parallel randomized trial

LEADER®

A Long-term, Multi-centre, International, Randomised Double-blind, Placebo-controlled Trial to Determine Liraglutide Effects on Cardiovascular Events

Type 2 diabetes (adults)NCT01179048S001496

Design

Randomized: 9,340
Start year: 2010
Treatment: 260.7 weeks, follow-up 264.99 weeks
Countries: multinational (410 sites)
Sponsor: Novo Nordisk A/S (industry)
Eligibility: T2D HbA1c 7.0 or more; age 50 or more with CVD, CKD stage 3 or more or HF, or age 60 or more with CV risk factors

Conduct and analysis

Blinding: double blind
Sequence generation: not reported
Allocation concealment: not reported
Outcome adjudication: yes
Primary estimand: not stated
Analysis population: full analysis
Missing data

Arms

Arm	Treatment	Background	Randomized	Analyzed	Completed treatment
A1	Liraglutide 1.8 mg subcutaneous once daily Liraglutide 1.8 mg or maximum tolerated dose	standard of care glucose lowering therapy except GLP-1 receptor agonists, DPP-4 inhibitors or pramlintide; lifestyle: standard	4,668	4,668
A2	Placebo Placebo	standard of care glucose lowering therapy except GLP-1 receptor agonists, DPP-4 inhibitors or pramlintide; lifestyle: standard	4,672	4,672

Baseline characteristics

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

Characteristic	Statistic	Liraglutide 1.8 mg subcutaneous once daily A1	Placebo A2	Whole trial ALL
age: 18 to 64	n	2512	2499
age: 65 to 84	n	2139	2148
age: 85 or more	n	17	25
age	mean (years)	64.2	64.4
age	sd (years)	7.2	7.2
asian	n	471	465
asian	percent	10.1	10.0
bmi	mean (kg/m2)	32.5	32.5
bmi	sd (kg/m2)	6.3	6.3
diabetes duration	mean (years)	12.8	12.9
diabetes duration	sd (years)	8.0	8.1
egfr: 30 to 59	n			1934
egfr: 30 to 59	percent			20.7
egfr: 60 to 89	n			3907
egfr: 60 to 89	percent			41.8
egfr: 90 or more	n			3275
egfr: 90 or more	percent			35.1
egfr: less than 30	n			224
egfr: less than 30	percent			2.4
egfr	mean (mL/min/1.73 m2)			81.5
egfr	sd (mL/min/1.73 m2)			27.7
established cvd	n	3831	3767
established cvd	percent	82.1	80.6
female	n	1657	1680
hba1c	mean (percent)	8.7	8.7
hba1c	sd (percent)	1.6	1.5
insulin dose	mean (U/kg/day)	0.55	0.55
insulin dose	sd (U/kg/day)	0.41	0.39
metformin use	n	3447	3520
other background: insulin and oad	n	1677	1754
other background: insulin and oad	percent	35.9	37.5
other background: insulin only	n	361	377
other background: insulin only	percent	7.7	8.1
other background: none	n	194	166
other background: none	percent	4.2	3.6
other background: oad only	n	2436	2375
other background: oad only	percent	52.2	50.8
other region: asia	n	360	351
other region: asia	percent	7.7	7.5
other region: europe	n	1639	1657
other region: europe	percent	35.1	35.5
other region: north america	n	1401	1446
other region: north america	percent	30.0	31.0
other region: rest of the world	n	1268	1218
other region: rest of the world	percent	27.2	26.1
sbp	mean (mmHg)	135.9	135.9
sbp	sd (mmHg)	17.8	17.7
uacr	median (mg/g)	23.3	26.2
uacr	q1 (mg/g)	7.0	7.2
uacr	q3 (mg/g)	134.4	156.6
weight	mean (kg)	91.9	91.6
weight	sd (kg)	21.2	20.8

Results

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

HbA1c change (6 lines; O01)

