Sodium-glucose cotransporter 2 inhibitors combined with dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes: a review of current clinical evidence and rationale

Figures & data

Table 1 Summary of pharmacokinetic characteristics of DPP-4 inhibitors (US-approved)^12,14,15

Parameters	Sitagliptin^Citation16	Saxagliptin^Citation17	Linagliptin^Citation18	Alogliptin^Citation19
Recommended (once-daily) dosea (mg)	100	2.5 and 5	5	25
Selectivity
vs DPP-8/9 (fold)	>2,600	<100	>10,000	>14,000
vs DPP-2 (fold)	>5,550	>50,000	>100,000	>14,000
Clinical PK
Bioavailability (%)	87	67b	~30	~100
Protein-bound (%)	38	Negligible	~99% at <1 nmol/L to 75%–89% at ≥30 nmol/L	20
CYP enzymes	Minor	CYP3A4/5	Minimal	Minimal
t1/2, h (after oral dosing)	~12	Saxagliptin: 2.5, BMS 5510849 (active metabolite): 3.1	>100	21
Renal excretion (%)	87	75	5	76
Dose reduction with renal impairment	Yes, dose adjustment for moderate RI (50 mg once daily), and severe RI or ESRD (25 mg once daily)	Yes, dose adjustment for moderate or severe RI, or ESRD (2.5 mg once daily)	No (not required)	Yes, dose adjustment for moderate RI (12.5 mg once daily), or severe RI, or ESRD (6.25 mg once daily)

Notes:

a See also Table 3 data on renal impairment.

b Predicted bioavailability.

Abbreviations: CYP, cytochrome P450; DPP, dipeptidyl peptidase; ESRD, end-stage renal disease; PK, pharmacokinetic; RI, renal impairment; t_1/2, elimination half-life.

Table 2 Summary of efficacy and safety data from Phase III clinical trials (≥24 weeks) using DPP-4 inhibitors (US-approved) as monotherapy

References	Regimen	N	Treatment and dose (mg/day)	Efficacy parameters (change from baseline)a			Safety parameters (number/percentage of patients with a special interest adverse event)a
				HbA1c (%)	FPG (mg/dL)b	Body weight (kg)	Hypoglycemia, n (%)	Any GI event, n (%)	Nasopharyngitis, n (%)
Aschner et al^Citation20	24 weeks				(FPG converted)			(Overall GI events)
		253	PBO	0.18	5.4	−1.1	2 (0.8)	29 (11.5)	12 (4.7)
		238	SITA 100	−0.61	−12.6	−0.2	3 (1.3)	39 (16.4)	17 (7.1)
Rosenstock et al^Citation21	24 weeks						c	(Diarrhea)
		95	PBO	0.19	6	−1.4	0	3 (3.2)	6 (6.3)
		102	SAXA 2.5	−0.43	−15	−1.2	0	7 (6.9)	6 (5.9)
		106	SAXA 5	−0.46	−9	−0.1	0	1 (0.9)	6 (5.7)
Del Prato et al^Citation22	24 weeks				(FPG converted)
		167	PBO	0.25	14.4	Reported as “no significant change”	1 (0.6)	Not reported	7 (4.2)
		336	LINA 5	−0.44	−9.0	Reported as “no significant change”	1 (0.3)	Not reported	13 (3.9)
DeFronzo et al^Citation23	26 weeks							Reported as “GI events 12.1%–14.3%” (not further specified)	Not reported
		65	PBO	−0.02	11.3	0.18	d
		133	ALO 25	−0.59	−16.4	−0.22	d

Notes:

a Data are presented as reported in each publication (for randomized double-blind arms unless otherwise stated); only data for US-approved doses reported; change in mean, least square mean, or adjusted mean data presented; efficacy parameters did not include blood pressure in these studies.

b Units converted from mmol/L to mg/dL where stated (mmol/L value × 18.0182 = mg/dL value).

c Confirmed hypoglycemia.

d Reported as “rare (1.5%–3.0%); no hypoglycemic event was considered an AE, or was severe enough to require assistance.”

Abbreviations: AE, adverse event; ALO, alogliptin; FPG, fasting plasma glucose; GI, gastrointestinal; HbA_1c, glycated hemoglobin; LINA, linagliptin; PBO, placebo; SAXA, saxagliptin; SITA, sitagliptin.

