CLINICAL PHARMACOLOGY
Mechanism of Action
Increased concentrations of the incretin
hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic
polypeptide (GIP) are released into the bloodstream from the small intestine
in response to meals. These hormones cause insulin release from the pancreatic
beta cells in a glucose-dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretion
from pancreatic alpha cells, reducing hepatic glucose production. In patients
with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin
response to GLP-1 is preserved. Saxagliptin is a competitive DPP4 inhibitor
that slows the inactivation of the incretin hormones, thereby increasing their
bloodstream concentrations and reducing fasting and postprandial glucose concentrations
in a glucose-dependent manner in patients with type 2 diabetes mellitus.
Pharmacodynamics
In patients with type 2 diabetes mellitus,
administration of ONGLYZA inhibits DPP4 enzyme activity for a 24-hour period.
After an oral glucose load or a meal, this DPP4 inhibition resulted in a 2-
to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased
glucagon concentrations, and increased glucose-dependent insulin secretion
from pancreatic beta cells. The rise in insulin and decrease in glucagon were
associated with lower fasting glucose concentrations and reduced glucose excursion
following an oral glucose load or a meal.
Cardiac Electrophysiology
In a randomized, double-blind, placebo-controlled,
4-way crossover, active comparator study using moxifloxacin in 40 healthy
subjects, ONGLYZA was not associated with clinically meaningful prolongation
of the QTc interval or heart rate at daily doses up to 40 mg (8 times the
MRHD).
Pharmacokinetics
The pharmacokinetics of saxagliptin
and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects
and in patients with type 2 diabetes mellitus. The Cmax and
AUC values of saxagliptin and its active metabolite increased proportionally
in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin
to healthy subjects, the mean plasma AUC values for saxagliptin and its active
metabolite were 78 ng•h/mL and 214 ng•h/mL, respectively. The corresponding
plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively.
The average variability (%CV) for AUC and Cmax for
both saxagliptin and its active metabolite was less than 25%.
No
appreciable accumulation of either saxagliptin or its active metabolite was
observed with repeated once-daily dosing at any dose level. No dose- and time-dependence
were observed in the clearance of saxagliptin and its active metabolite over
14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to
400 mg.
Absorption
The median time to maximum concentration
(Tmax) following the 5 mg once daily dose was 2 hours
for saxagliptin and 4 hours for its active metabolite. Administration with
a high-fat meal resulted in an increase in Tmax of
saxagliptin by approximately 20 minutes as compared to fasted conditions.
There was a 27% increase in the AUC of saxagliptin when given with a meal
as compared to fasted conditions. ONGLYZA may be administered with or without
food.
Distribution
The in vitro protein
binding of saxagliptin and its active metabolite in human serum is negligible.
Therefore, changes in blood protein levels in various disease states (e.g.,
renal or hepatic impairment) are not expected to alter the disposition of
saxagliptin.
Metabolism
The metabolism of saxagliptin is
primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite
of saxagliptin is also a DPP4 inhibitor, which is one-half as potent as saxagliptin.
Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics
of saxagliptin and its active metabolite. [See
Drug
Interactions (7)
.]
Excretion
Saxagliptin is eliminated by both
renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin,
24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its
active metabolite, and total radioactivity, respectively. The average renal
clearance of saxagliptin (~230 mL/min) was greater than the average estimated
glomerular filtration rate (~120 mL/min), suggesting some active renal excretion.
A total of 22% of the administered radioactivity was recovered in feces representing
the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug
from the gastrointestinal tract. Following a single oral dose of ONGLYZA 5
mg to healthy subjects, the mean plasma terminal half-life (t1/2)
for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.
Specific Populations
Renal Impairment
A single-dose, open-label study was
conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in
subjects with varying degrees of chronic renal impairment (N=8 per group)
compared to subjects with normal renal function. The study included patients
with renal impairment classified on the basis of creatinine clearance as mild
(>50 to ≤80 mL/min), moderate (30 to ≤50 mL/min), and severe (<30 mL/min),
as well as patients with end-stage renal disease on hemodialysis. Creatinine
clearance was estimated from serum creatinine based on the Cockcroft-Gault
formula:
CrCl = |
[140 − age (years)] × weight (kg) |
{× 0.85 for female patients} |
|
[72 × serum creatinine (mg/dL)] |
|
The degree of renal impairment did not affect the Cmax of
saxagliptin or its active metabolite. In subjects with mild renal impairment,
the AUC values of saxagliptin and its active metabolite were 20% and 70%
higher, respectively, than AUC values in subjects with normal renal function.
Because increases of this magnitude are not considered to be clinically relevant,
dosage adjustment in patients with mild renal impairment is not recommended.
In subjects with moderate or severe renal impairment, the AUC values of saxagliptin
and its active metabolite were up to 2.1- and 4.5-fold higher, respectively,
than AUC values in subjects with normal renal function. To achieve plasma
exposures of saxagliptin and its active metabolite similar to those in patients
with normal renal function, the recommended dose is 2.5 mg once daily in patients
with moderate and severe renal impairment, as well as in patients with end-stage
renal disease requiring hemodialysis. Saxagliptin is removed by hemodialysis.
Hepatic Impairment
In subjects with hepatic impairment
(Child-Pugh classes A, B, and C), mean Cmax and AUC
of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy
matched controls following administration of a single 10 mg dose of saxagliptin.
