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Nesina

"The U.S. Food and Drug Administration today approved three new related products for use with diet and exercise to improve blood sugar control in adults with type 2 diabetes: Nesina (alogliptin) tablets, Kazano (alogliptin and metformin hydrochlor"...

Nesina

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 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.

Pharmacodynamics

Single-dose administration of NESINA to healthy subjects resulted in a peak inhibition of DPP-4 within 2 to 3 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 3- to 4-fold greater with NESINA (at doses of 25 to 200 mg) than placebo. In a 16-week, double-blind, placebo-controlled study, NESINA 25 mg demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an 8-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, NESINA 25 mg demonstrated decreases in 2-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 1 to 2 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 NESINA, inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing.

Cardiac Electrophysiology

In a randomized, placebo-controlled, 4-arm, parallel-group study, 257 subjects were administered either alogliptin 50 mg, alogliptin 400 mg, moxifloxacin 400 mg, or placebo once-daily for a total of 7 days. No increase in QTc was observed with either dose of alogliptin. At the 400 mg dose, peak alogliptin plasma concentrations were 19-fold higher than the peak concentrations following the maximum recommended clinical dose of 25 mg.

Pharmacokinetics

The pharmacokinetics of NESINA has been studied in healthy subjects and in patients with type 2 diabetes. After administration of single, oral doses up to 800 mg in healthy subjects, the peak plasma alogliptin concentration (median Tmax) occurred 1 to 2 hours after dosing. At the maximum recommended clinical dose of 25 mg, NESINA was eliminated with a mean terminal half-life (T½) of approximately 21 hours.

After multiple-dose administration up to 400 mg for 14 days in patients with type 2 diabetes, accumulation of alogliptin was minimal with an increase in total (i.e., AUC) and peak (i.e., Cmax) alogliptin exposures of 34% and 9%, respectively. Total and peak exposure to alogliptin increased proportionally across single doses and multiple doses of alogliptin ranging from 25 mg to 400 mg. The inter-subject coefficient of variation for alogliptin AUC was 17%. The pharmacokinetics of NESiNa was also shown to be similar in healthy subjects and in patients with type 2 diabetes.

Absorption

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

Distribution

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.

Metabolism

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, N-demethylated, M-I ( < 1% of the parent compound), and N-acetylated alogliptin, M-II ( < 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 towards 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 ( > 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.

Excretion

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.

Specific Populations

Renal Impairment

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 2-fold increase in plasma AUC of alogliptin was observed. To maintain similar systemic exposures of NESINA to those with normal renal function, the recommended dose is 12.5 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 (CrCl < 15 mL/min or requiring dialysis), an approximate 3- and 4-fold increase in plasma AUC of alogliptin were observed, respectively. Dialysis removed approximately 7% of the drug during a 3-hour dialysis session. NESINA may be administered without regard to the timing of the dialysis. To maintain similar systemic exposures of NESINA to those with normal renal function, the recommended dose is 6.25 mg once daily in patients with severe renal impairment, as well as in patients with end-stage renal disease requiring dialysis.

Hepatic Impairment

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 NESINA to patients with liver disease [see Use in Specific Populations and WARNINGS AND PRECAUTIONS].

Gender

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

Geriatric

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

Pediatric

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

Race

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

Drug Interactions

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 NESlNA 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

*warfarin was given 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 NESINA 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

Clinical Studies

NESINA has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione (either alone or in combination with metformin or a sulfonylurea), and insulin (either alone or in combination with metformin). A total of 8673 patients with type 2 diabetes were randomized in 10 double-blind, placebo- or active-controlled clinical safety and efficacy studies conducted to evaluate the effects of NESINA on glycemic control. The racial distribution of patients exposed to study medication was 68% Caucasian, 15% Asian, 7% Black, and 9% other racial groups. The ethnic distribution was 30% Hispanic. Patients had an overall mean age of 55 years (range 21 to 80 years).

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

NESINA had similar changes from baseline in serum lipids compared to placebo.

Patients with Inadequate Glycemic Control on Diet and Exercise

A total of 1768 patients with type 2 diabetes participated in three double-blind studies to evaluate the efficacy and safety of NESINA in patients with inadequate glycemic control on diet and exercise. All three studies had a 4-week, single-blind, placebo run-in period followed by a 26-week randomized treatment period. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment periods received glycemic rescue therapy.

