Biomedical Engineering Reference
In-Depth Information
5.2.5 DPP-4 Inhibitors in Disease Therapy
5.2.5.1 DPP-4 Inhibitors in Type 2 Diabetes Therapy
DPP-4 inhibitors have been in development since the late 1980s, but it was not
until 1998 that their use as a treatment for type 2 diabetes was first demon-
strated.
61-64
The therapeutically useful, selective DPP-4 inhibitors are termed
the gliptins, and are an incretin-based therapy, meaning that they augment
glucose homeostasis by preventing DPP-4-mediated degradation of the incretin
hormones such as GLP-1 and GIP.
65,66
Incretin hormones are released, fol-
lowing food intake, to stimulate insulin release and suppress glucagon secretion
in a glucose-dependent manner, thereby lowering blood glucose. Moreover,
GLP-1 functions to slow gastric emptying, induce satiety, and promote pan-
creatic b-cell function, growth, and survival.
67-69
Owing to its multiple roles in
glucose homeostasis, GLP-1 has been a major pharmaceutical target for the
treatment of type 2 diabetes.
Administration of exogenous GLP-1 to type 2 diabetic patients effectively
improves glucose metabolism and improves b-cell function.
70
However, the
therapeutic potential of GLP-1 is largely limited, as it has a very short half-life,
of about 2 to 4 min. Once secreted or administered, active GLP-1
(7-36)
is rapidly
degraded at the N-terminus, due to proteolytic cleavage by DPP-4, to form the
inactive peptide, GLP-1
(9-36)
.
70
This has fostered interest in developing stra-
tegies to enhance GLP-1 activity without the need for continuous administra-
tion of native GLP-1. Such approaches include the development of
degradation-resistant GLP-1 receptor agonists such as exendin-4, and inhibi-
tors of DPP-4.
Sitagliptin (Januvia
t
/MK0431) was the first DPP-4 inhibitor medicine
approved by the United States and European regulatory authorities for the
treatment of type 2 diabetes in 2006. More recently available DPP-4 inhibitors
include Saxagliptin (Onglyza
t
/BMS-477118) and Linagliptin (Tradjenta/
BI1356), which are on sale in the USA, Vildagliptin (Galvus
s
/LAF237), on sale
in the European Union, and Alogliptin (Nesina
t
/SYR-322), on sale in Japan.
DPP-4 inhibitors are competitive inhibitors with a high anity for DPP-4,
blocking the access of GLP-1 to the active site. Rasmussen et al.
49
showed, by
X-ray crystallography, a competitive substrate-analog inhibitor, valine-pyrro-
lidide, in the active site of DPP-4. Sitagliptin is a similar triazolopiperazine-
based, small-molecule DPP-4 inhibitor.
50
Sitagliptin has been similarly shown
bound in the active site of DPP-4, with part of the molecule completely
occupying the substrate binding pocket (Figure 5.2A). It forms hydrogen-bond
interactions with crucial residues of DPP-4 including Glu204 and Glu205, thus
mimicking the binding of the N-terminus of GLP-1 into DPP-4.
50
5.2.5.2 In Vivo Data on DPP-4 Inhibitor Treatment
The DPP-4 inhibitors are orally active, are rapidly absorbed and produce
480% inhibition of serum DPP-4 activity. This leads to a two- to threefold