The corresponding Cmax and AUC of the active metabolite
were up to 59% and 33% lower, respectively, compared to healthy matched controls.
These differences are not considered to be clinically meaningful. No dosage
adjustment is recommended for patients with hepatic impairment.
Body Mass Index
No dosage adjustment is recommended
based on body mass index (BMI) which was not identified as a significant covariate
on the apparent clearance of saxagliptin or its active metabolite in the population
pharmacokinetic analysis.
Gender
No
dosage adjustment is recommended based on gender. There were no differences
observed in saxagliptin pharmacokinetics between males and females. Compared
to males, females had approximately 25% higher exposure values for the active
metabolite than males, but this difference is unlikely to be of clinical relevance.
Gender was not identified as a significant covariate on the apparent clearance
of saxagliptin and its active metabolite in the population pharmacokinetic
analysis.
Geriatric
No dosage adjustment is recommended
based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher
geometric mean Cmax and geometric mean AUC values,
respectively, for saxagliptin than young subjects (18-40 years). Differences
in active metabolite pharmacokinetics between elderly and young subjects generally
reflected the differences observed in saxagliptin pharmacokinetics. The difference
between the pharmacokinetics of saxagliptin and the active metabolite in young
and elderly subjects is likely due to multiple factors including declining
renal function and metabolic capacity with increasing age. Age was not identified
as a significant covariate on the apparent clearance of saxagliptin and its
active metabolite in the population pharmacokinetic analysis.
Pediatric
Studies characterizing the pharmacokinetics
of saxagliptin in pediatric patients have not been performed.
Race and Ethnicity
No dosage adjustment is recommended
based on race. The population pharmacokinetic analysis compared the pharmacokinetics
of saxagliptin and its active metabolite in 309 Caucasian subjects with 105
non-Caucasian subjects (consisting of six racial groups). No significant difference
in the pharmacokinetics of saxagliptin and its active metabolite were detected
between these two populations.
Drug-Drug Interactions
In Vitro Assessment of Drug Interactions
The metabolism of saxagliptin is primarily
mediated by CYP3A4/5.
In in vitro studies,
saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9,
2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin
is not expected to alter the metabolic clearance of coadministered drugs that
are metabolized by these enzymes. Saxagliptin is a P-glycoprotein (P-gp) substrate
but is not a significant inhibitor or inducer of P-gp.
In Vivo Assessment of Drug Interactions
Table 3: Effect of Coadministered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin
Coadministered Drug |
Dose of Coadministered Drug* |
Dosing of Saxagliptin* |
Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00
|
|
|
|
|
AUC†
|
Cmax
|
* Single dose unless otherwise noted |
† AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses |
‡ Results exclude one subject |
§ The plasma dipeptidyl peptidase-4 (DPP4) activity inhibition over a 24-hour dose interval was not affected by rifampin. |
ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting |
No dosing adjustments required for the following:
|
Metformin |
1000 mg |
100 mg |
saxagliptin 5-hydroxy saxagliptin |
0.98 0.99 |
0.79 0.88 |
Glyburide |
5 mg |
10 mg |
saxagliptin 5-hydroxy saxagliptin |
0.98 ND |
1.08 ND |
Pioglitazone‡
|
45 mg QD for 10 days |
10 mg QD for 5 days |
saxagliptin 5-hydroxy saxagliptin |
1.11 ND |
1.11 ND |
Digoxin |
0.25 mg q6h first day followed by q12h second day followed by QD for 5 days |
10 mg QD for 7 days |
saxagliptin 5-hydroxy saxagliptin |
1.05 1.06 |
0.99 1.02 |
Simvastatin |
40 mg QD for 8 days |
10 mg QD for 4 days |
saxagliptin 5-hydroxy saxagliptin |
1.12 1.02 |
1.21 1.08 |
Diltiazem |
360 mg LA QD for 9 days |
10 mg |
saxagliptin 5-hydroxy saxagliptin |
2.09 0.66 |
1.63 0.57 |
Rifampin§
|
600 mg QD for 6 days |
5 mg |
saxagliptin 5-hydroxy saxagliptin |
0.24 1.03 |
0.47 1.39 |
Omeprazole |
40 mg QD for 5 days |
10 mg |
saxagliptin 5-hydroxy saxagliptin |
1.13 ND |
0.98 ND |
Aluminum hydroxide + magnesium hydroxide + simethicone |
aluminum hydroxide: 2400 mg magnesium hydroxide: 2400 mg simethicone: 240 mg |
10 mg |
saxagliptin 5-hydroxy saxagliptin |
0.97 ND |
0.74 ND |
Famotidine |
40 mg |
10 mg |
saxagliptin 5-hydroxy saxagliptin |
1.03 ND |
1.14 ND |
Limit ONGLYZA dose to 2.5 mg once daily when coadministered with strong CYP3A4/5 inhibitors:
|
Ketoconazole |
200 mg BID for 9 days |
100 mg |
saxagliptin 5-hydroxy saxagliptin |
2.45 0.12 |
1.62 0.05 |
Ketoconazole |
200 mg BID for 7 days |
20 mg |
saxagliptin 5-hydroxy saxagliptin |
3.67 ND |
2.44 ND |
Table 4: Effect of Saxagliptin on Systemic Exposures of Coadministered Drugs
Coadministered Drug |
Dose of Coadministered Drug* |
Dosing of Saxagliptin* |
Geometric Mean Ratio (ratio with/without saxagliptin) No Effect = 1.00
|
|
|
|
|
AUC†
|
Cmax
|
* Single dose unless otherwise noted |
† AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses |
‡ Results include all subjects |
ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting |
No dosing adjustments required for the following:
|
Metformin |
1000 mg |
100 mg |
metformin |
1.20 |
1.09 |
Glyburide |
5 mg |
10 mg |
glyburide |
1.06 |
1.16 |
Pioglitazone‡
|
45 mg QD for 10 days |
10 mg QD for 5 days |
pioglitazone hydroxy-pioglitazone |
1.08 ND |
1.14 ND |
Digoxin |
0.25 mg q6h first day followed by q12h second day followed by QD for 5 days |
10 mg QD for 7 days |
digoxin |
1.06 |
1.09 |
Simvastatin |
40 mg QD for 8 days |
10 mg QD for 4 days |
simvastatin simvastatin acid |
1.04 1.16 |
0.88 1.00 |
Diltiazem |
360 mg LA QD for 9 days |
10 mg |
diltiazem |
1.10 |
1.16 |
Ketoconazole |
200 mg BID for 9 days |
100 mg |
ketoconazole |
0.87 |
0.84 |
Ethinyl estradiol and Norgestimate |
ethinyl estradiol 0.035 mg and norgestimate 0.250 mg
for 21 days |
5 mg QD for 21 days |
ethinyl estradiol norelgestromin norgestrel |
1.07 1.10 1.13
|
0.98 1.09 1.17
|
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Saxagliptin did not induce tumors
in either mice (50, 250, and 600 mg/kg) or rats (25, 75, 150, and 300 mg/kg)
at the highest doses evaluated. The highest doses evaluated in mice were equivalent
to approximately 870 (males) and 1165 (females) times the human exposure at
the MRHD of 5 mg/day. In rats, exposures were approximately 355 (males) and
2217 (females) times the MRHD.
Saxagliptin was not mutagenic
or clastogenic with or without metabolic activation in an in vitro Ames
bacterial assay, an in vitro cytogenetics assay in primary
human lymphocytes, an in vivo oral micronucleus assay in
rats, an in vivo oral DNA repair study in rats, and an oral in
vivo/in vitro cytogenetics study in rat peripheral
blood lymphocytes. The active metabolite was not mutagenic in an in
vitro Ames bacterial assay.
In a rat fertility
study, males were treated with oral gavage doses for 2 weeks prior to mating,
during mating, and up to scheduled termination (approximately 4 weeks total)
and females were treated with oral gavage doses for 2 weeks prior to mating
through gestation day 7. No adverse effects on fertility were observed at
exposures of approximately 603 (males) and 776 (females) times the MRHD. Higher
doses that elicited maternal toxicity also increased fetal resorptions (approximately
2069 and 6138 times the MRHD). Additional effects on estrous cycling, fertility,
ovulation, and implantation were observed at approximately 6138 times the
MRHD.
Animal Toxicology
Saxagliptin produced adverse skin
changes in the extremities of cynomolgus monkeys (scabs and/or ulceration
of tail, digits, scrotum, and/or nose). Skin lesions were reversible at ≥20
times the MRHD but in some cases were irreversible and necrotizing at higher
exposures. Adverse skin changes were not observed at exposures similar to
(1 to 3 times) the MRHD of 5 mg. Clinical correlates to skin lesions in monkeys
have not been observed in human clinical trials of saxagliptin.
|
CLINICAL STUDIES
ONGLYZA has been studied as monotherapy
and in combination with metformin, glyburide, and thiazolidinedione (pioglitazone
and rosiglitazone) therapy.
A total of 4148 patients with type 2 diabetes
mellitus were randomized in six, double-blind, controlled clinical trials
conducted to evaluate the safety and glycemic efficacy of ONGLYZA. A total
of 3021 patients in these trials were treated with ONGLYZA. In these trials,
the mean age was 54 years, and 71% of patients were Caucasian, 16% were Asian,
4% were black, and 9% were of other racial groups. An additional 423 patients,
including 315 who received ONGLYZA, participated in a placebo-controlled,
dose-ranging study of 6 to 12 weeks in duration.
In
these six, double-blind trials, ONGLYZA was evaluated at doses of 2.5 mg and
5 mg once daily. Three of these trials also evaluated a saxagliptin dose of
10 mg daily. The 10 mg daily dose of saxagliptin did not provide greater efficacy
than the 5 mg daily dose. Treatment with ONGLYZA at all doses produced clinically
relevant and statistically significant improvements in hemoglobin A1c (A1C),
fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG) following
a standard oral glucose tolerance test (OGTT), compared to control. Reductions
in A1C were seen across subgroups including gender, age, race, and baseline
BMI.
ONGLYZA was not associated with significant changes
from baseline in body weight or fasting serum lipids compared to placebo.
ONGLYZA has also been evaluated in three additional trials in patients with type 2 diabetes: an active-controlled trial comparing add-on therapy with ONGLYZA to glipizide in 858 patients inadequately controlled on metformin alone, a trial comparing ONGLYZA to placebo in 455 patients inadequately controlled on insulin alone or on insulin in combination with metformin, and a trial comparing ONGLYZA to placebo in 170 patients with type 2 diabetes and moderate or severe renal impairment or ESRD.
Monotherapy
A total of 766 patients with type
2 diabetes inadequately controlled on diet and exercise (A1C ≥7% to ≤10%)
participated in two 24-week, double-blind, placebo-controlled trials evaluating
the efficacy and safety of ONGLYZA monotherapy.
