May 3, 2016
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Oseni

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Oseni

CLINICAL PHARMACOLOGY

Mechanism Of Action

OSENI combines two antihyperglycemic agents with complementary and distinct mechanisms of action to improve glycemic control in patients with type 2 diabetes: alogliptin, a selective inhibitor of DPP-4, and pioglitazone, a member of the TZD class.

Alogliptin

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 dipeptidyl peptidase-4 (DPP-4) 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. Alogliptin is a DPP-4 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. Alogliptin selectively binds to and inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.

Pioglitazone

Pharmacologic studies indicate that pioglitazone improves insulin sensitivity in muscle and adipose tissue while inhibiting hepatic gluconeogenesis. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin-responsive genes involved in the control of glucose and lipid metabolism.

In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

Pharmacodynamics

Alogliptin And Pioglitazone

In a 26-week, randomized, active-controlled study, patients with type 2 diabetes received alogliptin 25 mg coadministered with pioglitazone 30 mg, alogliptin 12.5 mg coadministered with pioglitazone 30 mg, alogliptin 25 mg alone or pioglitazone 30 mg alone. Patients who were randomized to alogliptin 25 mg with pioglitazone 30 mg achieved a 26.2% decrease in triglyceride levels from a mean baseline of 214.2 mg/dL compared to an 11.5% decrease for alogliptin alone and a 21.8% decrease for pioglitazone alone. In addition, a 14.4% increase in HDL cholesterol levels from a mean baseline of 43.2 mg/dL was also observed for alogliptin 25 mg with pioglitazone 30 mg compared to a 1.9% increase for alogliptin alone and a 13.2% increase for pioglitazone alone. The changes in measures of LDL cholesterol and total cholesterol were similar between alogliptin 25 mg with pioglitazone 30 mg versus alogliptin alone and pioglitazone alone. A similar pattern of lipid effects was observed in a 26-week, placebo-controlled factorial study.

Alogliptin

Single-dose administration of alogliptin to healthy subjects resulted in a peak inhibition of DPP-4 within two to three hours after dosing. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Peak and total exposure over 24 hours to active GLP-1 were three-to four-fold greater with alogliptin (at doses of 25 to 200 mg) than placebo. In a 16-week, double-blind, placebo-controlled study alogliptin 25 mg demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an eight-hour period following a standardized meal. It is unclear how these findings relate to changes in overall glycemic control in patients with type 2 diabetes mellitus. In this study, alogliptin 25 mg demonstrated decreases in two-hour postprandial glucose compared to placebo (-30 mg/dL versus 17 mg/dL respectively).

Multiple-dose administration of alogliptin to patients with type 2 diabetes also resulted in a peak inhibition of DPP-4 within one to two hours and exceeded 93% across all doses (25 mg, 100 mg and 400 mg) after a single dose and after 14 days of once-daily dosing. At these doses of alogliptin, inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing.

Pioglitazone

Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, and improves hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations and lower A1C values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin or insulin [see Clinical Studies]. Patients with lipid abnormalities were included in clinical trials with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in serum triglycerides, mean increases in HDL cholesterol and no consistent mean changes in LDL and total cholesterol. There is no conclusive evidence of macrovascular benefit with pioglitazone or any other antidiabetic medication [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the pioglitazone 15 mg, 30 mg and 45 mg dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with pioglitazone than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with pioglitazone compared to placebo (Table 7).

Table 7: Lipids in a 26-Week, Placebo-Controlled, Monotherapy, Dose-Ranging Study

  Placebo Pioglitazone 15 mg Once Daily Pioglitazone 30 mg Once Daily Pioglitazone 45 mg Once Daily
Triglycerides (mg/dL) N=79 N=79 N=84 N=77
Baseline (mean) 263 284 261 260
Percent change from baseline (adjusted mean*) 4.8% -9%† -9.6%† -9.3%†
HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77
Baseline (mean) 42 40 41 41
Percent change from baseline (adjusted mean*) 8.1% 14.1%† 12.2% 19.1%†
LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62
Baseline (mean) 139 132 136 127
Percent change from baseline (adjusted mean*) 4.8% 7.2% 5.2% 6%
Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77
Baseline (mean) 225 220 223 214
Percent change from baseline (adjusted mean*) 4.4% 4.6% 3.3% 6.4%
*Adjusted for baseline, pooled center and pooled center by treatment interaction
†p < 0.05 versus placebo In the two other monotherapy studies (16 weeks and 24 weeks) and in combination therapy studies with sulfonylurea (16 weeks and 24 weeks), metformin (16 weeks and 24 weeks) or insulin (16 weeks and 24 weeks), the lipid results were generally consistent with the data above.

