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Tradjenta

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Tradjenta

CLINICAL PHARMACOLOGY

Mechanism Of Action

Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta-cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha-cells, resulting in a reduction in hepatic glucose output.

Pharmacodynamics

Linagliptin binds to DPP-4 in a reversible manner and thus increases the concentrations of incretin hormones. Linagliptin glucose dependently increases insulin secretion and lowers glucagon secretion, thus resulting in better regulation of glucose homeostasis. Linagliptin binds selectively to DPP-4, and selectively inhibits DPP4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.

Cardiac Electrophysiology

In a randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered a single oral dose of linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of 5 mg or the 100-mg dose. At the 100-mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following a 5-mg dose.

Pharmacokinetics

The pharmacokinetics of linagliptin has been characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a single 5-mg dose to healthy subjects, peak plasma concentrations of linagliptin occurred at approximately 1.5 hours post dose (Tmax); the mean plasma area under the curve (AUC) was 139 nmol*h/L and maximum concentration (Cmax) was 8.9 nmol/L.

Plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half-life ( > 100 hours), related to the saturable binding of linagliptin to DPP-4. The prolonged elimination phase does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin 5 mg, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin 5 mg are reached by the third dose, and Cmax and AUC increased by a factor of 1.3 at steady state compared with the first dose. The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Plasma AUC of linagliptin increased in a less than dose-proportional manner in the dose range of 1 to 10 mg. The pharmacokinetics of linagliptin is similar in healthy subjects and in patients with type 2 diabetes.

Absorption

The absolute bioavailability of linagliptin is approximately 30%. High-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant. TRADJENTA may be administered with or without food.

Distribution

The mean apparent volume of distribution at steady state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75%-89% at ≥ 30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.

Metabolism

Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin.

Excretion

Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady state was approximately 70 mL/min.

Specific Populations

Renal Impairment

An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin 5 mg in male and female patients with varying degrees of chronic renal impairment. The study included 6 healthy subjects with normal renal function (creatinine clearance [CrCl] ≥ 80 mL/min), 6 patients with mild renal impairment (CrCl 50 to < 80 mL/min), 6 patients with moderate renal impairment (CrCl 30 to < 50 mL/min), 10 patients with type 2 diabetes mellitus and severe renal impairment (CrCl < 30 mL/min), and 11 patients with type 2 diabetes mellitus and normal renal function. Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula.

Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects.

In patients with moderate renal impairment under steady-state conditions, mean exposure of linagliptin increased (AUCτ,ss by 71% and Cmax by 46%) compared with healthy subjects. This increase was not associated with a prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of linagliptin was below 5% of the administered dose and was not affected by decreased renal function.

Patients with type 2 diabetes mellitus and severe renal impairment showed steady-state exposure approximately 40% higher than that of patients with type 2 diabetes mellitus and normal renal function (increase in AUCτ,ss by 42% and Cmax by 35%). For both type 2 diabetes mellitus groups, renal excretion was below 7% of the administered dose.

These findings were further supported by the results of population pharmacokinetic analyses.

Hepatic Impairment

In patients with mild hepatic impairment (Child-Pugh class A), steady-state exposure (AUCτ,ss) of linagliptin was approximately 25% lower and Cmax,ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUCss of linagliptin was about 14% lower and Cmax,ss was approximately 8% lower than in healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of linagliptin in terms of AUC0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition.

Body Mass Index (BMI)/Weight

No dose adjustment is necessary based on BMI/weight. BMI/weight had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis.

Gender

No dose adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis.

Geriatric

Age did not have a clinically meaningful impact on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis.

Pediatric

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

Race

No dose adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of linagliptin based on available pharmacokinetic data, including subjects of White, Hispanic, Black, and Asian racial groups.

Drug Interactions

In vitro Assessment of Drug Interactions

Linagliptin is a weak to moderate inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes and is not an inducer of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11.

Linagliptin is a P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport of digoxin at high concentrations. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.

