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Table 1 Overview of CVOTs reporting significant reductions in 3P/4P-MACE

From: Cardiovascular outcomes trials: a paradigm shift in the current management of type 2 diabetes

Class*†

SGLT2 inhibitors

GLP-1 receptor agonists

Study

EMPA-REG OUTCOME

Empagliflozin

CANVAS Programme

Canagliflozin

AMPLITUDE-O

Liraglutide

LEADER

Liraglutide

SUSTAIN-6

Semaglutide

REWIND

Dulaglutide

MACE‡ HR (95% CI)

ER drug vs placebo/1,000 PY

0.86 (0.74–0.99)

37 vs 44

0.86 (0.75–0.97)

27 vs 32

0.73 (0.58–0.92)

39 vs 53

0.87 (0.78–0.97)

34 vs 39

0.74 (0.58–0.95)

32 vs 44

0.88 (0.79–0.99)

24 vs 27

CV death HR (95% CI)

0.62 (0.49–0.77)

All-cause death also reduced

0.87 (0.72–1.06)–N.S

0.72 (0.50–1.03)–N.S

0.78 (0.66–0.93)

All-cause death also reduced

0.98 (0.65–1.48)–N.S

0.91 (0.78–1.06)–N.S

Nonfatal MI HR (95% CI)

0.87 (0.70–1.09)–N.S

0.85 (0.69–1.05)–N.S

0.78 (0.55–1.10)–N.S

0.88 (0.75–1.03)–N.S

0.74 (0.51–1.08)–N.S

0.96 (0.79–1.16)–N.S

Nonfatal stroke HR (95% CI)

1.24 (0.92–1.67)–N.S

0.90 (0.71–1.15) – N.S

0.80 (0.48–1.31) – N.S

0.89 (0.72–1.11) – N.S

0.61 (0.38–0.99)

0.76 (0.61–0.95)

Other cardiorenal benefits (individual secondary endpoints)

Protective effect on:

• HHF

• Impaired renal function

• Albuminuria

Protective effect on:

• HHF

• Impaired renal function

• Albuminuria

Protective effect on:

• HF

• A composite of impaired renal function or albuminuria

• Albuminuria

Protective effect on albuminuria

Protective effect on albuminuria

Protective effect on:

• Impaired renal function

• Albuminuria

Cohort composition

Number of participants

7020

10,142

4076

9340

3297

9901

Established CVD % pts

99%

65%

91%

82%

83%

31%

Mean eGFR mL/min/1.73 m2

74

77

73

80

76

75

Key inclusion criteria (in addition to T2D)

Age ≥ 18 years with established CVD

• Age ≥ 30 years with symptomatic ASCVD

• or ≥ 50 years with ≥ 2 CV risk factors

• Age ≥ 18 years with history of CVD

• or ≥ 50 years (male) or ≥ 55 years (female) with kidney disease and ≥ 1 CV risk factor

• Age ≥ 50 years with ≥ 1 CV condition

• or ≥ 60 years with ≥ 1 CV risk factor

• Age ≥ 50 years with established CVD, chronic HF or chronic kidney disease (> stage 3)

• or ≥ 60 years with ≥ 1 CV risk factor

• Age ≥ 50 years with vascular disease

• or ≥ 55 years with ≥ 1 cardiorenal condition

• or ≥ 60 years with ≥ 2 CV risk factors

Subgroup analyses

Secondary vs primary CVD prevention

MACE‡ HR (95% CI)

N/A

Secondary prevention group: 0.82 (0.72–0.95)

Primary prevention group:

0.98 (0.74–1.30) P = 0.18

Secondary prevention group: 0.71 (0.57–0.90)

Primary prevention group:

1.71 (0.48–6.07)

Secondary prevention group: 0.83 (0.74–0.93)

Primary prevention group:

1.20 (0.86–1.67) P = 0.04

Secondary prevention group: 0.72 (0.55–0.93)

Primary prevention group:

1.00 (0.41–2.46) P = 0.49

Secondary prevention group: 0.87 (0.74–1.02)

Primary prevention group:

0.87 (0.74–1.02) P = 0.97

Other subgroups

Relative risk reduction for 3P-MACE was in most cases broadly similar across demographic and clinical baseline characteristics, including a range of cardiovascular and renal characteristics

  1. (For detailed overview of all diabetes CVOTs, and renal outcomes and HF studies, see Additional file 1: Table S1). Primary and key secondary endpoints, patient cohort composition, and key subgroup analyses for glucose-lowering agents that have demonstrated ASCVD benefits in diabetes CVOTs [15, 27, 28, 31, 32, 34, 96, 97]. As most CVOTs were not head-to-head trials, direct comparisons of agents cannot be made, due to possible differences in study design, definitions and cohorts. For example, absence of a demonstrated benefit may be due to such factors, especially for secondary outcomes where studies may not be powered to reach statistical significance. Differences in baseline CV risk are substantial between CVOTs, and even the definition of CV risk and individual risk factors differs between trials. CVOTs excluded here include: DECLARE-TIMI 58 (dapagliflozin), which did not show a significant effect on 3P-MACE, and a reduced risk for the composite of CV death or HHF was driven by reduction in HHF [37]; EXSCEL (once-weekly exenatide) found a non-significant trend towards a reduction of 3P-MACE [33]. References: EMPA-REG OUTCOME [27,28,29, 62]; CANVAS Program [30, 62, 92]; AMPLITUDE-O [23]; LEADER [32, 96]; SUSTAIN-6 [31, 136,137,138]; REWIND [34, 97]
  2. 3P/4P-MACE, 3-/4-point major adverse cardiovascular event; ASCVD, atherosclerotic CVD; CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; CVD, CV disease; CVOT, CV outcomes trial; eGFR, estimated glomerular filtration rate; ER, event rate; GLP-1, glucagon-like peptide 1; HR, hazard ratio; MI, myocardial infarction; N.S., not significant; PY, patient-years; SGLT2, sodium–glucose transport protein 2; T2D, type 2 diabetes
  3. *All drugs shown are currently licensed for T2D, except for efpeglenatide
  4. †In addition to the CVOTs shown, the HARMONY OUTCOMES trial showed reduced risks of 3P-MACE and MI with the GLP-1 receptor agonist albiglutide [35]; however, albiglutide is no longer an approved treatment
  5. ‡3P-MACE is shown for all CVOTs (a composite of CV death, nonfatal MI and nonfatal stroke), except for 4P-MACE for AMPLITUDE-O (3P-MACE outcomes plus death from undetermined causes)
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Cardiovascular Diabetology

ISSN: 1475-2840