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Drug Profile—Saxagliptin, a Novel DPP-4 Inhibitor for the Treatment of Type 2 Diabetes
healthy control group. A higher elevation of AUC values after saxagliptin
Figure 3: Efficacy of Saxagliptin in Monotherapy Studies—
(10–77% higher) was observed in the patients with hepatic impairment.
Effect on Glycated Hemoglobin
Correspondingly, the AUC values for the metabolite were 7–33% lower,
SAXA (mg)
depending on the severity of hepatic impairment. These results indicate SAXA (mg)
QAM QAM QAM QPM
a reduction in capacity to metabolize the drug with increasing hepatic
Dose 2.5 5 10 PBO 2.5 5 2.5/5 5 PBO
n = 100 103 95 92 67 69 69 70 68
dysfunction. Saxagliptin, however, was well tolerated in subjects with
BsI mean (%) 7.91 7.98 7.85 7.88 8.04 7.93 8.02 7.88 7.79
mild, moderate, or severe hepatic impairment.
17,31
0.6
0.4
Side Effects and Contraindications
0.19
0.2
Saxagliptin was tested in type 2 diabetes patients in doses up to 100mg
0.0
once daily without adverse reactions and in healthy volunteers at doses
-0.2
(%) with 95% CI
up to 400mg per day. Safety data and tolerability were good.
17,18,24 -0.26
1c
-0.4
-0.43
-0.46
-0.6 -0.54
∆HbA
-0.63
Additionally, data from longer studies examining the safety and
* -0.61
-0.66*
-0.71
-0.8
*
adverse effects of saxagliptin are available. As an add-on to
***
*
-1.0
metformin, saxagliptin at doses from 2.5 to 10mg once daily were well
*p<0.0001 vs PBO *p<0.01 vs PBO **p<0.02 vs PBO
tolerated and did not have a significant rise in specific adverse
Figure shows change from baseline (Bsl) in glycated hemoglobin (HbA ) at week 24 (last1c
reactions compared with placebo. The incidence of hypoglycemia was
observation carried forward [LOCF]). CI = confidence interval; PBO = placebo; QAM = once daily
morning; QPM = once daily evening; SAXA = saxagliptin.
not increased compared with placebo.
17,18,24
A small study using
doses of up to 40mg saxagliptin once daily in patients with type 2
diabetes did not reveal a higher incidence of specific adverse events
Figure 4: Efficacy of Saxagliptin in Combination Therapy—
Effect on Glycated Hemoglobin
compared with the placebo group.
30
Studies investigating possible
drug–drug interactions with saxagliptin did not reveal any interaction SAXA + TZD PBO SAXA + GLY PBOSAXA + TZD PBO
+ ++
between saxagliptin and common over-the-counter drugs, digitoxin
Dose 2.5 5 10 MET 2.5 5 TZD 2.5 5 GLY
and anticoagulants.
17,20–22 n = 186 186 180 175 192 183 180 246 250 264
BsI mean (%) 8.08 8.07 7.98 8.06 8.25 8.35 8.19 8.36 8.48 8.44
0.4
0.13
In patients with renal or hepatic impairment, more data have to be
0.08
0.2
collected to give a complete picture. In hepatic organ dysfunction, a
0.0
reduction to lower doses seems to be feasible without additional side
-0.2
effects. Saxagliptin was well tolerated in a small study of such patients
-0.4
receiving a single saxagliptin dose.
31
A study in patients with renal -0.3
(%) with 95% CI
1c -0.6
impairment is still ongoing.
17,18,24
HbA
∆ -0.8 -0.59
-0.58
-0.64-0.54
-0.66*
*-0.69
**
**
Discussion and Conclusion
-1.0 *
-0.94
-1.2
DPP-4 inhibitors are a relatively new class of oral agents for the
*
*p<0.0001 vs PBO + MET *p<0.0001 vs PBO + TZD *p<0.0001 vs PBO + GLY
treatment of type 2 diabetes. They have dual action on alpha- and beta-
**p=0.0007 vs PBO + TZD
cell function. This leads to an improved time-course of glucagon and
Figure shows change from baseline (Bsl) in glycated hemoglobin (HbA ) at week 24 (last1c
insulin secretion post-prandially and in other hyperglycemic states. With
observation carried forward [LOCF]). CI = confidence interval; GLY = glycoine; PBO = placebo;
MET = metformin; SAXA = saxagliptin; TZD = thiazolidinedione.
DPP-4 inhibitors, the secretion of these two hormones is regulated in a
glucose-dependent manner, resulting in a hypoglycemia risk comparable
Figure 5: Cardiovascular Safety Data of
to that seen with placebo. Hormonal counter-regulation at low glucose
Saxagliptin—Cumulative Incidence of Major
concentrations is not impaired, but actually improved.
32
Animal studies Adverse Cardiovascular Events
34
and in vitro data from isolated human islets suggest a potential for
5
DPP-4 inhibitors to increase beta-cell function and mass, pointing to a
putative beneficial effect on type 2 diabetes disease progression.
12,13
4
The DPP-4 inhibitors sitagliptin and vildagliptin have been in use for a few
3
years.
10,11
Saxagliptin, the third compound in the class, has now been
Control
2
approved and has demonstrated very satisfactory data on the
All SAXA
improvement of glycemic parameters. It has also shown a good safety
1
profile and tolerability over a time range of up to 24 weeks in clinical
Percent with first adverse event
0
studies in a large cohort of patients.
17,18,24–30
Compared with other DPP-4 Bsl 24 37 50 63 76 89 102 115 128
inhibitors, saxagliptin is comparably efficacious and safe as monotherapy
Weeks
Patients at risk

as well as in combination with metformin or a glitazone.
17,18,24,25,28
Further
Control 1,251 935 860 774 545 288 144 123 102 57
studies have demonstrated that there are no drug–drug interactions of
All SAXA 3,356 2,615 2,419 2,209 1,638 994 498 436 373 197
concern with over-the-counter drugs, anticoagulants, antacids, and Bsl = baseline; SAXA = saxagliptin.
US ENDOCRINOLOGY 73
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