parallel randomized trial

REWIND

The Effect of Dulaglutide on Major Cardiovascular Events in Patients With Type 2 Diabetes: Researching Cardiovascular Events With a Weekly INcretin in Diabetes (REWIND)

Type 2 diabetes (adults)NCT01394952S000147

Design

Randomized: 9,901
Start year: 2011
Treatment: , follow-up 365.26 weeks
Countries: multinational (371 sites)
Sponsor: Eli Lilly and Company (industry)
Eligibility: age 50 or older with T2D; HbA1c 9.5 percent or less; BMI 23 or more; CV disease or risk factors

Conduct and analysis

Blinding: double blind
Sequence generation: computer
Allocation concealment: central
Outcome adjudication: yes
Primary estimand: treatment policy
Analysis population: randomized
Missing data: censoring at last known follow up

Arms

Arm	Treatment	Background	Randomized	Analyzed	Completed treatment
A1	Placebo Placebo	usual care glucose lowering drugs; lifestyle: standard	4,952	4,952
A2	Dulaglutide 1.5 mg subcutaneous once weekly Dulaglutide 1.5 mg	usual care glucose lowering drugs; lifestyle: standard	4,949	4,949

Baseline characteristics

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

Characteristic	Statistic	Placebo A1	Dulaglutide 1.5 mg subcutaneous once weekly A2
age: 18 to 65	n	2315	2330
age: 65 or older	n	2637	2619
age	mean (years)	66.2	66.2
age	sd (years)	6.5	6.5
asian	n	218	216
black	n	346	331
bmi	mean (kg/m2)	32.3	32.3
bmi	sd (kg/m2)	5.8	5.7
diabetes duration	mean (years)	10.6	10.5
diabetes duration	median (years)	9.5	9.5
diabetes duration	q1 (years)	5.5	5.5
diabetes duration	q3 (years)	14.5	14.5
diabetes duration	sd (years)	7.2	7.3
egfr: less than 60	n	1118	1081
egfr: less than 60	percent	22.6	21.8
egfr	mean (mL/min/1.73 m2)	76.6	77.2
egfr	median (mL/min/1.73 m2)	74.7	75.3
egfr	q1 (mL/min/1.73 m2)	61.2	61.6
egfr	q3 (mL/min/1.73 m2)	90.6	91.8
egfr	sd (mL/min/1.73 m2)	22.8	22.7
established cvd	n	1554	1560
established cvd	percent	31.4	31.5
female	n	2283	2306
female	percent	46.1	46.6
hba1c	mean (percent)	7.4	7.3
hba1c	median (percent)	7.2	7.2
hba1c	q1 (percent)	6.6	6.6
hba1c	q3 (percent)	8.1	8.1
hba1c	sd (percent)	1.1	1.1
hispanic	n	64	60
insulin use	n	1174	1189
insulin use	percent	23.7	24.0
metformin use	n	4015	4022
metformin use	percent	81.1	81.3
other dpp4i use	n	298	266
other dpp4i use	percent	6.0	5.4
other race american indian alaska native	n	543	549
other race multiple	n	79	87
other race native hawaiian pacific islander	n	22	12
other sulfonylurea use	n	2282	2270
other sulfonylurea use	percent	46.1	45.9
other tzd use	n	68	100
other tzd use	percent	1.4	2.0
sbp	mean (mmHg)	137.3	137.1
sbp	sd (mmHg)	17.0	16.6
sglt2i use	n	1	2
uacr: 3.39 or more	n	1760	1707
uacr: 3.39 or more	percent	35.5	34.5
uacr: 3.39 to 33.9	n	1351	1325
uacr: 3.39 to 33.9	percent	27.3	26.8
uacr: more than 33.9	n	409	382
uacr: more than 33.9	percent	8.3	7.7
uacr	median (mg/mmol)	1.88	1.80
uacr	q1 (mg/mmol)	0.70	0.70
uacr	q3 (mg/mmol)	7.38	6.60
weight	mean (kg)	88.9	88.5
weight	sd (kg)	18.6	18.4
white	n	3744	3754
white	percent	75.6	75.9