Pharmacokinetics

Absorption And Bioavailability

Alogliptin and Pioglitazone

In bioequivalence studies of OSENI, the area under the plasma concentration curve (AUC) and maximum concentration (Cmax) of both the alogliptin and the pioglitazone component following a single dose of the combination tablet (12.5 mg/15 mg or 25 mg/45 mg) were bioequivalent to alogliptin (12.5 mg or 25 mg) concomitantly administered with pioglitazone (15 mg or 45 mg respectively) tablets under fasted conditions in healthy subjects.

Administration of OSENI 25 mg/45 mg with food resulted in no significant change in overall exposure of alogliptin or pioglitazone. OSENI may therefore be administered with or without food.

Alogliptin

The absolute bioavailability of alogliptin is approximately 100%. Administration of alogliptin with a high-fat meal results in no significant change in total and peak exposure to alogliptin. Alogliptin may therefore be administered with or without food.

Pioglitazone

Following oral administration of pioglitazone hydrochloride, peak concentrations of pioglitazone were observed within two hours. Food slightly delays the time to peak serum concentration (Tmax) to three to four hours but does not alter the extent of absorption (AUC).

Distribution

Alogliptin

Following a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues.

Alogliptin is 20% bound to plasma proteins.

Pioglitazone

The mean apparent Vd/F of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound ( > 99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound ( > 98%) to serum albumin.

Metabolism

Alogliptin

Alogliptin does not undergo extensive metabolism and 60% to 71% of the dose is excreted as unchanged drug in the urine.

Two minor metabolites were detected following administration of an oral dose of [14C] alogliptin, N­demethylated, M-I (less than 1% of the parent compound), and N-acetylated alogliptin, M-II (less than 6% of the parent compound). M-I is an active metabolite and is an inhibitor of DPP-4 similar to the parent molecule; M-II does not display any inhibitory activity toward DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin.

Alogliptin exists predominantly as the (R)-enantiomer (more than 99%) and undergoes little or no chiral conversion in vivo to the (S)-enantiomer. The (S)-enantiomer is not detectable at the 25 mg dose.

Pioglitazone

Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are the major circulating active metabolites in humans. Following once-daily administration of pioglitazone, steady-state serum concentrations of both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV (hydroxyl derivative of pioglitazone), are achieved within seven days. At steady-state, M-III and M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady-state, in both healthy volunteers and patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20% to 25% of the total AUC.

Maximum serum concentration (Cmax), AUC and trough serum concentrations (Cmin) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.

In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms, including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor, showed that pioglitazone is a CYP2C8 substrate [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS]. Urinary 6β-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.

Excretion And Elimination

Alogliptin

The primary route of elimination of [14C] alogliptin derived radioactivity occurs via renal excretion (76%) with 13% recovered in the feces, achieving a total recovery of 89% of the administered radioactive dose. The renal clearance of alogliptin (9.6 L/hr) indicates some active renal tubular secretion and systemic clearance was 14.0 L/hr.

Pioglitazone

Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.

The mean serum half-life of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr.

Special Populations

Renal Impairment

Alogliptin

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of alogliptin 50 mg in patients with chronic renal impairment compared with healthy subjects.

In patients with mild renal impairment (creatinine clearance [CrCl] ≥ 60 to < 90 mL/min), an approximate 1.2-fold increase in plasma AUC of alogliptin was observed. Because increases of this magnitude are not considered clinically relevant, dose adjustment for patients with mild renal impairment is not recommended.

In patients with moderate renal impairment (CrCl ≥ 30 to < 60 mL/min), an approximate two-fold increase in plasma AUC of alogliptin was observed. To maintain similar systemic exposures of OSENI to those with normal renal function, the recommended dose of OSENI is 12.5 mg/15 mg, 12.5 mg/30 mg or 12.5 mg/45 mg once daily in patients with moderate renal impairment.