Table 3 Summary of pharmacokinetic characteristics of SGLT2 inhibitors (US-approved)

Parameters	Canagliflozin^Citation38,Citation41	Dapagliflozin^Citation39,Citation42	Empagliflozin^Citation40,Citation43
Recommended (once-daily) dose (mg)	100 or 300	5 or 10	10 or 25
Selectivity SGLT2/SGLT1 (fold)^Citation44	>250	>1,200	>2,500
Clinical PK
Absorption	Rapid (tmax 1–2 h)	Rapid (tmax 1–2 h)	Rapid (tmax 1–2 h)
t1/2 (h)	10.6–13.1	~12.9 (10 mg)	12.4
Distribution	~99% protein-bound; Vd 119 L	~91% protein-bound; Vd 118 L	~86% protein-bound; Vd 74 L
Metabolism	Hepatic glucuronidation	Hepatic glucuronidation	Hepatic glucuronidation
Elimination	Urine and feces	Mainly in urine	Urine and feces
Use in renal impairment (dosage and administration and contraindications)	Assess renal function before initiating and periodically thereafter Do not initiate if eGFR <45 mL/min/1.73 m^2 Discontinue if eGFR falls persistently <45 mL/min/1.73 m^2 Contraindicated in severe renal impairment, ESRD, or dialysis Dose adjustment and more frequent renal function monitoring are recommended in patients with eGFR <60 mL/min/1.73 m^2	Assess renal function before initiating and periodically thereafter Do not initiate if eGFR <60 mL/min/1.73 m^2 Discontinue if eGFR falls persistently <60 mL/min/1.73 m^2 Contraindicated in severe renal impairment, ESRD, or dialysis	Assess renal function before initiating and periodically thereafter Do not initiate if eGFR <45 mL/min/1.73 m^2 Discontinue if eGFR falls persistently <45 mL/min/1.73 m^2 Contraindicated in severe renal impairment, ESRD, or dialysis
	Limit dose to 100 mg once daily in patients with eGFR 45–<60 mL/min/1.73 m^2 Dose may be increased from 100 mg once daily to 300 mg once daily in patients with eGFR ≥60 mL/min/1.73 m^2	No dose adjustment is needed in patients with mild renal impairment (eGFR ≥60 mL/min/1.73 m^2)	No dose adjustment is needed if eGFR ≥45 mL/min/1.73 m^2

Abbreviations: eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; PK, pharmacokinetic; SGLT1, sodium-glucose cotransporter 1; SGLT2, sodium-glucose cotransporter 2; t_1/2, elimination half-life; t_max, time to maximum plasma concentration; Vd, volume of distribution.

Table 4 Summary of efficacy and safety data from Phase III clinical trials (≥24 weeks) using SGLT2 inhibitors (US-approved) as monotherapy

References	Regimena	N	Treatment and dose, mg/day	Efficacy parameters (change from baseline) b				Safety parameters (number/percentage of patients with a special interest adverse event) c
				HbA1c (%)	FPG (mg/dL)d	Body weight (kg)	SBP (mmHg)	Hypoglycemia, n (%)	Urinary tract infection, n (%)	Genital infection, n (%)	Volume depletion events, n (%)
Ferrannini et al^Citation48	24 weeks; DAPA										(Hypotension)
		75	PBO	−0.23	−4.1	−2.2	−0.9	2 (2.7)	3 (4.0)	1 (1.3)	1 (1.3)
	Morning dose	64	DAPA 5	−0.77	−24.1	−2.8	−2.3	0	8 (12.5)	5 (7.8)	0
		70	DAPA 10	−0.89	−28.8	−3.2	−3.6	2 (2.9)	4 (5.7)	9 (12.9)	1 (1.4)
	Evening dose	68	DAPA 5	−0.79	−27.3	−3.6	−5.2	0	8 (11.8)	3 (4.4)	0
		76	DAPA 10	−0.79	−29.6	−3.1	−2.3	1 (1.3)	5 (6.6)	2 (2.6)	0
	High HbA1c (≥10.1%)	35	DAPA 5	−2.88	−77.1	−2.1	−5.7	1 (2.9)	3 (8.8)	2 (5.9)	1 (2.9)
		39	DAPA 10	−2.66	−84.3	−1.9	−2.5	0	6 (15.4)	7 (17.9)	1 (2.6)
Stenlöf et al^Citation49	26 weeks; CANA				(FPG converted)						(Postural dizziness + orthostatic hypotension)
		192	PBO	0.14	9.00	−0.5	0.4	5 (2.6)	8 (4.2)	4 (2.1)	0
		195	CANA 100	−0.77	−27.0	−2.5	−3.3	7 (3.6)	14 (7.2)	12 (6.2)	1 (0.5)
		197	CANA 300	−1.03	−34.2	−3.4	−5.0	6 (3.0)	10 (5.1)	13 (6.6)	4 (2.0)
	High1c HbA (>10.0 and ≤12.0%)	47	CANA 100	−2.1	−81.1	−3.0	−4.5	0	3 (6.4)	6 (12.8)	(Pollakiuria) 0
		44	CANA 300	−2.6	−86.5	−3.8	−5.0	0	2 (4.5)	2 (4.5)	1 (2.3)
Roden et al^Citation50	24 weeks; EMPA
		228	PBO	0.08	11.7	−0.33	−0.3	1 (<1)	12 (5)	0	Not reported
		224	EMPA 10	−0.66	−19.5	−2.26	−2.9	1 (<1)	15 (7)	7 (3)	Not reported
		224	EMPA 25	−0.78	−24.5	−2.48	−3.7	1 (<1)	12 (5)	9 (4)	Not reported
		223	SITA 100	−0.66	−6.85	0.18	0.5	1 (<1)	11 (5)	2 (1)	Not reported
	High HbA1c (>10.0%)	87	EMPA 25	−3.70	−87.6	−2.43	−4.0	0	3 (3)	1 (1)	Not reported