Analyses this trial contributes to

Results

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

HbA1c change (9 lines; O01)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Detail
52.14	A1	final	7.40 percent			not stated; modified itt; R0021370:Results
52.14	A2	final	6.70 percent			not stated; modified itt; R0021370:Results
52.14	A2 vs A1	md	-0.70 percent		-0.74 to -0.67	not stated; modified itt; R0021370:Results
281.77	A1	change	0.16 percent	0.01		treatment policy; randomized; R0018537:Supplement Table S6
281.77	A2 vs A1	md	-0.61 percent		-0.65 to -0.58	treatment policy; randomized; R0018537:Figure 4
281.77	A2	change	-0.46 percent	0.01		treatment policy; randomized; R0018537:Supplement Table S6
312.84	A1	final	7.59 percent			not stated; modified itt; R0021370:Results
312.84	A2	final	7.12 percent			not stated; modified itt; R0021370:Results
312.84	A2 vs A1	md	-0.47 percent		-0.55 to -0.40	not stated; modified itt; R0021370:Results

Body weight change in kilograms (diabetes) (3 lines; O02)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Detail
281.77	A1	change	-1.49 kg	0.08		treatment policy; randomized; R0018537:Supplement Table S6
281.77	A2	change	-2.95 kg	0.08		treatment policy; randomized; R0018537:Supplement Table S6
281.77	A2 vs A1	md	-1.46 kg		-1.67 to -1.25	treatment policy; randomized; R0018537:Figure 4

Level 2 or 3 hypoglycemia (participants) (7 lines; O04)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1	events			74 / 4952	treatment policy; randomized; R0018537:Table 3
A1	events			354 / 4949	not stated; safety; registry:adverse_events
A1	events			72 / 4949	not stated; safety; registry:adverse_events
A2	events			413 / 4943	not stated; safety; registry:adverse_events
A2 vs A1	hr	0.86	0.62 to 1.20		not stated; randomized; R0021955:Figure 3
A2	events			64 / 4949	treatment policy; randomized; R0018537:Table 3
A2	events			62 / 4943	not stated; safety; registry:adverse_events

Systolic blood pressure change (3 lines; O05)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Detail
281.77	A1	change	-1.44 mmHg	0.13		treatment policy; randomized; R0018537:Supplement Table S6
281.77	A2 vs A1	md	-1.70 mmHg		-2.07 to -1.33	treatment policy; randomized; R0018537:Figure 4
281.77	A2	change	-3.15 mmHg	0.13		treatment policy; randomized; R0018537:Supplement Table S6

Acute kidney injury (7 lines; O121)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1	events			67 / 4949	not stated; safety; registry:adverse_events
A1	events			93 / 4952	treatment policy; randomized; R0018537:Table 3
A1	events			67 / 4952	not stated; randomized; R0018694:Supplement Table S4
A2	events			60 / 4949	not stated; randomized; R0018694:Supplement Table S4
A2 vs A1	hr	0.90	0.67 to 1.20		not stated; randomized; R0018694:Table 2
A2	events			61 / 4943	not stated; safety; registry:adverse_events
A2	events			84 / 4949	treatment policy; randomized; R0018537:Table 3

All cause mortality (15 lines; O20)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1	events			370 / 2988	not stated; modified itt; hba1c:7_or_more; R0021955:Figure 2
A1	events			389 / 2637	not stated; randomized; age:65_or_older; R0022641:Results
A1	events			592 / 4952	treatment policy; randomized; R0018537:Table 2
A1	events			203 / 2315	not stated; randomized; age:less_than_65; R0022641:Results
A1	events			221 / 1949	not stated; modified itt; hba1c:less_than_7; R0021955:Figure 2
A2	events			208 / 1972	not stated; modified itt; hba1c:less_than_7; R0021955:Figure 2
A2 vs A1	hr	0.83	0.68 to 1.01		not stated; randomized; age:less_than_65; R0022641:Results
A2 vs A1	hr	0.88	0.76 to 1.02		not stated; modified itt; hba1c:7_or_more; R0021955:Figure 2
A2	events			365 / 2619	not stated; randomized; age:65_or_older; R0022641:Results
A2 vs A1	hr	0.94	0.81 to 1.08		not stated; randomized; age:65_or_older; R0022641:Results
A2	events			326 / 2967	not stated; modified itt; hba1c:7_or_more; R0021955:Figure 2
A2 vs A1	hr	0.93	0.77 to 1.12		not stated; modified itt; hba1c:less_than_7; R0021955:Figure 2
A2	events			536 / 4949	treatment policy; randomized; R0018537:Table 2
A2 vs A1	hr	0.90	0.80 to 1.01		treatment policy; randomized; R0018537:Table 2
A2	events			171 / 2330	not stated; randomized; age:less_than_65; R0022641:Results