In vivo Assessment of Drug Interactions

Strong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. In vivo studies indicated evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT). No dose adjustment of TRADJENTA is recommended based on results of the described pharmacokinetic studies.

Table 2 : Effect of Coadministered Drugs on Systemic Exposure of Linagliptin

Coadministered Drug Dosing of Coadministered Drug* Dosing of Linagliptin* Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.0
AUC† Cmax
No dosing adjustments required for TRADJENTA when given with following coadministered drugs:
Metformin 850mg TID 10mg QD 1.20 1.03
Glyburide 1.75mg# 5mg QD 1.02 1.01
Pioglitazone 45mg QD 10mg QD 1.13 1.07
Ritonavir 200mg BID 5mg# 2.01 2.96
The efficacy of TRADJENTA may be reduced when administered in combination with strong inducers of CYP3A4 or P-gp (e.g., rifampin). Use of alternative treatments is strongly recommended [see DRUG INTERACTIONS].
Rifampin 600mg QD 5mg QD 0.60 0.56
*Multiple dose (steady state) unless otherwise noted
#Single dose
†AUC = AUC(0 to 24 hours) for single dose treatments and AUC = AUC(TAU) for multiple dose treatments
QD = once daily BID = twice daily TID = three times daily

Table 3 : Effect of Linagliptin on Systemic Exposure of Coadministered Drugs

Coadministered Drug Dosing of Coadministered Drug* Dosing of Linagliptin* Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.0
  AUC† Cmax
No dosing adjustments required for the following coadministered drugs:
Metformin 850mg TID 10mg QD metformin 1.01 0.89
Glyburide 1.75 mg# 5 mg QD glyburide 0.86 0.86
Pioglitazone 45mg QD 10mg QD pioglitazone 0.94 0.86
metabolite M-III 0.98 0.96
metabolite M-IV 1.04 1.05
Digoxin 0.25 mg QD 5 mg QD digoxin 1.02 0.94
Simvastatin 40 mg QD 10 mg QD simvastatin 1.34 1.10
simvastatin acid 1.33 1.21
Warfarin 10 mg# 5 mg QD R-warfarin 0.99 1.00
S-warfarin 1.03 1.01
INR 0.93** 1.04**
PT 1.03** 1.15**
Ethinylestradiol and levonorgestrel ethinylestradiol 0.03 mg and levonorgestrel 0.150 mg QD 5 mg QD ethinylestradiol 1.01 1.08
levonorgestrel 1.09 1.13
*Multiple dose (steady state) unless otherwise noted
#Single dose
†AUC = AUC(INF) for single dose treatments and AUC = AUC(TAU) for multiple dose treatments
**AUC=AUC(0-168) and Cmax=Emax for pharmacodynamic end points
INR = International Normalized Ratio PT = Prothrombin Time QD = once daily TID = three times daily

Clinical Studies

TRADJENTA has been studied as monotherapy and in combination with metformin, glimepiride, pioglitazone, and insulin.

A total of 3648 patients with type 2 diabetes were randomized and exposed to linagliptin for at least 12 weeks in 10 double-blind, placebo-controlled clinical efficacy studies evaluating the effects of TRADJENTA on glycemic control. The overall ethnic/racial distribution in these studies was 69% White, 29% Asian, and 2.5% Black, and included 16% Hispanic/Latino patients. Fifty two percent of patients were male. Patients had an overall mean age of 57 years (range 20 to 91 years). In addition, an active (glimepiride)-controlled study of 104 weeks' duration was conducted in 1551 patients with type 2 diabetes who had inadequate glycemic control on metformin, and a placebo-controlled study of 52 weeks' duration was conducted in 133 patients with type 2 diabetes and severe chronic renal impairment (eGFR < 30 mL/min).

In patients with type 2 diabetes, treatment with TRADJENTA produced clinically significant improvements in hemoglobin A1c (A1C), fasting plasma glucose (FPG), and 2-hour post-prandial glucose (PPG) compared with placebo.

