Triple fixed-dose combination empagliflozin, linagliptin, and metformin for patients with type 2 diabetes

Figures & data

Table 1. Approved doses of FDCs of empagliflozin/linagliptin/metformin XR.

	Dose (mg)
FDC	Empagliflozin	Linagliptin	Metformin XR	Recommended administration
1	25	5	1000	One tablet daily
2	12.5	2.5	1000	Two tablets daily
3	10	5	1000	One tablet daily
4	5	2.5	1000	Two tablets daily

FDC = fixed-dose combination.

Figure 1. Plain language summary.

Figure 1. (Continued).

Figure 2. Study 1: Mean plasma concentration‒time profiles of empagliflozin (a), linagliptin (b), and metformin (c) after single oral administration of low-dose FDC (2x [empagliflozin 5 mg/linagliptin 2.5 mg/metformin 1000 mg XR]) or corresponding free tablets. Study 2: Mean plasma concentration‒time profiles of empagliflozin (d), linagliptin (e), and metformin (f) after single oral administration of high-dose FDC (empagliflozin 25 mg/linagliptin 5 mg/metformin 1000 mg XR) or corresponding free tablets.

Table 2. Pharmacokinetic profiles of FDC vs free combination of empagliflozin/linagliptin/metformin XR in healthy subjects under fed conditions.

	Empagliflozin/linagliptin/metformin XR, 2x  (5 mg/2.5 mg/1000 mg) (Study 1)		Empagliflozin/linagliptin/metformin XR, 25 mg/5 mg/1000 mg (Study 2)
	N FDC/Free	Adjusted GMR^a % (90% CI)	N FDC/Free	Adjusted GMR^a % (90% CI)
Empagliflozin
AUC0–tz (nmol*h/L)	27^b/28^c	100.42 (98.17, 102.72)	29^d/29^e	103.06 (100.36, 105.83)
Cmax (nmol/L)	27/28	92.57 (85.21, 100.57)	29/29	99.95 (94.52, 105.70)
Linagliptin
AUC0–72 (nmol*h/L)	27/28	100.16 (96.17, 104.31)	29/29	100.31 (96.65, 104.10)
Cmax (nmol/L)	27/28	97.33 (89.99, 105.26)	29/29	97.17 (92.63, 101.93)
Metformin
AUC0–tz (ng*h/mL)	27/28	95.34 (91.58, 99.24)	29/29	100.35 (96.11, 104.77)
Cmax (ng/mL)	27/28	104.83 (98.56, 111.50)	29/29	107.78 (102.52, 113.31)

^aFDC vs respective free combination, adjusted by treatment geometric mean (least squares mean).

^bOne subject was not treated, one subject was excluded due to vomiting, and one subject was excluded due to diarrhea.

^cOne subject was excluded due to vomiting and one subject was excluded due to diarrhea.

^dOne subject withdrew due to personal reasons.

^eOne subject was withdrawn due to protocol violation.

AUC_0-72 = area under the plasma concentration–time curve from time 0 to 72 hours; AUC_0-tz = area under the plasma concentration–time curve from time 0 to last quantifiable data point; CI = confidence interval; C_max = peak plasma concentration; FDC = fixed-dose combination; GMR = geometric mean ratio.

Table 3. Frequency of subjects with drug-related AEs.

	FDC tablet, N (%)	Free combination, N (%)
	Empagliflozin/linagliptin/metformin XR, 10 mg/5 mg/2000 mg (Study 1)
Preferred term	2x (5 mg/2.5 mg/1000 mg) FDC tablets	10 mg/5 mg/4x 500 mg free tablets	Total
Number treated	29 (100.0)	30 (100.0)	30 (100.0)
Number with AEs	9 (31.0)	8 (26.7)	14 (46.7)
Number with drug-related AEs	7 (24.1)	6 (20.0)	10 (33.3)
Nausea	4 (13.8)	3 (10.0)	5 (16.7)
Headache	4 (13.8)	2 (6.7)	5 (16.7)
Decreased appetite	1 (3.4)	2 (6.7)	3 (10.0)
Vomiting	1 (3.4)	1 (3.3)	2 (6.7)
Diarrhea	1 (3.4)	1 (3.3)	1 (3.3)
	Empagliflozin/linagliptin/metformin XR, 25 mg/5 mg/1000 mg (Study 2)
	25 mg/5 mg/1000 mg FDC tablet	25 mg/5 mg/2x 500 mg free tablets
Number treated	29 (100.0)	29 (100.0)	30 (100.0)
Number with AEs	14 (48.3)	7 (24.1)	17 (56.7)
Number with drug-related AEs	6 (20.7)	4 (13.8)	9 (30.0)
Headache	3 (10.3)	1 (3.4)	4 (13.3)
Nausea	1 (3.4)	2 (6.9)	3 (10.0)
Dyspepsia	0 (0.0)	1 (3.4)	1 (3.3)
Vomiting	1 (3.4)	0 (0.0)	1 (3.3)
Dizziness	0 (0.0)	1 (3.4)	1 (3.3)
Energy increased	1 (3.4)	0 (0.0)	1 (3.3)
Fatigue	1 (3.4)	0 (0.0)	1 (3.3)
Euphoric mood	1 (3.4)	0 (0.0)	1 (3.3)

AE = adverse event; FDC = fixed-dose combination.