In patients with severe renal impairment (CrCl ≥ 15 to < 30 mL/min) and end-stage renal disease (ESRD) (CrCl < 15 mL/min or requiring dialysis), an approximate three-and four-fold increase in plasma AUC of alogliptin were observed, respectively. Dialysis removed approximately 7% of the drug during a three-hour dialysis session. OSENI is not recommended for patients with severe renal impairment or ESRD. Coadministration of pioglitazone and alogliptin 6.25 mg once daily based on individual requirements may be considered in these patients.

Pioglitazone

The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 50 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore no dose adjustment in patients with renal impairment is required.

Hepatic Impairment

Alogliptin

Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment (Child-Pugh Grade B) compared to healthy subjects. The magnitude of these reductions is not considered to be clinically meaningful. Patients with severe hepatic impairment (Child-Pugh Grade C) have not been studied. Use caution when administering OSENI to patients with liver disease [see Use in Specific Populations and WARNINGS AND PRECAUTIONS].

Pioglitazone

Compared with healthy controls, subjects with impaired hepatic function (Child-Pugh Grade B and C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III and M­IV) mean peak concentrations but no change in the mean AUC values. Therefore, no dose adjustment in patients with hepatic impairment is required.

There are postmarketing reports of liver failure with pioglitazone and clinical trials have generally excluded patients with serum ALT > 2.5 times the upper limit of the reference range. Use caution in patients with liver disease [see WARNINGS AND PRECAUTIONS].

Gender

Alogliptin

No dose adjustment of alogliptin is necessary based on gender. Gender did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.

Pioglitazone

The mean Cmax and AUC values of pioglitazone were increased 20% to 60% in women compared to men. In controlled clinical trials, A1C decreases from baseline were generally greater for females than for males (average mean difference in A1C 0.5%). Because therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.

Geriatric

Alogliptin

No dose adjustment of alogliptin is necessary based on age. Age did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.

Pioglitazone

In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are approximately 21% higher than those achieved in younger subjects. The mean terminal half-life values of pioglitazone were also longer in elderly subjects (about 10 hours) as compared to younger subjects (about seven hours). These changes were not of a magnitude that would be considered clinically relevant.

Pediatrics

Alogliptin

Studies characterizing the pharmacokinetics of alogliptin in pediatric patients have not been performed.

Pioglitazone

Safety and efficacy of pioglitazone in pediatric patients have not been established. Pioglitazone is not recommended for use in pediatric patients [see Use In Specific Populations].

Race and Ethnicity

Alogliptin

No dose adjustment of alogliptin is necessary based on race. Race (White, Black and Asian) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.

Pioglitazone

Pharmacokinetic data among various ethnic groups are not available.

Drug Interactions

Coadministration of alogliptin 25 mg once daily with a CYP2C8 substrate, pioglitazone 45 mg once daily for 12 days had no clinically meaningful effects on the pharmacokinetics of pioglitazone and its active metabolites.

Specific pharmacokinetic drug interaction studies with OSENI have not been performed, although such studies have been conducted with the individual components of OSENI (alogliptin and pioglitazone).

Alogliptin

In Vitro Assessment of Drug Interactions

In vitro studies indicate that alogliptin is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4, nor an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant concentrations.

In Vivo Assessment of Drug Interactions

Effects of Alogliptin on the Pharmacokinetics of Other Drugs

In clinical studies, alogliptin did not meaningfully increase the systemic exposure to the following drugs that are metabolized by CYP isozymes or excreted unchanged in urine (Figure 1). No dose adjustment of alogliptin is recommended based on results of the described pharmacokinetic studies.

Figure 1: Effect of Alogliptin on the Pharmacokinetic Exposure to Other Drugs

Effect of Alogliptin on the Pharmacokinetic Exposure to Other Drugs - Illustration

*W arfarin was giv en once daily at a stable dose in the range of 1 mg to 10 mg. Alogliptin had no significant effect on the prothrombin time (PT) or International Normalized Ratio (INR). **Caffeine (1A2 substrate), tolbutamide (2C9 substrate), dextromethorphan (2D6 substrate), midazolam (3A4 substrate) and fexofenadine (P-gp substrate) were administered as a cocktail.