Monotherapy

A total of 730 patients with type 2 diabetes participated in 2 double-blind, placebo-controlled studies, one of 18 weeks' and another of 24 weeks' duration, to evaluate the efficacy and safety of TRADJENTA monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent and underwent a diet, exercise, and drug washout period of about 6 weeks that included an open-label placebo run-in during the last 2 weeks. Patients with inadequate glycemic control (A1C 7% to 10%) after the washout period were randomized; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week, open-label, placebo run-in period. In the 18-week study, only patients ineligible for metformin were recruited. In the 18-week study, 76 patients were randomized to placebo and 151 to TRADJENTA 5 mg; in the 24-week study, 167 patients were randomized to placebo and 336 to TRADJENTA 5 mg. Patients who failed to meet specific glycemic goals during the 18-week study received rescue therapy with pioglitazone and/or insulin; metformin rescue therapy was used in the 24-week trial.

Treatment with TRADJENTA 5 mg daily provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo (Table 4). In the 18week study, 12% of patients receiving TRADJENTA 5 mg and 18% who received placebo required rescue therapy. In the 24-week study, 10.2% of patients receiving TRADJENTA 5 mg and 20.9% of patients receiving placebo required rescue therapy. The improvement in A1C compared with placebo was not affected by gender, age, race, prior antihyperglycemic therapy, baseline BMI, or a standard index of insulin resistance (HOMA-IR). As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with TRADJENTA appears to be related to the degree of A1C elevation at baseline. In these 18-and 24-week studies, the changes from baseline in A1C were -0.4% and -0.4%, respectively, for those given TRADJENTA, and 0.1% and 0.3%, respectively, for those given placebo. Change from baseline in body weight did not differ significantly between the groups.

Table 4 : Glycemic Parameters in Placebo-Controlled Monotherapy Studies of TRADJENTA*

  18-Week Study 24-Week Study
TRADJENTA 5 mg Placebo TRADJENTA 5 mg Placebo
A1C (%)
Number of patients n= 147 n= 73 n= 333 n= 163
Baseline (mean) 8.1 8.1 8.0 8.0
Change from baseline (adjusted mean***) -0.4 0.1 -0.4 0.3
Difference from placebo (adjusted mean) (95% CI) -0.6(-0.9, -0.3) -- -0.7(-0.9, -0.5) --
Patients [n (%)] achieving A1C < 7%** 32 (23.5) 8 (11.8) 77 (25) 17 (12)
FPG (mg/dL)
Number of patients n= 138 n= 66 n= 318 n= 149
Baseline (mean) 178 176 164 166
Change from baseline (adjusted mean***) -13 7 -9 15
Difference from placebo (adjusted mean) (95% CI) -21 (-31, -10) -- -23 (-30, -16) --
2-hour PPG (mg/dL)
Number of patients Data not available Data not available n= 67 n= 24
Baseline (mean) -- -- 258 244
Change from baseline (adjusted mean***) -- -- -34 25
Difference from placebo (adjusted mean) (95% CI) -- -- -58 (-82, -34) --
* Full analysis population using last observation on study
**18-week study: Placebo, n=68; TRADJENTA, n=136 24-week study: Placebo, n=147; TRADJENTA, n=306
***18-week study. HbA1c: ANCOVA model included treatment, reason for metformin intolerance and number of prior oral anti-diabetic medicine(s) (OADs) as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment, reason for metformin intolerance and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. 24-week study. HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. PPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline postprandial glucose after two hours as covariate.

Combination Therapy

Add-on Combination Therapy with Metformin

A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with metformin. Patients already on metformin (n = 491) at a dose of at least 1500 mg per day were randomized after completing a 2week, open-label, placebo run-in period. Patients on metformin and another antihyperglycemic agent (n = 207) were randomized after a run-in period of approximately 6 weeks on metformin (at a dose of at least 1500 mg per day) in monotherapy. Patients were randomized to the addition of either TRADJENTA 5 mg or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with glimepiride rescue.

