Table 2 Summary of cardiovascular outcome trials

Biguanide

UKPDS/metformin

Newly diagnosed T2DM patients aged 25–65 years and had a fasting plasma glucose > 6 mmol/L on two mornings, 1–3 weeks apart

NR

0.68 (0.53–0.87)

NR

0.59 (0.29–1.18)

0.61 (0.41–0.69)

0.58 (0.37–0.91)

0.79 (0.27–1.07)

0.64 (0.45–0.91)

39

24

DPP4 inhibitors

SAVOR TIMI 5325/saxagliptin

T2DM and history of or multiple risk factors for CVD

78/13

3-point MACE

1.00 (0.89–1.12)

1.27 (1.07–1.51)

1.11 (0.88–1.39)

0.95 (0.80–1.12)

1.03 (0.87–1.22)

1.27 (1.07–1.51)

1.11 (0.96–1.27)

CARMELINA/linagliptin

T2DM and high CV risk [history of vascular disease and urine-albumin creatinine ratio > 200 mg/g)], and high renal risk (reduced eGFR and micro- or macroalbuminuria)

58/46

3-point MACE

1.02 (0.89–1.17)

0.87 (0.57–1.31)

0.88 (0.63–1.23)

1.15 (0.91–1.45)

0.96 (0.81–1.14)

0.90 (0.74–1.08)

0.98 (0.84–1.13)

EXAMINE/alogliptin

T2DM and ACS within 15–90 days before randomization

100/28

3-point MACE

0.96 (≤ 1.16)*

0.90 (0.60–1.37)

0.91 (0.55–1.50)

1.08 (0.88–1.33)

0.85 (0.66–1.10)

1.19 (0.90–1.58)

0.88 (0.71–1.09)

TECOS/sitagliptin

T2DM and pre-existing CVD

74/18

4-point MACE

0.98 (0.88–1.09)

0.90 (0.70–1.16)

0.97 (0.79–1.19)

0.95 (0.81–1.11)

1.03 (0.89–1.19)

1.00 (0.83–1.20)

1.01 (0.90–1.14)

SGLT2 inhibitor

EMPA-REG OUTCOME/empagliflozin

T2DM and pre-existing CVD, with BMI ≤ 45 kg/m² and eGFR ≥ 30 mL/min/1.73 m²

99/10

3-point MACE

0.86 (0.74–0.99)

0.99 (0.74–1.34)

1.18 (0.89–1.56)

0.87 (0.70–1.09)

0.62 (0.49–0.77)

0.65 (0.50–0.85)

0.68 (0.57–0.82)

14

24

13

38

35

32

Integrated CANVAS programme (CANVAS, CANVAS-R)/canagliflozin

T2DM and pre-existing CVD at ≥ 30 years of age or ≥ 2 CV risk factors (T2DM ≥ 10 years, systolic blood pressure > 140 mmHg and on anti-hypertensive agents, current smoking, micro- or macroalbuminuria) at ≥ 50 years of age

65.6/14.4

3-point MACE

0.86 (0.75–0.97)^b

NR

0.87 (0.69–1.09)^b

0.89 (0.73–1.09)^b

0.96 (0.77–1.18)^c, 0.87 (0.72–1.06)^b

0.67 (0.52–0.87)^b

0.87 (0.74–1.01), 0.90 (0.76–1.07)^b

14

10

15

13

33

10

DECLARE-TIMI 58/dapagliflozin

T2DM with creatinine clearance of ≥ 60 mL/min, eGFR < 60 mL/min/1.73 m², had multiple risk factors for ASCVD or had established ASCVD (clinically evident ischemic heart disease, ischemic cerebrovascular disease, or peripheral artery disease)

41/10

Total cohort, 0.93 (0.84–1.03); ASCVD, 0.90 (0.79–1.02); multiple risk factors without ASCVD, 1.01 (0.86–1.20)

NR

1.01 (0.84–1.21)

0.89 (0.77–1.01)

Total cohort, 0.98 (0.82–1.17); ASCVD, 0.83 (0.71–0.98); multiple risk factors without ASCVD, 0.84 (0.67–1.04)

Total cohort, 0.73 (0.61–0.88); ASCVD, 0.83 (0.71–0.98); multiple risk factors without ASCVD, 0.84 (0.67–1.04)

