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SAXAGLIPTIN: A NEW
"GLUPTIN" APPROVED FOR
TYPE II DIABETES
Johanna Kaharl, Pharm.D. Candidate
Saxagliptin was approved by the FDA July 31,
2009 under the brand name Onglyza.1 This
agent is a new dipeptidyl peptidase 4 inhibitor
(DPP-4 inhibitor), similar to Sitagliptin (Januvia).
Manufactured by Bristol Myers Squibb, saxagliptin is
indicated as an adjunct to diet and exercise to improve
glycemic control in patients with Type II Diabetes Mel-
litus (DM) and has been studied in combination with
other oral diabetic medications.2 The aim of this article
is to give a general overview of saxagliptin, including
its pharmacokinetics, efficacy as a monotherapy and in
combination with other diabetic medications, and ad-
verse effects.
PHARMACOLOGY
Saxagliptin inhibits DPP-4 mediated metabolism of
the incretin hormones glucagon-like peptide 1 (GLP-1)
and glucose-dependent insulinotropic polypeptide
(GIP), which are normally excreted by the small intes-
tine in response to meals and then inactivated by DPP-
4 within minutes.3 The incretins stimulate the beta
cells of the pancreas to release insulin in a glucose-
dependent manner, lower glucagon secretion from the
alpha cells, and slow gastric emptying.4 Saxagliptin
causes a 2- to 3-fold increase in circulating GLP-1 and
GIP levels, leading to decreased glucagon concentra-
tions and increased glucose-dependent insulin secre-
tion.2 In pre-clinical trials, incretin agents like the DPP-
4 inhibitors and the GLP-1 receptor agonist exenatide
(Byetta) have been associated with an increased
pancreatic beta-cell mass.4 Future clinical studies are
needed to assess their full effect on reversing pancre-
atic beta-cell dysfunction.
PHARMACOKINETICS
Saxagliptin's major metabolite is 5-hydroxy
saxagliptin. This active metabolite has 50% of the po-
tency of saxagliptin and a similar pharmacokinetic
profile (Table 1).
SPECIAL POPULATIONS
Renal Impairment
In a single-dose, open-label study, the pharmacoki-
netics of saxagliptin in subjects with varying degrees
of chronic renal impairment (N=8 per group) were
compared to subjects with normal renal function. The
area-under-the-curve (AUC) was 2.1 and 4.5 fold
higher in saxagliptin and 5-hydroxysaxagliptin in sub-
jects with moderate to severe renal impairment (CrCl
of _< 50ml/min) versus subjects with normal renal
function. Therefore, a lower dose of 2.5mg daily is rec-
ommended in patients with CrCl _< 50ml/min. As
saxagliptin is removed by hemodialysis, these patients
INSIDE THIS ISSUE:
SAXAGLIPTIN: A NEW "GLIPTIN" APPROVED FOR
TYPE II DIABETES
mm
PharmaNote
VOLUME 25, ISSUE 5 FEBRUARY 2010
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Volume25,lssue5 I February2010
PharmaNote
Table 1. Pharmacokinetics of saxagliptin.2
ABSORPTION Tmax: 2 hours for saxagliptin; 4 hours for 5-hydroxy saxagliptin
DISTRIBUTION No protein binding shown in vitro
METABOLISM Hepatic through CYP3A4/5 (to less potent metabolite)
Renal:
Median saxagliptin clearance was higher than glomerular filtration suggesting active tubular excretion
Following a single 50mg dose of 14C-saxagliptin, the following were recovered in urine: 24% as
saxagliptin and 36% as metabolite
EXCRETION Saxagliptin is removed by hemodialysis (23% of dose over 4 hours)
Fecal:
22% was recovered in feces representing drug excreted in bile and/or not absorbed from GI tract
Mean Terminal t1/2: 2.5 h
Tmax = time to maximal concentration; CYP = Cytochrome P450 enzymes; GI = Gastrointestinal; t1/2 = half-life
should take their doses after dialysis sessions.2
Hepatic Impairment
No dose adjustment is recommended for patients
with hepatic impairment owing to a lack of any clini-
cally significant impact on AUC.2
Geriatric Patients
Roughly 15% of diabetic subjects in phase III trials
were above age 65. No differences were noted in
safety and efficacy for those greater than 65 years
when compared with younger subjects.