Three point MACE (98 lines; O21)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1	events			254 / 2315	not stated; randomized; age:less_than_65; R0022641:Results
A1	events			146 / 1192	treatment policy; randomized; diabetes_duration:less_than_5; R0018537:Figure 3
A1	events			423 / 3920	treatment policy; randomized; established_cvd:no_prior_mi_or_stroke; R0018537:Supplement Table S4
A1	events			317 / 3128	treatment policy; randomized; established_cvd:no; R0018537:Figure 3
A1	events			236 / 1007	treatment policy; randomized; established_cvd:prior_mi_or_stroke; R0018537:Supplement Table S4
A1	events			315 / 1554	treatment policy; randomized; established_cvd:yes; R0018537:Figure 3
A1	events			423 / 2988	not stated; modified itt; hba1c:7_or_more; R0021955:Figure 2
A1	events			419 / 2973	treatment policy; randomized; hba1c:7_or_more; R0018537:Supplement Table S4
A1	events			373 / 2603	treatment policy; randomized; hba1c:7.2_or_more; R0018537:Figure 3
A1	events			289 / 2334	treatment policy; randomized; hba1c:less_than_7.2; R0018537:Figure 3
A1	events			239 / 1949	not stated; modified itt; hba1c:less_than_7; R0021955:Figure 2
A1	events			243 / 1964	treatment policy; randomized; hba1c:less_than_7; R0018537:Supplement Table S4
A1	events			663 / 4952	treatment policy; randomized; R0018537:Table 2
A1	events			30 / 218	treatment policy; randomized; race:asian; R0018537:Supplement Table S4
A1	events			409 / 2637	not stated; randomized; age:65_or_older; R0022641:Results
A1	events			51 / 346	treatment policy; randomized; race:black; R0018537:Supplement Table S4
A1	events			77 / 644	treatment policy; randomized; race:other; R0018537:Supplement Table S4
A1	events			384 / 2350	treatment policy; randomized; age:66_or_older; R0018537:Figure 3
A1	events			505 / 3744	treatment policy; randomized; race:white; R0018537:Supplement Table S4
A1	events			196 / 1476	treatment policy; randomized; diabetes_duration:5_to_less_than_10; R0018537:Figure 3
A1	events			41 / 238	treatment policy; randomized; region:asia_pacific; R0018537:Figure 3
A1	events			315 / 2165	treatment policy; randomized; region:europe; R0018537:Figure 3
A1	events			279 / 2602	treatment policy; randomized; age:less_than_66; R0018537:Figure 3
A1	events			190 / 1510	treatment policy; randomized; region:latin_america; R0018537:Figure 3
A1	events			117 / 1039	treatment policy; randomized; region:usa_and_canada; R0018537:Figure 3
A1	events			401 / 3031	treatment policy; randomized; bmi:30_or_more; R0018537:Supplement Table S4
A1	events			249 / 2283	treatment policy; randomized; sex:female; R0018537:Figure 3
A1	events			414 / 2669	treatment policy; randomized; sex:male; R0018537:Figure 3
A1	events			308 / 2302	treatment policy; randomized; bmi:32_or_more; R0018537:Figure 3
A1	events			262 / 1921	treatment policy; randomized; bmi:less_than_30; R0018537:Supplement Table S4
A1	events			355 / 2650	treatment policy; randomized; bmi:less_than_32; R0018537:Figure 3
A1	events			321 / 2284	treatment policy; randomized; diabetes_duration:10_or_more; R0018537:Figure 3
A2 vs A1	hr	0.86	0.74 to 1.00		treatment policy; randomized; hba1c:7.2_or_more; R0018537:Figure 3
