parallel randomized trial

SURPASS-4

Efficacy and Safety of LY3298176 Once Weekly Versus Insulin Glargine in Patients With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)

Type 2 diabetes (adults)NCT03730662S001287

Design

Randomized: 2,002
Start year: 2018
Treatment: 104 weeks, follow-up 108 weeks
Countries: multinational
Sponsor: Eli Lilly and Company (industry)
Eligibility: age 18 or older; HbA1c 7.5 to 10.5 percent; BMI 25 or more; increased cardiovascular risk; 1 to 3 oral agents

Conduct and analysis

Blinding: open label
Sequence generation: not reported
Allocation concealment: not reported
Outcome adjudication: yes
Primary estimand: not stated
Analysis population: modified itt
Missing data: MMRM

Arms

Arm	Treatment	Background	Randomized	Analyzed
A1	Tirzepatide 5 mg subcutaneous once weekly Tirzepatide 5 mg	metformin, sulfonylurea and/or SGLT2 inhibitor (1 to 3 oral agents); lifestyle: not reported	329	283
A2	Tirzepatide 10 mg subcutaneous once weekly Tirzepatide 10 mg	metformin, sulfonylurea and/or SGLT2 inhibitor (1 to 3 oral agents); lifestyle: not reported	330	289
A3	Tirzepatide 15 mg subcutaneous once weekly Tirzepatide 15 mg	metformin, sulfonylurea and/or SGLT2 inhibitor (1 to 3 oral agents); lifestyle: not reported	338	291
A4	Insulin glargine Insulin glargine	metformin, sulfonylurea and/or SGLT2 inhibitor (1 to 3 oral agents); lifestyle: not reported	1,005	887

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 glargine A4	Whole trial ALL
age	mean (years)	62.90	63.70	63.70	63.80
age	sd (years)	8.56	8.68	8.60	8.51
asian	n	15	16	8	31
black	n	13	18	11	34
bmi	mean (kg/m2)					32.6
bmi	sd (kg/m2)					5.5
diabetes duration	mean (years)					11.8
diabetes duration	sd (years)					7.5
egfr	mean (mL/min/1.73 m2)					81.3
egfr	sd (mL/min/1.73 m2)					21.1
established cvd	percent					86.9
female	n	131	121	135	364
hba1c	mean (percent)	8.52	8.59	8.52	8.50
hba1c	sd (percent)	0.84	0.91	0.98	0.85
hispanic	n	154	164	155	478
metformin use	n					1893
metformin use	percent					94.9
other race american indian alaska native	n	32	30	26	86
other race multiple	n	8	6	5	24
other race native hawaiian pacific islander	n	0	0	2	1
sbp	mean (mmHg)					134.4
sbp	sd (mmHg)					15.4
sglt2i use	n					501
sglt2i use	percent					25.1
weight	mean (kg)					90.3
weight	sd (kg)					18.7
white	n	260	260	285	827

Analyses this trial contributes to

Results

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

HbA1c change (18 lines; O01)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
52	A1	change	-2.3 percent				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Figure 1A
52	A1	change	-2.24 percent	0.053		283	not stated; modified itt; registry:outcomes
52	A1 vs A4	md	-0.80 percent		-0.93 to -0.66		not stated; modified itt; registry:outcomes
52	A2	change	-2.4 percent				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Figure 1A
52	A2	change	-2.43 percent	0.053		289	not stated; modified itt; registry:outcomes
52	A2 vs A4	md	-0.99 percent		-1.13 to -0.86		not stated; modified itt; registry:outcomes
52	A3 vs A4	md	-1.14 percent		-1.28 to -1.00		not stated; modified itt; registry:outcomes
52	A3	change	-2.7 percent				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Figure 1A
52	A3	change	-2.58 percent	0.053		291	not stated; modified itt; registry:outcomes
52	A4	change	-1.44 percent	0.030		887	not stated; modified itt; registry:outcomes
52	A4	change	-1.5 percent				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Figure 1A
104	A1 vs A4	md	-1.3 percent		-1.6 to -0.9		not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Results
104	A1	change	-2.3 percent				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Results
104	A2	change	-2.5 percent				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Results
104	A2 vs A4	md	-1.5 percent		-1.9 to -1.2		not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Results
104	A3 vs A4	md	-1.6 percent		-1.9 to -1.2		not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Results
104	A3	change	-2.6 percent				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Results
104	A4	change	-1.0 percent				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Results