0.93 (0.82–1.04)

GLP1-receptor agonist

LEADER/liraglutide

T2DM and pre-existing CVD, kidney disease, or HF at ≥ 50 years of age or ≥ 1 CV risk factor at ≥ 60 years of age (microalbuminuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction)

81/18

3-point MACE 0.87 (0.78–0.97)

0.98 (0.76–1.26)

0.86 (0.71–1.06)

0.86 (0.73–1.00)

0.78 (0.66–0.93)

0.87 (0.73–1.05)

0.85 (0.74–0.97)

13

11

12

22

13

15

SUSTAIN-6/semaglutide

T2DM and pre-existing CVD, HF, or CKD at ≥ 50 years

60/24

3-point MACE

0.74 (0.58–0.95)

0.82 (0.47–1.44)

0.61 (0.38–0.99)

0.74 (0.51–1.08)

0.98 (0.65–1.48)

1.11 (0.77–1.61)

1.05 (0.74–1.50)

6

39

26

2

11

5

ELIXA/lixisenatide

T2DM and an acute coronary event within 180 days before screening

100/22

4-point MACE

1.02 (0.89–1.17)

1.11 (0.47–2.62)

1.12 (0.79–1.58)

1.03 (0.87–1.22)

0.98 (0.78–1.22)

0.96 (0.75–1.23)

0.94 (0.78–1.13)

EXSCEL/exenatide

T2DM with or without pre-existing CVD

73.1/16.2

3-point MACE

0.91 (0.83–1.00)

1.05 (0.94–1.18)

0.85 (0.70–1.03)

0.97 (0.85–1.10)

0.88 (0.76–1.02)

0.94 (0.78–1.13)

0.86 (0.77–0.97)

Harmony/albiglutide

T2DM and established disease of MI, ≥ 50% carotid artery stenosis/peripheral artery circulation at ≥ 40 years

87/–

3-point MACE

0.78 (0.68–0.90)

NR

NR

0.75 (0.61–0.90)

0.93 (0.73–1.19)

0.85 (0.70–1.04) (composite of CV death and HF hospitalization)

0.95 (0.79–1.16)

Thiazolidinediones

IRIS/pioglitazone

Insulin resistance but not diabetes + ischemic stroke or TIA in 6 months before randomization

100/–

Composite of fatal and nonfatal stroke and MI

0.76 (0.62–0.93)

NR

0.82 (0.61–1.10)

NR

NR

–

0.93 (0.73–1.17)

18

20

PROactive/pioglitazone

T2DM with history of pre-existing macrovascular disease (MI, stroke, percutaneous coronary intervention or coronary artery bypass surgery ≥ 6 months of study, ACS ≥ 3 months before study entry, or objective evidence of coronary artery disease or obstructive arterial disease in the leg) making the patient population at very high-risk for macrovascular disease

100/–

Composite MACE

0.90 (0.80–1.02)^a

NR

0.80 (0.72–0.98) (composite of all-cause mortality, MI, stroke)

0.80 (0.72–0.98)

0.90 (0.80–1.02)

NR

0.80 (0.72–0.98)

10

16

16

16

Insulin

ORIGIN/insulin glargine

T2DM with CV risk factors plus impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes to receive insulin glargine

59/–

1.02 (0.94–1.11)

0.91 (0.76–1.08)

1.03 (0.89–1.21)

1.02 (0.88–1.19)

1.00 (0.89–1.13)

0.90 (0.77–1.05)

0.98 (0.90–1.08)

DEVOTE/degludec

T2DM, age > 50 years + history of CVD and/or CKD, age > 60 years + > 1 CV risk factors

83/–

3-point MACE 0.91 (0.78–1.06)

0.95 (0.68–1.31)

0.90 (0.65–1.23)

0.85 (0.68–1.06)

0.96 (0.76–1.21)

NR

0.91 (0.76–1.11)

α-glucosidase inhibitors

ACE/acarbose

Coronary heart disease and impaired glucose tolerance (conducted in China)

100/3.7

5-point MACE

0.98 (0.86–1.11)

1.02 (0.82–1.26)

0.97 (0.70–1.33)

1.12 (0.87–1.46)

0.89 (0.71–1.11)

0.89 (0.63–1.24)

0.98 (0.81–1.19)