Potential for dipeptidyl peptidase-4 inhibitor and sodium glucose cotransporter 2 inhibitor single-pill combinations

Figures & data

Figure 1. (A) Schematic representations of antihyperglycemic effects of GLP-1. (B) Schematic representation of antihyperglycemic effects of SGLT2 inhibition in the kidney.

Table 1. Pharmacokinetic characteristics of DPP-4 inhibitors and SGLT2 inhibitors administered together.

	AUCT,SS GMR^† (90% CI)	Cmax,SS GMR (90% CI)	tmax,SS median (range), h	t1/2,SS mean (SD) h
2008-006088-35 [31]^‡
Empagliflozin 50 mg (with sitagliptin 100 mg)	110.4 (103.9–117.3)	107.6 (97.0–119.4)	2.2 (0.7–4.0)	10.7 (26.8)
Sitagliptin 100 mg (with empagliflozin 50 mg)	103.1 (98.9–107.3)	108.5 (100.7–116.9)	3.0 (0.7–4.0)	13.2 (19.1)
2008-006089-27 [32]^‡
Empagliflozin 50 mg (with linagliptin 5 mg)	1.02 (0.97–1.07)	0.88 (0.79–0.99)	1.5 (1.0–4.0)	8.4 (10.7)
Linagliptin 5 mg (with empagliflozin 50 mg)	1.03 (0.12–0.96)	1.01 (0.25–087)	1.5 (0.5–4.0)	NR
Kasichayanula S [34]
Dapagliflozin 20 mg (with sitagliptin 100 mg)	1.00 (0.97–1.02)^§	0.96 (0.88–1.05)^¶	1.7 (1.0–6.0)	15.9 (7.1)
Sitagliptin 100 mg (with dapagliflozin 20 mg)	1.01 (0.98–1.04)^§	0.89 (0.81–0.97)^¶	4.0 (1.5–8.0)	14.4 (2.0)
NCT01662999 [35]
Dapagliflozin 10 mg (with saxagliptin 5 mg)	0.99 (0.97–1.04)^§	0.94 (0.87–1.03) ^¶	1.0 (0.5–2.0)	13.8 (4.8)
Saxagliptin 5 mg (with dapagliflozin 10 mg)	0.99 (0.96–1.02)^§	0.93 (0.88–0.97) ^¶	1.0 (0.5–2.0)	5.4 (2.2)

^†GMR of drug alone versus in combination.

^‡European Union Drug Regulating Authorities Clinical Trials number.

^§GMRs of AUC values from time 0 to time of last quantifiable concentration after single dose.

^¶GMRs of C_max values after single dose.

AUC_ss: Area under the curve at steady state; C_max: Maximum concentration; DPP-4: Dipeptidyl peptidase-4; GMR: Geometric mean ratio; SGLT-2: Sodium glucose cotransporter 2; t_1/2: Half-life; t_max: Time to reach C_max.

Table 2. Efficacy of DPP-4 inhibitors and SGLT2 inhibitors given as SPC or LPC.