Pregnancy
Saxagliptin is designated as category B as it was
not teratogenic in animal studies, but no adequate,
well-controlled studies have been performed in preg-
nant women.2
DRUG INTERACTIONS
Saxagliptin is a substrate of CYP3A4/5 enzymes,
but in vitro studies showed no inhibition or induce-
ment of any CYP enzyme subfamilies. Saxagliptin is
also a substrate of P-glycoprotein (PGP), but causes no
significant interaction in PGP binding. Furthermore,
saxagliptin undergoes no significant protein binding.
In vivo studies showed no significant saxagliptin-
induced effect on AUC of metformin, glyburide, piogli-
tazone, digoxin, simvastatin, diltiazem, or ketocona-
zole.
Drugs known to affect the metabolism of
saxagliptin are summarized in Table 2.
EFFICACY
Monotherapy
The efficacy and safety of saxagliptin as monother-
apy was evaluated in a phase III, 24 week, four-arm,
parallel-group, double blind, randomized, placebo-
controlled trial (RCT).5 The main treatment cohort
(MTC) inclusion criteria required that patients be be-
tween the ages of 18 and 77 with type 2 diabetes in-
adequately controlled (which the study defined as Alc
_ 7.0% and <: 10%) with diet and exercise. Patients
were required to be treatment naive, defined as not
Table 2. Effects of other drugs on saxagliptin.2
CYP3A4 INDUCERS Rifampin l, AUC of saxagliptin but not 5-hydroxy saxagliptin. No effect on the activity of
saxagliptin at the DPP4 enzyme.
No dose adjustment is recommended
CYP3A4 INHIBITORS
Moderate Inhibitors Diltiazem /" AUC of saxagliptin 2-fold, causing a decrease in the AUC of 5-hydroxy saxagliptin.
No dose adjustment is recommended
Strong Inhibitors Ketoconazole tAUC of saxagliptin from 2.5-3.7 fold with a subsequent l, in 5-hydroxy saxagliptin.
A lower dose of saxagliptin 2.5mg daily is recommended if concurrent therapy with strong inhibi-
tors such as ketoconazole, itraconazole, clarithromycin, and protease inhibitors.
n6 a I Of*I%-I nm I. r_ IU.r AnnI AU
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having received insulin or oral antihyperglycemic
medication for at least 6 months since diagnosis. Ex-
clusion criteria included symptoms of poorly con-
trolled diabetes, history of diabetic ketoacidosis, or
any significant comorbidities such as a CV event with 6
months, NYHA stage III/IV CHF, morbid obesity, renal
or liver impairment. After a 2 week, single blind, diet,
exercise, and placebo lead-in period, the 401 subjects
in the MTC were randomized to saxagliptin 2.5 mg
daily, 5 mg daily, 10 mg daily, or placebo. Patients with
a Alc > 10% and 12%, but who met all other inclu-
sion/exclusion criteria were eligible to enroll in an
open-label cohort (OLC) with saxagliptin 10mg daily.
All patients who were deemed to have inadequate glu-
cose control during the study based on fasting plasma
glucose levels were eligible for addition of open-label
metformin as rescue therapy. In rescue patients, effi-
cacy was evaluated as the last value measured before
rescue therapy. Rescue therapy was required in 15%
of the 2.5 mg group, 20% of the 5mg group, 14% in the
10mg group, and 26% of the placebo group. The pri-
mary endpoint was Alc adjusted mean change from
baseline using last observation carried forward
(LOCF) at week 24. At week 24, saxagliptin 2.5 and 5
mg caused statistically significant reductions in Alc (p
< 0.0001) and FPG (p < 0.05) from baseline versus
those randomized to placebo (Table 3).5
Combination therapy
Coadministration of saxagliptin with metformin in
treatment naive patients was evaluated in a phase III,
24 week, double-blind, randomized controlled trial
(RCT) of diabetic patients with the primary outcome
measured as reduction in Alc from baseline at 24
weeks.6 Secondary endpoints included change from
baseline at 24 weeks of FPG and postprandial glucose
area-under-the-curve (PPG-AUC). Besides having in-
adequate glycemic control, defined as Alc 8% and <
12%, inclusion/exclusion criteria were the same as
those defined in the monotherapy trial. After a single
blind, 1 week dietary and exercise lead-in period,
1306 subjects were randomized to 1 of 4 treatment
arms: saxagliptin 5 mg daily plus metformin 500 mg
daily, saxagliptin 10 mg daily plus metformin 500 mg
daily, saxagliptin 10 mg plus placebo, or metformin
500mg plus placebo. The metformin dose could be up-
titrated weekly in 500mg increments as tolerated to