Effects Of Other Drugs On The Pharmacokinetics Of Alogliptin

There are no clinically meaningful changes in the pharmacokinetics of alogliptin when alogliptin is administered concomitantly with the drugs described below (Figure 2).

Figure 2: Effect of Other Drugs on the Pharmacokinetic Exposure of Alogliptin

Effect of Other Drugs on the Pharmacokinetic Exposure of Alogliptin - Illustration

Pioglitazone

Table 8: Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs

  Coadministered Drug
Pioglitazone Dosage Regimen (mg)* Name and Dose Regimens Change in AUC† Change in Cmax†
45 mg (N=12) Warfarin‡
Daily loading then maintenance doses based PT and INR values Quick's Value=35 ± 5% R-Warfarin ↓3% R-Warfarin ↓2%
S-Warfarin ↓1% S-Warfarin ↑1%
45 mg (N=12) Digoxin
0.200 mg twice daily (loading dose) then 0.250 mg daily (maintenance dose, 7 days) ↑15% ↑17%
45 mg daily for 21 days (N=35) Oral Contraceptive
[Ethinyl Estradiol (EE) 0.035 mg plus Norethindrone (NE) 1 mg] for 21 days EE ↓11% EE ↓13%
NE ↑3% NE ↓7%
45 mg (N=23) Fexofenadine
60 mg twice daily for 7 days ↑30% ↑37%
45 mg (N=14) Glipizide
5 mg daily for 7 days ↓3% ↓8%
45 mg daily for 8 days (N=16) Metformin
1000 mg single dose on 8 days ↓3% ↓5%
45 mg (N=21) Midazolam
7.5 mg single dose on day 15 ↓26% ↓26%
45 mg (N=24) Ranitidine
150 mg twice daily for 7 days ↑1% ↓1%
45 mg daily for 4 days (N=24) Nifedipine ER
30 mg daily for 4 days ↓13% ↓17%
45 mg (N=25) Atorvastatin Ca
80 mg daily for 7 days ↓14% ↓23%
45 mg (N=22) Theophylline
400 mg twice daily for 7 days ↑2% ↑5%
*Daily for sev en days unless otherwise noted
†% change (with/without coadministered drug and no change=0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively
‡Pioglitazone had no clinically significant effect on prothrombin time

Table 9:Effect of Coadministered Drugs on Pioglitazone Systemic Exposure

Coadministered Drug and Dosage Regimen Pioglitazone
Dose Regimen (mg)* Change in AUC† Change in Cmax†
Gemfibrozil 600 mg twice daily for 2 days (N=12) 30 mg single dose ↑3.4-fold‡ ↑6%
Ketoconazole 200 mg twice daily for 7 days (N=28) 45 mg ↑34% ↑14%
Rifampin 600 mg daily for 5 days (N=10) 30 mg single dose ↓54% ↓5%
Fexofenadine 60 mg twice daily for 7 days (N=23) 45 mg ↑1% 0%
Ranitidine 150 mg twice daily for 4 days (N=23) 45 mg ↓13% ↓16%
Nifedipine ER 30 mg daily for 7 days (N = 23) 45 mg ↑5% ↑4%
Atorvastatin Ca 80 mg daily for 7 days (N=24) 45 mg ↓24% ↓31%
Theophylline 400 mg twice daily for 7 days (N=22) 45 mg ↓4% ↓2%
*Daily for seven days unless otherwise noted
†Mean ratio (with/without coadministered drug and no change=one-fold) % change (with/without coadministered drug and no change=0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively
‡The half-life of pioglitazone increased from 6.5 hours to 15.1 hours in the presence of gemfibrozil [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS]

Animal Toxicology And/Or Pharmacology

Pioglitazone

Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone (approximately 11, one, and two times the MRHD for mice, rats and dogs, respectively, based on mg/m²). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg (approximately 35 times the MRHD based on mg/m²). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately four times the MRHD based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the MRHD based on mg/m²).

