Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy – focus on alogliptin

Figures & data

Table 1 DPP-4 inhibitors-based medicines authorized through central procedure by the European Medicines Agency (EMA)

DPP-4 inhibitors	Medicines	Date of authorization
Sitagliptin	Januvia®	21/03/2007
	Xelevia®	21/03/2007
	Tesavel®	10/01/2008
	Ristaben® *	15/03/2010
Sitagliptin + metformin	Efficib®	16/07/2008
	Janumet®	16/07/2008
	Vlmetia®	16/07/2008
	Ristfor®	15/03/2010
Vildagliptin	Galvus®	26/09/2007
	Jalra® *	19/11/2008
	Xiliarx® *	19/11/2008
Vildagliptin + metformin	Eucreas®	14/11/2007
	Icandra®	01/12/2008
	Zomarist® *	01/12/2008
Saxagliptin	Onglyza®	01/10/2009
Saxagliptin + metformin	Komboglize®	24/11/2011
Linagliptin	Trajenta® *	24/08/2011
Linagliptin + metformin	Jentadueto®	20/07/2012

Note:

* Not available in Italy. Data from European Medicines Agency [homepage on the Internet]. European public assessment reports (EPAR). [updated August, 2013]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=wC0b01ac058001d124. August 29, 2013.⁷²

Abbreviation: DPP, dipeptidyl peptidase.

Table 2 The combinations between DPP-4 inhibitors and other oral glucose-lowering agents authorized by the European Medicines Agency (EMA)

Indications	Sitagliptin	Sita + Met	Vildagliptin	Vilda + Met	Saxagliptin	Saxa + Met	Linagliptin	Lina + Met
Alone	Yes	Yes	Yes	Yes	–	Yes	Yes	Yes
+ Met	Yes	–	Yes	–	Yes	–	Yes	–
+ TZD	Yes	Yes	Yes	–	Yes	–	–	–
+ SU	Yes	Yes	Yes	Yes	Yes	–	–	Yes
+ Met and SU	Yes	–	Yes	–	–	–	Yes	–
+ Met and TZD	Yes	–	–	–	–	–	–	–
+ Insulin and ± Met	Yes	Yes	Yes	Yes	Yes	Yes	–	–
Previous gliptin + Met (separately)	–	Yes	–	Yes	–	Yes	–	Yes
Dose adjustment in kidney impairment	Yes	Yes	Yes	Yes	Yes	–	–	–

Abbreviations: DPP, dipeptidyl peptidase; Lina, linagliptin; Met, metformin; Saxa, saxagliptin; Sita, sitagliptin; Vilda, vildagliptin; SU, sulfonylurea; TZD, thiazolidinedione.

Table 3 Main pharmacokinetic and pharmacodynamic properties of DPP-4 inhibitors available on the European market

Parameters	Sitagliptin	Vildagliptin	Saxagliptin	Alogliptin	Linagliptin
Pharmacodynamics
In vitro DPP-4 inhibition (IC50 in nM)	19	62	50	24	1
DPP-4 selectivity (vs DPP-8 and DPP-9)	>2,600	<100	<100	>14,000	>10,000
Pharmacokinetics
Oral bioavailability (%)	87	85	75	70	30
Volume distribution (L)	198	71	151	300	368–918
Fraction bound to proteins (%)	38	9.3	<10	20	70
Half life (T1/2) (h)	8–14	2–3	2.2–3.8	12.4–21.4	120–184
Liver excretion (%)	13	4.5	22	13	85
Kidney excretion (%)	87	85	75	76	5
Proportion excreted unchanged (%)	79	23	24	95	~90
Substrate for CYP3A4/5	Low	No	Yes	No	No
Drug–drug interactions	Unknown	Unknown	CYP3A4/5 inducers and inhibitors	Unknown	Unknown

Note: Data were obtained from references 19, 25, 28, 29, 32.

Abbreviations: DPP, dipeptidyl peptidase; CYP, cytochrome P450.