max of 2g daily over the first 5 weeks. Subjects who
failed to meet specific glycemic goals were treated
with pioglitazone as rescue add-on therapy. At week
24, patients randomized to saxagliptin 5 and 10 mg
plus metformin demonstrated statistically significant
reductions in Alc (p < 0.0001), FPG (p < 0.05) and PPG-
AUC (p < 0.0001) from baseline versus both mono-
therapy groups (Table 3).6
Addition of saxagliptin to metformin was evalu-
ated in a phase III, 24 week, double blind RCT of 743
patients.7 Patients had to have been on at least 8
weeks of metformin at a stable dose of 1500-2500 mg
per day with inadequate glycemic control defined as
Ac 7% and < 10%. All other inclusion/exclusion cri-
teria were similar to previously mentioned trials. After
a single blind, 2 week dietary and exercise lead in pe-
riod with patients receiving pre-study doses of met-
formin, patients were randomized to add on 2.5 mg
saxagliptin daily, 5 mg saxagliptin daily, 10 mg
saxagliptin daily, or placebo. The primary endpoint
was Ac change from baseline and secondary end-
points included FPG and PPG-AUC. Patients who failed
to meet glycemic goals were treated with pioglitazone
rescue therapy. At week 24, saxagliptin added to met-
formin was well tolerated with statistically significant
improvement in Alc (p < 0.0001), FPG (p < 0.0001),
and PPG-AUC (p < 0.0001) versus placebo added to
metformin.7
Addition of saxagliptin to thiazolidinedione (TZD)
was evaluated in a phase III, 24 week, double blind
RCT with 565 patients.8 Patients had to have been on a
stable dose of either pioglitazone 30 to 45 mg daily or
rosiglitazone 4 mg once to twice daily or 8 mg daily
with inadequate glycemic control defined as Alc _> 7%
and < 10%. All other inclusion/exclusion criteria
match those of previously discussed trials. After a sin-
gle blind, 2 week dietary and exercise lead in period
with patients receiving pre-study doses of TZD, pa-
tients were randomized to add on saxagliptin 2.5 mg
daily, 5 mg daily, or placebo with no dose titration of
either medication. Change from rosiglitazone to piogli-
tazone at equivalent doses was permitted if deemed
medically appropriate by the study investigator. Pa-
tients who failed to meet specified glycemic goals
were treated with metformin as rescue therapy. Res-
cue occurred in 10% of the saxagliptin 2.5 mg group,
6% of the 5 mg group, and 10% of the placebo group.
At week 24, saxagliptin 2.5 and 5 mg added to TZD had
statistically significant greater reductions in Alc (p <
0.05) and FPG (p <0.05) versus placebo added to TZD.8
Addition of saxagliptin to a sulfonylurea was
evaluated in a 24 week, double blind RCT of 768 pa-
tients.9 Patients had to have been on a sub maximal
dose of a sulfonylurea for at least 2 months prior to
enrolling in the study with inadequate glycemic con-
trol, defined as Alc 7% and < 10%. All other inclu-
sion/exclusion criteria match those of the trials previ-
ously discussed. During the 4 week, single blind, die-
tary and exercise lead-in period patients discontinued
previous sulfonylurea and started receiving open-label
glyburide 7.5 mg daily. Patients with Ac _> 7% and FPG
aI
Volume25,lssue5 i February2010
PharmaNote
Table 3. Summary of saxagliptin trial results.5"9
MEAN Alc CHANGE FPG PPG-AUC PERCENT
BASELINE (ADJUSTED CHANGE CHANGEc ACHIEVING PERCENT
THERAPY N Alc (%) MEAN') (mg/dL) (mg-min/dL) Alc <7% ON RESCUE
Monotherapy5
2.5 mg daily 100 7.9 -0.4 -15 -6868 35 15
5 mg daily 103 8.0 0.5 -9 -6896 38 20
10 mg daily 95 7.9 -0.5 -17 -8084 41 14
Placebo 92 7.9 + 0.2 +6 -647 24 26
OLC 64 10.7 1.9 -33 -11078 14
Combination Therapy
Coadministration with metformin6 in treatment naive
Saxagliptin 5 mg + metformin 320 9.4 -2.5 -60 -21080 60 7.5
Saxagliptin 10 mg + metformin 323 9.5 -2.5 -62 -21336 60 5.9
Placebo + saxagliptin 10 mg 335 9.6 -1.7 -31 -16054 32 21.2
Placebo + metformin 328 9.4 -2.0 -47 -15005 41 10.1
Add-on to metformin7
2.5 mg daily 192 8.1 -0.6 -14 -8891 37 ND
5 mg daily 191 8.1 -0.7 -22 -9586 44 ND
10 mg daily 181 -0.6 -21 -8137 44 ND
Placebo 179 8.1 +0.1 +1 -3291 17 ND
Add-on to TZD8
2.5 mg daily 195 8.3 -0.7 ND ND 42 ND
5 mg daily 186 8.4 -0.9 ND ND 42 ND
Placebo 184 8.2 -0.3 ND ND 26 ND
Add-on to glyburide9
2.5 mg 248 8.4 -0.5 -7 -4296 22 18
5 mg 253 8.5 -0.6 -10 -5000 23 17
Placebo + Up-titrated glyburide 267 8.4 +0.1 +1 +1196 9 30
a Mean change from baseline, using last observation carried forward at study end.
