Spotlight on empagliflozin/metformin fixed-dose combination for the treatment of type 2 diabetes: a systematic review

Figures & data

Figure 1 Mechanism of action for SGLT-2 inhibitors.

Notes: Renal glucose handling. In healthy individuals, the vast majority of the glucose filtered by the kidney is reabsorbed by SGLT-2 in the S1 and S2 segments of the proximal convoluted tubule, and the remaining glucose is reabsorbed by SGLT-1 in the S3 segment. Reprinted with permission of the American Diabetes Association, Inc. Copyright 2014.⁸
Abbreviations: SGLT-2, sodium–glucose co-transporter 2; SGLT-1, sodium–glucose co-transporter 1.

Table 1 Summary of efficacy in randomized clinical trials of EMPA combined with MET

Reference	Intervention	HgA1c change from baseline (%)	Weight change from baseline (kg)	Change in systolic blood pressure (mmHg)
Haring et al^Citation18	MET + EMPA 10 mg	−0.70	−2.08	−4.5
24-week trial	MET + EMPA 25 mg	−0.77	−2.46	−5.2
	MET + placebo	−0.13	−0.45	−0.4
Rosenstock et al^Citation19	MET + EMPA 10 mg	−0.56	−2.7	−4.39
12-week trial	MET + EMPA 25 mg	−0.55	−2.6	−8.51
	MET + placebo	0.15	−1.2	−2.23
	MET + SITA 100 mg	−0.45	−0.8	−1.79
Ferrannini et al^Citation26	MET + EMPA 10 mg	−0.34	−3.1	−3.3
78-week trial	MET + EMPA 25 mg	−0.63	−4.0	−3.0
	MET + SITA 100 mg	−0.40	−0.4	1.8
	MET	−0.56	−1.3	2.0
Ridderstråle et al^Citation20	MET + EMPA 25 mg	−0.66	−3.1	−3.1
104-week trial	MET + GLIM (1–4 mg)	−0.55	1.3	2.5
Merker et al^Citation27	MET + EMPA 10 mg	−0.6	−2.4	−5.2
76-week trial	MET + EMPA 25 mg	−0.70	−2.7	−4.5
	MET + placebo	0	−0.5	−0.8
DeFronzo et al^Citation28	MET + EMPA 10 mg	−0.66*	−2.9	−3.5
52-week trial	MET + EMPA 25 mg	−0.62*	−2.8	−2.8
	MET + LINA 5 mg	−0.70*	−0.3	0.3

Notes:

* 24 week data. Reproduced with permission from Rosenstock J, Seman LJ, Jelaska A, et al. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab. 2013;15(12):1154–1160. © 2013 John Wiley & Sons Ltd.¹⁹ Reproduced with permission from Ridderstråle M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC. EMPA-REG H2H-SU Trial Investigators. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(9):691–700. © 2013 John Wiley & Sons Ltd.²⁰ Copyright ©2013 American Diabetes Association From: Diabetes Care 2013 Dec; 36(12):4015–4021. Reprinted with permission from “The American Diabetes Association”.²⁶

Abbreviations: EMPA, empagliflozin; MET, metformin; SITA, sitagliptin; GLIM, glimepiride; LINA, linagliptin; HgA1c, hemoglobin A1c.

Table 2 Summary of side effects in randomized clinical trials of EMPA combined with MET

Reference	Intervention used	One or more drug-related adverse events (%)	One or more serious or severe adverse events or death (%)	Adverse events leading to discontinuation (%)	Hypoglycemic events (%)	Events consistent with urinary tract infection (%)	Events consistent with genital infection (%)
Haring et al^Citation18	MET + EMPA 10 mg	16.1	3.2	0.9	1.8	5.1	3.7
	MET + EMPA 25 mg	12.6	2.3	2.3	1.4	5.6	4.7
	MET + placebo	12.1	3.4	3.4	0.5	4.9	0
Rosenstock et al^Citation19	MET + EMPA 10 mg	42.3	2.8	5.6	0	4.2	9.9
	MET + EMPA 25 mg	35.7	2.9	0	0	5.7	0
	MET + placebo	36.6	2.8	0	0	2.8	0
	MET + SITA 100 mg	35.2	1.4	0	2.8	4.2	2.8
Ferrannini et al^Citation26	MET + EMPA 10 mg	13.9	8.4	2.4	1.8	9	3
	MET + EMPA 25 mg	14.5	10.8	5.4	2.4	12.7	3.6
	MET + SITA 100 mg	8.9	25	3.6	3.6	12.5	0
	MET	7.1	12.5	1.8	3.6	3.6	1.8
Ridderstråle et al^Citation20	MET + EMPA 25 mg	25	25	5	4	14	12
	MET + GLIM (1–4 mg)	32	20	4	25	13	2
Merker et al^Citation27	MET + EMPA 10 mg	30.4	15.7	3.2	4.1	14.3	8.3
	MET + EMPA 25 mg	20.1	15.8	5.6	4.2	10.3	9.3
	MET + placebo	22.3	20	4.9	3.4	13.6	0.5
DeFronzo et al^Citation28	MET + EMPA 10 mg	18.6	10	6.4	1.4	11.4	7.9
	MET + EMPA 25 mg	18.4	9.9	2.8	3.5	13.5	8.5
	MET + LINA 5 mg	11.4	12.2	3	2.3	15.2	2.3

Notes: Reproduced with permission from Rosenstock J, Seman LJ, Jelaska A, et al. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab. 2013;15(12):1154–1160. © 2013 John Wiley & Sons Ltd.¹⁹ Reproduced with permission from Ridderstråle M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC. EMPA-REG H2H-SU Trial Investigators. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(9):691–700. © 2013 John Wiley & Sons Ltd.²⁰ Copyright ©2013 American Diabetes Association From: Diabetes Care. 2013;36(12):4015–4021. Reprinted with permission from “The American Diabetes Association”.²⁶

Abbreviations: EMPA, empagliflozin; MET, metformin; SITA, sitagliptin; GLIM, glimepiride; LINA, linagliptin.

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