In the
first trial, following a 2-week single-blind diet, exercise, and placebo lead-in
period, 401 patients were randomized to 2.5 mg, 5 mg, or 10 mg of ONGLYZA
or placebo. Patients who failed to meet specific glycemic goals during the
study were treated with metformin rescue therapy, added on to placebo or ONGLYZA.
Efficacy was evaluated at the last measurement prior to rescue therapy for
patients needing rescue. Dose titration of ONGLYZA was not permitted.
Treatment
with ONGLYZA 2.5 mg and 5 mg daily provided significant improvements in A1C,
FPG, and PPG compared to placebo (Table 5). The percentage of patients who
discontinued for lack of glycemic control or who were rescued for meeting
prespecified glycemic criteria was 16% in the ONGLYZA 2.5 mg treatment group,
20% in the ONGLYZA 5 mg treatment group, and 26% in the placebo group.
Table 5: Glycemic Parameters at Week 24 in a Placebo-Controlled Study
of ONGLYZA Monotherapy in Patients with Type 2 Diabetes*
Efficacy
Parameter
|
ONGLYZA 2.5
mg N=102
|
ONGLYZA 5
mg N=106
|
Placebo
N=95
|
* Intent-to-treat population
using last observation on study or last observation prior to metformin rescue
therapy for patients needing rescue. |
† Least
squares mean adjusted for baseline value. |
‡ p-value
<0.0001 compared to placebo |
§ p-value
<0.05 compared to placebo |
¶ Significance
was not tested for the 2-hour PPG for the 2.5 mg dose of ONGLYZA. |
Hemoglobin A1C (%)
|
N=100
|
N=103
|
N=92
|
Baseline (mean) |
7.9 |
8.0 |
7.9 |
Change from
baseline (adjusted mean†) |
−0.4 |
−0.5 |
+0.2 |
Difference
from placebo (adjusted mean†) |
−0.6‡
|
−0.6‡
|
|
95%
Confidence Interval |
(−0.9, −0.3) |
(−0.9, −0.4) |
|
Percent
of patients achieving A1C <7% |
35% (35/100) |
38%§ (39/103) |
24% (22/92) |
Fasting Plasma Glucose (mg/dL)
|
N=101
|
N=105
|
N=92
|
Baseline (mean) |
178 |
171 |
172 |
Change from
baseline (adjusted mean†) |
−15 |
−9 |
+6 |
Difference
from placebo (adjusted mean†) |
−21§
|
−15§
|
|
95%
Confidence Interval |
(−31, −10) |
(−25, −4) |
|
2-hour Postprandial Glucose (mg/dL)
|
N=78
|
N=84
|
N=71
|
Baseline (mean) |
279 |
278 |
283 |
Change from
baseline (adjusted mean†) |
−45 |
−43 |
−6 |
Difference
from placebo (adjusted mean†) |
−39¶
|
−37§
|
|
95%
Confidence Interval |
(−61, −16) |
(−59, −15) |
|
A second 24-week monotherapy trial
was conducted to assess a range of dosing regimens for ONGLYZA. Treatment-naive
patients with inadequately controlled diabetes (A1C ≥7% to ≤10%) underwent
a 2-week, single-blind diet, exercise, and placebo lead-in period. A total
of 365 patients were randomized to 2.5 mg every morning, 5 mg every morning,
2.5 mg with possible titration to 5 mg every morning, or 5 mg every evening
of ONGLYZA, or placebo. Patients who failed to meet specific glycemic goals
during the study were treated with metformin rescue therapy added on to placebo
or ONGLYZA; the number of patients randomized per treatment group ranged from
71 to 74.
Treatment with either ONGLYZA 5 mg every morning
or 5 mg every evening provided significant improvements in A1C versus placebo
(mean placebo-corrected reductions of −0.4% and −0.3%, respectively). Treatment
with ONGLYZA 2.5 mg every morning also provided significant improvement in
A1C versus placebo (mean placebo-corrected reduction of −0.4%).
Combination Therapy
Add-On Combination Therapy with Metformin
A total of 743 patients with type 2 diabetes
participated in this 24-week, randomized, double-blind, placebo-controlled
trial to evaluate the efficacy and safety of ONGLYZA in combination with metformin
in patients with inadequate glycemic control (A1C ≥7% and ≤10%) on metformin
alone. To qualify for enrollment, patients were required to be on a stable
dose of metformin (1500-2550 mg daily) for at least 8 weeks.
Patients
who met eligibility criteria were enrolled in a single-blind, 2-week, dietary
and exercise placebo lead-in period during which patients received metformin
at their pre-study dose, up to 2500 mg daily.
Following the lead-in period, eligible patients were randomized to 2.5 mg,
5 mg, or 10 mg of ONGLYZA or placebo in addition to their current dose of
open-label metformin. Patients who failed to meet specific glycemic goals
during the study were treated with pioglitazone rescue therapy, added on to
existing study medications. Dose titrations of ONGLYZA and metformin were
not permitted.
ONGLYZA 2.5 mg and 5 mg add-on to metformin
provided significant improvements in A1C, FPG, and PPG compared with placebo
add-on to metformin (Table 6). Mean changes from baseline for A1C over time
and at endpoint are shown in Figure 1. The proportion of patients who discontinued
for lack of glycemic control or who were rescued for meeting prespecified
glycemic criteria was 15% in the ONGLYZA 2.5 mg add-on to metformin group,
13% in the ONGLYZA 5 mg add-on to metformin group, and 27% in the placebo
add-on to metformin group.