b Least squares mean adjusted for baseline value.
c Comparison or oral glucose tolerance test results from baseline to week 24.
FPG = fasting plasma glucose; ND = No Data, only abstract could be viewed; OLC = open-label cohort; PPG-AUC = post-prandial glucose area
under the curve
> 140 mg/dL continued treatment with glyburide 7.5
mg daily and were randomized to add-on saxagliptin
2.5 mg daily, saxagliptin 5 mg daily, or placebo plus
blinded glyburide 2.5 mg daily (uptitrated to initial
total daily dose of glyburide 10 mg). Patients in pla-
cebo plus blinded glyburide were eligible to up-titrate
the glyburide dose to 15 mg daily. However, glyburide
could be down-titrated in all three groups for hypogly-
cemia when deemed necessary by investigator. The
primary study endpoint was change in Aic from base-
line to 24 weeks and secondary endpoints included
changes in FPG and PPG-AUC. Those who failed to
meet glycemic goals were treated with metformin res-
cue. Rescue or discontinuation due to lack of glycemic
control occurred in 18% of the saxagliptin 2.5 mg add-
on group, 17% of the 5 mg group, and 30% of the pla-
cebo plus up-titrated glyburide group. At week 24,
saxagliptin 2.5 and 5 mg daily added to a sulfonylurea
caused significantly greater reductions in Aic (p <
0.0001), FPG (p = 0.002), and PPG-AUC (p < 0.0001)
versus placebo added to sulfonylurea (Table 3).9
No studies have assessed saxagliptin in combina-
tion with insulin.
Pha rma Note Volume 25, Issue 5 I February 2010
Volume25,lssue5 I February2010
PharmaNote
Table 4. Commonly reported adverse reactions in saxagliptin clinical trials.2
ADVERSE EFFECT SAXAGLIPTIN 5 MG (%) PLACEBO (%)
Upper respiratory tract infection 7.7 7.6
Urinary tract infection 6.8 6.1
Headache 6.5 5.9
Sinusitis 2.6 1.6
Abdominal Pain 1.7 0.5
Gastroenteritis 2.3 0.9
Vomiting 2.3 1.3
Hypersensitivity-related event urticariaa or facial swelling) 1.5 0.4
2As summarized by manufacturer in package insert- pooled data from the 5 RCTs including monotherapy trials and add-on to metformin, TZD,
and glyburide.
ADVERSE DRUG REACTIONS
Due to adverse cardiovascular effects of rosiglita-
zone, the FDA now requires specific studies to prove a
new diabetic medication has no effect on cardiac con-
duction. In a double-blind, 4-way crossover, active
comparator RCT using moxifloxacin in 40 healthy sub-
jects, saxagliptin did not cause a clinically meaningful
prolongation of the QTc interval or effect the heart
rate at daily doses up to 40 mg.2 The FDA also requires
post-marketing studies to assess possible adverse ef-
fects on patients with comorbid cardiac conditions, as
phase III trials exclude patients with major comorbid-
ities.
From a pooled analysis of five Phase III RCT's, a
mean decrease of 100 and 120 cells/mcL relative to
placebo was seen after 24 weeks of therapy with
saxagliptin 5mg and 10mg respectively. The mean ab-
solute lymphocyte count at baseline was 2200 cells/
mcL. These decreases were seen in some patients
upon rechallenge. The decrease in absolute lympho-
cyte count did not cause any clinically significant prob-
lems, but may need to be considered in patients with
prolonged infection.