A2	events			594 / 4949	treatment policy; randomized; R0018537:Table 2
A2 vs A1	hr	0.88	0.79 to 0.99		treatment policy; randomized; R0018537:Table 2
A2	events			368 / 2619	not stated; randomized; age:65_or_older; R0022641:Results
A2 vs A1	hr	0.89	0.78 to 1.03		not stated; randomized; age:65_or_older; R0022641:Results
A2	events			331 / 2314	treatment policy; randomized; age:66_or_older; R0018537:Figure 3
A2 vs A1	hr	0.86	0.74 to 1.00		treatment policy; randomized; age:66_or_older; R0018537:Figure 3
A2	events			226 / 2330	not stated; randomized; age:less_than_65; R0022641:Results
A2 vs A1	hr	0.87	0.72 to 1.04		not stated; randomized; age:less_than_65; R0022641:Results
A2	events			263 / 2635	treatment policy; randomized; age:less_than_66; R0018537:Figure 3
A2 vs A1	hr	0.92	0.78 to 1.09		treatment policy; randomized; age:less_than_66; R0018537:Figure 3
A2 vs A1	hr	0.93	0.82 to 1.06		not stated; other; background:metformin; R0007143:Figure 4
A2 vs A1	hr	0.78	0.61 to 1.00		not stated; other; background:no_metformin; R0007143:Figure 4
A2	events			353 / 3027	treatment policy; randomized; bmi:30_or_more; R0018537:Supplement Table S4
A2 vs A1	hr	0.86	0.75 to 1.00		treatment policy; randomized; bmi:30_or_more; R0018537:Supplement Table S4
A2	events			254 / 2281	treatment policy; randomized; bmi:32_or_more; R0018537:Figure 3
A2 vs A1	hr	0.82	0.69 to 0.96		treatment policy; randomized; bmi:32_or_more; R0018537:Figure 3
A2	events			241 / 1921	treatment policy; randomized; bmi:less_than_30; R0018537:Supplement Table S4
A2 vs A1	hr	0.91	0.76 to 1.08		treatment policy; randomized; bmi:less_than_30; R0018537:Supplement Table S4
A2	events			340 / 2667	treatment policy; randomized; bmi:less_than_32; R0018537:Figure 3
A2 vs A1	hr	0.94	0.81 to 1.09		treatment policy; randomized; bmi:less_than_32; R0018537:Figure 3
A2	events			292 / 2276	treatment policy; randomized; diabetes_duration:10_or_more; R0018537:Figure 3
A2 vs A1	hr	0.90	0.77 to 1.06		treatment policy; randomized; diabetes_duration:10_or_more; R0018537:Figure 3
A2	events			174 / 1446	treatment policy; randomized; diabetes_duration:5_to_less_than_10; R0018537:Figure 3
A2 vs A1	hr	0.89	0.73 to 1.09		treatment policy; randomized; diabetes_duration:5_to_less_than_10; R0018537:Figure 3
A2	events			128 / 1227	treatment policy; randomized; diabetes_duration:less_than_5; R0018537:Figure 3
A2 vs A1	hr	0.84	0.66 to 1.06		treatment policy; randomized; diabetes_duration:less_than_5; R0018537:Figure 3
A2	events			396 / 3896	treatment policy; randomized; established_cvd:no_prior_mi_or_stroke; R0018537:Supplement Table S4
A2 vs A1	hr	0.93	0.81 to 1.07		treatment policy; randomized; established_cvd:no_prior_mi_or_stroke; R0018537:Supplement Table S4
A2	events			277 / 3093	treatment policy; randomized; established_cvd:no; R0018537:Figure 3
A2 vs A1	hr	0.87	0.74 to 1.02		treatment policy; randomized; established_cvd:no; R0018537:Figure 3
A2	events			196 / 1028	treatment policy; randomized; established_cvd:prior_mi_or_stroke; R0018537:Supplement Table S4
A2 vs A1	hr	0.79	0.66 to 0.96		treatment policy; randomized; established_cvd:prior_mi_or_stroke; R0018537:Supplement Table S4
