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Onglyza

"The U.S. Food and Drug Administration today approved Invokana (canagliflozin) tablets, used with diet and exercise, to improve glycemic control in adults with type 2 diabetes.

Type 2 diabetes is the most common form of the disease, affe"...

Onglyza

Onglyza

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]

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 (t½) 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 10 mg dosage is not an approved dosage. 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:

Males: (weight in kg) x (140 – age)
(72) x serum creatinine (mg/100 mL)
Females (0.85) x (above value)

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 10 mg dosage is not an approved dosage. 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.

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 Interaction Studies

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 Dosage of Coadministered Drug* Dosage of Saxagliptin* Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00
  AUC† Cmax
No dosing adjustments required for the following:
Metformin 1000 mg 100 mg Saxagliptin 0.98 0.79
5-hydroxy saxagliptin 0.99 0.88
Glyburide 5 mg 10 mg Saxagliptin 0.98 1.08
5-hydroxy saxagliptin ND ND
Pioglitazone‡ 45 mg QD for 10 days 10 mg QD for 5 days Saxagliptin 1.11 1.11
5-hydroxy saxagliptin ND 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 1.05 0.99
5-hydroxy saxagliptin 1.06 1.02
Simvastatin 40 mg QD for 8 days 10 mg QD for 4 days Saxagliptin 1.12 1.21
5-hydroxy saxagliptin 1.02 1.08
Diltiazem 360 mg LA QD for 9 days 10 mg Saxagliptin 2.09 1.63
5-hydroxy saxagliptin 0.66 0.57
Rifampin§ 600 mg QD for 6 days 5 mg Saxagliptin 0.24 0.47
5-hydroxy saxagliptin 1.03 1.39
Omeprazole 40 mg QD for 5 days 10 mg Saxagliptin 1.13 0.98
5-hydroxy saxagliptin ND ND
Aluminum hydroxide + magnesium hydroxide + simethicone aluminum hydroxide: 2400 mg magnesium hydroxide: 2400 mg simethicone: 240 mg 10 mg Saxagliptin 0.97 0.74
5-hydroxy saxagliptin ND ND
Famotidine 40 mg 10 mg Saxagliptin 1.03 1.14
5-hydroxy saxagliptin ND ND
Limit ONGLYZA dose to 2.5 mg once daily when coadministered with strong CYP3A4/5 inhibitors [see DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION]:
Ketoconazole 200 mg BID for 9 days 100 mg Saxagliptin 2.45 1.62
5-hydroxy saxagliptin 0.12 0.05
Ketoconazole 200 mg BID for 7 days 20 mg Saxagliptin 3.67 2.44
5-hydroxy saxagliptin ND ND
* 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

Table 4: Effect of Saxagliptin on Systemic Exposures of Coadministered Drugs

Coadministered Drug Dosage of Coadministered Drug* Dosage of Saxagliptin* Geometric Mean Ratio (ratio with/without saxagliptin) No Effect = 1.00
  AUC† Cmax
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 1.08 1.14
hydroxy-pioglitazone ND 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 1.04 0.88
simvastatin acid 1.16 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 1.07 0.98
norelgestromin 1.10 1.09
norgestrel 1.13 1.17
* 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

Animal Toxicology and/or Pharmacology

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. The 10 mg dosage is not an approved dosage. Treatment with ONGLYZA 5 mg and 2.5 mg 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 four 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, a trial comparing ONGLYZA to placebo in 257 patients inadequately controlled on metformin plus a sulfonylurea, 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. The 10 mg dosage is not an approved dosage. 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
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†) -391¶ -37§
   95% Confidence Interval (-61, -16) (-59, -15)
* 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
Ά Significance was not tested for the 2-hour PPG for the 2.5 mg dose of ONGLYZA.