Week	Arm	Statistic	Estimate	95% CI	Detail
156.42	A1 vs A2	md	-0.40 percent	-0.45 to -0.34	not stated; full analysis; R0011044:Table 2
156.42	A1 vs A2	md	-0.48 percent	-0.57 to -0.39	not stated; other; background:basal_insulin_only; R0011044:Table 2
156.42	A1 vs A2	md	-0.36 percent	-0.43 to -0.29	not stated; other; background:no_insulin; R0011044:Table 2
156.42	A1 vs A2	md	-0.37 percent	-0.54 to -0.21	not stated; other; background:other_insulin; R0011044:Table 2
156.42	A1	change	-1.16 percent		not stated; other; R0025563:Results
156.42	A2	change	-0.77 percent		not stated; other; R0025563:Results

Body weight change in kilograms (diabetes) (6 lines; O02)

Week	Arm	Statistic	Estimate	95% CI	Detail
156.42	A1 vs A2	md	-2.92 kg	-3.51 to -2.33	not stated; other; egfr:less_than_60; R0015703:Results
156.42	A1 vs A2	md	-2.3 kg	-2.5 to -2.0	not stated; full analysis; R0011044:Table 2
156.42	A1 vs A2	md	-2.5 kg	-2.9 to -2.1	not stated; other; background:basal_insulin_only; R0011044:Table 2
156.42	A1 vs A2	md	-1.9 kg	-2.3 to -1.6	not stated; other; background:no_insulin; R0011044:Table 2
156.42	A1 vs A2	md	-3.5 kg	-4.2 to -2.8	not stated; other; background:other_insulin; R0011044:Table 2
156.42	A1 vs A2	md	-2.07 kg	-2.38 to -1.76	not stated; other; egfr:60_or_more; R0015703:Results

HbA1c below 7 percent (2 lines; O03)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
156.42	A1	responders	41.6				not stated; other; R0025563:Results
156.42	A2	responders	25.8				not stated; other; R0025563:Results

Level 2 or 3 hypoglycemia (participants) (8 lines; O04)

Arm	Statistic	Events / N	Detail
A1	events	44 / 4668	not stated; safety; registry:adverse_events
A1	events	1 / 4668	not stated; safety; registry:adverse_events
A1	events	2 / 4668	not stated; safety; registry:adverse_events
A1	events	21 / 4668	not stated; safety; registry:adverse_events
A2	events	75 / 4672	not stated; safety; registry:adverse_events
A2	events	2 / 4672	not stated; safety; registry:adverse_events
A2	events	0 / 4672	not stated; safety; registry:adverse_events
A2	events	28 / 4672	not stated; safety; registry:adverse_events

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

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1 vs A2	rate ratio	0.81		0.74 to 0.88		not stated; other; R0025563:Results
	A1 vs A2	rate ratio	0.69		0.51 to 0.93		not stated; other; R0025563:Results

Systolic blood pressure change (1 lines; O05)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
156.42	A1 vs A2	md	-1.2 mmHg		-1.9 to -0.5		not stated; full analysis; R0011044:Table 2

Acute kidney injury (4 lines; O121)

Arm	Statistic	Events / N	Detail
A1	events	108 / 4668	not stated; safety; registry:adverse_events
A1	events	1 / 4668	not stated; safety; acute prerenal failure; registry:adverse_events
A2	events	1 / 4672	not stated; safety; acute prerenal failure; registry:adverse_events
A2	events	94 / 4672	not stated; safety; registry:adverse_events