A2	events			280 / 1560	treatment policy; randomized; established_cvd:yes; R0018537:Figure 3
A2 vs A1	hr	0.87	0.74 to 1.02		treatment policy; randomized; established_cvd:yes; R0018537:Figure 3
A2	events			365 / 2967	not stated; modified itt; hba1c:7_or_more; R0021955:Figure 2
A2 vs A1	hr	0.85	0.74 to 0.98		not stated; modified itt; hba1c:7_or_more; R0021955:Figure 2
A2	events			364 / 2957	treatment policy; randomized; hba1c:7_or_more; R0018537:Supplement Table S4
A2 vs A1	hr	0.86	0.74 to 0.98		treatment policy; randomized; hba1c:7_or_more; R0018537:Supplement Table S4
A2	events			328 / 2610	treatment policy; randomized; hba1c:7.2_or_more; R0018537:Figure 3
A2	events			263 / 2329	treatment policy; randomized; hba1c:less_than_7.2; R0018537:Figure 3
A2 vs A1	hr	0.90	0.76 to 1.06		treatment policy; randomized; hba1c:less_than_7.2; R0018537:Figure 3
A2	events			226 / 1972	not stated; modified itt; hba1c:less_than_7; R0021955:Figure 2
A2 vs A1	hr	0.93	0.77 to 1.11		not stated; modified itt; hba1c:less_than_7; R0021955:Figure 2
A2	events			227 / 1982	treatment policy; randomized; hba1c:less_than_7; R0018537:Supplement Table S4
A2 vs A1	hr	0.92	0.76 to 1.10		treatment policy; randomized; hba1c:less_than_7; R0018537:Supplement Table S4
A2	events			21 / 216	treatment policy; randomized; race:asian; R0018537:Supplement Table S4
A2 vs A1	hr	0.71	0.40 to 1.24		treatment policy; randomized; race:asian; R0018537:Supplement Table S4
A2	events			39 / 331	treatment policy; randomized; race:black; R0018537:Supplement Table S4
A2 vs A1	hr	0.77	0.51 to 1.17		treatment policy; randomized; race:black; R0018537:Supplement Table S4
A2	events			72 / 648	treatment policy; randomized; race:other; R0018537:Supplement Table S4
A2 vs A1	hr	0.92	0.67 to 1.28		treatment policy; randomized; race:other; R0018537:Supplement Table S4
A2	events			462 / 3754	treatment policy; randomized; race:white; R0018537:Supplement Table S4
A2 vs A1	hr	0.90	0.79 to 1.02		treatment policy; randomized; race:white; R0018537:Supplement Table S4
A2	events			23 / 232	treatment policy; randomized; region:asia_pacific; R0018537:Figure 3
A2 vs A1	hr	0.54	0.32 to 0.89		treatment policy; randomized; region:asia_pacific; R0018537:Figure 3
A2	events			248 / 2174	treatment policy; randomized; region:europe; R0018537:Figure 3
A2 vs A1	hr	0.77	0.65 to 0.90		treatment policy; randomized; region:europe; R0018537:Figure 3
A2	events			191 / 1511	treatment policy; randomized; region:latin_america; R0018537:Figure 3
A2 vs A1	hr	0.99	0.81 to 1.21		treatment policy; randomized; region:latin_america; R0018537:Figure 3
A2	events			132 / 1032	treatment policy; randomized; region:usa_and_canada; R0018537:Figure 3
A2 vs A1	hr	1.14	0.89 to 1.47		treatment policy; randomized; region:usa_and_canada; R0018537:Figure 3
A2	events			218 / 2306	treatment policy; randomized; sex:female; R0018537:Figure 3
A2 vs A1	hr	0.85	0.71 to 1.02		treatment policy; randomized; sex:female; R0018537:Figure 3
A2	events			376 / 2643	treatment policy; randomized; sex:male; R0018537:Figure 3
A2 vs A1	hr	0.90	0.79 to 1.04		treatment policy; randomized; sex:male; R0018537:Figure 3