Table 6: Glycemic Parameters at Week 24 in a Placebo-Controlled Study
of ONGLYZA as Add-On Combination Therapy with Metformin*
Efficacy
Parameter
|
ONGLYZA
2.5 mg + Metformin N=192
|
ONGLYZA
5 mg + Metformin N=191
|
Placebo + Metformin N=179
|
* Intent-to-treat population
using last observation on study or last observation prior to pioglitazone
rescue therapy for patients needing rescue. |
† Least
squares mean adjusted for baseline value. |
‡ p-value
<0.0001 compared to placebo + metformin |
§ p-value
<0.05 compared to placebo + metformin |
Hemoglobin A1C (%)
|
N=186
|
N=186
|
N=175
|
Baseline (mean) |
8.1 |
8.1 |
8.1 |
Change from
baseline (adjusted mean†) |
−0.6 |
−0.7 |
+0.1 |
Difference
from placebo (adjusted mean†) |
−0.7‡
|
−0.8‡
|
|
95%
Confidence Interval |
(−0.9, −0.5) |
(−1.0, −0.6) |
|
Percent
of patients achieving A1C <7% |
37%§ (69/186) |
44%§ (81/186) |
17% (29/175) |
Fasting Plasma Glucose (mg/dL)
|
N=188
|
N=187
|
N=176
|
Baseline (mean) |
174 |
179 |
175 |
Change from
baseline (adjusted mean†) |
−14 |
−22 |
+1 |
Difference
from placebo (adjusted mean†) |
−16§
|
−23§
|
|
95%
Confidence Interval |
(−23, −9) |
(−30, −16) |
|
2-hour Postprandial Glucose (mg/dL)
|
N=155
|
N=155
|
N=135
|
Baseline (mean) |
294 |
296 |
295 |
Change from
baseline (adjusted mean†) |
−62 |
−58 |
−18 |
Difference
from placebo (adjusted mean†) |
−44§
|
−40§
|
|
95%
Confidence Interval |
(−60, −27) |
(−56, −24) |
|
Figure 1: Mean Change from Baseline in A1C in a Placebo-Controlled
Trial of ONGLYZA as Add-On Combination Therapy with Metformin*
* Includes patients with a baseline
and week 24 value. Week 24 (LOCF) includes intent-to-treat population
using last observation on study prior to pioglitazone rescue therapy for
patients needing rescue. Mean change from baseline is adjusted for baseline
value. |
|
Add-On Combination Therapy with a Thiazolidinedione
A total of 565 patients with type
2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled
trial to evaluate the efficacy and safety of ONGLYZA in combination with a
thiazolidinedione (TZD) in patients with inadequate glycemic control (A1C
≥7% to ≤10.5%) on TZD alone. To qualify for enrollment, patients were required
to be on a stable dose of pioglitazone (30-45 mg once daily) or rosiglitazone
(4 mg once daily or 8 mg either once daily or in two divided doses of 4 mg)
for at least 12 weeks.
Patients who met eligibility
criteria were enrolled in a single-blind, 2-week, dietary and exercise placebo
lead-in period during which patients received TZD at their pre-study dose. Following the lead-in period, eligible patients
were randomized to 2.5 mg or 5 mg of ONGLYZA or placebo in
addition to their current dose of TZD. Patients who failed to meet specific
glycemic goals during the study were treated with metformin rescue, added
on to existing study medications. Dose titration of ONGLYZA or TZD was not
permitted during the study. A change in TZD regimen from rosiglitazone to
pioglitazone at specified, equivalent therapeutic doses was permitted at the
investigator’s discretion if believed to be medically appropriate.
ONGLYZA
2.5 mg and 5 mg add-on to TZD provided significant improvements in A1C, FPG,
and PPG compared with placebo add-on to TZD (Table 7). The proportion of patients
who discontinued for lack of glycemic control or who were rescued for meeting
prespecified glycemic criteria was 10% in the ONGLYZA 2.5 mg add-on to TZD
group, 6% for the ONGLYZA 5 mg add-on to TZD group, and 10% in the placebo
add-on to TZD group.
Table 7: Glycemic Parameters at Week 24 in a Placebo-Controlled Study
of ONGLYZA as Add-On Combination Therapy with a Thiazolidinedione*
Efficacy
Parameter
|
ONGLYZA
2.5 mg + TZD N=195
|
ONGLYZA
5 mg + TZD N=186
|
Placebo + TZD N=184
|
* Intent-to-treat population
using last observation on study or last observation prior to metformin rescue
therapy for patients needing rescue. |
† Least
squares mean adjusted for baseline value. |
‡ p-value
<0.0001 compared to placebo + TZD |
§ p-value
<0.05 compared to placebo + TZD |
Hemoglobin A1C (%)
|
N=192
|
N=183
|
N=180
|
Baseline (mean) |
8.3 |
8.4 |
8.2 |
Change from
baseline (adjusted mean†) |
−0.7 |
−0.9 |
−0.3 |
Difference
from placebo (adjusted mean†) |
−0.4§
|
−0.6‡
|
|
95%
Confidence Interval |
(−0.6, −0.2) |
(−0.8, −0.4) |
|
Percent
of patients achieving A1C <7% |
42%§ (81/192) |
42%§ (77/184) |
26% (46/180) |
Fasting Plasma Glucose (mg/dL)
|
N=193
|
N=185
|
N=181
|
Baseline (mean) |
163 |
160 |
162 |
Change from
baseline (adjusted mean†) |
−14 |
−17 |
−3 |
Difference
from placebo (adjusted mean†) |
−12§
|
−15§
|
|
95%
Confidence Interval |
(−20, −3) |
(−23, −6) |
|
2-hour Postprandial Glucose (mg/dL)
|
N=156
|
N=134
|
N=127
|
Baseline (mean) |
296 |
303 |
291 |
Change from
baseline (adjusted mean†) |
−55 |
−65 |
−15 |
Difference
from placebo (adjusted mean†) |
−40§
|
−50§
|
|
95%
Confidence Interval |
(−56, −24) |
(−66, −34) |
|
Add-On Combination Therapy with Glyburide
A total of 768 patients with type
2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled
trial to evaluate the efficacy and safety of ONGLYZA in combination with a
sulfonylurea (SU) in patients with inadequate glycemic control at enrollment
(A1C ≥7.5% to ≤10%) on a submaximal dose of SU alone. To qualify for enrollment,
patients were required to be on a submaximal dose of SU for 2 months or greater.
