Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes

Table 4 Meta-data of three-point composite of major adverse cardiovascular events, heart failure hospitalization, and renal outcome in cardiovascular outcome trials of SGLT-2 inhibitors and GLP-1 receptor agonists

Trial eponym, drugs	Background GLP-1RA + SGLT-2I therapy; n	Active arm (n/N), % or rate-per 100-patient-yr1	Placebo arm (n/N), % or rate-per 100-patient-yr1	HR, (95%CI)	P value of interaction
3-point composite of major adverse cardiovascular events outcome
CANVAS[46], Canagliflozin	Yes; 407	NR	NR	0.73 (0.36-1.46)	0.94
	No; 9735	NR	NR	0.86 (0.76-0.98)
DECLARE-TIMI[47], Dapagliflozin	Yes; 750	31/397, 7.8%	31/353, 8.8%	0.87 (0.53-1.43)	0.84
	No; 16410	725/8185, 8.9%	772/8225, 9.4%	0.94 (0.85-1.04)
VERTIS-CV[48], Ertugliflozin	Yes; 277	21/192, 3.541	9/85, 3.791	0.94 (0.43-2.05)	NR
	No; 7961	632/5301, 3.911	318/2660, 4.021	0.97 (0.85-1.11)
EXSCEL[43], Exenatide QW	Yes; 11442	NR/572, 3.291	NR/572, 4.811	0.68 (0.39-1.17)	NR
	No	NR	NR	NR
AMPLITUDE-O[45], Efpeglenatide	Yes; 618	25/412, 6.1%, 3.41	17/206, 8.3%, 5.01	0.70 (0.37-1.30)	0.68
	No; 3458	164/2305, 7.1%, 4.01	108/1153, 9.4%, 5.41	0.74 (0.58-0.94)
Heart failure hospitalization outcome
DECLARE-TIMI[47], Dapagliflozin	Yes; 750	4/397, 1.0%	18/353, 5.1%	0.20 (0.07-0.60)	0.01
	No; 16410	208/8185, 2.5%	268/8225, 3.3%	0.77 (0.64-0.92)
AMPLITUDE-O[45], Efpeglenatide	Yes; 618	3/412, 0.7%; 0.41	6/206, 2.9%, 1.61	0.23 (0.05-0.97)	0.35
	No; 3458	37/2305, 1.6%, 0.91	25/1153, 2.2%, 1.21	0.70 (0.42-1.17)
Renal outcome
DECLARE-TIMI[47], Dapagliflozin3	Yes; 750	4/397, 1.0%	10/353, 2.8%	0.36 (0.11-1.15)	0.49
	No; 16410	123/8185, 1.5%	228/8225, 2.8%	0.54 (0.43-0.67)
AMPLITUDE-O[45], Efpeglenatide4	Yes; 618	37/412, 9.0%, 5.11	34/206, 16.5%, 10.01	0.52 (0.33-0.83)	0.38
	No; 3458	316/2305, 13.7%, 8.21	216/1153, 18.7%, 11.91	0.70 (0.59-0.83)

¹Rate-per 100-patient-yr.

²Open-label, propensity-matched.

³Renal composite outcome consist of sustained decrease of 40% or more in eGFR to less than 60 mL/min/1.73 m², new end-stage renal disease, or death from renal causes.

⁴Renal composite outcome consists of incident macroalbuminuria (UACR > 300 mg/g or 33.9 mg/mmol) plus ≥ 30% rise of UACR from baseline, a sustained ≥ 30 d decrease in eGFR by ≥ 40%, renal replacement therapy, and a sustained (≥ 30 d) eGFR < 15 mL/min/1.73 m².

3P-MACE: Three-point composite of major adverse cardiovascular events; CVOTs: Cardiovascular outcome trials; HHF: Heart failure hospitalization; GLP-1RA: Glucagon-like petide-1 receptor agonists; HR: Hazard ratio; n: Number of events; N: Total number of patients; NR: Not reported/retrievable; PBO: Placebo; SGLT-2I: Sodium glucose transporter-2 inhibitors.