Four point MACE including unstable angina (2 lines; O21B)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				720 / 4952	not stated; randomized; R0012279:Supplement Table S1
	A2	events				666 / 4949	not stated; randomized; R0012279:Supplement Table S1

Kidney composite including albuminuria or smaller eGFR declines (10 lines; O22E)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1	events			751 / 4952	not stated; randomized; R0018694:Table 2
A1	events			649 / 4952	not stated; randomized; R0018694:Table 2
A1	events			970 / 4952	treatment policy; randomized; R0018537:Table 2
A2 vs A1	hr	0.76	0.68 to 0.84		not stated; randomized; R0018694:Table 2
A2 vs A1	hr	0.86	0.78 to 0.94		not stated; randomized; R0018694:Results
A2	events			496 / 4949	not stated; randomized; R0018694:Table 2
A2 vs A1	hr	0.74	0.66 to 0.84		not stated; randomized; R0018694:Table 2
A2 vs A1	hr	0.85	0.77 to 0.93		treatment policy; randomized; R0018537:Table 2
A2	events			848 / 4949	treatment policy; randomized; R0018537:Table 2
A2	events			587 / 4949	not stated; randomized; R0018694:Table 2

Hospitalization for heart failure (8 lines; O23)

Arm	Statistic	Events / N	Detail
A1	events	21 / 4949	not stated; safety; cardiac failure chronic; registry:adverse_events
A1	events	9 / 4949	not stated; safety; cardiac failure acute; registry:adverse_events
A1	events	47 / 4949	not stated; safety; cardiac failure congestive; registry:adverse_events
A1	events	104 / 4949	not stated; safety; cardiac failure; registry:adverse_events
A2	events	8 / 4943	not stated; safety; cardiac failure acute; registry:adverse_events
A2	events	14 / 4943	not stated; safety; cardiac failure chronic; registry:adverse_events
A2	events	38 / 4943	not stated; safety; cardiac failure congestive; registry:adverse_events
A2	events	78 / 4943	not stated; safety; cardiac failure; registry:adverse_events

Heart failure events (3 lines; O23B)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1	events			226 / 4952	treatment policy; randomized; R0018537:Table 2
A2	events			213 / 4949	treatment policy; randomized; R0018537:Table 2
A2 vs A1	hr	0.93	0.77 to 1.12		treatment policy; randomized; R0018537:Table 2

Serious adverse events (2 lines; O25)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				2044 / 4949	not stated; safety; registry:adverse_events
	A2	events				1991 / 4943	not stated; 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				310 / 4952	treatment policy; randomized; R0018537:Results
	A2	events				451 / 4949	treatment policy; randomized; R0018537:Results

Nausea (4 lines; O27A)

Arm	Statistic	Events / N	Detail
A1	events	269 / 4949	not stated; safety; registry:adverse_events
A1	events	2 / 4949	not stated; safety; registry:adverse_events
A2	events	735 / 4943	not stated; safety; registry:adverse_events
A2	events	2 / 4943	not stated; safety; registry:adverse_events

Vomiting (4 lines; O27B)

Arm	Statistic	Events / N	Detail
A1	events	154 / 4949	not stated; safety; registry:adverse_events
A1	events	5 / 4949	not stated; safety; registry:adverse_events
A2	events	325 / 4943	not stated; safety; registry:adverse_events
A2	events	6 / 4943	not stated; safety; registry:adverse_events

Diarrhea (4 lines; O27C)

Arm	Statistic	Events / N	Detail
A1	events	436 / 4949	not stated; safety; registry:adverse_events
A1	events	8 / 4949	not stated; safety; registry:adverse_events
A2	events	665 / 4943	not stated; safety; registry:adverse_events
A2	events	10 / 4943	not stated; safety; registry:adverse_events

Constipation (4 lines; O27D)

Arm	Statistic	Events / N	Detail
A1	events	208 / 4949	not stated; safety; registry:adverse_events
A1	events	6 / 4949	not stated; safety; registry:adverse_events
A2	events	361 / 4943	not stated; safety; registry:adverse_events
A2	events	6 / 4943	not stated; safety; registry:adverse_events

Gallbladder and biliary disease (24 lines; O28)

