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 2 Effect modification of co-treatment with sodium-glucose co-transporter-2 inhibitors on cardiovascular benefit of glucagon-like peptide-1 receptor agonists and vice versa in type 2 diabetes

Cardiovascular outcome	Covariate	Intervention	HR with 95%CI
MACE	NA	GLP-1RA vs Placebo	0.84 (0.77-0.90)
MACE	0	GLP-1RA vs Placebo	0.89 (0.77-0.99)
MACE	NA	SGLT-2I vs Placebo	0.90 (0.82-0.98)
MACE	0	SGLT-2I vs Placebo	0.95 (0.82-1.08)
MACE	1	Combination vs GLP-1RA	0.51 (0.16-1.65)
MACE	1	Combination vs SGLT-2I	0.48 (0.15-1.54)
Cardiovascular death	NA	GLP-1RA vs Placebo	0.85 (0.76-0.94)
Cardiovascular death	0	GLP-1RA vs Placebo	0.88 (0.73-1.07)
Cardiovascular death	NA	SGLT-2I vs Placebo	0.90 (0.79-1.02)
Cardiovascular death	0	SGLT-2I vs Placebo	0.93 (0.76-1.16)
Cardiovascular death	1	Combination vs GLP-1RA	0.58 (0.08-3.39)
Cardiovascular death	1	Combination vs SGLT-2I	0.55 (0.07-3.25)
Fatal and non-fatal MI	NA	GLP-1RA vs Placebo	0.89 (0.79-0.98)
Fatal and non-fatal MI	0	GLP-1RA vs Placebo	0.94 (0.79-1.09)
Fatal and non-fatal MI	NA	SGLT-2I vs Placebo	0.92 (0.81-1.05)
Fatal and non-fatal MI	0	SGLT-2I vs Placebo	0.98 (0.81-1.19)
Fatal and non-fatal MI	1	Combination vs GLP-1RA	0.45 (0.10-2.18)
Fatal and non-fatal MI	1	Combination vs SGLT-2I	0.44 (0.09-2.10)
Fatal and non-fatal stroke	NA	GLP-1RA vs Placebo	0.81 (0.72-0.91)
Fatal and non-fatal stroke	0	GLP-1RA vs Placebo	0.82 (0.67-1.00)
Fatal and non-fatal stroke	NA	SGLT-2I vs Placebo	0.94 (0.82-1.08)
Fatal and non-fatal stroke	0	SGLT-2I vs Placebo	0.95 (0.75-1.20)
Fatal and non-fatal stroke	1	Combination vs GLP-1RA	0.86 (0.12-6.23)
Fatal and non-fatal stroke	1	Combination vs SGLT-2I	0.74 (0.10-5.47)
Hospitalization for HF	NA	GLP-1RA vs Placebo	0.90 (0.79-1.02)
Hospitalization for HF	0	GLP-1RA vs Placebo	0.97 (0.80-1.19)
Hospitalization for HF	NA	SGLT-2I vs Placebo	0.68 (0.59-0.79)
Hospitalization for HF	0	SGLT-2I vs Placebo	0.75 (0.59-0.96)
Hospitalization for HF	1	Combination vs GLP-1RA	0.26 (0.03-1.88)
Hospitalization for HF	1	Combination vs SGLT-2I	0.33 (0.04-2.53)

The covariates of percentages of patients receiving postbaseline co-treatment with sodium-glucose co-transporter-2 inhibitors (SGLT-2I)/glucagon-like peptide-1 receptor agonists (GLP-1RA) were incorporated into the meta-regressions. Hazard ratios (HR)_{0/GLP-1RA/SGLT-2IvsPlacebo} and HR_{1/CombinationvsGLP-1RA/SGLT-2I} with 95% confidence intervals (95%CI) were estimated, assuming either 0% or 100% patients receiving the co-treatment. The network meta-analyses were run in parallel to calculate HR_NA with 95%CI. The HR_NA indicated effect sizes observed from the cardiovascular outcome trials with the actual percentages of patients receiving the co-treatment. HR: Hazard ratios; 95%CI: 95% confidence intervals; MACE: Major adverse cardiovascular events; 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; NA: Not available.