Dipeptidyl peptidase-4 inhibitors as add-on therapy to insulin in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials

Figures & data

Figure 1 Summarized flowchart of literature search.

Table 1 Characteristics of the included RCTs

Study	Design	Country	Sample size	Mean age	Male	BMI	Baseline HbA1c	DM duration	Treatment arm	Control arm	Follow-up duration	Insulin titration	Insulin type
				years	%	kg/m2	%	years			weeks
Fonseca 2007 [21]	R, DB, PC	Germany, Finland, Spain and USA	296	59.2	51.4	33.1	8.4	14.7	Vildagliptin (50mg Bid)+I	P+I	24	N	Multiple
Rosenstock 2009–12.5mg [22]	R, DB, PC	13 countries	196	55.3	43.8	32.6	9.3	12.1	Alogliptin (12.5mg Qd)+I	P+I	26	N	Multiple
Rosenstock 2009-25mg [22]	R, DB, PC	13 countries	194	55.7	38.6	32.3	9.3	13.1	Alogliptin (25mg Qd)+I	P+I	26	N	Multiple
Vilsbøll 2010 [23]	R, DB, PC	Multiple countries	641	57.7	51.1	31	8.7	12.5	Sitagliptin (100 mg Qd)+I	P+I	24	N	Multiple
Barnett 2012 [24]	R, DB, PC	Ten countries	455	57.3	41.3	32.2	8.7	12	Saxagliptin (5mg Qd)+I	P+I	24	N	Multiple
Hong 2012 [25]	R, PC	Korea	140	59.2	52.3	25.6	9.2	15.9	Sitagliptin (100mg Qd)+I	I increasing by 25%	24	N	Multiple
Yki-Jarvinen 2013 [28]	R, DB, PC	19 countries	1261	60.1	52.1	31	8.3	NA	Linagliptin (5mg Qd)+I	P+I	52	N	Multiple
Kadowaki 2013 [26]	R, DB, PC	Japan	266	61.2	58.7	25.2	8.9	14.1	Sitagliptin (100mg Qd)+I	P+I	16	N	Multiple
Kothny 2013 [27]	R, DB, PC	Multiple countries	449	59.2	50.1	29	8.8	13.1	Vildagliptin (50mg Bid)+I	P+I	24	N	Multiple
Kaku 2014 [29]	R, DB, PC	Japan	179	62.7	54.2	24.3	8.4	14.9	Alogliptin (25mg Qd)+I	P+I	12	N	Multiple
Takahashi 2015 [35]	R	Japan	44	65.5	61.4	23.9	7.5	NA	Sitagliptin (50mg Qd)+insulin glargine (50% of basal dose)	Insulin glargine (80% of basal dose)	24	Y	Basal insulin
Mathieu 2015 [32]	R, DB, PC	USA	660	58.8	47.3	32.1	8.7	13.5	Sitagliptin (100mg Qd)+insulin glargine	P+insulin glargine titration	24	Y	Basal insulin
Hirose 2015 [30]	R, DB, PC	Japan	156	59.3	71.2	25.7	8.1	12.9	Vildagliptin (50mg Bid)+I	P+I	12	N	Multiple
Otsuka 2015 [33]	R	Japan	21	63.1	61.9	23.2	8.3	17.6	Sitagliptin (50mg Qd)+I	I	12	N	Multiple
Linjawi 2015 [31]	R	Ten countries	389	55.3	52.1	29.4	8.4	NA	Sitagliptin (100mg Qd)+BIAsp30	BIAsp30	24	Y	BIAsp30
Sato 2015 [34]	R	Japan	50	66	69.4	25.7	7.9	19.5	Sitagliptin (100mg Qd)+I	I	24	Y	Multiple
Mita 2016 [36]	R, SB	Japan	282	63.7	60.5	25	8.1	17.3	Sitagliptin (100mg Qd)+I	I	104	Y	Multiple
Ning 2016 [37]	R, DB, PC	China, Thailand, Philippines, and Singapore	293	58.1	43.3	26.1	8.7	11.3	Vildagliptin (50mg Bid)+I	P+I	24	N	Multiple
Kanazawa 2017 [41]	R	Japan	73	69.1	63	24.3	7.9	18	Vildagliptin (50mg Qd or Bid)+I	I	104	N	Multiple
Cao 2017 [38]	R	China	65	51	51.6	25.4	8.2	6	Sitagliptin (100mg Qd)+insulin glargine	BIAsp30	16	Y	Multiple
Shankar 2017 [42]	R, DB, PC	China	467	57.7	53.3	26	8.7	11.2	Sitagliptin (100 mg Qd)+I	P+I	24	Y	Multiple
Kadowaki 2017a [39]	R, DB, PC	Japan	232	63.4	61	25.1	8.3	15.8	Saxagliptin (5mg Qd)+I	P+I	16	N	Multiple
Kadowaki 2017b [40]	R, DB, PC	Japan	148	58.5	75.6	24.9	8.7	12.6	Teneligliptin (20 mg Qd)+I	P+I	16	Y	Multiple

Notes: The study by Rosenstock 2009 had two intervention arms with alogliptin 12.5 mg/d and 25 mg/d, respectively, and two comparisons were considered.

Abbreviations: R, randomized; DB, double-blinded; SB, single-blinded; PC, placebo-controlled; BMI, body mass index; DM, diabetes mellitus; I, insulin; P, placebo; BIAsp30, biphasic insulin aspart 30; N, no; Y, yes.