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

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
52	A1	change	-7.1 kg	0.34		285	not stated; modified itt; registry:outcomes
52	A1 vs A4	md	-9.0 kg		-9.8 to -8.3		not stated; modified itt; registry:outcomes
52	A1	change	-7.4 kg				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Figure 2A
52	A2	change	-9.5 kg	0.34		288	not stated; modified itt; registry:outcomes
52	A2 vs A4	md	-11.4 kg		-12.1 to -10.6		not stated; modified itt; registry:outcomes
52	A2	change	-9.3 kg				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Figure 2A
52	A3	change	-11.7 kg	0.33		291	not stated; modified itt; registry:outcomes
52	A3 vs A4	md	-13.5 kg		-14.3 to -12.8		not stated; modified itt; registry:outcomes
52	A3	change	-11.7 kg				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Figure 2A
52	A4	change	1.9 kg	0.19		891	not stated; modified itt; registry:outcomes
52	A4	change	1.8 kg				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Figure 2A
104	A1 vs A4	md	-9.7 kg		-11.3 to -8.2		not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Results
104	A1	change	-7.6 kg				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Results
104	A2 vs A4	md	-12.1 kg		-13.7 to -10.5		not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Results
104	A2	change	-10.0 kg				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Results
104	A3	change	-11.4 kg				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Results
104	A3 vs A4	md	-13.5 kg		-15.0 to -11.9		not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Results
104	A4	change	2.1 kg				not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Results

HbA1c below 7 percent (7 lines; O03)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
52	A1	responders	80.98		326	not stated; modified itt; registry:outcomes
52	A1 vs A4	or	4.78	3.47 to 6.58		not stated; modified itt; registry:outcomes
52	A2	responders	88.16		321	not stated; modified itt; registry:outcomes
52	A2 vs A4	or	9.23	6.31 to 13.49		not stated; modified itt; registry:outcomes
52	A3	responders	90.72		334	not stated; modified itt; registry:outcomes
52	A3 vs A4	or	11.87	7.88 to 17.89		not stated; modified itt; registry:outcomes
52	A4	responders	50.72		978	not stated; modified itt; registry:outcomes

Level 2 or 3 hypoglycemia (participants) (4 lines; O04)

Arm	Statistic	Events / N	Detail
A1	events	1 / 329	not stated; safety; registry:adverse_events
A2	events	0 / 328	not stated; safety; registry:adverse_events
A3	events	3 / 338	not stated; safety; registry:adverse_events
A4	events	12 / 1000	not stated; safety; registry:adverse_events

Level 2 or 3 hypoglycemia (episode rate) (4 lines; O04B)

Arm	Statistic	Estimate	SE or SD	Events / N	Detail
A1	rate	0.10	0.023	329	not stated; safety; registry:outcomes
A2	rate	0.09	0.025	328	not stated; safety; registry:outcomes
A3	rate	0.11	0.030	338	not stated; safety; registry:outcomes
A4	rate	0.35	0.044	1000	not stated; safety; registry:outcomes

Systolic blood pressure change (3 lines; O05)

Week	Arm	Statistic	Estimate	95% CI	Detail
42	A1 vs A4	md	-4.7 mmHg	-6.5 to -3.0	treatment policy; safety; R0009496:Results
42	A2 vs A4	md	-5.6 mmHg	-7.4 to -3.9	treatment policy; safety; R0009496:Results
42	A3 vs A4	md	-7.2 mmHg	-8.9 to -5.5	treatment policy; safety; R0009496:Results

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

Week	Arm	Statistic	Estimate	Detail
52	A1	responders	62.9	hypothetical; modified itt; R0007531:Table 2
52	A2	responders	77.6	hypothetical; modified itt; R0007531:Table 2
52	A3	responders	85.3	hypothetical; modified itt; R0007531:Table 2
52	A4	responders	8.0	hypothetical; modified itt; R0007531:Table 2