	N^†	HbA1c, %			FPG, mg/dl			Body weight, kg
		BL	Change vs BL	Change vs comparator^‡	BL	Change vs BL	Change vs comparator^‡	BL	Change vs BL	Change vs comparator^‡
Post hoc analysis of NCT01032629 [42]; 18 weeks
Cana 100 mg + a DPP-4i ± other AHA	103	8.1 (0.8)	−0.46	vs placebo −0.56 (−0.77, −0.35)	–	–	–	91.5 (18.3)	−3.2^§	vs placebo −2.3 (−3.1, −1.5)^§
Cana 300 mg + a DPP-4i ± other AHA	111	8.0 (0.8)	−0.64	vs placebo −0.75 (−0.95, −0.54)	–	–	–	92.4 (18.0)	−3.9^§	vs placebo −3.0 (−3.8, –2.2)^§
NCT00984867 [43]; 24 weeks
Dapa 10 mg + sita 100 mg ± metformin	223	7.9 (0.8)	−0.5 (−0.6, −0.4)^‡	vs placebo −0.5 (−0.6, −0.3)	162.2 (36.8)	−24.1 (−28.7, −19.5)^‡	vs placebo −27.9 (−34.5, −21.4)	91.0 (21.6)	−2.1 (−2.5, −1.8)^‡	vs placebo −1.9 (−2.4, −1.4)
NCT01606007 [44]; 24 weeks
Dapa 10 mg + saxa 5 mg + metformin	–	8.9 (1.2)	−1.47	vs saxa, −0.59 (−0.81, −0.37) vs dapa, −0.27 (−0.48, −0.05)	–	–	–	–	–	–
NCT01422876 [45]; 24 weeks
Empa 25 mg + lina 5 mg (drug-naïve patients)	134	7.99 (0.08)	−1.08 (0.07)	vs empa, −0.14 (−0.33, 0.06) vs lina, −0.41 (−0.61, −0.22)***	156.1 (3.1)	−29.6 (2.7)	vs empa, −5.3 (−12.7, 2.1) vs lina, −23.6 (−31.1, −16.2)***	87.9 (1.6)	−2.0 (0.4)	vs empa, 0.1 (−0.9, 1.1) vs lina, −1.2 (−2.2, −0.2)*
Empa 10 mg + lina 5 mg (drug-naïve patients)	135	8.04 (0.08)	−1.24 (0.07)	vs empa, −0.41 (−0.61, −0.21)*** vs lina, −0.57 (−0.76, −0.37)***	157.2 (3.1)	−28.2 (2.7)	vs empa, −5.8 (−13.3, 1.6) vs lina, −22.3 (−29.7, −14.9)***	87.3 (1.6)	−2.7 (0.4)	vs empa, −0.5 (−1.5, 0.5) vs lina, −2.0 (−3.0, −1.0)***
NCT01422876 [46]; 24 weeks
Empa 25 mg + lina 5 mg + metformin	134	7.90 (0.07)	−1.19 (0.06)	vs empa, −0.58 (−0.75, −0.41)*** vs lina, −0.50 (−0.67, −0.32)***	154.6 (2.9)	−35.3 (2.5)	vs empa, −16.4 (−23.4, −9.5)*** vs lina, −22.2 (−29.5, −15.1)***	85.5 (1.8)	−3.0 (0.3)	vs empa, 0.2 (−0.7, 1.0) vs lina, −2.3 (−3.2, −1.4)***
Empa 10 mg + lina 5 mg + metformin	135	7.95 (0.07)	−1.08 (0.06)	vs empa, −0.42 (−0.59, −0.25)*** vs lina, −0.39 (−0.56, −0.21)***	156.7 (3.0)	−32.2 (2.5)	vs empa, −11.3 (−18.3, −4.4)** vs lina, −19.1 (−26.2, −12.0)***	86.6 (1.6)	−2.6 (0.3)	vs empa, −0.1 (−0.9, 0.8) vs lina, −1.9 (−2.8, −1.1)***

BL values are mean (SD), except for NCT01422876 BL values are mean (SE). Changes are adjusted mean, for NCT01422876 changes are adjusted mean (SE).

*p < 0.05; **p < 0.05; ***p < 0.001.

^†Number of patients randomized.

^‡95% CI.

^§% change.

AHA: Antihyperglycemic agents; BL: Baseline; cana: Canagliflozin; dapa: Dapagliflozin; DPP-4i: Dipeptidyl peptidase-4 inhibitor; empa: Empagliflozin; FPG: Fasting plasma glucose; HbA1c: Glycated hemoglobin; lina: Linagliptin; saxa: Saxagliptin; sita: Sitagliptin; SGLT2: Sodium glucose cotransporter 2.

Table 3. Ongoing clinical trials of DPP-4/SGLT2-inhibitor combination.

