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Kombiglyze XR

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Kombiglyze XR

CLINICAL PHARMACOLOGY

Mechanism of Action

KOMBIGLYZE XR

KOMBIGLYZE XR combines two antihyperglycemic medications with complementary mechanisms of action to improve glycemic control in adults with type 2 diabetes: saxagliptin, a dipeptidyl-peptidase-4 (DPP4) inhibitor, and metformin hydrochloride, a biguanide.

Saxagliptin

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.

Metformin hydrochloride

Metformin improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in unusual circumstances [see WARNINGS AND PRECAUTIONS] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacodynamics

Saxagliptin

In patients with type 2 diabetes mellitus, administration of saxagliptin 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

Saxagliptin

In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study using moxifloxacin in 40 healthy subjects, saxagliptin 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

KOMBIGLYZE XR

Bioequivalence and food effect of KOMBIGLYZE XR was characterized under low calorie diet. The low calorie diet consisted of 324 kcal with meal composition that contained 11.1% protein, 10.5% fat, and 78.4% carbohydrate. The results of bioequivalence studies in healthy subjects demonstrated that KOMBIGLYZE XR combination tablets are bioequivalent to coadministration of corresponding doses of saxagliptin (ONGLYZA®) and metformin hydrochloride extended-release (GLUCOPHAGE® XR) as individual tablets under fed conditions.

Saxagliptin

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.

Metformin hydrochloride

Metformin extended-release Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. At steady state, the AUC and Cmax are less than dose proportional for metformin extended-release within the range of 500 to 2000 mg. After repeated administration of metformin extended-release, metformin did not accumulate in plasma. Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism. Peak plasma levels of metformin extended-release tablets are approximately 20% lower compared to the same dose of metformin immediate-release tablets, however, the extent of absorption (as measured by AUC) is similar between extended-release tablets and immediate-release tablets.

Absorption

Saxagliptin

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. Saxagliptin may be administered with or without food. Food has no significant effect on the pharmacokinetics of saxagliptin when administered as KOMBIGLYZE XR combination tablets.

Metformin hydrochloride

Following a single oral dose of metformin extended-release, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. Although the extent of metformin absorption (as measured by AUC) from the metformin extended-release tablet increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin extended-release. Food has no significant effect on the pharmacokinetics of metformin when administered as KOMBIGLYZE XR combination tablets.

Distribution

Saxagliptin

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.

Metformin hydrochloride

Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

Metabolism

Saxagliptin

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]

Metformin hydrochloride

Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.

Metabolism studies with extended-release metformin tablets have not been conducted.

Excretion

Saxagliptin

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 saxagliptin 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.

Metformin hydrochloride

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Specific Populations

Renal Impairment

KOMBIGLYZE XR

In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance. Use of metformin in patients with renal impairment increases the risk for lactic acidosis. Because KOMBIGLYZE XR contains metformin, KOMBIGLYZE XR is contraindicated in patients with renal impairment [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Hepatic Impairment

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment. Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Because KOMBIGLYZE XR contains metformin, KOMBIGLYZE XR is not recommended in patients with hepatic impairment [see WARNINGS AND PRECAUTIONS].

Body Mass Index

Saxagliptin

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

Saxagliptin

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.

Metformin hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Geriatric

Saxagliptin

No dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years of age) had 23% and 59% higher geometric mean Cmax and geometric mean AUC values, respectively, for saxagliptin than young subjects (18-40 years of age). 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.

Metformin hydrochloride

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.

KOMBIGLYZE XR should not be initiated in patients of any age unless measurement of creatinine clearance demonstrates that renal function is normal [see WARNINGS AND PRECAUTIONS].

Race and Ethnicity

Saxagliptin

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.

Metformin hydrochloride

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Drug Interaction Studies

Specific pharmacokinetic drug interaction studies with KOMBIGLYZE XR have not been performed, although such studies have been conducted with the individual saxagliptin and metformin components.

In Vitro Assessment of Drug Interactions

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 Drug on Saxagliptin and 5-hydroxy Saxagliptin Systemic Exposures

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 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 KOMBIGLYZE XR dose to 2.5 mg/1000 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 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
* 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 Coadministered Drug Systemic Exposures

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 1.2 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 1.1 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 0.98
1.10 1.09
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

Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

Coadministered Drug Dose of Coadministered Drug* Dose of Metformin* Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00
  AUC† Cmax
No dosing adjustments required for the following:
Glyburide 5 mg 850 mg metformin 0.91‡ 0.93‡
Furosemide 40 mg 850 mg metformin 1.09‡ 1.22‡
Nifedipine 10 mg 850 mg metformin 1.16 1.21
Propranolol 40 mg 850 mg metformin 0.9 0.94
Ibuprofen 400 mg 850 mg metformin 1.05‡ 1.07‡
Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination: use with caution. [See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS.]
Cimetidine 400 mg 850 mg metformin 1.4 1.61
* All metformin and coadministered drugs were given as single doses.
† AUC = AUC(INF)
‡ Ratio of arithmetic means

Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure

Coadministered Drug Dose of Coadministered Drug* Dose of Metformin* Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00
  AUC† Cmax
No dosing adjustments required for the following:
Glyburide 5 mg 850 mg glyburide 0.78‡ 0.63‡
Furosemide 40 mg 850 mg furosemide 0.87‡ 0.69‡
Nifedipine 10 mg 850 mg nifedipine 1.10§ 1.08
Propranolol 40 mg 850 mg propranolol 1.01§ 1.02
Ibuprofen 400 mg 850 mg ibuprofen 0.97¶ 1.01¶
Cimetidine 400 mg 850 mg cimetidine 0.95§ 1.01
* All metformin and coadministered drugs were given as single doses.
† AUC = AUC(INF) unless otherwise noted
‡ Ratio of arithmetic means, p-value of difference < 0.05
§ AUC(0-24 hr) reported
¶ Ratio of arithmetic means

Animal Toxicology and/or Pharmacology

Saxagliptin

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 (1-3 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

There have been no clinical efficacy or safety studies conducted with KOMBIGLYZE XR to characterize its effect on hemoglobin A1c (A1C) reduction. Bioequivalence of KOMBIGLYZE XR with coadministered saxagliptin and metformin hydrochloride extended-release tablets has been demonstrated; however, relative bioavailability studies between KOMBIGLYZE XR and coadministered saxagliptin and metformin hydrochloride immediate-release tablets have not been conducted. The metformin hydrochloride extended-release tablets and metformin hydrochloride immediate-release tablets have a similar extent of absorption (as measured by AUC) while peak plasma levels of extended-release tablets are approximately 20% lower than those of immediate-release tablets at the same dose.

The coadministration of saxagliptin and metformin immediate-release tablets has been studied in adults with type 2 diabetes inadequately controlled on metformin alone and in treatment-naive patients inadequately controlled on diet and exercise alone. In these two trials, treatment with saxagliptin dosed in the morning plus metformin immediate-release tablets 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.

In these two trials, decrease in body weight in the treatment groups given saxagliptin in combination with metformin immediate-release was similar to that in the groups given metformin immediate-release alone. Saxagliptin plus metformin immediate-release was not associated with significant changes from baseline in fasting serum lipids compared to metformin alone.

The coadministration of saxagliptin and metformin immediate-release tablets has also been evaluated in an active-controlled trial comparing add-on therapy with saxagliptin to glipizide in 858 patients inadequately controlled on metformin alone, and in a placebo-controlled trial where a subgroup of 314 patients inadequately controlled on insulin plus metformin received add-on therapy with saxagliptin or placebo, and a trial comparing saxagliptin to placebo in 257 patients inadequately controlled on metformin plus a sulfonylurea.

In a 24-week, double-blind, randomized trial, patients treated with metformin immediate-release 500 mg twice daily for at least 8 weeks were randomized to continued treatment with metformin immediate-release 500 mg twice daily or to metformin extended-release either 1000 mg once daily or 1500 mg once daily. The mean change in A1C from baseline to Week 24 was 0.1% (95% confidence interval 0%, 0.3%) for the metformin immediate-release treatment arm, 0.3% (95% confidence interval 0.1%, 0.4%) for the 1000 mg metformin extended-release treatment arm, and 0.1% (95% confidence interval 0%, 0.3%) for the 1500 mg metformin extended-release treatment arm. Results of this trial suggest that patients receiving metformin immediate-release treatment may be safely switched to metformin extended-release once daily at the same total daily dose, up to 2000 mg once daily. Following a switch from metformin immediate-release to metformin extended-release, glycemic control should be closely monitored and dosage adjustments made accordingly.

Saxagliptin Morning and Evening Dosing

A 24-week monotherapy trial was conducted to assess a range of dosing regimens for saxagliptin. 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 saxagliptin, or placebo. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue therapy added on to placebo or saxagliptin; the number of patients randomized per treatment group ranged from 71 to 74.

Treatment with either saxagliptin 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).

Coadministration of Saxagliptin with Metformin Immediate-Release in Treatment-Naive Patients

A total of 1306 treatment-naive patients with type 2 diabetes mellitus participated in this 24week, randomized, double-blind, active-controlled trial to evaluate the efficacy and safety of saxagliptin coadministered with metformin immediate-release 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: saxagliptin 5 mg + metformin immediate-release 500 mg, saxagliptin 10 mg + metformin immediate-release 500 mg, saxagliptin 10 mg + placebo, or metformin immediate-release 500 mg + placebo (the maximum recommended approved saxagliptin dose is 5 mg daily; the 10 mg daily dose of saxagliptin does not provide greater efficacy than the 5 mg daily dose and the 10 mg dosage is not an approved dosage). Saxagliptin was dosed once daily. In the 3 treatment groups using metformin immediate-release, 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 this study were treated with pioglitazone rescue as add-on therapy.

