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Diabetes Management DPP-4 Inhibitors
Figure 2: Overview of the Saxagliptin Clinical Study Program Leading to Approval
36
All subjects:
n=5,346
Clinical Phase IIb:
Phase III:
pharmacology: n=423
n=4,250
n=673 (Study 008)
Initial combination Mechanism of action: Add-on
Healthy subjects:
Monotherapy:
with MET: n=1,306n=36 combination:
n=583
n=832
(Study 039)(Study 041) n=2,076
(21 studies)
Patients with type 2
diabetes: n=40 Add-on to MET:
n=401
(Study 002) n=743
+66 OL
(Study 014)
(Study 011)
Patients with hepatic
impairment: n=18
Add-on to SU:
n=365
(Study 020)
n=768
(Study 038)
(Study 040)
Patients with renal
impairment: n=32
Add-on to TZD:
(Study 019)
n=565
(Study 013)
MET = metformin; OL = open-label; SU = sulfonylurea; TZD = thiazolidinedione.
In oral glucose tolerance tests, saxagliptin significantly reduced the demonstrated that saxagliptin 5mg plus metformin and saxagliptin
glucose and glucagon area under the curves (AUCs) while increasing 10mg plus metformin demonstrated statistically significant decreases
the AUCs for insulin and C-peptide. Treatment with saxagliptin was well in glycemic parameters.
28
The HbA
1c
was lowered by an additional
tolerated. The incidence of hypoglycemia was not increased compared 0.5% by the 5mg saxagliptin dose and by 0.8% by the 10mg dose.
28
As
with placebo. Treatment with saxagliptin was weight-neutral add-on therapy to metformin, saxagliptin (2.5, 5, or 10mg once daily)
(bodyweight change of -1.5, -0.9, -0.5, and -1.0kg for 2.5, 5, and 10mg or placebo plus a stable dose of metformin (1,500–2,500mg daily) also
saxagliptin and placebo, respectively).
17
led to statistically significant improvements in glycemic parameters,
and the combination was well tolerated.
29
When added to a
Saxagliptin has been extensively tested in phase III studies. Figure 2 submaximal dose of the sulfonylurea glyburide, saxagliptin also
gives an overview of the studies and number of patients involved.
25–29
significantly improved glycemia and was superior to uptitration of
the sulfonylurea.
27
A dose-ranging study in patients with an average HbA
1c
of 7.9% (range
6.8–9.7%) at baseline with saxaglitptin doses from 2.5 to 40mg once daily Saxagliptin as add-on therapy was also investigated in combination with
showed a dose-dependent drop in HbA
1c
by 0.7–0.9% (placebo- glitazones in 555 patients not optimally controlled with a stable dose of
subtratced HbA
1c
reduction 0.45–0.63%). Fasting plasma glucose was either pioglitazone or rosiglitazone who had a baseline HbA
1c
ranging
also dose-dependently lowered. Saxaglitpin did not cause hypoglycemia, from 7.0 to 10.5%. The primary end-point was change in HbA
1c
.
17,18,24
was well tolerated, and was weight-neutral.
30
Saxagliptin lowered HbA
1c
by 0.58–0.94% (see Figure 4).
One placebo-controlled, randomized, double-blind multicenter study A study assessing the efficacy of 5mg saxagliptin daily used different
investigated change in HbA
1c
as the primary end-point in more than 400 insulin secretion parameters after 12 weeks as efficacy measures in 156
drug-naïve type 2 diabetes patients. The baseline HbA
1c
range was patients who were not well controlled with diet and exercise (HbA
1c
7–10%, and HbA
1c
was reduced by 0.7–0/9%.
26
Saxagliptin was given between 6.0 and 8.0%).
17,18,24
once daily in doses ranging from 2.5 to 10mg as a monotherapy for 24
weeks. It was generally well tolerated and demonstrated clinically A study in patients with impaired renal function (creatinine clearance
meaningful reductions in key parameters of glycemic control compared <50ml/min) investigating the efficacy and safety of 2.5mg saxagliptin
with placebo (see Figure 3). once daily is still ongoing.
17,18,24
An initial combination therapy with saxagliptin plus metformin versus A study in 18 patients with hepatic impairment (Child-Pugh Score A–C)
saxagliptin or metformin monotherapy lasting for 24 weeks compared the pharmacokinetics of 10mg saxagliptin with that of a
72 US ENDOCRINOLOGY
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