Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment

Table 1 Characteristics of dipeptidyl peptidase 4 inhibitors

	Chemistry	Half-life	HbA1c reduction (%)	Metabolism	Eliminationroute
Alogliptin	Modifiedpyrimidinedione	20 h	0.6 (mean value)	Minimal	Predominantly (> 70%) renal
Linagliptin	Xanthine-based	Approxmately 12 h (effective), > 100 h (terminal)	0.5-0.7	Minimal	Predominantly biliary (< 6% renal)
Saxagliptin	Cyanopyrrolidine	2.5 h (parent), 3 h (metabolite)	0.5-1.0	Hydrolysis (cytochrome P450 3A4 or P450 3A5) to form an active metabolite	Metabolism (parent) and renal (metabolite)
Sitagliptin	β-aminoacid based	12.5 h	0.5-1.0	Minimal	Predominantly (> 80%)
Vildagliptin	Cyanopyrrolidine	Approxmately 2 h	0.9 (mean value)	Hydrolysis (cytochrome-independent) to form an inactive metabolite	Metabolism (parent) and renal (metabolite)

Table 2 Renal dosing of dipeptidyl peptidase 4 inhibitors

Renal impairment	Alogliptin	Linagliptin	Sitagliptin	Vildagliptin	Saxagliptin
Mild (eGFR > 50 mL/min)	25 mg o.d.	5 mg o.d.	100 mg o.d.	50 mg b.i.d.	5 mg o.d.
Moderate (eGFR 30-50 mL/min)	12.5 mg o.d.	5mg o.d.	50 mg o.d.	50 mg o.d.	2.5 mg o.d.
Severe (eGFR < 30 mL/min)	6.25 mg o.d.	5 mg o.d.	25 mg o.d.	50 mg o.d.	2.5 mg o.d.
ESRD	6.25 mg o.d.	5 mg o.d.	25 mg o.d.	50 mg o.d.	Contraindicated
Renal dialysis	6.25 mg o.d.	5 mg o.d.	25 mg o.d.	50 mg o.d.	Contraindicated

eGFR: Estimated glomerular filtration rate; ESRD: End-stage renal disease.

Table 3 Modification of dosing for dipeptidyl peptidase 4 inhibitors in hepatic impairment

Hepatic impairment	Alogliptin	Linagliptin	Sitagliptin	Vildagliptin	Saxagliptin
Mild	25 mg o.d.	5 mg o.d.	100 mg o.d.	Not recommended in liver disease, including AST or ALT > 3 × ULN	5 mg o.d.
Moderate	25 mg o.d.	5mg o.d.	100 mg o.d.		Can be used with caution
Severe	Not recommended	5 mg o.d.	Can be used with caution		Not recommended

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ULN: Upper limit normal.

Table 4 Cardiovascular outcome trials with dipeptidyl peptidase 4 inhibitors

	CVOT	Comparator	Cardiovascular safety (MACE) (HR)	Risk of hospitalization for heart failure (HR)
Alogliptin	EXAMINE	Placebo	0.96	1.07
Linagliptin	CARMELINA	Placebo	1.02	0.90
	CAROLINA	Glimepiride	0.98	1.21
Saxagliptin	SAVOR-TIMI	Placebo	1.00	1.27
Sitagliptin	TECOS	Placebo	0.98	1.00

CVOT: Cardiovascular outcome trial; HR: Hazard ratio; MACE: Major adverse cardiovascular events.