In a 26-week, double-blind, placebo-controlled study, a total of 329 patients (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg, or placebo once daily. Treatment with NESINA 25 mg resulted in statistically significant improvements from baseline in A1C and fasting plasma glucose (FPG) compared to placebo at Week 26 (Table 3). A total of 8% of patients receiving NESINA 25 mg and 30% of those receiving placebo required glycemic rescue therapy.

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

The mean change in body weight with NESINA was similar to placebo.

Table 3: Glycemic Parameters at Week 26 in a Placebo-Controlled Monotherapy Study of NESINA*

A1C (%) NESINA 25 mg
N=128
Placebo
N=63
  Baseline (mean) 7.9 8
  Change from baseline (adjusted mean†) -0.6 0
  Difference from placebo (adjusted mean† with 95% confidence interval) -0.6‡ (-0.8, -0.3)
  % of patients (n/N) achieving A1C ≤ 7% 44% (58/131)‡ 23% (15/64)
Fasting Plasma Glucose (mg/dL) N=129 N=64
  Baseline (mean) 172 173
  Change from baseline (adjusted mean†) -16 11
  Difference from placebo (adjusted mean† with 95% confidence interval) -28‡ (-40, -15)
*lntent-to-treat population using last observation on study.
†Least squares means adjusted for treatment, baseline value, geographic region, and duration of diabetes.
‡p < 0.01 compared to placebo.

In a 26-week, double-blind, active-controlled study, a total of 655 patients (mean baseline A1C = 8.8%) were randomized to receive NESINA 25 mg alone, pioglitazone 30 mg alone, NESINA 12.5 mg with pioglitazone 30 mg, or NESINA 25 mg with pioglitazone 30 mg once daily. Coadministration of NESINA 25 mg with pioglitazone 30 mg resulted in statistically significant improvements from baseline in A1C and FPG compared to NESINA 25 mg alone and to pioglitazone 30 mg alone (Table 4). A total of 3% of patients receiving NESINA 25 mg coadministered with pioglitazone 30 mg, 11% of those receiving NESINA 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 NESINA when coadministered with pioglitazone.

Table 4: Glycemic Parameters at Week 26 in an Active-Controlled Study of NESINA, Pioglitazone, and NESINA in Combination with Pioglitazone*

  NESINA 25 mg Pioglitazone 30 mg NESINA 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 NESINA 25 mg (adjusted mean† with 95% confidence interval) -0.8‡ (-1.0, -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)‡
Fasting Plasma Glucose (mg/dL) N=162 N=157 N=162
  Baseline (mean) 189 189 185
  Change from baseline (adjusted mean†) -26 -37 -50
  Difference from NESINA 25 mg (adjusted mean† with 95%confidence interval) -24‡ (-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 NESINA 25 mg or pioglitazone 30 mg.

In a 26-week, double-blind, placebo-controlled study, a total of 784 patients inadequately controlled on diet and exercise alone (mean baseline A1C = 8.4%) were randomized to 1 of 7 treatment groups: placebo; metformin HCl 500 mg or metformin HCl 1000 mg twice daily, NESINA 12.5 mg twice daily, or NESINA 25 mg daily; NESINA 12.5 mg in combination with metformin HCl 500 mg or metformin HCl 1000 mg twice daily. Both coadministration treatment arms (NESINA 12.5 mg + metformin HCl 500 mg and NESINA 12.5 mg + metformin HCl 1000 mg) resulted in statistically significant improvements in A1C and FPG when compared with their respective individual alogliptin and metformin component regimens (Table 5). Coadministration treatment arms demonstrated improvements in 2-hour postprandial glucose (PPG) compared to NESINA alone or metformin alone (Table 5). A total of 12.3% of patients receiving NESINA 12.5 mg + metformin HCl 500 mg, 2.6% of patients receiving NESINA 12.5 mg + metformin HCl 1000 mg, 17.3% of patients receiving NESINA 12.5 mg, 22.9% of patients receiving metformin HCl 500 mg, 10.8% of patients receiving metformin HCl 1000 mg and 38.7% of patients receiving placebo required glycemic rescue.

Improvements in A1C were not affected by gender, age, race, or baseline BMI. The mean decrease in body weight was similar between metformin alone and NESINA when coadministered with metformin.