All cause mortality (16 lines; O20)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1 vs A2	hr	0.80	0.58 to 1.12		not stated; other; egfr:45_to_less_than_60; R0019679:Figure 2
A1 vs A2	hr	0.90	0.75 to 1.07		not stated; other; egfr:60_or_more; R0015703:Results
A1 vs A2	hr	0.99	0.79 to 1.24		not stated; other; egfr:60_to_less_than_90; R0019679:Figure 2
A1 vs A2	hr	0.72	0.53 to 0.97		not stated; other; egfr:90_or_more; R0019679:Figure 2
A1 vs A2	hr	0.71	0.41 to 1.23		not stated; other; egfr:less_than_30; R0019679:Figure 2
A1 vs A2	hr	0.74	0.60 to 0.92		not stated; other; egfr:less_than_60; R0015703:Results
A1 vs A2	hr	0.81	0.55 to 1.20		not stated; other; uacr:100_to_less_than_300; R0019679:Figure 2
A1 vs A2	hr	0.80	0.54 to 1.19		not stated; other; uacr:15_to_less_than_30; R0019679:Figure 2
A1 vs A2	hr	0.75	0.55 to 1.03		not stated; other; uacr:30_to_less_than_100; R0019679:Figure 2
A1 vs A2	hr	0.82	0.61 to 1.11		not stated; other; uacr:300_or_more; R0019679:Figure 2
A1 vs A2	hr	1.12	0.75 to 1.69		not stated; other; uacr:below_lloq; R0019679:Figure 2
A1 vs A2	hr	0.86	0.64 to 1.16		not stated; other; uacr:more_than_0_to_less_than_15; R0019679:Figure 2
A1	events			381 / 4668	not stated; full analysis; R0019679:Figure 2
A1 vs A2	hr	0.85	0.74 to 0.97		not stated; full analysis; R0019679:Figure 2
A1 vs A2	hr	0.71	0.49 to 1.03		not stated; other; egfr:30_to_less_than_45; R0019679:Figure 2
A2	events			447 / 4672	not stated; full analysis; R0019679:Figure 2

Three point MACE (37 lines; O21)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1 vs A2	hr	0.69	0.57 to 0.85		not stated; other; egfr:less_than_60; R0015703:Results
A1	events			608 / 4668	not stated; full analysis; R0012296:Results
A1 vs A2	hr	0.87	0.78 to 0.97		not stated; full analysis; R0012296:Results
A1 vs A2	hr	0.87	0.72 to 1.05		not stated; other; bmi:30_to_less_than_35; R0006154:Figure 1
A1 vs A2	hr	0.75	0.61 to 0.93		not stated; other; bmi:35_or_more; R0006154:Figure 1
A1 vs A2	hr	0.88	0.61 to 1.28		not stated; other; bmi:less_than_25; R0006154:Figure 1
A1 vs A2	hr	0.91	0.75 to 1.12		not stated; other; diabetes_duration:15_to_less_than_25; R0017025:Figure 1
A1 vs A2	hr	0.70	0.49 to 1.02		not stated; other; diabetes_duration:25_or_more; R0017025:Figure 1
A1 vs A2	hr	0.90	0.77 to 1.05		not stated; other; diabetes_duration:5_to_less_than_15; R0017025:Figure 1
A1 vs A2	hr	0.77	0.57 to 1.05		not stated; other; diabetes_duration:less_than_5; R0017025:Figure 1
A1 vs A2	hr	0.93	0.82 to 1.05		not stated; other; egfr_uacr:60_or_more_or_less_than_30; R0015703:Results
A1 vs A2	hr	0.63	0.49 to 0.82		not stated; other; egfr_uacr:less_than_60_and_30_or_more; R0015703:Results
A1 vs A2	hr	0.76	0.54 to 1.07		not stated; other; egfr:30_to_less_than_45; R0019679:Figure 2
A1 vs A2	hr	0.66	0.50 to 0.87		not stated; other; egfr:45_to_less_than_60; R0019679:Figure 2
A1 vs A2	hr	0.94	0.83 to 1.07		not stated; other; egfr:60_or_more; R0015703:Results
A1 vs A2	hr	0.99	0.83 to 1.18		not stated; other; egfr:60_to_less_than_90; R0019679:Figure 2
A1 vs A2	hr	0.88	0.72 to 1.09		not stated; other; egfr:90_or_more; R0019679:Figure 2
A1 vs A2	hr	0.83	0.47 to 1.46		not stated; other; egfr:less_than_30; R0019679:Figure 2
A1 vs A2	hr	0.62	0.37 to 1.04		not stated; other; region:asia; R0012296:Table 2
A1 vs A2	hr	0.82	0.68 to 0.98		not stated; other; region:europe; R0012296:Table 2
A1 vs A2	hr	0.80	0.42 to 1.52		not stated; other; region:north_america_canada; R0012296:Results
A1 vs A2	hr	1.03	0.84 to 1.25		not stated; other; region:north_america_us; R0012296:Results
A1 vs A2	hr	1.01	0.83 to 1.22		not stated; other; region:north_america; R0012296:Table 2
A1 vs A2	hr	0.83	0.68 to 1.03		not stated; other; region:rest_of_the_world; R0012296:Table 2
A1 vs A2	hr	0.70	0.51 to 0.98		not stated; other; uacr:100_to_less_than_300; R0019679:Figure 2
A1 vs A2	hr	0.75	0.55 to 1.04		not stated; other; uacr:15_to_less_than_30; R0019679:Figure 2
A1 vs A2	hr	0.83	0.71 to 0.97		not stated; other; uacr:30_or_more; R0015703:Results
A1 vs A2	hr	0.83	0.64 to 1.08		not stated; other; uacr:30_to_less_than_100; R0019679:Figure 2
A1 vs A2	hr	0.95	0.74 to 1.24		not stated; other; uacr:300_or_more; R0019679:Figure 2
A1 vs A2	hr	0.90	0.66 to 1.21		not stated; other; uacr:below_lloq; R0019679:Figure 2
A1 vs A2	hr	0.92	0.79 to 1.07		not stated; other; uacr:less_than_30; R0015703:Results
A1 vs A2	hr	1.01	0.81 to 1.25		not stated; other; uacr:more_than_0_to_less_than_15; R0019679:Figure 2
A1 vs A2	hr	0.83	0.73 to 0.95		while on treatment; other; R0012296:Results
A1 vs A2	hr	0.97	0.85 to 1.10		not stated; other; background:metformin; R0007143:Figure 4A
A1 vs A2	hr	0.79	0.64 to 0.97		not stated; other; background:no_metformin; R0007143:Figure 4B
A1 vs A2	hr	0.99	0.81 to 1.21		not stated; other; bmi:25_to_less_than_30; R0006154:Figure 1
A2	events			694 / 4672	not stated; full analysis; R0012296:Results

