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 1 Study-level characteristics of included major cardiovascular outcome trials and associated post-hoc analyses

Year	CVOT	Intervention	Median follow-up (year)	History of MI (yes, %)	History of HF (yes, %)	Post-baseline GLP-1RA/SGLT-2I (yes, %), intervention/placebo
2013	EXAMINE[25]	Alogliptin	1.5	N/A	N/A	N/A
2013	SAVOR-TIMI 53[26]	Saxagliptin	2.1	N/A	N/A	N/A
2015	TECOS[27]	Sitagliptin	3.0	N/A	N/A	N/A
2019 2015	CARMELINA[28] ELIXA[29]	Linagliptin Lixisenatide	2.2 2.1	N/A 22	N/A 22	N/A N/A
2016	SUSTAIN-6[30]	Semaglutide	2.1	32	17[31]	1.5/1.2
2016	LEADER[32]	Liraglutide	3.8	31	18[33]	2.1/2.81
2017	EXSCEL[34]	Exenatide	3.2	32[35]	16	4.4/5.8
2018	HARMONY OUTCOMES[36]	Albiglutide	1.5	47	20	9.7/10.8
2019	REWIND[37]	Dulaglutide	5.4	16[38]	9	5.2/7.3
2019	PIONEER-6[39]	Semaglutide	1.3	36[31]	12[31]	13.5/15.8
2021	AMPLITUDE-O[40]	Efpeglenatide	1.8	N/A	18	17.5/21.2
2015	EMPA-REG OUTCOME[41]	Empagliflozin	3.1	47	10	N/A
2017	CANVAS[42]	Canagliflozin	2.4	29[43]	14	6.2/7.72
2019	DECLARE-TIMI 58[44]	Dapagliflozin	4.2	21[45]	10	9.5/11.5[19]
2019	CREDENCE[46]	Canagliflozin	2.6	10[47]	15	6.5/6.9
2020	VERTIS CV[48]	Ertugliflozin	3.5	48	24	4.9/5.6

¹Data kindly provided by Dr. Kajsa Kvist from Novo Nordisk.

²Data extracted from the drug approval package (application number: 204042Orig1s027) kindly provided by Dr. Frank Vercruysse from Janssen Pharmaceuticals.

Data for analysis were extracted from 17 primary investigations and 9 post-hoc analyses (including a drug approval package retrieved from Center for Drug Evaluation and Research). Covariates of percentages of patients having baseline prior myocardial infarction or heart failure; percentages of patients receiving postbaseline co-treatment with sodium-glucose co-transporter-2 inhibitors (SGLT-2I)/glucagon-like peptide-1 receptor agonists (GLP-1RA) in the placebo and GLP-1RA or SGLT-2I groups of the cardiovascular outcome trials (CVOT), were incorporated into the network meta-regression analyses. The numbers in square brackets denoting the CVOT and data correspond to the cited references. 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; N/A: Not applicable.

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.

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.