Table 5: Glycemic Parameters at Week 26 for NESINA and Metformin Alone and in Combination in Patients with Type 2 Diabetes

  Placebo NESINA 12.5 mg twice daily Metformin HCl 500 mg twice daily Metformin HCl 1000 mg twice daily NESINA 12.5 mg + Metformin HCl 500 mg twice daily NESINA 12.5 mg + Metformin HCl 1000 mg twice daily
A1C (%)* N=102 N=104 N=103 N=108 N=102 N=111
Baseline (mean) 8.5 8.4 8.5 8.4 8.5 8.4
Change from baseline (adjusted mean†) 0.1 -0.6 -0.7 -1.1 -1.2 -1.6
Difference from metformin (adjusted mean† with 95% confidence interval) - - - - -0.6‡ (-0.9, -0.3) -0.4‡ (-0.7, -0.2)
Difference from NESINA (adjusted mean† with 95% confidence interval) - - - - -0.7‡ (-1.0, -0.4) -1.0‡ (-1.3, -0.7)
% Patients (n/N) achieving A1C < 7%§ 4% (4/102) 20% (21/104) 27% (28/103) 34% (37/108) 47%‡ (48/102) 59%‡ (66/111)
FPG (mg/dL)* N=105 N=106 N=106 N=110 N=106 N=112
Baseline (mean) 187 177 180 181 176 185
Change from baseline (adjusted mean†) 12 -10 -12 -32 -32 -46
Difference from metformin (adjusted mean† with 95% confidence interval) - - - - -20‡ (-33, -8) -14‡ (-26, -2)
Difference from NESINA (adjusted mean† with 95% confidence interval) - - - - -22‡ (-35, -10) -36‡ (-49, -24)
2-Hour PPG (mg/dL) ¶ N=26 N=34 N=28 N=37 N=31 N=37
Baseline (mean) 263 272 247 266 261 268
Change from baseline (adjusted mean†) -21 -43 -49 -54 -68 -86‡
Difference from metformin (adjusted mean† with 95% confidence interval) - - - - -19 (-49, 11) -32‡ (-58, -5)
Difference from NESINA (adjusted mean† with 95% confidence interval) - - - - -25 (-53, -3) -43‡ (-70, -16)
*lntent-to-treat population using last observation on study prior to discontinuation of double-blind study medication or sulfonylurea rescue therapy for patients needing rescue.
†Least squares means adjusted for treatment, geographic region and baseline value.
‡ p < 0.05 when compared to metformin and NESINA alone.
§Compared using logistic regression.
¶Intent-to-treat population using data available at Week 26.

Combination Therapy

Add-On Therapy to Metformin

A total of 2081 patients with type 2 diabetes participated in two 26-week double-blind, placebo-controlled studies to evaluate the efficacy and safety of NESINA as add-on therapy to metformin. In both studies, patients were inadequately controlled on metformin at a dose of at least 1500 mg per day or at the maximum tolerated dose. All patients entered a 4-week, single-blind, placebo run-in period prior to randomization. Patients who failed to meet pre-specified hyperglycemic goals during the 26-week treatment periods received glycemic rescue therapy.

In the first 26-week, placebo-controlled study, a total of 527 patients already on metformin (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg, or placebo. Patients were maintained on a stable dose of metformin (median dose = 1700 mg) during the treatment period. NESINA 25 mg in combination with metformin resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 6). A total of 8% of patients receiving NESINA 25 mg and 24% of patients receiving placebo required glycemic rescue.

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

The mean decrease in body weight was similar between NESINA and placebo when given in combination with metformin.

Table 6: Glycemic Parameters at Week 26 in a Placebo-Controlled Study of NESINA as Add-on Therapy to Metformin*

  NESINA 25 mg + Metformin Placebo + Metformin
A1C (%) N=203 N=103
  Baseline (mean) 7.9 8
  Change from baseline (adjusted mean†) -0.6 -0.1
  Difference from placebo (adjusted mean† with 95% confidence interval) -0.5‡ (-0.7, -0.3)
  % of patients (n/N) achieving A1C ?7% 44% (92/207)‡ 18% (19/104)
Fasting Plasma Glucose (mg/dL) N=204 N=104
  Baseline (mean) 172 180
  Change from baseline (adjusted mean†) -17 0
  Difference from placebo (adjusted mean† with 95%confidence interval) -17‡ (-26, -9)
*lntent-to-treat population using last observation on study.
†Least squares means adjusted for treatment, baseline value, geographic region, and baseline metformin dose.
‡p < 0.001 compared to placebo.