Table 2 Quality evaluation of the included RCTs via Cochrane’s risk of bias tool

	Random sequence generation	Allocation concealment	Blinding in performance	Blinding in outcome detection	Incomplete outcome data	Reporting bias	Other bias	Total
Fonseca 2007 [21]	Unclear	Unclear	Low	Low	Low	Low	Unclear	4
Rosenstock 2009–12.5 mg [22]	Unclear	Unclear	Low	Low	Low	Low	Unclear	4
Rosenstock 2009-25 mg [22]	Unclear	Unclear	Low	Low	Low	Low	Unclear	4
Vilsbøll 2010 [23]	Low	Unclear	Low	Low	Low	Low	Low	6
Barnett 2012 [24]	Unclear	Unclear	Low	Low	Low	Low	Unclear	4
Hong 2012 [25]	Unclear	Unclear	Low	High	Low	Low	Unclear	3
Yki-Jarvinen 2013 [28]	Low	Unclear	Low	Low	Low	Low	Low	6
Kadowaki 2013 [26]	Low	Unclear	Low	Low	Low	Low	Low	6
Kothny 2013[27]	Unclear	Unclear	Low	Low	Low	Low	Low	5
Kaku 2014 [29]	Unclear	Unclear	Low	Low	Low	Low	Unclear	4
Takahashi 2015 [35]	Unclear	Unclear	High	High	Low	Low	Unclear	2
Mathieu 2015 [32]	Unclear	Unclear	Low	Low	Low	Low	Low	5
Hirose 2015 [30]	Unclear	Unclear	Low	Low	Low	Low	Unclear	4
Otsuka 2015 [33]	Unclear	Unclear	High	High	Low	Low	Unclear	2
Linjawi 2015[31]	Unclear	Unclear	High	High	Low	Low	Low	3
Sato 2015 [34]	Unclear	Unclear	High	High	Low	Low	Low	3
Mita 2016 [36]	Low	Unclear	Low	Low	Low	Low	Low	6
Ning 2016 [37]	Unclear	Unclear	Low	Low	Low	Low	Low	5
Kanazawa 2017 [41]	Unclear	Unclear	High	High	Low	Low	Low	3
Cao 2017 [38]	Low	Unclear	High	High	Low	Low	Unclear	3
Shankar 2017 [42]	Unclear	Unclear	Low	Low	Low	Low	Low	5
Kadowaki 2017a [39]	Low	Low	Low	Low	Low	Low	Unclear	6
Kadowaki 2017b [40]	Low	Unclear	Low	Low	Low	Low	Unclear	5

Table 3 Subgroup analysis for the effects of DPP4i combined with insulin on HbA1c

Variables	Datasets (patients)	WMD (95% CI)	P for subgroup effect	I^2	P for subgroup difference
Study design
R, DB, PC	15 (5610)	−0.64 [−0.75, −0.53]	<0.001	77%
Others	8 (1006)	−0.29 [−0.50, −0.09]	0.005	62%	0.004
Sample size
>200	12 (5367)	−0.54 [−0.70, −0.39]	<0.001	86%
≤200	11 (1249)	−0.53 [−0.72, −0.34]	<0.001	75%	0.92
Mean age (years)
>59	12 (2980)	−0.56 [−0.76, −0.36]	<0.001	85%
≤59	11 (3636)	−0.51 [−0.62, −0.39]	<0.001	69%	0.64
Follow-up duration (weeks)
<24 weeks	7 (1040)	−0.72 [−0.90, −0.53]	<0.001	80%
24~26 weeks	13 (4199)	−0.45 [−0.57, −0.34]	<0.001	65%
>26 weeks	3 (1377)	−0.48 [−0.70, −0.25]	<0.001	45%	0.06
Insulin titration
Yes	8 (2038)	−0.39 [−0.58, −0.20]	<0.001	79%
No	15 (4578)	−0.63 [−0.75, −0.50]	<0.001	75%	0.05
DPP4i medications
Alogliptin	3 (569)	−0.63 [−0.77, −0.49]	<0.001	0%
Linagliptin	1 (1063)	−0.53 [−0.75, −0.31]	<0.001	—
Saxagliptin	2 (671)	−0.71 [−1.28, −0.13]	0.02	96%
Sitagliptin	11 (2905)	−0.40 [−0.57, −0.23]	<0.001	80%
Teneligliptin	1 (148)	−0.80 [−1.02, −0.58]	<0.001	—
Vildagliptin	5 (1260)	−0.68 [−0.91, −0.44]	<0.001	70%	0.09

Abbreviations: WMD, weighed mean difference; R, randomized; DB, double-blinded; PC, placebo-controlled; DPP4i, dipeptidyl peptidase-4 inhibitors.

Figure 2 Forest plots for the meta-analyses of addition of the dipeptidyl peptidase-4 inhibitors to insulin on glycemic control in patients with type 2 diabetes mellitus. (A) HbA1c (%); (B) fasting blood glucose (mmol/L); and (C) postprandial glucose at 2 hrs.

Figure 3 Forest plots for the meta-analyses of addition of the dipeptidyl peptidase-4 inhibitors to insulin on daily insulin dose and safety outcomes. (A) daily insulin dose (U/d); (B) body weight (kg); and (C) incidence of systematic hypoglycemia.

Figure 4 Funnel plots for the meta-analyses. (A) HbA1c (%); (B) fasting blood glucose (mmol/L); (C) postprandial glucose at 2 hrs; (D) daily insulin dose (U/d); (E) body weight (kg); and (F) incidence of systematic hypoglycemia.