In this study, ONGLYZA in combination with a fixed, intermediate dose of SU
was compared to titration to a higher dose of SU.
Patients
who met eligibility criteria were enrolled in a single-blind, 4-week, dietary
and exercise lead-in period, and placed on glyburide 7.5 mg once daily. Following
the lead-in period, eligible patients with A1C ≥7% to ≤10% were randomized
to either 2.5 mg or 5 mg of ONGLYZA add-on to 7.5 mg glyburide or to placebo
plus a 10 mg total daily dose of glyburide. Patients who received placebo
were eligible to have glyburide up-titrated to a total daily dose of 15 mg.
Up-titration of glyburide was not permitted in patients who received ONGLYZA
2.5 mg or 5 mg. Glyburide could be down-titrated in any treatment group once
during the 24-week study period due to hypoglycemia as deemed necessary by
the investigator. Approximately 92% of patients in the placebo plus glyburide
group were up-titrated to a final total daily dose of 15 mg during the first
4 weeks of the study period. Patients who failed to meet specific glycemic
goals during the study were treated with metformin rescue, added on to existing
study medication. Dose titration of ONGLYZA was not permitted during the study.
In
combination with glyburide, ONGLYZA 2.5 mg and 5 mg provided significant improvements
in A1C, FPG, and PPG compared with the placebo plus up-titrated glyburide
group (Table 8). The proportion of patients who discontinued for lack of glycemic
control or who were rescued for meeting prespecified glycemic criteria was
18% in the ONGLYZA 2.5 mg add-on to glyburide group, 17% in the ONGLYZA 5
mg add-on to glyburide group, and 30% in the placebo plus up-titrated glyburide
group.
Table 8: Glycemic Parameters at Week 24 in a Placebo-Controlled Study
of ONGLYZA as Add-On Combination Therapy with Glyburide*
Efficacy
Parameter
|
ONGLYZA 2.5
mg + Glyburide 7.5 mg N=248
|
ONGLYZA 5
mg + Glyburide 7.5 mg N=253
|
Placebo
+ Up-Titrated
Glyburide N=267
|
* Intent-to-treat population
using last observation on study or last observation prior to metformin rescue
therapy for patients needing rescue. |
† Least
squares mean adjusted for baseline value. |
‡ p-value
<0.0001 compared to placebo + up-titrated glyburide |
§ p-value
<0.05 compared to placebo + up-titrated glyburide |
Hemoglobin A1C (%)
|
N=246
|
N=250
|
N=264
|
Baseline (mean) |
8.4 |
8.5 |
8.4 |
Change from
baseline (adjusted mean†) |
−0.5 |
−0.6 |
+0.1 |
Difference
from up-titrated glyburide (adjusted mean†) |
−0.6‡
|
−0.7‡
|
|
95%
Confidence Interval |
(−0.8, −0.5) |
(−0.9, −0.6) |
|
Percent
of patients achieving A1C <7% |
22%§ (55/246) |
23%§ (57/250) |
9% (24/264) |
Fasting Plasma Glucose (mg/dL)
|
N=247
|
N=252
|
N=265
|
Baseline (mean) |
170 |
175 |
174 |
Change from
baseline (adjusted mean†) |
−7 |
−10 |
+1 |
Difference
from up-titrated glyburide (adjusted mean†) |
−8§
|
−10§
|
|
95%
Confidence Interval |
(−14, −1) |
(−17, −4) |
|
2-hour Postprandial Glucose (mg/dL)
|
N=195
|
N=202
|
N=206
|
Baseline (mean) |
309 |
315 |
323 |
Change from
baseline (adjusted mean†) |
−31 |
−34 |
+8 |
Difference
from up-titrated glyburide (adjusted mean†) |
−38§
|
−42§
|
|
95%
Confidence Interval |
(−50, −27) |
(−53, −31) |
|
Coadministration with Metformin in Treatment-Naive Patients
A total of 1306 treatment-naive patients
with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind,
active-controlled trial to evaluate the efficacy and safety of ONGLYZA coadministered
with metformin in patients with inadequate glycemic control (A1C ≥8% to ≤12%)
on diet and exercise alone. Patients were required to be treatment-naive to
be enrolled in this study.