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

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1 vs A2	hr	0.88	0.81 to 0.96		not stated; full analysis; R0019679:Figure 2
A1	events			948 / 4668	not stated; full analysis; R0019679:Figure 2
A2	events			1062 / 4672	not stated; full analysis; R0019679:Figure 2

Kidney composite with doubling of serum creatinine (3 lines; O22C)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1 vs A2	hr	0.88	0.68 to 1.13		not stated; full analysis; R0019679:Figure 2
A1	events			114 / 4668	not stated; full analysis; R0019679:Figure 2
A2	events			129 / 4672	not stated; full analysis; R0019679:Figure 2

Kidney composite including albuminuria or smaller eGFR declines (3 lines; O22E)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1 vs A2	hr	0.78	0.67 to 0.92		not stated; full analysis; R0019679:Figure 2
A1	events			268 / 4668	not stated; full analysis; R0019679:Figure 2
A2	events			337 / 4672	not stated; full analysis; R0019679:Figure 2

Hospitalization for heart failure (3 lines; O23)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1 vs A2	hr	0.87	0.73 to 1.05		not stated; full analysis; R0019679:Figure 2
A1	events			218 / 4668	not stated; full analysis; R0019679:Figure 2
A2	events			248 / 4672	not stated; full analysis; R0019679:Figure 2

Health related quality of life total score (any instrument) (4 lines; O24C)

Week	Arm	Statistic	Estimate	95% CI	Detail
156.42	A1 vs A2	md	0.023 points	0.004 to 0.043	not stated; other; R0025377:Results
156.42	A1	change	-0.058 points		not stated; other; R0025377:Results
156.42	A1 vs A2	md	0.018 points	0.001 to 0.035	not stated; other; R0025377:Results
156.42	A2	change	-0.082 points		not stated; other; R0025377:Results