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

Week	Arm	Statistic	Estimate	Detail
52	A1	responders	35.9	hypothetical; modified itt; R0007531:Table 2
52	A2	responders	53.0	hypothetical; modified itt; R0007531:Table 2
52	A3	responders	65.6	hypothetical; modified itt; R0007531:Table 2
52	A4	responders	1.5	hypothetical; modified itt; R0007531:Table 2

Weight loss of 15 percent or more (4 lines; O11C)

Week	Arm	Statistic	Estimate	Detail
52	A1	responders	13.8	hypothetical; modified itt; R0007531:Table 2
52	A2	responders	24.0	hypothetical; modified itt; R0007531:Table 2
52	A3	responders	36.5	hypothetical; modified itt; R0007531:Table 2
52	A4	responders	0.5	hypothetical; modified itt; R0007531:Table 2

Acute kidney injury (4 lines; O121)

Arm	Statistic	Events / N	Detail
A1	events	2 / 329	not stated; safety; Acute kidney injury; registry:adverse_events
A2	events	1 / 328	not stated; safety; Acute kidney injury; registry:adverse_events
A3	events	0 / 338	not stated; safety; Acute kidney injury; registry:adverse_events
A4	events	3 / 1000	not stated; safety; Acute kidney injury; registry:adverse_events

All cause mortality (8 lines; O20)

Arm	Statistic	Events / N	Detail
A1	events	15 / 329	not stated; safety; registry:adverse_events
A1	events	12 / 251	not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Supplement Table S3
A2	events	2 / 247	not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Supplement Table S3
A2	events	2 / 328	not stated; safety; registry:adverse_events
A3	events	8 / 338	not stated; safety; registry:adverse_events
A3	events	6 / 252	not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Supplement Table S3
A4	events	25 / 743	not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Supplement Table S3
A4	events	35 / 1000	not stated; safety; registry:adverse_events

Three point MACE (4 lines; O21)

Arm	Statistic	Events / N	Detail
A1	events	18 / 251	not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Supplement Table S3
A2	events	16 / 247	not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Supplement Table S3
A3	events	14 / 252	not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Supplement Table S3
A4	events	62 / 743	not stated; modified itt; background:met_or_su_no_sglt2i; R0015279:Supplement Table S3

Physical functioning (any instrument) (7 lines; O24B)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
52	A1 vs A4	md	7.0 points	4.6 to 9.4		hypothetical; modified itt; R0007531:Supplement Table S3
52	A1	change	5.9 points		285	hypothetical; modified itt; R0007531:Supplement Table S3
52	A2	change	5.6 points		291	hypothetical; modified itt; R0007531:Supplement Table S3
52	A2 vs A4	md	6.7 points	4.3 to 9.1		hypothetical; modified itt; R0007531:Supplement Table S3
52	A3 vs A4	md	7.2 points	4.8 to 9.5		hypothetical; modified itt; R0007531:Supplement Table S3
52	A3	change	6.1 points		296	hypothetical; modified itt; R0007531:Supplement Table S3
52	A4	change	-1.1 points		903	hypothetical; modified itt; R0007531:Supplement Table S3