Hypoglycemia was reported more often when
saxagliptin 5 mg was added to glyburide versus gly-
buride monotherapy (14.6% versus 10.1%). However,
confirmed incidence of hypoglycemia (defined as
symptoms of hypoglycemia and fingerstick glucose of
< 50 mg/dL) was similar in saxagliptin add-on and gly-
buride only groups (0.8% and 0.7% respectively). The
incidence of hypoglycemia in other RCT's including
saxagliptin as monotherapy and in combination with
metformin or TZD was similar in treatment and pla-
cebo groups.2
Saxagliptin generally has no effect on weight.10
Other commonly reported adverse reactions to
saxagliptin are summarized in Table 4.
DOSING
Saxagliptin is dosed at 2.5 mg or 5 mg PO once
daily. The lower dose of saxagliptin 2.5 mg daily is pre-
ferred in patients with a CrCl of < 50 ml/min or in pa-
tients who are concurrently on a strong CYP3A4/5
inhibitor such as ketoconazole. Saxagliptin is not ap-
proved for use in children under the age of 18 as there
have been no studies in pediatric patients.
DOSING
The average monthly retail cost of Onglyza 2.5
mg is $217.22 ($212.99-$223.68), and of Onglyza 5
mgis $219.55 ($214.99-$223.68).
SUMMARY
Saxagliptin is a DPP-4 inhibitor with many simi-
larities to the other commercially available DPP-4 in-
hibitor, sitagliptin, including once daily administra-
tion, good tolerability and no evidence of cardiac toxic-
ity in diabetic patients without comorbidities.
Saxagliptin is effective in lowering Alc as monotherapy
and can cause additional lowering of Alc in patients
with uncontrolled diabetes when added to TZDs, sul-
fonylureas, and when added to or started with met-
formin.
REFERENCES
1. FDA Approves New Drug Treatment for Type 2
Diabetes. FDA News Release. http://www.fda.gov/
NewsEvents/Newsroom/PressAnnouncements/
Ph m oeVlue2,Ise5 eray21
Volume25,lssue5 I February2010
PharmaNote
ucml74780.htm Page last updated 7/31/2009.
2. Onglyza Package Insert. Last revised 7/2009.
3. Deacon CF, Holst JJ. Saxagliptin: a new dipeptidyl
peptidase-4 inhibitor for the treatment of type 2
diabetes. Adv Ther 2009;26(5):488-99.
4. Drucker DJ, Nauck MA. The incretin system: gluca-
gon-like peptide-1 receptor agonists and dipepti-
dyl peptidase-4 inhibitors in type 2 diabetes. Lan-
cet 2006;368:1696-705.
5. Rosenstock J, Aguilar-Salinas C, Klein E, et al. Ef-
fect of saxagliptin monotherapy in treatment-naive
patients with type 2 diabetes. Curr Med Research
and Opinion 2009;25:10:2401-11.
6. Jadzinsky M, Pftitzner A, Paz-Pacheco E, Xu Z, Allen
E, Chen R for the CV181-039 Investigators.
Saxagliptin given in combination with metformin
as initial therapy improves glycemic control in pa-
tients with type 2 diabetes compared with either
monotherapy: a randomized controlled trial. Dia-
betes Obes Metab 2009;11(6):611-22.
7. Defronzo RA, Hissa MN, Garber AJ, et al for the
Saxagliptin 014 Study Group. The efficacy and
safety of saxagliptin when added to metformin
therapy in patients with inadequately controlled
type 2 diabetes with metformin alone. Diabetes
Care 2009;32:1649-55.
8. Hollander P, Allen E, Li J, Chen R. Saxagliptin added
to a thiazolidinedione improves glycemic control
in patients with inadequately controlled type 2
diabetes [abstract]. Diabetologia 2008;51(suppl
1.):S342.
9. Chacra AR, Tan GH, Apanovitch A, et al for the
CV181-040 Investigators. Saxagliptin added to a
submaximal dose of sulphonylurea improves gly-
caemic control compared with uptitration of sul-
phonylurea in patients with type 2 diabetes: a ran-
domized controlled trial. Int J Clin Pract 2009;63
(9):1395-1406.
10. Dhillon S, Weber J. Adis Drug Profile: Saxagliptin.
Drugs 2009;69(15)2103-14.
11. Ahren B. Clinical results of treating type 2 diabetic
patients with sitagliptin, vildagliptin or
saxagliptin-diabetes control and potential ad-
verse events. Best Pract Res Clin Endocrinol Metab
2009;23(4):487-98.
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