Arm	Statistic	Events / N	Detail
A1	events	1 / 4949	not stated; safety; bile duct obstruction; registry:adverse_events
A1	events	7 / 4949	not stated; safety; bile duct stone; registry:adverse_events
A1	events	1 / 4949	not stated; safety; biliary colic; registry:adverse_events
A1	events	0 / 4949	not stated; safety; cholangitis acute; registry:adverse_events
A1	events	0 / 4949	not stated; safety; cholangitis chronic; registry:adverse_events
A1	events	2 / 4949	not stated; safety; cholangitis; registry:adverse_events
A1	events	17 / 4949	not stated; safety; cholecystitis acute; registry:adverse_events
A1	events	120 / 4952	treatment policy; randomized; R0018537:Supplement Table S5
A1	events	49 / 4949	not stated; safety; cholelithiasis; registry:adverse_events
A1	events	15 / 4949	not stated; safety; cholecystitis; registry:adverse_events
A1	events	2 / 4949	not stated; safety; cholecystitis infective; registry:adverse_events
A1	events	2 / 4949	not stated; safety; cholecystitis chronic; registry:adverse_events
A2	events	42 / 4943	not stated; safety; cholelithiasis; registry:adverse_events
A2	events	0 / 4943	not stated; safety; bile duct obstruction; registry:adverse_events
A2	events	8 / 4943	not stated; safety; bile duct stone; registry:adverse_events
A2	events	1 / 4943	not stated; safety; biliary colic; registry:adverse_events
A2	events	3 / 4943	not stated; safety; cholangitis acute; registry:adverse_events
A2	events	1 / 4943	not stated; safety; cholangitis chronic; registry:adverse_events
A2	events	6 / 4943	not stated; safety; cholangitis; registry:adverse_events
A2	events	26 / 4943	not stated; safety; cholecystitis acute; registry:adverse_events
A2	events	7 / 4943	not stated; safety; cholecystitis chronic; registry:adverse_events
A2	events	2 / 4943	not stated; safety; cholecystitis infective; registry:adverse_events
A2	events	25 / 4943	not stated; safety; cholecystitis; registry:adverse_events
A2	events	138 / 4949	treatment policy; randomized; R0018537:Supplement Table S5

Acute pancreatitis (8 lines; O29)

Arm	Statistic	Events / N	Detail
A1	events	8 / 4949	not stated; safety; registry:adverse_events
A1	events	5 / 4949	not stated; safety; pancreatitis; registry:adverse_events
A1	events	2 / 4949	not stated; safety; obstructive pancreatitis; registry:adverse_events
A1	events	13 / 4952	treatment policy; randomized; R0018537:Table 3
A2	events	0 / 4943	not stated; safety; obstructive pancreatitis; registry:adverse_events
A2	events	9 / 4943	not stated; safety; pancreatitis; registry:adverse_events
A2	events	23 / 4949	treatment policy; randomized; R0018537:Table 3
A2	events	15 / 4943	not stated; safety; registry:adverse_events

Medullary thyroid carcinoma (4 lines; O32A)

Arm	Statistic	Events / N	Detail
A1	events	0 / 4949	not stated; safety; registry:adverse_events
A1	events	0 / 4952	treatment policy; randomized; R0018537:Table 3
A2	events	1 / 4943	not stated; safety; registry:adverse_events
A2	events	0 / 4949	treatment policy; randomized; R0018537:Table 3

Thyroid cancer (any) (8 lines; O32B)

Arm	Statistic	Events / N	Detail
A1	events	0 / 4949	not stated; safety; papillary thyroid cancer; registry:adverse_events
A1	events	0 / 4949	not stated; safety; registry:adverse_events
A1	events	0 / 4949	not stated; safety; medullary thyroid cancer; registry:adverse_events
A1	events	3 / 4952	treatment policy; randomized; R0018537:Table 3
A2	events	1 / 4943	not stated; safety; medullary thyroid cancer; registry:adverse_events
A2	events	4 / 4943	not stated; safety; papillary thyroid cancer; registry:adverse_events
A2	events	7 / 4949	treatment policy; randomized; R0018537:Table 3
A2	events	1 / 4943	not stated; safety; registry:adverse_events