Clinical Studies

The coadministration of alogliptin and pioglitazone has been studied in patients with type 2 diabetes inadequately controlled on either diet and exercise alone or on metformin alone.

There have been no clinical efficacy studies conducted with OSENI; however, bioequivalence of OSENI with coadministered alogliptin and pioglitazone tablets was demonstrated, and efficacy of the combination of alogliptin and pioglitazone has been demonstrated in four Phase 3 efficacy studies.

In patients with type 2 diabetes, treatment with OSENI produced clinically meaningful and statistically significant improvements in A1C compared to either alogliptin or pioglitazone alone. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with OSENI appears to be related to the degree of A1C elevation at baseline.

Alogliptin And Pioglitazone Coadministration In Patients With Type 2 Diabetes Inadequately Controlled On Diet And Exercise

In a 26-week, double-blind, active-controlled study, a total of 655 patients inadequately controlled on diet and exercise alone (mean baseline A1C = 8.8%) were randomized to receive alogliptin 25 mg alone, pioglitazone 30 mg alone, alogliptin 12.5 mg with pioglitazone 30 mg or alogliptin 25 mg with pioglitazone 30 mg once daily. Coadministration of alogliptin 25 mg with pioglitazone 30 mg resulted in statistically significant improvements from baseline in A1C and FPG compared to either alogliptin 25 mg alone or to pioglitazone 30 mg alone (Table 10). Coadministration of alogliptin 25 mg with pioglitazone 30 mg once daily resulted in statistically significant reductions in fasting plasma glucose (FPG) starting from W eek 2 through Week 26 compared to either alogliptin 25 mg or pioglitazone 30 mg alone. A total of 3% of patients receiving alogliptin 25 mg coadministered with pioglitazone 30 mg, 11% of those receiving alogliptin 25 mg alone, and 6% of those receiving pioglitazone 30 mg alone required glycemic rescue.

Improvements in A1C were not affected by gender, age or baseline BMI.

The mean increase in body weight was similar between pioglitazone alone and alogliptin when coadministered with pioglitazone.

Table 10: Glycemic Parameters at Week 26 in a Coadministration Study of Alogliptin and Pioglitazone in Patients Inadequately Controlled on Diet and Exercise*

  Alogliptin 25 mg Pioglitazone 30 mg Alogliptin 25 mg + Pioglitazone 30 mg
A1C (%) N=160 N=153 N=158
Baseline (mean) 8.8 8.8 8.8
Change from Baseline (adjusted mean†) -1 -1.2 -1.7
Difference from alogliptin 25 mg (adjusted mean† with 95% confidence interval)     -0.8‡ (-1, -0.5)
Difference from pioglitazone 30 mg (adjusted mean† with 95% confidence interval)     -0.6‡ (-0.8, -0.3)
% of Patients (n/N) achieving A1C ≤ 7% 24% (40/164) 34% (55/163) 63% (103/164)‡
FPG (mg/dL) N=162 N=157 N=162
Baseline (mean) 189 189 185
Change from Baseline (adjusted mean†) -26 -37 -50
Difference from alogliptin 25 mg (adjusted mean† with 95% confidence interval)     -25‡ (-34, -15)
Difference from pioglitazone 30 mg (adjusted mean† with 95% confidence interval)     -13‡ (-22, -4)
*Intent-to-treat population using last observation carried forward
†Least squares means adjusted for treatment, geographic region and baseline value
‡p 0.01 compared to alogliptin 25 mg or pioglitazone 30 mg

Alogliptin And Pioglitazone Coadministration In Patients With Type 2 Diabetes Inadequately Controlled On Metformin Alone

In the second 26-week, double-blind, placebo-controlled study, a total of 1554 patients already on metformin (mean baseline A1C=8.5%) were randomized to one of 12 double-blind treatment groups: placebo; 12.5 mg or 25 mg of alogliptin alone; 15 mg, 30 mg or 45 mg of pioglitazone alone; or 12.5 mg or 25 mg of alogliptin in combination with 15 mg, 30 mg or 45 mg of pioglitazone. Patients were maintained on a stable dose of metformin (median dose=1700 mg) during the treatment period. Coadministration of alogliptin and pioglitazone provided statistically significant improvements in A1C and FPG compared to placebo, to alogliptin alone, or to pioglitazone alone when added to background metformin therapy (Table 11, Figure 3). A total of 4%, 5% or 2% of patients receiving alogliptin 25 mg with 15 mg, 30 mg or 45 mg pioglitazone, 33% of patients receiving placebo, 13% of patients receiving alogliptin 25 mg, and 10%, 15% or 9% of patients receiving pioglitazone 15 mg, 30 mg or 45 mg alone required glycemic rescue.

