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Table 1 Summary of main CVOTs for GLP-1RAs

From: DPP-4 inhibitors and GLP-1RAs: cardiovascular safety and benefits

Characteristic

ELIXA (2015) [56]

SUSTAIN-6 (2016) [53]

LEADER (2016) [54]

EXSCEL (2017) [59]

HARMONY (2018) [60]

PIONEER 6 (2019) [61]

REWIND (2019) [62]

AMPLITUDE-O (2021) [63]

Drug

Lixisenatide

Semaglutide

Liraglutide

Exenatide

Albiglutide

Semaglutide

Dulaglutide

Efpeglenatide

Control

Placebo

Placebo

Placebo

Placebo

Placebo

Placebo

Placebo

Placebo

Median follow-up (years)

2.1

2.1

3.5

3.2

1.6

1.3

5.4

1.81

Inclusion criteria

T2DM and acute coronary events within the past 180 d

 ≥ 50 years of age with established CVD, HF (class I or II), CKD (stage 3 +), or ≥ 60 with cardiovascular risk factor

 ≥ 50 years of age with established CVD, HF (class I or II), CKD (stage 3 +), or ≥ 60 with cardiovascular risk factor

T2DM on 0–3 oral or insulin antidiabetic drugs; HbA1c 6.5–10.0%

 ≥ 40 years of age with T2DM; HbA1c > 7.0%; established CVD

 ≥ 50 years; T2DM with established CVD; or ≥ 60 with cardiovascular risk factor

 ≥ 50 years; T2DM with HbA1c ≤ 9.5%; two or less oral glucose-lowering drugs

T2DM with history of CVD or eGFR 25.0 to 59.9 ml/(min‧1.73 m2)

Exclusion criteria

 < 30 years of age, PCI within past 15 d, CABG for the qualifying event, planned revascularization, eGFR < 30 ml/(min‧1.73 m2), HbA1c < 5.5% or > 11.0%

Treatment with DPP-4i, GLP-1R, or insulin other than basal within 30 d; premixed insulin treatment within 90 d; acute coronary or cerebrovascular event within 90 d; planned coronary intervention

T1DM; use of GLP-1RAs, DPP-4i, or rapid-acting insulin; familial history of medullary thyroid cancer or type 2 endocrine neoplasia; acute coronary or cerebrovascular event within 14 d

T1DM; use of GLP-1RAs; history of gastroparesis, pancreatitis; pregnancy; eGFR < 30 ml/(min‧1.73 m2); planned revascularization

eGFR < 30 ml/(min‧1.73 m2); use of GLP-1RAs; severe gastroparesis; history of pancreatitis, pancreatic tumors, medullary carcinoma of the thyroid; pregnancy, breastfeeding

Use of DPP-4i, GLP-1R; malignant neoplasms; pancreatitis; HF class IV; planned revascularisation; eGFR < 30 ml/(min‧1.73 m2)

eGFR < 15 ml/(min‧1.73 m2); cancer; severe hypoglycemia history; life expectancy < 1 year; coronary or cerebrovascular event within 2 months; planned revascularization

History of GI disease, pancreatitis; hypertension; personal or family history of medullary thyroid cancer; planned coronary procedure; use of DPP-4i, GLP-1R; retinopathy or maculopathy

Results of primary endpoint (vs. placebo)

Non-inferiority; HR = 1.02 (95% CI 0.89–1.17)

6.6% vs. 8.9%; HR = 0.74 (95% CI 0.58–0.95); P < 0.001 for non-inferiority; P = 0.02 for superiority

HR = 0.87 (95% CI 0.78–0.97); P < 0.001 for non-inferiority; P = 0.01 for superiority

11.4% vs. 12.2%; HR = 0.91 (95% CI 0.83–1.00); P = 0.06 for superiority

7% vs. 9%; HR = 0.78 (95% CI 0.68–0.90); P < 0.0001 for non-inferiority; P = 0.0006 for superiority

3.8% vs. 4.8%; HR = 0.79 (95% CI 0.57–1.11); P = 0.17*

12.0% vs. 13.4%; HR = 0.88 (95% CI 0.79–0.99); P = 0.026 for superiority

7.0% vs. 9.2%; HR = 0.73 (95% CI 0.58–0.92); P < 0.001 for non-inferiority; P = 0.007 for superiority

HF

HR = 0.96 (95% CI 0.75–1.23)

HR = 1.11 (95% CI 0.77–1.61)

4.7% vs. 5.3%; HR = 0.87 (95% CI 0.73–1.05)

HR = 0.94 (95% CI 0.78–1.13)

HR = 0.85 (95% CI 0.70–1.04)

1.3% vs. 1.5%; HR = 0.86 (95% CI 0.48–1.55)

HR = 0.93 (95% CI 0.77–1.12)

HR = 0.61 (95% CI 0.38–0.98)

Myocardial infarction

HR = 1.03 (95% CI 0.87–1.22)

HR = 0.74 (95% CI 0.51–1.08)

6.3% vs. 7.3%; HR = 0.86 (95% CI 0.73–1.00)

HR = 0.97 (95% CI 0.85–1.10)

HR = 0.75 (95% CI 0.61–0.90)

HR = 1.18 (95% CI 0.73–1.90)

4.1% vs. 4.3%; P = 0.65

HR = 0.75 (95% CI 0.54–1.05)

  1. *Significant improvement in all-cause mortality (1.4% vs. 2.8%, HR = 0.51; 95% CI 0.31–0.84), cardiovascular mortality (0.9% vs. 1.9%, HR = 0.49; 95% CI 0.27–0.92). CVOTs cardiovascular outcome trials, T2DM type 2 diabetes mellitus, CVD cardiovascular disease, HF heart failure, CKD chronic kidney disease, HbA1c glycated hemoglobin, eGFR estimated glomerular filtration rate, PCI percutaneous coronary intervention, CABG coronary artery bypass graft, GLP-1R GLP-1 receptor, T1DM type 1 diabetes mellitus, GLP-1RAs glucagon-like peptide-1 receptor agonists, DPP-4i DPP-4 inhibitor, HR hazard ratio, CI confidence interval