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Drug Profile—Saxagliptin, a Novel DPP-4 Inhibitor for the Treatment of Type 2 Diabetes
type 2 diabetes, exogenous GLP-1 stimulates insulin secretion and
Figure 1: Structural Formula of Saxagliptin
normalizes both fasting and post-prandial blood glucose. It further restores
the defective first phase of insulin secretion in type 2 diabetes.
6
H
O
Besides its glucose-lowering effects, GLP-1 has additional non-
insulinotropic physiological actions that may be advantageous in type
2 diabetes therapy: it suppresses glucagon secretion from the alpha
N
H
cells and slows gastric emptying. Additionally, GLP-1 acts as a
mediator of satiety in the hypothalamus, where it is also found as a
neurotransmitter.
3
In patients with type 2 diabetes, exogenous GLP-1
NH
infusions cause weight loss.
7
Furthermore, GLP-1 stimulates beta-cell
2
OH
formation from precursor cells and also inhibits their apoptosis,
leading to an increase in beta-cell mass and improvement in beta-
N
cell function.
8
Due to dipeptidyl peptidase-4 (DPP-4) action, the biological half-life of 4,000-fold greater than DPP-4 when tested against a number of other
exogenous GLP-1 is only one to two minutes; therefore, treatment with proteases,
17
making it more potent than sitagliptin or vildagliptin.
native GLP-1 is not feasible. In order to utilize GLP-1 effects, long-acting Regarding toxicity, no data have been published so far. Saxagliptin is
GLP-1 receptor agonists have been developed as an injectable therapy. partially metabolized in the liver, generating a metabolite that also
The alternative way to utilize GLP-1 action is inhibition of  the degrading inhibits DPP-4.
17,18
enzyme with orally active DPP-4 inhibitors.
6
Pharmacokinetics
DPP-4 is a ubiquitous enzyme that can be detected in the endothelium The half maximal inhibitory concentration (IC
50
) for DPP-4 inhibition is
of different organs. It is measurable as circulating enzymatic activity in 30nM, and the effective dose 50 (ED
50
) after a single dose of 0.1µmol/kg
plasma. Besides GLP-1 and GIP, additional peptides, such as pituitary and 0.5µmol/kg is 0.5 and six hours, respectively, showing sufficient
adenylate cyclase-activating polypeptide and gastrin-releasing peptide, activity over time for once-daily dosing. Endogenous GLP-1 concentrations
are substrates of DPP-4. The affinity of DPP-4 is higher towards GLP-1, rise 1.5- to three-fold after saxagliptin administration.
17,19
however, than towards other peptides, including GIP.
Pharmacokinetic and pharmacodynamic characteristics were
DPP-4 cleaves and inactivates GLP-1 within a few minutes.
9
It is also investigated in healthy subjects at doses up to 400mg daily and in
expressed on the cell membrane of activated T lymphocytes as CD26.
9
patients with type 2 diabetes in doses from 2.5 to 50mg once daily. A
Here, the enzymatic properties of the DPP-4/CD26 molecule do not seem dose-dependent inhibition of DPP-4 was observed, with a maximal
to be important. The influence of DPP-4 inhibitors on immunological inhibiting effect at 150mg. DPP-4 inhibition 24 hours post-dose for 2.5mg
CD26-mediated functions is therefore not expected. The broad clinical and 400mg saxagliptin was 50 and 79% of pre-dose activity, respectively.
use of DPP-4 inhibitors has not revealed serious side effects or adverse
events on immunological regulatory mechanisms.
6
Doses of 400mg once-daily saxagliptin for two weeks were safe and well-
tolerated.
17,18
No specific drug–drug interactions between saxagliptin and
The increase of endogenous, biologically active GLP-1 by DPP-4 other common medications were observed.
20,23
inhibition offers an attractive therapeutic principle. DPP-4 inhibitors are
orally active, in contrast to GLP-1 receptor agonists.
6
DPP-4 is a member Clinical Studies
of the endopeptidase enzyme family. It must therefore have a high Phase I studies demonstrated a dose-dependent inhibition of DPP-4 in a
selectivity for inhibiton of DPP-4 and not other DPPs. dose range from 2.5 to 100mg once daily, as described above. Results
from phase II studies are reported in references 17, 18, and 24. A phase
The DPP-4 inhibitors sitagliptin
10
and vildaglitpin
11
have been approved in IIb study with 10mg saxagliptin once daily generated good efficacy and
many countries and have been shown to be efficacious and safe. tolerability data.
17,18,24
Saxagliptin (Onglyza
®
), another DPP-4 inhibitor, has been developed by
AstraZeneca and Brystol-Myers Squibb and has just been approved for A subsequent phase IIb/III study investigated saxagliptin as an add-on to
use. Further DPP-4 inhibitors, such as alogliptin, dutogliptin, and metformin (stable metformin dose 1,500–2,550mg/dl and glycated
linagliptin, are in development.
12,13
hemoglobin [HbA
1c
] 7–10%). Saxagliptin was given in a placebo-
controlled manner in doses of 2.5, 5, or 10mg once daily in addition to
Pharmacology metformin. Saxagliptin led to an adjusted-mean placebo-subtracted
Saxagliptin binds covalently in the active center of DPP-4.
14
The HbA
1c
of -0.73, -0.83, and -0.71% from a baseline of 8.0±0.9% for the 2.5,
structural formula of saxagliptin in shown in Figure 1. It has a low K(i) 5, and 10mg doses after 24 weeks, respectively. Fasting plasma glucose
of 3.6nM for DPP-4
15
in vitro. The formation of the covalent enzyme– was significantly reduced in this study by, respectively, 16, 24, and
inhibitor complex is reversible and dissociates with a k
off
of (5.5+0.4) x 21mg/dl from a baseline of 176±46mg/dl (p<0.0001 for all glycemic
10
-5
s
-1
.
16
Saxagliptin also demonstrated potency that was more than parameters of saxagliptin versus placebo).
US ENDOCRINOLOGY 71
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