Improvements in A1C were not affected by gender, age or baseline BMI.

The mean increase in body weight was similar between pioglitazone alone and alogliptin when coadministered with pioglitazone.

Table 11: Glycemic Parameters at Week 26 for Alogliptin and Pioglitazone Alone and in Combination in Patients with Type 2 Diabetes*

  Placebo Alogliptin 25 mg Pioglitazone 15 mg Pioglitazone 30 mg Pioglitazone 45 mg Alogliptin 25 mg + Pioglitazone 15 mg Alogliptin 25 mg + Pioglitazone 30 mg Alogliptin 25 mg + Pioglitazone 45 mg
A1C ( %) N=126 N=123 N=127 N=123 N=126 N=127 N=124 N=126
Baseline (mean) 8.5 8.6 8.5 8.5 8.5 8.5 8.5 8.6
Change from baseline (adjusted mean† with 95% confidence interval) -0.1 -0.9 -0.8 -0.9 -1 -1.3‡ -1.4‡ -1.6‡
Difference from pioglitazone (adjusted mean† with 95% confidence interval) - - - - - -0.5‡
(-0.7, -0.3)
-0.5‡
(-0.7, -0.3)
-0.6‡
(-0.8, -0.4)
Difference from alogliptin (adjusted mean† with 95% confidence interval) - - - - - -0.4‡
(-0.6, -0.1)
-0.5‡
(-0.7, -0.3)
-0.7‡
(-0.9, -0.5)
Patients (%) ac hieving A1C < 7% 6% (8/129) 27% (35/129) 26% (33/129) 30% (38/129) 36% (47/129) 55% (71/130)‡ 53% (69/130)‡ 60% (78/130)‡
FPG (mg/dL) N=129 N=126 N=127 N=125 N=129 N=130 N=126 N=127
Baseline (mean) 177 184 177 175 181 179 179 178
Change from baseline (adjusted mean† with 95% confidence interval) 7 -19 -24 -29 -32 -38‡ -42‡ -53‡
Difference from pioglitazone (adjusted mean† with 95% confidence interval) - - - - - -14‡
(-24, -5)
-13‡
(-23, -3)
-20‡
(-30, -11)
Difference from alogliptin (adjusted mean† with 95% confidence interval) - - - - - -19‡
(-29, -10)
-23‡
(-33, -13)
-34‡
(-44, -24)
*Intent-to-treat population using last observation carried forward
†Least squares means adjusted for treatment, geographic region metformin dose and baseline value
‡p ≤ 0.01 when compared to pioglitazone and alogliptin alone

Figure 3: Change from Baseline in A1C at Week 26 with Alogliptin and Pioglitazone Alone and Alogliptin in Combination with Pioglitazone when Added to Metformin

Change from Baseline in A1C at Week 26 - illustration

Alogliptin Add-On Therapy In Patients With Type 2 Diabetes Inadequately Controlled On Metformin In Combination With Pioglitazone

In a 52-week, active-comparator study, a total of 803 patients inadequately controlled (mean baseline A1C = 8.2%) on a current regimen of pioglitazone 30 mg and metformin at least 1500 mg per day or at the maximum tolerated dose were randomized to either receive the addition of alogliptin 25 mg or the titration of pioglitazone 30 mg to 45 mg following a four-week, single-blind, placebo run-in period. Patients were maintained on a stable dose of metformin (median dose = 1700 mg). Patients who failed to meet prespecified hyperglycemic goals during the 52-week treatment period received glycemic rescue therapy.