Patients who met eligibility
criteria were enrolled in a single-blind, 1-week, dietary and exercise placebo
lead-in period. Patients were randomized to one of four treatment arms: ONGLYZA
5 mg + metformin 500 mg, saxagliptin 10 mg + metformin 500 mg, saxagliptin
10 mg + placebo, or metformin 500 mg + placebo. ONGLYZA was dosed once daily.
In the 3 treatment groups using metformin, the metformin dose was up-titrated
weekly in 500 mg per day increments, as tolerated, to a maximum of 2000 mg
per day based on FPG. Patients who failed to meet specific glycemic goals
during the studies were treated with pioglitazone rescue as add-on therapy.
Coadministration
of ONGLYZA 5 mg plus metformin provided significant improvements in A1C, FPG,
and PPG compared with placebo plus metformin (Table 9).
Table 9: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial
of ONGLYZA Coadministration with Metformin in Treatment-Naive Patients*
Efficacy
Parameter
|
ONGLYZA
5 mg + Metformin N=320
|
Placebo + Metformin N=328
|
* Intent-to-treat population
using last observation on study or last observation prior to pioglitazone
rescue therapy for patients needing rescue. |
† Least
squares mean adjusted for baseline value. |
‡ p-value
<0.0001 compared to placebo + metformin |
§ p-value
<0.05 compared to placebo + metformin |
Hemoglobin A1C (%)
|
N=306
|
N=313
|
Baseline (mean) |
9.4 |
9.4 |
Change from
baseline (adjusted mean†) |
−2.5 |
−2.0 |
Difference
from placebo + metformin (adjusted mean†) |
−0.5‡
|
|
95%
Confidence Interval |
(−0.7, −0.4) |
|
Percent
of patients achieving A1C <7% |
60%§ (185/307) |
41% (129/314) |
Fasting Plasma Glucose (mg/dL)
|
N=315
|
N=320
|
Baseline (mean) |
199 |
199 |
Change from
baseline (adjusted mean†) |
−60 |
−47 |
Difference
from placebo + metformin (adjusted mean†) |
−13§
|
|
95%
Confidence Interval |
(−19, −6) |
|
2-hour Postprandial Glucose (mg/dL)
|
N=146
|
N=141
|
Baseline (mean) |
340 |
355 |
Change from
baseline (adjusted mean†) |
−138 |
−97 |
Difference
from placebo + metformin (adjusted mean†) |
−41§
|
|
95%
Confidence Interval |
(−57, −25) |
|
Add-On Combination Therapy with Metformin versus Glipizide Add-On Combination Therapy with Metformin
In this 52-week, active-controlled trial, a total of 858 patients with type 2 diabetes and inadequate glycemic control (A1C >6.5% and ≤10%) on metformin alone were randomized to double-blind add-on therapy with ONGLYZA or glipizide. Patients were required to be on a stable dose of metformin (at least 1500 mg daily) for at least 8 weeks prior to enrollment.
Patients who met eligibility criteria were enrolled in a single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received metformin (1500-3000 mg based on their pre-study dose). Following the lead-in period, eligible patients were randomized to 5 mg of ONGLYZA or 5 mg of glipizide in addition to their current dose of open-label metformin. Patients in the glipizide plus metformin group underwent blinded titration of the glipizide dose during the first 18 weeks of the trial up to a maximum glipizide dose of 20 mg per day. Titration was based on a goal FPG ≤110 mg/dL or the highest tolerable glipizide dose. Fifty percent (50%) of the glipizide-treated patients were titrated to the 20-mg daily dose; 21% of the glipizide-treated patients had a final daily glipizide dose of 5 mg or less. The mean final daily dose of glipizide was 15 mg.
After 52 weeks of treatment, ONGLYZA and glipizide resulted in similar mean reductions from baseline in A1C when added to metformin therapy (Table 10). This conclusion may be limited to patients with baseline A1C comparable to those in the trial (91% of patients had baseline A1C <9%).
From a baseline mean body weight of 89 kg, there was a statistically significant mean reduction of 1.1 kg in patients treated with ONGLYZA compared to a mean weight gain of 1.1 kg in patients treated with glipizide (p<0.0001).
Table 10: Glycemic Parameters at Week 52 in an Active-Controlled Trial of ONGLYZA versus Glipizide in Combination with Metformin*
Efficacy Parameter
|
ONGLYZA 5 mg + Metformin N=428
|
Titrated Glipizide + Metformin N=430
|
* Intent-to-treat population using last observation on study. |
† Least squares mean adjusted for baseline value. |
‡ Saxagliptin + metformin is considered non-inferior to glipizide + metformin because the upper limit of this confidence interval is less than the prespecified non-inferiority margin of 0.35%. |
§ Significance not tested. |
Hemoglobin A1C (%)
|
N=423
|
N=423
|
Baseline (mean) |
7.7 |
7.6 |
Change from baseline (adjusted mean†) |
−0.6 |
−0.7 |
Difference from glipizide + metformin (adjusted mean†) |
0.1
|
|
95% Confidence Interval |
(−0.02, 0.2)‡
|
|
Fasting Plasma Glucose (mg/dL)
|
N=420
|
N=420
|
Baseline (mean) |
162 |
161 |
Change from baseline (adjusted mean†) |
−9 |
−16 |
Difference from glipizide + metformin (adjusted mean†) |
6 |
|
95% Confidence Interval |
(2, 11)§
|
|
Add-On Combination Therapy with Insulin (with or without metformin)
A total of 455 patients with type 2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with insulin in patients with inadequate glycemic control (A1C ≥7.5% and ≤11%) on insulin alone (N=141) or on insulin in combination with a stable dose of metformin (N=314). Patients were required to be on a stable dose of insulin (≥30 units to ≤150 units daily) with ≤20% variation in total daily dose for ≥8 weeks prior to screening. Patients entered the trial on intermediate- or long-acting (basal) insulin or premixed insulin. Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of a premixed insulin.