Clinical trial registry number	Study population	Intervention	Duration, weeks	Estimated completion date	Ref.
NCT01734785	Insufficiently controlled T2DM after 16-week treatment with lina 5 mg on metformin background	SPCs of empa 10 mg/lina 5 mg and empa 25 mg/lina 5 mg vs lina 5 mg with metformin background	24	May 2015	[72]
NCT01778049	Insufficiently controlled T2DM after 16-week treatment with empa 10 mg or 25 mg on metformin background	SPCs of empa 10 mg/lina 5 mg and empa 25 mg/lina 5 mg vs empa 10 and 25 mg with metformin background	16	March 2015	[73]
NCT01646320	Insufficiently controlled T2DM with saxa 5 mg and metformin	Dapa 10 mg as add-on to saxa 5 mg and metformin	24	February 2015	[74]
NCT01619059	Insufficiently controlled T2DM with dapa 10 mg and metformin	Saxa 5 mg as add-on to dapa 10 mg and metformin	24	January 2015	[75]
NCT02025907	Insufficiently controlled T2DM with maximal or near-maximal doses of sita and metformin	Cana 100 and 300 mg as add-on to sita 100 mg and metformin	26	April 2015	[76]

cana: Canagliflozin; dapa: Dapagliflozin; DPP-4: Dipeptidyl peptidase-4; empa: Empagliflozin; lina: Linagliptin; saxa: Saxagliptin; sita: Sitagliptin; SGLT2: Sodium glucose cotransporter 2; SPC: Single-pill combination; T2DM: Type 2 diabetes mellitus.

Table 4. Safety and tolerability of DPP-4 inhibitors and SGLT2 inhibitors given as SPC or LPC.

	N	Overall AEs, %	Hypoglycemia, n (%)
Post hoc analysis of NCT01032629 [42]; 18 weeks
Cana 100 mg + a DPP-4 inhibitor ± other AHA	103	64.1	17/70 (24.3)^†
Cana 300 mg + a DPP-4 inhibitor ± other AHA	111	63.1	29/87 (33.3)^†
Placebo ± other AHA	102	58.8	12/74 (16.2)^†
NCT00984867 [43]; 48 weeks
Dapa 10 mg + sita 100 mg ± metformin	225	66.2	12 (5.3)
Placebo + sita 100 mg ± metformin	226	61.1	14 (6.2)
NCT01606007 [44]; 24 weeks
Dapa 10 mg + saxa 5 mg + metformin	–	48.6	–(1.1)
Saxa 5 mg + placebo + metformin	–	52.8	–(0.6)
Dapa 10 mg + placebo + metformin	–	48.6	–(1.1)
NCT01422876 [45]; 24 weeks
Empa 25 mg + lina 5 mg	134	58.8	–
Empa 10 mg + lina 5 mg	135	63.2	–
Empa 25 mg	133	57.8	2 (1.5)
Empa 10 mg	132	62.2	1 (0.8)
Lina 5 mg	133	64.4	1 (0.8)
NCT01422876 [46]; 24 weeks
Empa 25 mg + lina 5 mg + metformin	134	54.7	2 (1.5)
Empa 10 mg + lina 5 mg + metformin	135	54.4	2 (1.5)
Empa 25 mg + metformin	140	63.1	4 (2.9)
Empa 10 mg + metformin	137	57.1	2 (1.5)
Lina 5 mg + metformin	128	54.5	2 (1.6)

^†Incidence data shown are for patients receiving study drug combination in addition to insulin, sulfonylurea or meglitinide.

AEs: Adverse events; AHA: Antihyperglycemic agents; cana: Canagliflozin; dapa: Dapagliflozin; DPP-4: Dipeptidyl peptidase-4; empa: Empagliflozin; lina: Linagliptin; N: Number of patients randomized; saxa: Saxagliptin; SGLT2: Sodium glucose cotransporter 2.

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