Serious adverse events (2 lines; O25)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				2320 / 4668	not stated; safety; registry:adverse_events
	A2	events				2354 / 4672	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				0 / 4668	not stated; randomized; registry:flow
	A2	events				0 / 4672	not stated; randomized; registry:flow

Nausea (4 lines; O27A)

Arm	Statistic	Events / N	Detail
A1	events	517 / 4668	not stated; safety; registry:adverse_events
A1	events	8 / 4668	not stated; safety; registry:adverse_events
A2	events	129 / 4672	not stated; safety; registry:adverse_events
A2	events	9 / 4672	not stated; safety; registry:adverse_events

Vomiting (2 lines; O27B)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				17 / 4668	not stated; safety; registry:adverse_events
	A2	events				11 / 4672	not stated; safety; registry:adverse_events

Diarrhea (4 lines; O27C)

Arm	Statistic	Events / N	Detail
A1	events	14 / 4668	not stated; safety; registry:adverse_events
A1	events	266 / 4668	not stated; safety; registry:adverse_events
A2	events	102 / 4672	not stated; safety; registry:adverse_events
A2	events	11 / 4672	not stated; safety; registry:adverse_events

Constipation (2 lines; O27D)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				11 / 4668	not stated; safety; registry:adverse_events
	A2	events				7 / 4672	not stated; safety; registry:adverse_events

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

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 4668	not stated; randomized; registry:flow
	A2	events				0 / 4672	not stated; randomized; registry:flow

Gallbladder and biliary disease (36 lines; O28)

Arm	Statistic	Events / N	Detail
A1	events	4 / 4668	not stated; safety; cholangitis acute; registry:adverse_events
A1	events	2 / 4668	not stated; safety; cholangitis; registry:adverse_events
A1	events	0 / 4668	not stated; safety; gallbladder abscess; registry:adverse_events
A1	events	35 / 4668	not stated; safety; cholecystitis acute; registry:adverse_events
A1	events	8 / 4668	not stated; safety; cholecystitis chronic; registry:adverse_events
A1	events	3 / 4668	not stated; safety; cholecystitis infective; registry:adverse_events
A1	events	11 / 4668	not stated; safety; cholecystitis; registry:adverse_events
A1	events	44 / 4668	not stated; safety; cholelithiasis; registry:adverse_events
A1	events	1 / 4668	not stated; safety; gallbladder disorder; registry:adverse_events
A1	events	0 / 4668	not stated; safety; gallbladder empyema; registry:adverse_events
A1	events	1 / 4668	not stated; safety; gallbladder perforation; registry:adverse_events
A1	events	3 / 4668	not stated; safety; bile duct stone; registry:adverse_events
A1	events	2 / 4668	not stated; safety; gallbladder polyp; registry:adverse_events
A1	events	5 / 4668	not stated; safety; biliary colic; registry:adverse_events
A1	events	0 / 4668	not stated; safety; bile duct stenosis; registry:adverse_events
A1	events	1 / 4668	not stated; safety; biliary fistula; registry:adverse_events
A1	events	0 / 4668	not stated; safety; biliary sepsis; registry:adverse_events
A1	events	0 / 4668	not stated; safety; biliary tract infection; registry:adverse_events
A2	events	18 / 4672	not stated; safety; cholecystitis acute; registry:adverse_events
A2	events	1 / 4672	not stated; safety; bile duct stenosis; registry:adverse_events
A2	events	2 / 4672	not stated; safety; biliary colic; registry:adverse_events
A2	events	0 / 4672	not stated; safety; biliary fistula; registry:adverse_events
A2	events	1 / 4672	not stated; safety; biliary sepsis; registry:adverse_events
A2	events	1 / 4672	not stated; safety; biliary tract infection; registry:adverse_events
A2	events	0 / 4672	not stated; safety; cholangitis acute; registry:adverse_events
A2	events	4 / 4672	not stated; safety; cholangitis; registry:adverse_events
A2	events	1 / 4672	not stated; safety; gallbladder abscess; registry:adverse_events
A2	events	1 / 4672	not stated; safety; gallbladder disorder; registry:adverse_events
A2	events	1 / 4672	not stated; safety; gallbladder empyema; registry:adverse_events
A2	events	0 / 4672	not stated; safety; gallbladder perforation; registry:adverse_events
A2	events	1 / 4672	not stated; safety; gallbladder polyp; registry:adverse_events
A2	events	5 / 4672	not stated; safety; cholecystitis chronic; registry:adverse_events
A2	events	1 / 4672	not stated; safety; cholecystitis infective; registry:adverse_events
A2	events	12 / 4672	not stated; safety; cholecystitis; registry:adverse_events
A2	events	1 / 4672	not stated; safety; bile duct stone; registry:adverse_events
A2	events	30 / 4672	not stated; safety; cholelithiasis; registry:adverse_events