Coadministration of saxagliptin 5 mg plus metformin immediate-release provided significant improvements in A1C, FPG, and PPG compared with placebo plus metformin immediate-release (Table 7).

Table 7: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of Saxagliptin Coadministration with Metformin Immediate-Release in Treatment-Naive Patients*

Efficacy Parameter Saxagliptin 5 mg + Metformin
N=320
P la cebo + Metformin
N=328
H emoglobin 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 Glu cose (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 Post pr a ndia l 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

Addition of Saxagliptin to Metformin Immediate-Release

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 saxagliptin in combination with metformin immediate-release 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 immediate-release at their pre study dose, up to 2500 mg daily, for the duration of the study. Following the lead-in period, eligible patients were randomized to 2.5 mg, 5 mg, or 10 mg of saxagliptin or placebo in addition to their current dose of open-label metformin immediate-release (the maximum recommended approved saxagliptin dose is 5 mg daily; the 10 mg daily dose of saxagliptin does not provide greater efficacy than the 5 mg daily dose and 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 saxagliptin and metformin immediate-release were not permitted.

Saxagliptin 2.5 mg and 5 mg add-on to metformin immediate-release provided significant improvements in A1C, FPG, and PPG compared with placebo add-on to metformin immediate-release (Table 8). 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 saxagliptin 2.5 mg add-on to metformin immediate-release group, 13% in the saxagliptin 5 mg add-on to metformin immediate-release group, and 27% in the placebo add-on to metformin immediate-release group.

Table 8: Glycemic Parameters at Week 24 in a Placebo-Controlled Study of Saxagliptin as Add-On Combination Therapy with Metformin Immediate-Release*

Efficacy Parameter Saxagliptin 2.5 mg + Metformin
N=192
Saxagliptin 5 mg + Metformin
N=191
Placebo + Metformin
N=179
H emoglobin 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 Saxagliptin as Add-On Combination Therapy with Metformin Immediate-Release*

KOMBIGLYZE XR (saxagliptin and metformin hydrochloride extended-release) Figure 1 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.

Saxagliptin Add-On Combination Therapy with Metformin Immediate-Release versus Glipizide Add-On Combination Therapy with Metformin Immediate-Release

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 immediate-release alone were randomized to double-blind add-on therapy with saxagliptin or glipizide. Patients were required to be on a stable dose of metformin immediate-release (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 immediate-release (15003000 mg based on their prestudy dose). Following the lead-in period, eligible patients were randomized to 5 mg of saxagliptin or 5 mg of glipizide in addition to their current dose of open-label metformin immediate-release. Patients in the glipizide plus metformin immediate-release 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, saxagliptin and glipizide resulted in similar mean reductions from baseline in A1C when added to metformin immediate-release therapy (Table 9). 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 saxagliptin compared to a mean weight gain of 1.1 kg in patients treated with glipizide (p < 0.0001).

Table 9: Glycemic Parameters at Week 52 in an Active-Controlled Trial of Saxagliptin versus Glipizide in Combination with Metformin Immediate-Release*

Efficacy Parameter Saxagliptin 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.
‡ 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.

Saxagliptin Add-On Combination Therapy with Insulin (with or without Metformin Immediate-Release)

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 saxagliptin 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 immediate-release (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 immediate-release if applicable) at their pretrial dose(s). Following the lead-in period, eligible patients were randomized to add-on therapy with either saxagliptin 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 saxagliptin 5 mg provided significant improvements from baseline to Week 24 in A1C and PPG compared with add-on placebo (Table 10). Similar mean reductions in A1C versus placebo were observed for patients using saxagliptin 5 mg add-on to insulin alone and saxagliptin 5 mg add-on to insulin in combination with metformin immediate-release (-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 saxagliptin group and 32% in the placebo group.

The mean daily insulin dose at baseline was 53 units in patients treated with saxagliptin 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 saxagliptin 5 mg group and 5 units for the placebo group.

Table 10: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with Insulin*

Efficacy Parameter Saxagliptin 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 saxagliptin in combination with insulin compared to 7% (10/149) with placebo. Significance was not tested.

Saxagliptin Add-On Combination Therapy with Metformin plus Sulfonylurea

A total of 257 subjects with type 2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin 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 saxagliptin (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.

Saxagliptin 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 11). The percentage of patients who discontinued for lack of glycemic control was 6% in the saxagliptin group and 5% in the placebo group.

Table 11: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with Metformin plus Sulfonylurea*

Efficacy Parameter Saxagliptin 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 saxagliptin in combination with metformin plus a sulfonylurea compared to 9% (12/127) with placebo. Significance was not tested.

Last reviewed on RxList: 6/17/2013
This monograph has been modified to include the generic and brand name in many instances.

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