In combination with pioglitazone and metformin, alogliptin 25 mg was shown to be statistically superior in lowering A1C and FPG compared with the titration of pioglitazone from 30 mg to 45 mg at Week 26 and Week 52 (Table 12, results shown only for Week 52). A total of 11% of patients who were receiving alogliptin 25 mg in combination with pioglitazone 30 mg and metformin and 22% of patients receiving a dose titration of pioglitazone from 30 mg to 45 mg in combination with metformin required glycemic rescue.

Improvements in A1C were not affected by gender, age, race or baseline BMI. The mean increase in body weight was similar in both treatment arms. Lipid effects were neutral.

Table 12: Glycemic Parameters at Week 52 in an Active-Controlled Study of Alogliptin as Add-On Combination Therapy to Metformin and Pioglitazone*

  Alogliptin 25 mg + Pioglitazone 30 mg + Metformin Pioglitazone 45 mg + Metformin
A1C (%) N=397 N=394
Baseline (mean) 8.2 8.1
Change from Baseline (adjusted mean†) -0.7 -0.3
Difference from Pioglitazone 45 mg + Metformin (adjusted mean† with 95% confidence interval) -0.4‡ (-0.5, -0.3)
% of Patients (n/N) achieving A1C ≤ 7% 33% (134/404)§ 21% (85/399)
FPG (mg/dL) N=399 N=396
Baseline (mean) 162 162
Change from Baseline (adjusted mean†) -15 -4
Difference from Pioglitazone 45 mg + Metformin (adjusted mean† with 95% confidence interval) -11§ (-16, -6)
*Intent-to-treat population using last observation on study
†Least squares means adjusted for treatment, baseline value, geographic region and baseline metformin dose
‡Noninferior and statistically superior to metformin plus pioglitazone at the 0.025 one-sided significance level§p0.001 compared to pioglitazone 45 mg + metformin

Alogliptin Add-On Therapy To A Thiazolidinedione

A 26-week, placebo-controlled study, was conducted to evaluate the efficacy and safety of alogliptin as add-on therapy to pioglitazone in patients with type 2 diabetes. A total of 493 patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea (mean baseline A1C = 8%) were randomized to receive alogliptin 12.5 mg, alogliptin 25 mg or placebo. Patients were maintained on a stable dose of pioglitazone (median dose = 30 mg) during the treatment period and those who were also previously treated on metformin (median dose = 2000 mg) or sulfonylurea (median dose = 10 mg) prior to randomization were maintained on the combination therapy during the treatment period. All patients entered into a four-week, single-blind, placebo run-in period prior to randomization. Following randomization, all patients continued to receive instruction on diet and exercise. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment period received glycemic rescue.

The addition of alogliptin 25 mg once daily to pioglitazone therapy resulted in significant improvements from baseline in A1C and FPG at Week 26 when compared to the addition of placebo (Table 13). A total of 9% of patients who were receiving alogliptin 25 mg and 12% of patients receiving placebo required glycemic rescue.

The improvement in A1C was not affected by gender, age, baseline BMI or baseline pioglitazone dose. The mean increase in body weight was similar between alogliptin and placebo when given in combination with pioglitazone. Lipid effects were neutral.

Table 13: Glycemic Parameters at Week 26 in a Placebo-Controlled Study of Alogliptin as Add-On Therapy to Pioglitazone*

  Alogliptin 25 mg + Pioglitazone ± Metformin ± Sulfonylurea Placebo + Pioglitazone ± Metformin ± Sulfonylurea
A1C (%) N=195 N=95
Baseline (mean) 8 8
Change from baseline (adjusted mean†) -0.8 -0.2
Difference from placebo (adjusted mean† with 95% confidence interval) -0.6‡ (-0.8, -0.4)
% of patients (n/N) achieving A1C < 7% 49% (98/199)‡ 34% (33/97)
FPG (mg/dL) N=197 N=97
Baseline (mean) 170 172
Change from baseline (adjusted mean†) -20 -6
Difference from placebo (adjusted mean† with 95% confidence interval) -14* (-23, -5)
*Intent-to-treat population using last observation on study
†Least squares means adjusted for treatment, baseline value, geographic region, baseline treatment regimen (pioglitazone, pioglitazone + metformin or pioglitazone + sulfonylurea) and baseline pioglitazone dose
‡p□0.01 compared to placebo

Cardiovascular Safety Trial

A randomized, double-blind, placebo-controlled cardiovascular outcomes trial (EXAMINE) was conducted to evaluate the cardiovascular risk of alogliptin. The trial compared the risk of major adverse cardiovascular events (MACE) between alogliptin (N=2701) and placebo (N=2679) when added to standard of care therapies for diabetes and atherosclerotic vascular disease (ASCVD). The trial was event driven and patients were followed until a sufficient number of primary outcome events accrued.