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 NESINA alone; 15 mg, 30 mg, or 45 mg of pioglitazone alone; or 12.5 mg or 25 mg of NESINA 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 NESINA and pioglitazone provided statistically significant improvements in A1C and FPG compared to placebo, to NESINA alone, or to pioglitazone alone when added to background metformin therapy (Table 7, Figure 3). In addition, improvements from baseline A1C were comparable between NESINA alone and pioglitazone alone (15 mg, 30 mg, and 45 mg) at Week 26. A total of 4%, 5%, or 2% of patients receiving NESINA 25 mg with 15 mg, 30 mg, or 45 mg pioglitazone, 33% of patients receiving placebo, 13% of patients receiving NESINA 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 NESINA when coadministered with pioglitazone.

Table 7: Glycemic Parameters in a 26-Week Study of NESINA, Pioglitazone, and NESINA in Combination with Pioglitazone when Added to Metformin*

  Placebo NESINA 25 mg Pioglitazone 15 mg Pioglitazone 30 mg Pioglitazone 45 mg NESINA 25 mg + Pioglitazone 15 mg NESINA 25 mg + Pioglitazone 30 mg NESINA 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†) -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 NESINA (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 (%) achieving 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)‡
Fasting Plasma Glucose (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†) 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 NESINA (adjusted mean† with 95% confidence interval) - - - - - -19‡ (-29, -10) -23‡ (-33, -13) -34‡ (-44, -24)
*Intent-to-treat population using last observation on study.
†Least squares means adjusted for treatment, geographic region, metformin dose and baseline value.
‡& ≤ 0.01 when compared to corresponding doses of pioglitazone and NESINA alone.

Figure 3: Change From Baseline in A1C at Week 26 with NESINA and Pioglitazone Alone and NESINA in Combination with Pioglitazone When Added to Metformin

Change From Baseline in A1C at Week 26 - Illustration

Add-On Therapy to a Thiazolidinedione

In a 26-week, placebo-controlled study, a total of 493 patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea (10 mg) (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg, or placebo. Patients were maintained on a stable dose of pioglitazone (median dose = 30 mg) during the treatment period; 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 4-week single-blind, placebo run-in period prior to randomization. Patients who failed to meet pre-specified hyperglycemic goals during the 26-week treatment period received glycemic rescue therapy.

The addition of NESINA 25 mg once daily to pioglitazone therapy resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, compared to placebo (Table 8). A total of 9% of patients who were receiving NESINA 25 mg and 12% of patients receiving placebo required glycemic rescue.

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

Clinically meaningful reductions in A1C were observed with NESINA compared to placebo regardless of whether subjects were receiving concomitant metformin or sulfonylurea (-0.2% placebo versus -0.9% NESINA) therapy or pioglitazone alone (0% placebo versus -0.52% NESINA).

The mean increase in body weight was similar between NESINA and placebo when given in combination with pioglitazone.

Table 8: Glycemic Parameters in a 26-Week, Placebo-Controlled Study of NESINA as Add-on Therapy to Pioglitazone*

  NESINA 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)
Fasting Plasma Glucose (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.

Add-on Combination Therapy with Pioglitazone and Metformin

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 NESINA 25 mg or the titration of pioglitazone 30 mg to 45 mg following a 4-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, NESINA 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 at Week 52 (Table 9; results shown only for Week 52). A total of 11% of patients in the NESINA 25 mg treatment group and 22% of patients in the pioglitazone up titration group 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.

Table 9: Glycemic Parameters in a 52-Week, Controlled Study of NESINA as Add-On Combination Therapy With Pioglitazone and Metformin*

  NESINA 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)
Fasting Plasma Glucose (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.
‡ Non-inferior and statistically superior to metformin + pioglitazone at the 0.025 one-sided significance level.
§ p < 0.001 compared to pioglitazone 45 mg + metformin

Add-On Therapy to a Sulfonylurea

In a 26-week, placebo-controlled study, a total of 500 patients inadequately controlled on a sulfonylurea (mean baseline A1C = 8.1%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg, or placebo. Patients were maintained on a stable dose of glyburide (median dose = 10 mg) during the treatment period. All patients entered into a 4-week single-blind, placebo run-in period prior to randomization. Patients who failed to meet pre-specified hyperglycemic goals during the 26-week treatment period received glycemic rescue therapy.

