarrhea; R0009666:Table 3
A2	events	1 / 238	while on treatment; safety; dyspepsia; R0009666:Table 3
A2	events	1 / 238	while on treatment; safety; gastritis; R0009666:Table 3
A2	events	1 / 238	while on treatment; safety; nausea; R0009666:Table 3
A2	events	0 / 238	while on treatment; safety; vomiting; R0009666:Table 3
A3	events	0 / 236	while on treatment; safety; diarrhea; R0009666:Table 3
A3	events	1 / 236	while on treatment; safety; dyspepsia; R0009666:Table 3
A3	events	1 / 236	while on treatment; safety; gastritis; R0009666:Table 3
A3	events	6 / 236	while on treatment; safety; nausea; R0009666:Table 3
A3	events	5 / 236	while on treatment; safety; vomiting; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; diarrhea; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; dyspepsia; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; gastritis; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; nausea; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; vomiting; R0009666:Table 3

Gallbladder and biliary disease (20 lines; O28)

Arm	Statistic	Events / N	Detail
A1	events	1 / 243	while on treatment; safety; acute cholecystitis; R0009666:Table 3
A1	events	0 / 243	not stated; safety; cholecystitis acute; R0009666:Supplement eTable 12
A1	events	0 / 243	not stated; safety; cholecystitis; registry:adverse_events
A1	events	0 / 243	not stated; safety; cholelithiasis; registry:adverse_events
A1	events	2 / 243	while on treatment; safety; cholelithiasis; R0009666:Table 3
A2	events	3 / 238	while on treatment; safety; cholelithiasis; R0009666:Table 3
A2	events	1 / 238	not stated; safety; cholecystitis acute; R0009666:Supplement eTable 12
A2	events	0 / 238	not stated; safety; cholecystitis; registry:adverse_events
A2	events	1 / 238	not stated; safety; cholelithiasis; registry:adverse_events
A2	events	1 / 238	while on treatment; safety; acute cholecystitis; R0009666:Table 3
A3	events	0 / 236	not stated; safety; cholelithiasis; registry:adverse_events
A3	events	4 / 236	while on treatment; safety; cholelithiasis; R0009666:Table 3
A3	events	1 / 236	while on treatment; safety; acute cholecystitis; R0009666:Table 3
A3	events	0 / 236	not stated; safety; cholecystitis acute; R0009666:Supplement eTable 12
A3	events	1 / 236	not stated; safety; cholecystitis; registry:adverse_events
A4	events	0 / 708	not stated; safety; cholelithiasis; registry:adverse_events
A4	events	1 / 708	not stated; safety; cholecystitis acute; R0009666:Supplement eTable 12
A4	events	0 / 708	not stated; safety; cholecystitis; registry:adverse_events
A4	events	1 / 708	while on treatment; safety; acute cholecystitis; R0009666:Table 3
A4	events	2 / 708	while on treatment; safety; cholelithiasis; R0009666:Table 3

Acute pancreatitis (4 lines; O29)

Arm	Statistic	Events / N	Detail
A1	events	0 / 243	while on treatment; safety; pancreatitis; R0009666:Table 3
A2	events	0 / 238	while on treatment; safety; pancreatitis; R0009666:Table 3
A3	events	0 / 236	while on treatment; safety; pancreatitis; R0009666:Table 3
A4	events	0 / 708	while on treatment; safety; pancreatitis; R0009666:Table 3

Medullary thyroid carcinoma (4 lines; O32A)

Arm	Statistic	Events / N	Detail
A1	events	0 / 243	while on treatment; safety; R0009666:Results
A2	events	0 / 238	while on treatment; safety; R0009666:Results
A3	events	0 / 236	while on treatment; safety; R0009666:Results
A4	events	0 / 708	while on treatment; safety; R0009666:Results

Thyroid cancer (any) (4 lines; O32B)

Arm	Statistic	Events / N	Detail
A1	events	0 / 243	while on treatment; safety; R0009666:Results
A2	events	0 / 238	while on treatment; safety; R0009666:Results
A3	events	0 / 236	while on treatment; safety; R0009666:Results
A4	events	0 / 708	while on treatment; safety; R0009666:Results

Diabetic retinopathy complications (4 lines; O33)

Arm	Statistic	Events / N	Detail
A1	events	2 / 243	while on treatment; safety; diabetic retinopathy; R0009666:Table 3
A2	events	0 / 238	while on treatment; safety; diabetic retinopathy; R0009666:Table 3
A3	events	0 / 236	while on treatment; safety; diabetic retinopathy; R0009666:Table 3
A4	events	4 / 708	while on treatment; safety; diabetic retinopathy; R0009666:Table 3

Suicidal ideation or behavior (4 lines; O35A)

Arm	Statistic	Events / N	Detail
A1	events	0 / 243	not stated; safety; suicide attempt; registry:adverse_events
A2	events	0 / 238	not stated; safety; suicide attempt; registry:adverse_events
A3	events	0 / 236	not stated; safety; suicide attempt; registry:adverse_events
A4	events	1 / 708	not stated; safety; suicide attempt; registry:adverse_events

eGFR total slope (7 lines; O51)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Detail
52	A1	change	-3.6 mL/min/1.73 m2	0.65		not stated; safety; R0009666:Supplement eTable 14
52	A1 vs A4	md	-0.8 mL/min/1.73 m2		-2.3 to 0.7	not stated; safety; R0009666:Supplement eTable 14
52	A2	change	-2.8 mL/min/1.73 m2	0.66		not stated; safety; R0009666:Supplement eTable 14
52	A2 vs A4	md	0.0 mL/min/1.73 m2		-1.5 to 1.5	not stated; safety; R0009666:Supplement eTable 14
52	A3	change	-1.9 mL/min/1.73 m2	0.66		not stated; safety; R0009666:Supplement eTable 14
52	A3 vs A4	md	0.9 mL/min/1.73 m2		-0.6 to 2.4	not stated; safety; R0009666:Supplement eTable 14
52	A4	change	-2.7 mL/min/1.73 m2	0.39		not stated; safety; R0009666:Supplement eTable 14