Eligible patients were adults with type 2 diabetes who had inadequate glycemic control at baseline (e.g., HbA1c > 6.5%) and had been hospitalized for an acute coronary syndrome event (e.g., acute myocardial infarction or unstable angina requiring hospitalization) 15 to 90 days prior to randomization. The dose of alogliptin was based on estimated renal function at baseline per dosage and administration recommendations [see DOSAGE AND ADMINISTRATION]. The average time between an acute coronary syndrome event and randomization was approximately 48 days.

The mean age of the population was 61 years. Most patients were male (68%), Caucasian (73%), and were recruited from outside of the United States (86%). Asian and Black patients contributed 20% and 4% of the total population, respectively. At the time of randomization patients had a diagnosis of type 2 diabetes mellitus for approximately 9 years, 87% had a prior myocardial infarction and 14% were current smokers. Hypertension (83%) and renal impairment (27% with an eGFR ≤ 60 ml/min/1.73 m²) were prevalent co-morbid conditions. Use of medications to treat diabetes (e.g., metformin 73%, sulfonylurea 54%, insulin 41%), and ASCVD (e.g., statin 94%, aspirin 93%, renin­angiotensin system blocker 88%, beta-blocker 87%) was similar between patients randomized to alogliptin and placebo at baseline. During the trial, medications to treat diabetes and ASCVD could be adjusted to ensure care for these conditions adhered to standard of care recommendations set by local practice guidelines.

The primary endpoint in EXAMINE was the time to first occurrence of a MACE defined as the composite of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. The study was designed to exclude a pre-specified risk margin of 1.3 for the hazard ratio of MACE. The median exposure to study drug was 526 days and 95% of the patients were followed to study completion or death.

Table 14 shows the study results for the primary MACE composite endpoint and the contribution of each component to the primary MACE endpoint. The upper bound of the confidence interval was 1.16 and excluded a risk margin larger than 1.3.

Table 14: Patients with MACE in EXAMINE

Composite of first event of CV death, nonfatal MI or nonfatal stroke (MACE) Alogliptin Placebo Hazard Ratio (98% CI)
Number of Patients (%) Rate per 100 PY* Number of Patients (%) Rate per 100 PY*
N=2701   N=2679    
305 (11.3) 7.6 316 (11.8) 7.9 0.96 (0.80, 1.16)
CV Death 89 (3.3) 2.2 111 (4.1) 2.8  
Non-fatal MI 187 (6.9) 4.6 173 (6.5) 4.3  
Non-fatal stroke 29 (1.1) 0.7 32 (1.2) 0.8  
*Patient Years (PY)

The Kaplan-Meier based cumulative event probability is presented in Figure 4 for the time to first occurrence of the primary MACE composite endpoint by treatment arm. The curves for placebo and alogliptin overlap throughout the duration of the study. The observed incidence of MACE was highest within the first 60 days after randomization in both treatment arms (14.8 MACE per 100 PY), decreased from day 60 to the end of the first year (8.4 per 100 PY) and was lowest after 1 year of follow-up (5.2 per 100 PY).

Figure 4: Observed Cumulative Rate of MACE in EXAMINE

Observed Cumulative Rate of MACE in EXAMINE - Illustration

The rate of all cause death was similar between treatment arms with 153 (3.6 per 100 PY) recorded among patients randomized to alogliptin and 173 (4.1 per 100 PY) among patients randomized to placebo. A total of 112 deaths (2.9 per 100 PY) among patients on alogliptin and 130 among patients on placebo (3.5 per 100 PY) were adjudicated as cardiovascular deaths.

Last reviewed on RxList: 4/20/2016
This monograph has been modified to include the generic and brand name in many instances.

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