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.