Empagliflozin in the treatment of type 2 diabetes: evidence to date

Figures & data

Figure 1 Physiology of glucose reabsorption in the proximal convoluted tubule.

Note: Reproduced from Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diab Vasc Dis Res. 2015;12(2):78–89,⁶ copyright ©2015 by (SAGE Publications). Reprinted by Permission of SAGE Publications, Ltd.
Abbreviations: GLUT, glucose transporter; PT, proximal tubule; KCNE1, potassium voltage-gated channel Isk-related family member 1; KCNQ1, potassium voltage-gated channel KQT-like subfamily member 1; SGLT, sodium-dependent glucose transporter.

Figure 2 Downstream renal effects of SGLT1 and SGLT2 inhibition.

Note: Reproduced from Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diab Vasc Dis Res 2015;12(2):78–89,⁶ copyright ©2015 by (SAGE Publications). Reprinted by Permission of SAGE Publications, Ltd.
Abbreviations: GLUT, glucose transporter; SGLT, sodium glucose transporter; PT, proximal tubule; LOH, loop of Henle; DT, distal tubule; CD, collecting duct; NHE3, sodium hydrogen exchanger-3; EGP, endogenous glucose production; SNGFR, single nephron glomerular filtration rate; TGF, tubuloglomerular feedback.

Figure 3 Chemical structure of empagliflozin (Jardiance^®).

Table 1 Summary of key pharmacokinetic parameters of empagliflozin 10 and 25 mg at steady state after oral dosing

Pharmacokinetic parameters	Empagliflozin dose
	10 mg qd (n=8)	25 mg qd (n=9)
AUC0–t, ss (nmol h/L)	2,030 (362)	4,990 (1,080)
Cmax, ss (nmol h/L)	283 (90.1)	630 (106)
tmax, ss (h)a	1.5 (1.0–2.0)	2.0 (0.7–4.2)
t1/2, ss (h)	14.3 (2.4)	10.7 (2.1)
Fe0–24, ss (%)	18.7 (4.5)	12.7 (6.4)
CLR, t, ss (mL/min)	34.4 (7.9)	23.5 (8.7)

Notes: Data are mean (SD) unless otherwise indicated

a Median (range) is denoted. Reproduced from McGill J. The SGLT2 inhibitor empagliflozin for the treatment of type 2 diabetes mellitus: a bench to bedside review. Diabetes Ther. 2014;5:43–63.⁵⁷

Abbreviations: AUC, area under concentration–time curve; C_max, maximum plasma concentration; CLR, renal clearance; Fe, fraction of dose that was excreted unchanged in urine; qd, once daily; SD, standard deviation; ss, steady state; t, dosing interval; t_1/2, terminal half-life in plasma; t_max, time to maximum plasma concentration.

Table 2 Empagliflozin pharmacokinetics after administration of a single 50 mg dose in patients with renal or hepatic impairment

Impairment severity	Total plasma exposure AUC0–∞ (nmol h/L)	Cmax, ss (nmol/L)
Renal impairment study^Citation57
Mild (n=9)	118.2% (96.2, 145.4)	118.8% (93.6, 150.8)
Moderate (n=7)	119.9% (96.3, 149.5)	102.3% (79.3, 131.9)
Severe (n=8)	166.3% (134.4, 205.7)	120.7% (94.4, 154.3)
Failure/ESRD (n=8)	148.3% (119.9, 183.4)	103.8% (81.2, 132.6)
Hepatic impairment study^Citation30
Mild (n=8)	123.15% (98.9, 153.4)	103.8% (82.3, 131.0)
Moderate (n=8)	146.97% (118.0, 183.0)	123.3% (97.7, 155.6)
Severe (n=8)	174.70% (140.3, 217.6)	148.4% (117.7, 187.2)

Notes: For both studies, values are adjusted GMR (impaired/normal group), with 90% CI for adjusted GMR. Reproduced from McGill J. The SGLT2 inhibitor empagliflozin for the treatment of type 2 diabetes mellitus: a bench to bedside review. Diabetes Ther. 2014;5:43–63.⁵⁷

Abbreviations: AUC, area under the concentration–time curve; CI, confidence interval; C_max, ss, maximum plasma concentration at steady state; ESRD, end-stage renal disease; GMR, geometric mean ratio.

Table 3 Efficacy and safety of EMPA in randomized, double-blind Phase III trials of patients with type 2 diabetes mellitus

Study	Regimen and duration	Efficacy			Safety
		A1c (%)	Body weight (kg)	SBP (mmHg)	UTIs (%)	Events consistent with GMIs (%)	Events consistent with UTIs (%)
Monotherapy
Roden et al^Citation35	EMPA 10 mg (n=224)	−0.66	−2.26	−2.9	6	3 M, 4 F	2 M, 15 F
	EMPA 25 mg (n=87)	−0.78	−2.48	−3.7	4	1 M, 9 F	1 M, 13 F
	PBO (n=228)	0.08	−0.33	−0.3	4	0 M, 0 F	2 M, 9 F
	24 weeks
Combination therapy
Häring et al^Citation37	MET + SU + one of:
	EMPA 10 mg (n=225)	−0.82	−2.16	−4.1	9.4	0.9 M, 4.5 F	2.7 M, 18.0 F
	EMPA 25 mg (n=216)	−0.77	−2.39	−3.5	6.9	0.9 M, 3.9 F	0 M, 17.5 F
	PBO (n=225)	−0.17	−0.39	−1.4	6.7	0.9 M, 0.9 F	2.7 M, 13.3 F
	24 weeks
Häring et al^Citation38	MET + one of:
	EMPA 10 mg (n=217)	−0.70	−2.08	−4.5	5.1	0.8 M, 7.6 F	0 M, 12.0 F
	EMPA 25 mg (n=213)	−0.77	−2.46	−5.2	5.6	0.8 M, 9.7 F	0.8 M, 11.8 F
	PBO (n=207)	−0.13	−0.45	−0.4	4.9	0 M, 0 F	2.6 M, 7.7 F
	24 weeks
Ridderstråle et al^Citation39	MET + one of:
	EMPA 25 mg (n=765)	−0.66	−3.1	−3.1	14	9 M, 15 F	7 M, 22 F
	GLIM 1–4 mg (n=780)	−0.55	1.3	2.5	13	1 M, 3 F	5 M, 23 F
	104 weeks
Kovacs et al^Citation40	PIO ± MET + one of:				1
	EMPA 10 mg (n=165)	−0.59	−1.62	−3.14	4.5	7.2 M, 9.8 F	3.6 M, 30.5 F
	EMPA 25 mg (n=168)	−0.72	−1.47	−4.00	10.7	1.2 M, 6.0 F	2.4 M, 21.7 F
	PBO (n=165)	−0.11	0.34	0.72	10.9	1.4 M, 3.3 F	8.2 M, 22.8 F
	24 weeks

Note: Adapted with permission from Miller E, Shubrook JH. Role of the kidneys and sodium glucose co-transporter 2 (sglt2) inhibitors in the treatment of type 2 diabetes mellitus. Osteopathic Family Physician. 2015;1(5):10–30.⁵⁸ Copyright © 2015.

Abbreviations: EMPA, empagliflozin; F, female; GLIM, glimepiride; GMI, genital mycotic infections; M, male; MET, metformin; PBO, placebo; PIO, pioglitazone; SBP, systolic blood pressure; SU, sulfonylurea; UTI, urinary tract infection.

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