In combination with metformin, TRADJENTA provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo (Table 5). Rescue glycemic therapy was used in 7.8% of patients treated with TRADJENTA 5 mg and in 18.9% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.

Table 5 : Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination with Metformin*

  TRADJENTA 5 mg + Metformin Placebo + Metformin
A1C (%)
Number of patients n = 513 n = 175
Baseline (mean) 8.1 8.0
Change from baseline (adjusted mean***) -0.5 0.15
Difference from placebo + metformin (adjusted mean) (95% CI) -0.6(-0.8, -0.5) --
Patients [n (%)] achieving A1C < 7%** 127(26.2) 15(9.2)
FPG (mg/dL)
Number of patients n= 495 n= 159
Baseline (mean) 169 164
Change from baseline (adjusted mean***) -11 11
Difference from placebo + metformin (adjusted mean) (95% CI) -21(-27, -15) --
2-hour PPG (mg/dL)
Number of patients n= 78 n= 21
Baseline (mean) 270 274
Change from baseline (adjusted mean***) -49 18
Difference from placebo + metformin (adjusted mean) (95% CI) -67(-95, -40) --
* Full analysis population using last observation on study
**TRADJENTA 5 mg + Metformin, n=485; Placebo + Metformin, n=163
***HbA1c: ANCOVA model included treatment and number of prior oral OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. PPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline postprandial glucose after two hours as covariate.

Initial Combination Therapy with Metformin

A total of 791 patients with type 2 diabetes mellitus and inadequate glycemic control on diet and exercise participated in the 24-week, randomized, double-blind, portion of this placebo-controlled factorial study designed to assess the efficacy of TRADJENTA as initial therapy with metformin. Patients on an antihyperglycemic agent (52%) underwent a drug washout period of 4 weeks' duration. After the washout period and after completing a 2-week single-blind placebo run-in period, patients with inadequate glycemic control (A1C ≥ 7.0% to ≤ 10.5%) were randomized. Patients with inadequate glycemic control (A1C ≥ 7.5% to < 11.0%) not on antihyperglycemic agents at study entry (48%) immediately entered the 2-week, single-blind, placebo run-in period and then were randomized. Randomization was stratified by baseline A1C ( < 8.5% vs ≥ 8.5%) and use of a prior oral antidiabetic drug (none vs monotherapy). Patients were randomized in a 1:2:2:2:2:2 ratio to either placebo or one of 5 active-treatment arms. Approximately equal numbers of patients were randomized to receive initial therapy with 5 mg of TRADJENTA once daily, 500 mg or 1000 mg of metformin twice daily, or 2.5 mg of linagliptin twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were treated with sulfonylurea, thiazolidinedione, or insulin rescue therapy.

Initial therapy with the combination of linagliptin and metformin provided significant improvements in A1C and fasting plasma glucose (FPG) compared to placebo, to metformin alone, and to linagliptin alone (Table 6).

The adjusted mean treatment difference in A1C from baseline to week 24 (LOCF) was -0.5% (95% CI -0.7, -0.3; p < 0.0001) for linagliptin 2.5 mg/metformin 1000 mg twice daily compared to metformin 1000 twice daily; -1.1% (95% CI -1.4, -0.9; p < 0.0001) for linagliptin 2.5 mg/metformin 1000 mg twice daily compared to TRADJENTA 5 mg once daily; -0.6% (95% CI -0.8, -0.4; p < 0.0001) for linagliptin 2.5 mg/metformin 500 mg twice daily compared to metformin 500 mg twice daily; and -0.8% (95% CI -1.0, -0.6; p < 0.0001) for linagliptin 2.5 mg/metformin 500 mg twice daily compared to TRADJENTA 5 mg once daily.

Lipid effects were generally neutral. No meaningful change in body weight was noted in any of the 6 treatment groups.