Acute pancreatitis (8 lines; O29)

Arm	Statistic	Events / N	Detail
A1	events	18 / 4668	not stated; safety; pancreatitis; registry:adverse_events
A1	events	14 / 4668	not stated; safety; registry:adverse_events
A1	events	0 / 4668	not stated; safety; oedematous pancreatitis; registry:adverse_events
A1	events	1 / 4668	not stated; safety; pancreatitis relapsing; registry:adverse_events
A2	events	1 / 4672	not stated; safety; pancreatitis relapsing; registry:adverse_events
A2	events	19 / 4672	not stated; safety; registry:adverse_events
A2	events	1 / 4672	not stated; safety; oedematous pancreatitis; registry:adverse_events
A2	events	10 / 4672	not stated; safety; pancreatitis; registry:adverse_events

Medullary thyroid carcinoma (2 lines; O32A)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 4668	not stated; safety; registry:adverse_events
	A2	events				1 / 4672	not stated; safety; registry:adverse_events

Thyroid cancer (any) (8 lines; O32B)

Arm	Statistic	Events / N	Detail
A1	events	0 / 4668	not stated; safety; registry:adverse_events
A1	events	5 / 4668	not stated; randomized; R0000453:Table 1
A1	events	4 / 4668	not stated; safety; papillary thyroid cancer; registry:adverse_events
A1	events	0 / 4668	not stated; safety; medullary thyroid cancer; registry:adverse_events
A2	events	5 / 4672	not stated; randomized; R0000453:Table 1
A2	events	1 / 4672	not stated; safety; registry:adverse_events
A2	events	1 / 4672	not stated; safety; medullary thyroid cancer; registry:adverse_events
A2	events	3 / 4672	not stated; safety; papillary thyroid cancer; registry:adverse_events

Diabetic retinopathy complications (15 lines; O33)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1 vs A2	hr	1.149	0.869 to 1.519		not stated; randomized; registry:outcomes
A1	events	2.3		4668	not stated; randomized; registry:outcomes
A1	events			1 / 4668	not stated; safety; diabetic blindness; registry:adverse_events
A1	events			9 / 4668	not stated; safety; diabetic retinopathy; registry:adverse_events
A1	events			1 / 4668	not stated; safety; retinopathy haemorrhagic; registry:adverse_events
A1	events			0 / 4668	not stated; safety; retinopathy proliferative; registry:adverse_events
A1	events			2 / 4668	not stated; safety; retinopathy; registry:adverse_events
A1	events			6 / 4668	not stated; safety; vitreous haemorrhage; registry:adverse_events
A2	events			4 / 4672	not stated; safety; retinopathy; registry:adverse_events
A2	events	2.0		4672	not stated; randomized; registry:outcomes
A2	events			1 / 4672	not stated; safety; diabetic blindness; registry:adverse_events
A2	events			15 / 4672	not stated; safety; diabetic retinopathy; registry:adverse_events
A2	events			0 / 4672	not stated; safety; retinopathy haemorrhagic; registry:adverse_events
A2	events			1 / 4672	not stated; safety; retinopathy proliferative; registry:adverse_events
A2	events			5 / 4672	not stated; safety; vitreous haemorrhage; registry:adverse_events

Nonarteritic anterior ischemic optic neuropathy (4 lines; O34)