Notes:

a Patients with T2DM treated by diet and exercise,^48,49 and/or who had not received oral or injected glucose-lowering medication in the 10 weeks⁴⁹ or 12 weeks⁵⁰ prior to randomization.

b Data are presented as reported in each publication (for randomized double-blind arms unless otherwise stated); data for US-approved doses reported; change in mean, least square mean, or adjusted mean data presented.

c Canagliflozin study stated as “genital mycotic infection.”

d Units converted from mmol/L to mg/dL where stated (mmol/L value × 18.0182 = mg/dL value).

Abbreviations: CANA, canagliflozin; DAPA, dapagliflozin; EMPA, empagliflozin; FPG, fasting plasma glucose; HbA_1c, glycated hemoglobin; PBO, placebo; SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter 2; SITA, sitagliptin; T2DM, type 2 diabetes mellitus.

Table 5 Summary of efficacy and safety data from published Phase III clinical trials (≥24 weeks) using DPP-4 inhibitors in combination with SGLT2 inhibitors

Study, duration (primary outcome)	Combinationa	Background therapy	N	Treatment and dose (mg/day)	Efficacy parameters (change from baseline) b				Safety parameters (percentage of patients with a special interest adverse event)
					HbA1c (%)	FPG (mg/dL)c	Body weight (kg)	SBP (mmHg)	Hypoglycemia, n (%)	Urinary tract infection, n (%)	Genital infection, n (%)	Volume depletion events, n (%)
Jabbour et al^Citation68 24-week double- blind treatment period (+ 24-week extension)	DAPA 10 mg/day add-on to SITA 100 mg/day ± MET	(With/without) MET ≥ 1,500 mg/day		Loose-pill combinationd				(Week 8 vs week 24)				(Hypotension or dehydration or hypovolemia at 48 weeks)
			224	PBO + SITA 100	0	3.8	−0.3	−5.1	4/226 (1.8)	9/226 (4.0)	1/226 (0.4)	2/226 (0.9)
			223	DAPA 10 + SITA 100	−0.5	−24.1	−2.1	−6.0	6/225 (2.7)	11/225 (4.9)	19/225 (8.4)	3/225 (1.3)
Rosenstock et al^Citation69 24-week double- blind treatment period	DAPA 10 mg/day + SAXA 5 mg/day as dual add-on to MET	MET XR ≥1,500 mg/day		Loose-pill combinationd
			179	SAXA 5 + DAPA 10 + MET	−1.47	−38	−2.1	−1.9	2 (1)	1 (0.6)	0	Not reported
			176	SAXA 5 + MET	−0.88	−14	0	0.3	2 (1)	9 (5)	1 (0.6)	Not reported
			179	DAPA 10 + MET	−1.20	−32	−2.4	−3.5	2 (1)	7 (5)	10 (6)	Not reported
Mathieu et al^Citation70 24-week double- blind treatment period (+ 28-week extension)	DAPA 10 mg/day add-on to SAXA 5 mg/day + MET	MET IR ≥1,500 mg/day		Loose-pill combinationd
			160	PBO + SAXA 5 + MET	−0.10	−5	−0.4	2.0	0	10 (6.3)	1 (0.6)	Not reported
			160	DAPA 10 + SAXA 5 + MET	−0.82	−33	−1.9	−1.9	2 (1.3)	8 (5.0)	8 (5.0)	Not reported
Matthaei et al^Citation71 24-week double- blind treatment period (+ 28-week extension)	SAXA 5 mg/day add-on to DAPA 10 mg/day + MET	MET IR ≥1,500 mg/day		Loose-pill combinationd
			162	PBO + DAPA 10 + MET	−0.16	−5	−0.51	Reported as <1 mmHg change in both treatment arms	4 (2.5)	6 (3.7)	4 (2.5)	2 (1.2)
			153	SAXA 5 + DAPA 10 + MET	−0.51	−9	−0.53	(As above)	2 (1.3)	8 (5.2)	0	0
Lewin et al^Citation72 24 weeks; study duration 52 weeks	EMPA 10 or 25 mg/day + LINA 5 mg/day	Treatment- naïve		Single-pill combinationd	(Week 24)	(Week 24)	(Week 24)	(Week 52)