Health related quality of life total score (any instrument) (14 lines; O24C)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
52	A1	final	15.3 points		278	hypothetical; modified itt; R0007531:Supplement Table S3
52	A1	change	0.04 points		282	hypothetical; modified itt; R0007531:Supplement Table S3
52	A1 vs A4	md	1.6 points	1.0 to 2.3		hypothetical; modified itt; R0007531:Supplement Table S3
52	A1 vs A4	md	0.04 points	0.02 to 0.07		hypothetical; modified itt; R0007531:Supplement Table S3
52	A2 vs A4	md	0.04 points	0.01 to 0.06		hypothetical; modified itt; R0007531:Supplement Table S3
52	A2	change	0.04 points		289	hypothetical; modified itt; R0007531:Supplement Table S3
52	A2	final	15.7 points		286	hypothetical; modified itt; R0007531:Supplement Table S3
52	A2 vs A4	md	2.0 points	1.4 to 2.6		hypothetical; modified itt; R0007531:Supplement Table S3
52	A3 vs A4	md	1.6 points	1.0 to 2.3		hypothetical; modified itt; R0007531:Supplement Table S3
52	A3	change	0.04 points		295	hypothetical; modified itt; R0007531:Supplement Table S3
52	A3	final	15.3 points		290	hypothetical; modified itt; R0007531:Supplement Table S3
52	A3 vs A4	md	0.04 points	0.01 to 0.06		hypothetical; modified itt; R0007531:Supplement Table S3
52	A4	change	0.00 points		887	hypothetical; modified itt; R0007531:Supplement Table S3
52	A4	final	13.7 points		884	hypothetical; modified itt; R0007531:Supplement Table S3

Serious adverse events (4 lines; O25)

Arm	Statistic	Events / N	Detail
A1	events	48 / 329	not stated; safety; registry:adverse_events
A2	events	54 / 328	not stated; safety; registry:adverse_events
A3	events	41 / 338	not stated; safety; registry:adverse_events
A4	events	193 / 1000	not stated; safety; registry:adverse_events

Discontinuation due to adverse events (12 lines; O26)

Arm	Statistic	Events / N	Detail
A1	events	37 / 329	not stated; safety; R0007531:Supplement Table S2
A1	events	3 / 329	not stated; randomized; registry:flow
A1	events	1 / 308	not stated; randomized; registry:flow
A2	events	2 / 319	not stated; randomized; registry:flow
A2	events	2 / 330	not stated; randomized; registry:flow
A2	events	28 / 328	not stated; safety; R0007531:Supplement Table S2
A3	events	36 / 338	not stated; safety; R0007531:Supplement Table S2
A3	events	0 / 329	not stated; randomized; registry:flow
A3	events	0 / 338	not stated; randomized; registry:flow
A4	events	3 / 1005	not stated; randomized; registry:flow
A4	events	54 / 1000	not stated; safety; R0007531:Supplement Table S2
A4	events	7 / 953	not stated; randomized; registry:flow

Nausea (8 lines; O27A)

Arm	Statistic	Events / N	Detail
A1	events	39 / 329	not stated; safety; registry:adverse_events
A1	events	39 / 329	not stated; safety; R0007531:Supplement Table S2
A2	events	53 / 328	not stated; safety; R0007531:Supplement Table S2
A2	events	53 / 328	not stated; safety; registry:adverse_events
A3	events	76 / 338	not stated; safety; R0007531:Supplement Table S2
A3	events	76 / 338	not stated; safety; registry:adverse_events
A4	events	23 / 1000	not stated; safety; R0007531:Supplement Table S2
A4	events	23 / 1000	not stated; safety; registry:adverse_events

Vomiting (12 lines; O27B)

Arm	Statistic	Events / N	Detail
A1	events	16 / 329	not stated; safety; R0007531:Supplement Table S2
A1	events	16 / 329	not stated; safety; registry:adverse_events
A1	events	0 / 329	not stated; safety; registry:adverse_events
A2	events	0 / 328	not stated; safety; registry:adverse_events
A2	events	27 / 328	not stated; safety; R0007531:Supplement Table S2
A2	events	27 / 328	not stated; safety; registry:adverse_events
A3	events	29 / 338	not stated; safety; registry:adverse_events
A3	events	0 / 338	not stated; safety; registry:adverse_events
A3	events	29 / 338	not stated; safety; R0007531:Supplement Table S2
A4	events	16 / 1000	not stated; safety; R0007531:Supplement Table S2
A4	events	15 / 1000	not stated; safety; registry:adverse_events
A4	events	1 / 1000	not stated; safety; registry:adverse_events

Diarrhea (8 lines; O27C)