Figure 1 Proportion of patients with HbA_1c <7%, and absolute decrease of HbA_1c from baseline at endpoint in patients with type 2 diabetes on gliptins after failure of previous treatments.

Note: Basal HbA_1c represents the mean baseline HbA_1c level at randomization.

Figure 2 Proportion of patients with hypoglycemia (%) and changes in weight (kg) in patients with type 2 diabetes on gliptins after failure of previous treatments.

Table 4 Characteristics of the studies with alogliptin

Studies (author, year, reference)	No	Mean age (years)	FU (weeks)	Alogliptin dosage	Add-on to	Mean HbA1c, basai (%)	HbA1c Δ(%)	HbA1c <7%	Weight Δ (kg)	Overall hypoglycemia (%)	Any AE (drug-related) %
DeFronzo et al^Citation38	133	53.4	26	12.5 mg	Naïve	7.9	−0.56	47.4	−0.09	3	23
Nauck et al^Citation39	213	55	26	12.5 mg	Met	7.9	−0.6	52	0	1	11
Pratley et al^Citation40	197	55.5	26	12.5 mg	Pio/+Met/+Su	8.1	−0.66	44	0.42	5.1	19
Pratley et al^Citation41	203	56.5	26	12.5 mg	Su	8.1	−0.39	29.6	0.6	15.8	15
Seino et al^Citation42	76	61.0	12	12.5 mg	Voglibose	8.02	−0.96	46	0.19	0	9
Seino et al^Citation45,*	84	58.7	12	12.5 mg	Naïve	7.99	−0.68	35.7	0.45	1	14.3
Kaku et al^Citation46,*	111	60.8	12	12.5 mg	Pio	7.9	−0.91	49.5	0.48	1	7.2
DeFronzo et al^Citation47	128	55.2	26	12.5 mg	Met	8.6	−0.65	20	−0.02	1	20.3
Seino et al^Citation48,*	92	53.4	12	12.5 mg	Met	7.9	−0.55	28.3	0.17	1	8.3
DeFronzo et al^Citation38	131	53.4	26	25 mg	Naïve	7.9	−0.59	44.4	0.22	2	23
Nauck et al^Citation39	210	54	26	25 mg	Met	7.9	−0.6	43.8	−0.3	0	13
Pratley et al^Citation40	198	56.5	26	25 mg	Su	8.1	−0.53	34.8	0.68	9.6	18
Pratley et al^Citation41	199	55.4	26	25 mg	Pio/+Met/+Su	8	−0.80	49.2	0.05	7	19
Rosenstock et al^Citation49	164	53	26	25 mg	Naïve	8.8	−0.96	24.5	−0.29	2	18.8
Seino et al^Citation42	79	62.9	12	25 mg	Voglibose	7.91	−0.91	50.6	−0.19	0	12
Seino et al^Citation45,*	80	59.7	12	25 mg	Naïve	7.9	−0.77	44.3	0.2	1	32
Bosi et al^Citation50	404	54.3	52	25 mg	Met + Pio	8.2	−0.7	33.2	1.1	4.5	21.8
Kaku et al^Citation46,*	113	59.3	12	25 mg	Pio	7.9	−0.97	49.6	0.46	1	8.8
DeFronzo et al^Citation47	129	53.1	26	25 mg	Met	8.6	−0.92	28	−0.7	1	22.1
Seino et al^Citation48,*	96	52.3	12	25 mg	Met	8.02	−0.64	27.1	−0.09	2	10
Kutoh and Ukai^Citation51	25	47.9	12	25 mg	Naïve	10.5	−1.77	7	−0.7	16	NR

Note:

* HbA_1c target <6.9%.

Abbreviations: AE, adverse events; FU, follow-up; Met, metformin; NR, not reported; Pio, pioglitazone; Su, sulfonylurea.

European Medicines Agency (EMA) EMA recommends suspension of Avandia, Avandamet and Avaglim [press release] London, UK European Medicines Agency [cited May 30, 2011]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/09/WC500096996.pdf Accessed June 18, 2013

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