Arm	Statistic	Events / N	Detail
A1	events	1 / 4668	not stated; safety; optic ischaemic neuropathy; registry:adverse_events
A1	events	0 / 4668	not stated; safety; optic nerve infarction; registry:adverse_events
A2	events	3 / 4672	not stated; safety; optic ischaemic neuropathy; registry:adverse_events
A2	events	1 / 4672	not stated; safety; optic nerve infarction; registry:adverse_events

Suicidal ideation or behavior (4 lines; O35A)

Arm	Statistic	Events / N	Detail
A1	events	1 / 4668	not stated; safety; suicidal ideation; registry:adverse_events
A1	events	4 / 4668	not stated; safety; suicide attempt; registry:adverse_events
A2	events	1 / 4672	not stated; safety; suicidal ideation; registry:adverse_events
A2	events	2 / 4672	not stated; safety; suicide attempt; registry:adverse_events

Death by suicide (2 lines; O35B)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				1 / 4668	not stated; safety; registry:adverse_events
	A2	events				4 / 4672	not stated; safety; registry:adverse_events

Gastroparesis (2 lines; O37A)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				5 / 4668	not stated; safety; impaired gastric emptying; registry:adverse_events
	A2	events				1 / 4672	not stated; safety; impaired gastric emptying; registry:adverse_events

Intestinal obstruction or ileus (14 lines; O37B)

Arm	Statistic	Events / N	Detail
A1	events	1 / 4668	not stated; safety; colonic pseudo-obstruction; registry:adverse_events
A1	events	1 / 4668	not stated; safety; ileus paralytic; registry:adverse_events
A1	events	2 / 4668	not stated; safety; intestinal obstruction; registry:adverse_events
A1	events	0 / 4668	not stated; safety; mechanical ileus; registry:adverse_events
A1	events	4 / 4668	not stated; safety; ileus; registry:adverse_events
A1	events	10 / 4668	not stated; safety; small intestinal obstruction; registry:adverse_events
A1	events	1 / 4668	not stated; safety; volvulus; registry:adverse_events
A2	events	5 / 4672	not stated; safety; small intestinal obstruction; registry:adverse_events
A2	events	0 / 4672	not stated; safety; colonic pseudo-obstruction; registry:adverse_events
A2	events	2 / 4672	not stated; safety; ileus paralytic; registry:adverse_events
A2	events	7 / 4672	not stated; safety; ileus; registry:adverse_events
A2	events	7 / 4672	not stated; safety; intestinal obstruction; registry:adverse_events
A2	events	2 / 4672	not stated; safety; mechanical ileus; registry:adverse_events
A2	events	0 / 4672	not stated; safety; volvulus; registry:adverse_events

Pancreatic cancer (8 lines; O38)

Arm	Statistic	Events / N	Detail
A1	events	4 / 4668	not stated; safety; adenocarcinoma pancreas; registry:adverse_events
A1	events	4 / 4668	not stated; safety; registry:adverse_events
A1	events	2 / 4668	not stated; safety; pancreatic carcinoma metastatic; registry:adverse_events
A1	events	1 / 4668	not stated; safety; pancreatic carcinoma stage iv; registry:adverse_events
A2	events	1 / 4672	not stated; safety; adenocarcinoma pancreas; registry:adverse_events
A2	events	7 / 4672	not stated; safety; registry:adverse_events
A2	events	2 / 4672	not stated; safety; pancreatic carcinoma metastatic; registry:adverse_events
A2	events	0 / 4672	not stated; safety; pancreatic carcinoma stage iv; registry:adverse_events

eGFR total slope (3 lines; O51)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
104.36	A1	slope	-1.72 mL/min/1.73 m2 per year	-1.84 to -1.61	4512	not stated; full analysis; R0010293:Figure 2
104.36	A1 vs A2	md	0.26 mL/min/1.73 m2 per year			not stated; full analysis; R0010293:Figure 2
104.36	A2	slope	-1.98 mL/min/1.73 m2 per year	-2.10 to -1.87	4498	not stated; full analysis; R0010293:Figure 2