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

Table 2 Meta-analysis of randomized controlled trials comparing GLP-1 receptor agonists + SGLT-2I vs SGLT-2I or GLP-1 receptor agonists

Ref.	Types of studies included, n	Comparator arm	N	∆HbA1c (%), (95%CI)	∆Weight (kg), (95%CI)	∆SBP (mmHg), (95%CI)	Adverse events (GI, GTI, Hypo’s) with SGLT-2I + GLP-1RA vs SGLT-2I
Zhou et al[31], 2019	RCT, 3	GLP-1RA + SGLT-2I vs SGLT-2I	1421	-0.80 (-1.14; -0.45)	-1.46 (-2.38; -0.54)	-2.88 (-4.52; -1.25)	Increased risk of GI S/E (RR: 1.68; 95%CI: 1.14-2.47) but similar GTI (RR: 0.82; 95%CI: 0.39-1.75) and hypo’s (RR: 2.10; 95%CI: 0.75-5.90) in combo arm
Castellana et al[32], 2019	RCT, 4	GLP-1RA + SGLT-2I vs SGLT-2I	1610	-0.74 (-1.15; -0.33)	-1.61 (-2.83; -0.38)	-3.32 (-4.96; -1.68)	Similar hypo’s (RR: 1.43; 95%CI: 0.46-4.52). GTI and GI S/E not reported
Patoulias et al[33], 2019	RCT, 3	GLP-1RA + SGLT-2I vs SGLT-2I	1042	-0.91 (-1.41; -0.42)	-1.95 (-3.83; -0.07)	-3.64 (-6.24; -1.03)	Increased risk of nausea (RR: 3.21; 95%CI: 1.36-7.54) and hypo’s (RR: 2.62; 95%CI: 1.15-5.96) in combo arm. GTI not reported
Mantsiou et al[34], 2020	RCT, 7	GLP-1RA + SGLT-2I vs SGLT-2I	1913	-0.85 (-1.19; -0.52)	-1.46 (-2.94; +0.03)	-2.66 (-5.26; -0.06)	No difference in severe hypo’s (OR: 2.39; 95%CI: 0.47-12.27). GTI and GI S/E not reported
		GLP-1RA + SGLT-2I vs GLP-1RA		-0.61 (-1.09; -0.14)	-2.59 (-3.68; -1.51)	-4.13 (-7.28; -0.99)	No difference in severe hypo’s (OR: 1.38; 95%CI: 0.14-13.14). GTI and GI S/E not reported

GI: Gastrointestinal; GLP-1RA: GLP-1 receptor agonists; GTI: Genital tract infections; Hypo’s: Hypoglycemia; OR: Odds ratio; RR: Risk ratio; RCT: Randomized controlled trial; SBP: Systolic blood pressure; S/E: Side effect; SGLT-2I: SGLT-2 inhibitors.