Arm	Statistic	Events / N	Detail
A1	events	41 / 329	not stated; safety; R0007531:Supplement Table S2
A1	events	41 / 329	not stated; safety; registry:adverse_events
A2	events	65 / 328	not stated; safety; R0007531:Supplement Table S2
A2	events	65 / 328	not stated; safety; registry:adverse_events
A3	events	74 / 338	not stated; safety; R0007531:Supplement Table S2
A3	events	74 / 338	not stated; safety; registry:adverse_events
A4	events	44 / 1000	not stated; safety; registry:adverse_events
A4	events	44 / 1000	not stated; safety; R0007531:Supplement Table S2

Constipation (4 lines; O27D)

Arm	Statistic	Events / N	Detail
A1	events	17 / 329	not stated; safety; registry:adverse_events
A2	events	14 / 328	not stated; safety; registry:adverse_events
A3	events	14 / 338	not stated; safety; registry:adverse_events
A4	events	5 / 1000	not stated; safety; registry:adverse_events

Gallbladder and biliary disease (12 lines; O28)

Arm	Statistic	Events / N	Detail
A1	events	0 / 329	not stated; safety; Cholecystitis; registry:adverse_events
A1	events	0 / 329	not stated; safety; Biliary dilatation; registry:adverse_events
A1	events	0 / 329	not stated; safety; Cholecystitis acute; registry:adverse_events
A2	events	1 / 328	not stated; safety; Cholecystitis; registry:adverse_events
A2	events	1 / 328	not stated; safety; Cholecystitis acute; registry:adverse_events
A2	events	0 / 328	not stated; safety; Biliary dilatation; registry:adverse_events
A3	events	0 / 338	not stated; safety; Cholecystitis acute; registry:adverse_events
A3	events	0 / 338	not stated; safety; Biliary dilatation; registry:adverse_events
A3	events	0 / 338	not stated; safety; Cholecystitis; registry:adverse_events
A4	events	2 / 1000	not stated; safety; Cholecystitis acute; registry:adverse_events
A4	events	1 / 1000	not stated; safety; Biliary dilatation; registry:adverse_events
A4	events	2 / 1000	not stated; safety; Cholecystitis; registry:adverse_events

Acute pancreatitis (12 lines; O29)

Arm	Statistic	Events / N	Detail
A1	events	1 / 329	not stated; safety; Obstructive pancreatitis; registry:adverse_events
A1	events	0 / 329	not stated; safety; Pancreatitis acute; registry:adverse_events
A1	events	2 / 329	not stated; safety; Pancreatitis; registry:adverse_events
A2	events	0 / 328	not stated; safety; Obstructive pancreatitis; registry:adverse_events
A2	events	1 / 328	not stated; safety; Pancreatitis acute; registry:adverse_events
A2	events	1 / 328	not stated; safety; Pancreatitis; registry:adverse_events
A3	events	0 / 338	not stated; safety; Obstructive pancreatitis; registry:adverse_events
A3	events	0 / 338	not stated; safety; Pancreatitis acute; registry:adverse_events
A3	events	0 / 338	not stated; safety; Pancreatitis; registry:adverse_events
A4	events	0 / 1000	not stated; safety; Obstructive pancreatitis; registry:adverse_events
A4	events	0 / 1000	not stated; safety; Pancreatitis acute; registry:adverse_events
A4	events	0 / 1000	not stated; safety; Pancreatitis; registry:adverse_events

Pancreatic cancer (8 lines; O38)

Arm	Statistic	Events / N	Detail
A1	events	1 / 329	not stated; safety; Pancreatic carcinoma; registry:adverse_events
A1	events	0 / 329	not stated; safety; Pancreatic neoplasm; registry:adverse_events
A2	events	0 / 328	not stated; safety; Pancreatic carcinoma; registry:adverse_events
A2	events	1 / 328	not stated; safety; Pancreatic neoplasm; registry:adverse_events
A3	events	0 / 338	not stated; safety; Pancreatic carcinoma; registry:adverse_events
A3	events	0 / 338	not stated; safety; Pancreatic neoplasm; registry:adverse_events
A4	events	0 / 1000	not stated; safety; Pancreatic neoplasm; registry:adverse_events
A4	events	0 / 1000	not stated; safety; Pancreatic carcinoma; registry:adverse_events