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, doubleblind, 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. The 10 mg dosage is not an approved dosage. 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
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)
* 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

Figure 1: Mean Change from Baseline in A1C in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with Metformin*

Mean Change from Baseline in A1C in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with Metformin - Illustration

* 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, doubleblind, 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
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)
* 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

Add-On Combination Therapy with Glyburide

A total of 768 patients with type 2 diabetes participated in this 24-week, randomized, doubleblind, 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 addon 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
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)
* 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

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. The 10 mg dosage is not an approved dosage. 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-Naοve Patients*

Efficacy Parameter ONGLYZA 5 mg + Metformin
N=320
Placebo + Metformin
N=328
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†) -13s
  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)
* 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

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 glipizidetreated 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
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)§
* Intent-to-treat population using last observation on study.
† Least squares mean adjusted for baseline value.
‡ ONGLYZA + 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.

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, doubleblind, 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 33 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
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)
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)
* 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

The change in fasting plasma glucose from baseline to Week 24 was also tested, but was not statistically significant. The percent of patients achieving an A1C < 7% was 17% (52/300) with ONGLYZA in combination with insulin compared to 7% (10/149) with placebo. Significance was not tested.

Add-On Combination Therapy with Metformin plus Sulfonylurea

A total of 257 patients with type 2 diabetes participated in this 24-week, randomized, doubleblind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with metformin plus a sulfonylurea in patients with inadequate glycemic control (A1C ≥ 7% and ≤ 10%). Patients were to be on a stable combined dose of metformin extended-release or immediate-release (at maximum tolerated dose, with minimum dose for enrollment being 1500 mg) and a sulfonylurea (at maximum tolerated dose, with minimum dose for enrollment being ≥ 50% of the maximum recommended dose) for ≥ 8 weeks prior to enrollment.

Patients who met eligibility criteria were entered in a 2-week enrollment period to allow assessment of inclusion/exclusion criteria. Following the 2-week enrollment period, eligible patients were randomized to either double-blind ONGLYZA (5 mg once daily) or double-blind matching placebo for 24 weeks. During the 24-week double-blind treatment period, patients were to receive metformin and a sulfonylurea at the same constant dose ascertained during enrollment. Sulfonylurea dose could be down titrated once in the case of a major hypoglycemic event or recurring minor hypoglycemic events. In the absence of hypoglycemia, titration (up or down) of study medication during the treatment period was prohibited.

ONGLYZA in combination with metformin plus a sulfonylurea provided significant improvements in A1C and PPG compared with placebo in combination with metformin plus a sulfonylurea (Table 12). The percentage of patients who discontinued for lack of glycemic control was 6% in the ONGLYZA group and 5% in the placebo group.

Table 12: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with Metformin plus Sulfonylurea*

Efficacy Parameter ONGLYZA 5 mg + Metformin plus Sulfonylurea
N=129
Placebo + Metformin plus Sulfonylurea
N=128
Hemoglobin A1C (%) N=127 N=127
Baseline (mean) 8.4 8.2
Change from baseline (adjusted mean†) -0.7 -0.1
Difference from placebo (adjusted mean†) −0.7‡
  95% Confidence Interval (-0.9, -0.5)
2-hour Postprandial Glucose (mg/dL) N=115 N=113
Baseline (mean) 268 262
Change from baseline (adjusted mean†) -12 5
Difference from placebo (adjusted mean†) −17§
  95% Confidence Interval (-32, -2)
* Intent-to-treat population using last observation prior to discontinuation.
† Least squares mean adjusted for baseline value.
‡ p-value < 0.0001 compared to placebo + metformin plus sulfonylurea
§ p-value < 0.05 compared to placebo + metformin plus sulfonylurea

The change in fasting plasma glucose from baseline to Week 24 was also tested, but was not statistically significant. The percent of patients achieving an A1C < 7% was 31% (39/127) with ONGLYZA in combination with metformin plus a sulfonylurea compared to 9% (12/127) with placebo. Significance was not tested.

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 13). 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 13: 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
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)
* Intent-to-treat population using last observation on study.
† Least squares mean adjusted for baseline value.
‡ p-value < 0.01 compared to placebo

Last reviewed on RxList: 6/13/2013
This monograph has been modified to include the generic and brand name in many instances.

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