Combining GLP-1 receptor agonists and SGLT-2 inhibitors for cardiovascular disease prevention in type 2 diabetes: A systematic review with multiple network meta-regressions

Table 3 Effect modification of prior cardiovascular diseases on cardiovascular outcomes of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors in type 2 diabetes

Cardiovascular outcome	Covariate		Intervention	HR with 95%CI
Fatal and non-fatal MI	Prior history of MI	NA	GLP-1RA vs Placebo	0.91 (0.84-1.01)
Fatal and non-fatal MI	Prior history of MI	0	GLP-1RA vs Placebo	1.13 (0.85-1.51)
Fatal and non-fatal MI	Prior history of MI	1	GLP-1RA vs Placebo	0.57 (0.30-1.05)
Fatal and non-fatal MI	Prior history of MI	NA	SGLT-2I vs Placebo	0.91 (0.82-1.02)
Fatal and non-fatal MI	Prior history of MI	0	SGLT-2I vs Placebo	0.84 (0.66-1.07)
Fatal and non-fatal MI	Prior history of MI	1	SGLT-2I vs Placebo	1.09 (0.66-1.80)
Cardiovascular death	Prior history of MI	NA	GLP-1RA vs Placebo	0.88 (0.76-0.99)
Cardiovascular death	Prior history of MI	0	GLP-1RA vs Placebo	0.93 (0.59-1.48)
Cardiovascular death	Prior history of MI	1	GLP-1RA vs Placebo	0.74 (0.26-2.01)
Cardiovascular death	Prior history of MI	NA	SGLT-2I vs Placebo	0.84 (0.72-0.96)
Cardiovascular death	Prior history of MI	0	SGLT-2I vs Placebo	0.92 (0.62-1.32)
Cardiovascular death	Prior history of MI	1	SGLT-2I vs Placebo	0.68 (0.32-1.48)
Hospitalization for HF	Prior history of HF	NA	GLP-1RA vs Placebo	0.91 (0.82-1.02)
Hospitalization for HF	Prior history of HF	0	GLP-1RA vs Placebo	0.93 (0.61-1.42)
Hospitalization for HF	Prior history of HF	1	GLP-1RA vs Placebo	0.84 (0.20-3.67)
Hospitalization for HF	Prior history of HF	NA	SGLT-2I vs Placebo	0.68 (0.60-0.76)
Hospitalization for HF	Prior history of HF	0	SGLT-2I vs Placebo	0.69 (0.52-0.90)
Hospitalization for HF	Prior history of HF	1	SGLT-2I vs Placebo	0.62 (0.14-2.80)
Cardiovascular death	Prior history of HF	NA	GLP-1RA vs Placebo	0.86 (0.76-0.97)
Cardiovascular death	Prior history of HF	0	GLP-1RA vs Placebo	0.77 (0.51-1.08)
Cardiovascular death	Prior history of HF	1	GLP-1RA vs Placebo	1.52 (0.30-10.07)
Cardiovascular death	Prior history of HF	NA	SGLT-2I vs Placebo	0.84 (0.73-0.96)
Cardiovascular death	Prior history of HF	0	SGLT-2I vs Placebo	0.76 (0.52-1.04)
Cardiovascular death	Prior history of HF	1	SGLT-2I vs Placebo	1.51 (0.29-10.38)

The covariates of percentages of patients having baseline prior cardiovascular diseases including myocardial infarction and heart failure were incorporated in the network meta-regressions. Hazard ratios (HR)_0/Disease- and HR_1/Disease+ with 95% confidence intervals (95%CI) were estimated with the assumption of either 0% or 100% patients having the co-morbidities in the cardiovascular outcome trials (CVOT). The network meta-analyses were run in parallel to calculate HR_NA with 95%CI. The HR_NA indicated effect sizes observed from the CVOT with the actual percentages of patients having the co-morbidities. HR: Hazard ratios; 95%CI: 95% confidence intervals; CVOT: Cardiovascular outcome trials; GLP-1RA: Glucagon-like peptide-1 receptor agonists; SGLT-2I: Sodium-glucose co-transporter-2 inhibitors; MI: Myocardial infarction; HF: Heart failure.