Patients who met eligibility criteria were enrolled in a single-blind, four-week, dietary and exercise placebo lead-in period during which patients received insulin (and metformin if applicable) at their pretrial dose(s). Following the lead-in period, eligible patients were randomized to add-on therapy with either ONGLYZA 5 mg or placebo. Doses of the antidiabetic therapies were to remain stable but patients were rescued and allowed to adjust the insulin regimen if specific glycemic goals were not met or if the investigator learned that the patient had self-increased the insulin dose by >20%. Data after rescue were excluded from the primary efficacy analyses.
Add-on therapy with ONGLYZA 5 mg provided significant improvements from baseline to Week 24 in A1C and PPG compared with add-on placebo (Table 11). Similar mean reductions in A1C versus placebo were observed for patients using ONGLYZA 5 mg add-on to insulin alone and ONGLYZA 5 mg add-on to insulin in combination with metformin (−0.4% and −0.4%, respectively). The percentage of patients who discontinued for lack of glycemic control or who were rescued was 23% in the ONGLYZA group and 32% in the placebo group.
The mean daily insulin dose at baseline was 53 units in patients treated with ONGLYZA 5 mg and 55 units in patients treated with placebo. The mean change from baseline in daily dose of insulin was 2 units for the ONGLYZA 5 mg group and 5 units for the placebo group.
Table 11: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with Insulin*
Efficacy
Parameter
|
ONGLYZA
5 mg + Insulin (+/− Metformin) N=304
|
Placebo + Insulin (+/− Metformin) N=151
|
* Intent-to-treat population using last observation on study or last observation prior to insulin rescue therapy for patients needing rescue. |
† Least squares mean adjusted for baseline value and metformin use at baseline. |
‡ p-value
<0.0001 compared to placebo + insulin |
§ p-value <0.05 compared to placebo + insulin |
Hemoglobin A1C (%)
|
N=300
|
N=149
|
Baseline (mean) |
8.7 |
8.7 |
Change from
baseline (adjusted mean†) |
−0.7 |
−0.3 |
Difference
from placebo (adjusted mean†) |
−0.4‡
|
|
95%
Confidence Interval |
(−0.6, −0.2) |
|
Percent
of patients achieving A1C <7% |
17% (52/300) |
7% (10/149) |
Fasting Plasma Glucose (mg/dL)
|
N=300
|
N=149
|
Baseline (mean) |
173 |
173 |
Change from
baseline (adjusted mean†) |
−10 |
−6 |
Difference
from placebo (adjusted mean†) |
−4
|
|
95%
Confidence Interval |
(−13, 5) |
|
2-hour Postprandial Glucose (mg/dL)
|
N=262
|
N=129
|
Baseline (mean) |
251 |
255 |
Change from
baseline (adjusted mean†) |
−27 |
−4 |
Difference
from placebo (adjusted mean†) |
−23§
|
|
95%
Confidence Interval |
(−37, −9) |
|
Renal Impairment
A total of 170 patients participated in a 12-week, randomized, double-blind, placebo-controlled trial conducted to evaluate the efficacy and safety of ONGLYZA 2.5 mg once daily compared with placebo in patients with type 2 diabetes and moderate (n=90) or severe (n=41) renal impairment or ESRD (n=39). In this trial, 98% of the patients were using background antidiabetic medications (75% were using insulin and 31% were using oral antidiabetic medications, mostly sulfonylureas).
After 12 weeks of treatment, ONGLYZA 2.5 mg provided significant improvement in A1C compared to placebo (Table 12). In the subgroup of patients with ESRD, ONGLYZA and placebo resulted in comparable reductions in A1C from baseline to Week 12. This finding is inconclusive because the trial was not adequately powered to show efficacy within specific subgroups of renal impairment.
After 12 weeks of treatment, the mean change in FPG was −12 mg/dL with ONGLYZA 2.5 mg and −13 mg/dL with placebo. Compared to placebo, the mean change in FPG with ONGLYZA was −12 mg/dL in the subgroup of patients with moderate renal impairment, −4 mg/dL in the subgroup of patients with severe renal impairment, and +44 mg/dL in the subgroup of patients with ESRD. These findings are inconclusive because the trial was not adequately powered to show efficacy within specific subgroups of renal impairment.
Table 12: A1C at Week 12 in a Placebo-Controlled Trial of ONGLYZA in Patients with Renal Impairment*
Efficacy Parameter
|
ONGLYZA 2.5 mg N=85
|
Placebo N=85
|
* Intent-to-treat population using last observation on study. |
† Least squares mean adjusted for baseline value. |
‡ p-value <0.01 compared to placebo |
Hemoglobin A1C (%)
|
N=81
|
N=83
|
Baseline (mean) |
8.4 |
8.1 |
Change from baseline (adjusted mean†) |
−0.9 |
−0.4 |
Difference from placebo (adjusted mean†) |
−0.4‡
|
|
95% Confidence Interval |
(−0.7, −0.1) |
|
|