Diabetic retinopathy complications (7 lines; O33)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1	events			4 / 4949	not stated; safety; diabetic retinopathy; registry:adverse_events
A1	events			1 / 4949	not stated; safety; vitreous haemorrhage; registry:adverse_events
A1	events			76 / 4952	treatment policy; randomized; R0018537:Table 2
A2	events			3 / 4943	not stated; safety; vitreous haemorrhage; registry:adverse_events
A2	events			95 / 4949	treatment policy; randomized; R0018537:Table 2
A2 vs A1	hr	1.24	0.92 to 1.68		treatment policy; randomized; R0018537:Table 2
A2	events			1 / 4943	not stated; safety; diabetic retinopathy; registry:adverse_events

Nonarteritic anterior ischemic optic neuropathy (2 lines; O34)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 4949	not stated; safety; optic ischaemic neuropathy; registry:adverse_events
	A2	events				1 / 4943	not stated; safety; optic ischaemic neuropathy; registry:adverse_events

Suicidal ideation or behavior (6 lines; O35A)

Arm	Statistic	Events / N	Detail
A1	events	1 / 4949	not stated; safety; suicidal ideation; registry:adverse_events
A1	events	1 / 4949	not stated; safety; depression suicidal; registry:adverse_events
A1	events	0 / 4949	not stated; safety; suicide attempt; registry:adverse_events
A2	events	0 / 4943	not stated; safety; depression suicidal; registry:adverse_events
A2	events	1 / 4943	not stated; safety; suicide attempt; registry:adverse_events
A2	events	1 / 4943	not stated; safety; suicidal ideation; registry:adverse_events

Gastroparesis (2 lines; O37A)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 4949	not stated; safety; diabetic gastroparesis; registry:adverse_events
	A2	events				1 / 4943	not stated; safety; diabetic gastroparesis; registry:adverse_events

Intestinal obstruction or ileus (12 lines; O37B)

Arm	Statistic	Events / N	Detail
A1	events	1 / 4949	not stated; safety; mechanical ileus; registry:adverse_events
A1	events	10 / 4949	not stated; safety; small intestinal obstruction; registry:adverse_events
A1	events	14 / 4949	not stated; safety; registry:adverse_events
A1	events	0 / 4949	not stated; safety; gallstone ileus; registry:adverse_events
A1	events	2 / 4949	not stated; safety; ileus paralytic; registry:adverse_events
A1	events	2 / 4949	not stated; safety; ileus; registry:adverse_events
A2	events	1 / 4943	not stated; safety; ileus; registry:adverse_events
A2	events	9 / 4943	not stated; safety; registry:adverse_events
A2	events	1 / 4943	not stated; safety; gallstone ileus; registry:adverse_events
A2	events	1 / 4943	not stated; safety; ileus paralytic; registry:adverse_events
A2	events	0 / 4943	not stated; safety; mechanical ileus; registry:adverse_events
A2	events	5 / 4943	not stated; safety; small intestinal obstruction; registry:adverse_events

Pancreatic cancer (10 lines; O38)

Arm	Statistic	Events / N	Detail
A1	events	1 / 4949	not stated; safety; ductal adenocarcinoma of pancreas; registry:adverse_events
A1	events	5 / 4949	not stated; safety; registry:adverse_events
A1	events	5 / 4949	not stated; safety; pancreatic carcinoma metastatic; registry:adverse_events
A1	events	12 / 4952	treatment policy; randomized; R0018537:Table 3
A1	events	0 / 4949	not stated; safety; adenocarcinoma pancreas; registry:adverse_events
A2	events	1 / 4943	not stated; safety; ductal adenocarcinoma of pancreas; registry:adverse_events
A2	events	8 / 4943	not stated; safety; registry:adverse_events
A2	events	4 / 4943	not stated; safety; adenocarcinoma pancreas; registry:adverse_events
A2	events	4 / 4943	not stated; safety; pancreatic carcinoma metastatic; registry:adverse_events
A2	events	19 / 4949	treatment policy; randomized; R0018537:Table 3

Any cancer (2 lines; O39)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				348 / 4952	treatment policy; randomized; R0018537:Table 3
	A2	events				351 / 4949	treatment policy; randomized; R0018537:Table 3