			134	EMPA 25/LINA 5	−1.08	−29.55	−2.0	−2.5	0	17 (12.5)	8 (5.9)	1 (0.7)
			135	EMPA 10/LINA 5	−1.24	−28.21	−2.7	−2.1	0	21 (15.4)	4 (2.9)	3 (2.2)
			133	EMPA 25	−0.95	−24.24	−2.1	−2.1	1 (0.7)	14 (10.4)	6 (4.4)	0
			132	EMPA 10	−0.83	−22.39	−2.3	−2.2	4 (3.0)	22 (16.3)	7 (5.2)	0
			133	LINA 5	−0.67	−5.92	−0.8	−0.4	1 (0.7)	14 (10.4)	4 (3.0)	0
DeFronzo et al^Citation73 24 weeks; study duration 52 weeks	EMPA 10 or 25 mg/day + LINA 5 mg/day as add-on to MET	MET IR ≥1,500 mg/day, MTD, or maximum dose per local label		Single-pill combinationd	(Week 24)	(Week 24)	(Week 24)	(Week 52)
			134	EMPA 25/LINA 5 + MET	−1.19	−35.3	−3.0	−3.6	5 (3.6)	14 (10.2)	3 (2.2)	1 (0.7)
			135	EMPA 10/LINA 5 + MET	−1.08	−32.2	−2.6	−2.8	3 (2.2)	13 (9.6)	8 (5.9)	2 (1.5)
			140	EMPA 25 + MET	−0.62	−18.8	−3.2	−2.8	5 (3.5)	19 (13.5)	12 (8.5)	2 (1.4)
			137	EMPA 10 + MET	−0.66	−20.8	−2.5	−3.5	2 (1.4)	16 (11.4)	11 (7.9)	1 (0.7)
			128	LINA 5 + MET	−0.70	−13.1	−0.7	0.3	3 (2.3)	20 (15.2)	3 (2.3)	4 (3.0)
Søfteland et al^Citation74 24 weeks	EMPA (10 or 25 mg/day) add-on to LINA 5 mg/day + MET	MET IR ≥1,500 mg/day, MTD, or maximum dose per local label		Single-pill combinationd		(FPG converted)
			108	PBO + LINA + MET	0.14	5.4	−0.3	−1.7	1 (0.9)	8 (7.3)	2 (1.8)	Not reported
			109	EMPA 10/LINA 5 + MET	−0.65	−27.0	−3.1	−3.0	0	8 (7.1)	2 (1.8)	Not reported
			110	EMPA 25/LINA 5 + MET	−0.56	−32.4	−2.5	−4.3	3 (2.7)	4 (3.6)	5 (4.5)	Not reported
Tinahones et al^Citation75 24 weeks	LINA 5 mg/day add-on to EMPA 10 or 25 mg/day + MET	MET IR ≥1,500 mg/day, MTD, or maximum dose per local label		Single-pill combinationd		(FPG converted)
			125	PBO + EMPA 10 + MET	−0.21	3.6	−0.8	1.0	0	10 (7.8)	4 (3.1)	Not reported
			122	LINA 5/EMPA 10 + MET	−0.53	−7.2	−0.2	0	0	12 (9.5)	3 (2.4)	Not reported
			110	PBO + EMPA 25 + MET	−0.10	−3.6	−0.3	−1.6	3 (2.7)	9 (8.0)	9 (8.0)	Not reported
			110	LINA 5/EMPA 25 + MET	−0.58	−12.6	−0.2	−0.2	0	15 (13.4)	3 (2.7)	Not reported

Notes:

a Prespecified analyses of Phase III clinical trials data for DPP-4 inhibitor plus canagliflozin combination therapy were not available.

b Data are presented as reported in each publication for the randomized double-blind arm(s), unless otherwise stated; change in mean, least square mean, or adjusted mean data presented.

c Units converted from mmol/L to mg/dL where stated (mmol/L value × 18.0182 = mg/dL value).

d Loose pill refers to separate dosage forms of each active agent (ie, separate pills for DPP-4 inhibitor and SGLT2 inhibitor), whereas single pill refers to a fixed-dose formulation containing both the active agents in a single dosage form (ie, single pill containing DPP-4 inhibitor and SGLT2 inhibitor).

Abbreviations: DAPA, dapagliflozin; DPP-4, dipeptidyl pepti dase-4; EMPA, empagliflozin; FPG, fasting plasma glucose; HbA_1c, glycated hemoglobin; IR, immediate release (formulation); LINA, linagliptin; MET, metformin; MTD, maximum tolerated dose; PBO, placebo; SAXA, saxagliptin; SBP, systolic blood pressure; SITA, sitagliptin; SGLT2, sodium-glucose cotransporter 2; XR, extended release (formulation).

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