Table 6 : Glycemic Parameters at Final Visit (24-Week Study) for Linagliptin and Metformin, Alone and in Combination in Randomized Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise**

  Placebo TRADJENTA 5 mg Once Daily* Metformin 500 mg Twice Daily Linagliptin 2.5 mg Twice Daily* + Metformin 500 mg Twice Daily Metformin 1000 mg Twice Daily Linagliptin 2.5 mg Twice Daily* + Metformin 1000 mg Twice Daily
A1C (%)
Number of patients n= 65 n= 135 n= 141 n= 137 n= 138 n= 140
Baseline (mean) 8.7 8.7 8.7 8.7 8.5 8.7
Change from baseline (adjusted mean****) 0.1 -0.5 -0.6 -1.2 -1.1 -1.6
Difference from placebo (adjusted mean) (95% CI) -- -0.6 (-0.9, -0.3) -0.8 (-1.0, -0.5) -1.3 (-1.6, -1.1) -1.2 (-1.5, -0.9) -1.7 (-2.0, -1.4)
Patients [n (%)1 achieving A1C < 7%*** 7 (10.8) 14 (10.4) 26 (18.6) 41 (30.1) 42 (30.7) 74 (53.6)
Patients (%) receiving rescue medication 29.2 11.1 13.5 7.3 8.0 4.3
FPG (mg/dL)
Number of patients n= 61 n= 134 n= 136 n= 135 n= 132 n= 136
Baseline (mean) 203 195 191 199 191 196
Change from baseline (adjusted mean****) 10 -9 -16 -33 -32 -49
Difference from placebo (adjusted mean) (95% CI) -- -19 (-31, -6) -26 (-38, -14) -43 (-56, -31) -42 (-55, -30) -60 (-72, -47)
*Total daily dose of TRADJENTA is equal to 5 mg
**Full analysis population using last observation on study
***Metformin 500 mg twice daily, n=140; Linagliptin 2.5 mg twice daily + Metformin 500 twice daily, n=136; Metformin 1000 mg twice daily, n=137; Linagliptin 2.5 mg twice daily + Metformin 1000 mg twice daily, n=138
****HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.

Active-Controlled Study vs Glimepiride in Combination with Metformin

The efficacy of TRADJENTA was evaluated in a 104-week, double-blind, glimepiride-controlled, non-inferiority study in patients with type 2 diabetes with insufficient glycemic control despite metformin therapy. Patients being treated with metformin only entered a run-in period of 2 weeks' duration, whereas patients pretreated with metformin and one additional antihyperglycemic agent entered a run-in treatment period of 6 weeks' duration with metformin monotherapy (dose of ≥ 1500 mg/day) and washout of the other agent. After an additional 2-week placebo run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of TRADJENTA 5 mg once daily or glimepiride. Randomization was stratified by baseline HbA1c ( < 8.5% vs ≥ 8.5%), and the previous use of antidiabetic drugs (metformin alone vs metformin plus one other OAD). Patients receiving glimepiride were given an initial dose of 1 mg/day and then electively titrated over the next 12 weeks to a maximum dose of 4 mg/day as needed to optimize glycemic control. Thereafter, the glimepiride dose was to be kept constant, except for downtitration to prevent hypoglycemia.

After 52 and 104 weeks, TRADJENTA and glimepiride both had reductions from baseline in A1C (52 weeks: -0.4% for TRADJENTA, -0.6% for glimepiride; 104 weeks: -0.2% for TRADJENTA, -0.4% for glimepiride) from a baseline mean of 7.7% (Table 7). The mean difference between groups in A1C change from baseline was 0.2% with 2-sided 97.5% confidence interval (0.1%, 0.3%) for the intent-to-treat population using last observation carried forward. These results were consistent with the completers analysis.