The addition of NESINA 25 mg to glyburide therapy resulted in statistically significant improvements from baseline in A1C at Week 26 when compared to placebo (Table 10). Improvements in FPG observed with NESINA 25 mg were not statistically significant compared with placebo. A total of 16% of patients receiving NESINA 25 mg and 28% of those receiving placebo required glycemic rescue.

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

The mean change in body weight was similar between NESINA and placebo when given in combination with glyburide.

Table 10: Glycemic Parameters in a 26-Week, Placebo-Controlled Study of NESINA as Add-on Therapy to Glyburide*

  NESINA 25 mg + Glyburide Placebo + Glyburide
A1C (%) N=197 N=97
  Baseline (mean) 8.1 8.2
  Change from baseline (adjusted mean†) -0.5 0
  Difference from placebo (adjusted mean† with 95% confidence interval) -0.5‡ (-0.7, -0.3)
  % of patients (n/N) achieving A1C ≤ 7% 35% (69/198)‡ 18% (18/99)
Fasting Plasma Glucose (mg/dL) N=198 N=99
  Baseline (mean) 174 177
  Change from baseline (adjusted mean†) -8 2
  Difference from placebo (adjusted mean† with 95% confidence interval) -11 (-22, 1)
*Intent-to-treat population using last observation on study.
†Least squares means adjusted for treatment, baseline value, geographic region, and baseline glyburide dose.
‡p < 0.01 compared to placebo.

Add-On Therapy to Insulin

In a 26-week, placebo-controlled study, a total of 390 patients inadequately controlled on insulin alone (42%) or in combination with metformin (58%) (mean baseline A1C = 9.3%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg, or placebo. Patients were maintained on their insulin regimen (median dose = 55 IU) upon randomization and those previously treated with insulin in combination with metformin (median dose = 1700 mg) prior to randomization continued on the combination regimen during the treatment period. Patients entered the trial on short-, intermediate- or longacting (basal) insulin or premixed insulin. Patients who failed to meet pre-specified hyperglycemic goals during the 26 month treatment period received glycemic rescue therapy.

The addition of NESINA 25 mg once daily to insulin therapy resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 11). A total of 20% of patients receiving NESINA 25 mg and 40% of those receiving placebo required glycemic rescue.

Improvements in A1C were not affected by gender, age, baseline BMI, or baseline insulin dose. Clinically meaningful reductions in A1C were observed with NESINA compared to placebo regardless of whether subjects were receiving concomitant metformin and insulin (-0.2% placebo versus -0.8% NESINA) therapy or insulin alone (0.1% placebo versus -0.7% NESINA).

The mean increase in body weight was similar between NESINA and placebo when given in combination with insulin.

Table 11: Glycemic Parameters in a 26-Week, Placebo-Controlled Study of NESINA as Add-on Therapy to Insulin*

  NESINA 25 mg + Insulin ± Metformin Placebo + Insulin ± Metformin
A1C (%) N=126 N=126
  Baseline (mean) 9.3 9.3
  Change from baseline (adjusted mean†) -0.7 -0.1
  Difference from placebo (adjusted mean† with 95% confidence interval) -0.6‡ (-0.8, -0.4)
  % of patients (n/N) achieving A1C ≤ 7% 8% (10/129) 1% (1/129)
Fasting Plasma Glucose (mg/dL) N=128 N=127
  Baseline (mean) 186 196
  Change from baseline (adjusted mean†) -12 6
  Difference from placebo (adjusted mean† with 95% confidence interval) -18‡ (-33, -2)
*lntent-to-treat population using last observation on study.
†Least squares means adjusted for treatment, baseline value, geographic region, baseline treatment regimen (insulin or insulin + metformin), and baseline daily insulin dose.
‡p < 0.05 compared to placebo.

Last reviewed on RxList: 2/11/2013
This monograph has been modified to include the generic and brand name in many instances.

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