Table 7 : Glycemic Parameters at 52 and 104 Weeks in Study Comparing TRADJENTA to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin**

  Week 52 Week 104
TRADJENTA 5 mg + Metformin Glimepiride + Metformin (mean Glimepiride dose 3 mg) TRADJENTA 5 mg + Metformin Glimepiride + Metformin (mean Glimepiride dose 3 mg)
A1C (%)
Number of patients n = 764 n = 755 n = 764 n = 755
Baseline (mean) 7.7 7.7 7.7 7.7
Change from baseline (adjusted mean****) -0.4 -0.6 -0.2 -0.4
Difference from glimepiride (adjusted mean)(97.5% CI) 0.2 (0.1, 0.3) 0.2 (0.1, 0.3)
FPG (mg/dL)
Number of patients n = 733 n = 725 n = 733 n = 725
Baseline (mean) 164 166 164 166
Change from baseline (adjusted mean****) -8* -15 -21" -9
Hypoglycemia incidence (%)***
Number of patients n = 776 n = 775 n = 776 n = 775
Incidence**** 5.3 * 31.1 7.5 * 36.1
*p < 0.0001 vs glimepiride;
†p=0.0012 vs glimepiride
**Full analysis population using last observation on study
***Hypoglycemic incidence included both asymptomatic events (not accompanied by typical symptoms and plasma glucose concentration of ≤ 70 mg/dL) and symptomatic events with typical symptoms of hypoglycemia and plasma glucose concentration of ≤ 70 mg/dL.
****HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. Hypoglycemia incidence (%): Cochran-Mantel-Haenszel test was performed on the patient population contained in the treated set, to compare the proportion of patients with hypoglycemic events between patients treated with linagliptin and patients treated with glimepiride.

Patients treated with linagliptin had a mean baseline body weight of 86 kg and were observed to have an adjusted mean decrease in body weight of 1.1 kg at 52 weeks and 1.4 kg at 104 weeks. Patients on glimepiride had a mean baseline body weight of 87 kg and were observed to have an adjusted mean increase from baseline in body weight of 1.4 kg at 52 weeks and 1.3 kg at 104 weeks (treatment difference p < 0.0001 for both timepoints).

Add-On Combination Therapy with Pioglitazone

A total of 389 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with pioglitazone. Therapy was stopped in patients on oral antihyperglycemic therapy for a period of 6 weeks (4 weeks followed by a 2week, open-label, placebo run-in period). Drug-na´ve patients entered directly into the 2-week placebo run-in period. After the run-in period, patients were randomized to receive either TRADJENTA 5 mg or placebo, both in addition to pioglitazone 30 mg daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured were A1C and FPG.

In initial combination with pioglitazone 30 mg, TRADJENTA 5 mg provided statistically significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 8). Rescue therapy was used in 7.9% of patients treated with TRADJENTA 5 mg/pioglitazone 30 mg and 14.1% of patients treated with placebo/pioglitazone 30 mg. Patient weight increased in both groups during the study with an adjusted mean change from baseline of 2.3 kg and 1.2 kg in the TRADJENTA 5 mg/pioglitazone 30 mg and placebo/pioglitazone 30 mg groups, respectively (p = 0.0141).

Table 8 : Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination Therapy with Pioglitazone*

  TRADJENTA 5 mg + Pioglitazone Placebo + Pioglitazone
A1C (%)
Number of patients n = 252 n = 128
Baseline (mean) 8.6 8.6
Change from baseline (adjusted mean**) -1.1 -0.6
Difference from placebo + pioglitazone (adjusted mean) (95% CI) -0.5 (-0.7, -0.3) --
Patients [n (%)] achieving A1C < 7% 108 (42.9) 39 (30.5)
FPG (mg/dL)
Number of patients n = 243 n = 122
Baseline (mean) 188 186
Change from baseline (adjusted mean**) -33 -18
Difference from placebo + pioglitazone (adjusted mean) (95% CI) -14 (-21, -7) --
* Full analysis population using last observation on study
**HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.

Add-On Combination with Sulfonylureas

A total of 245 patients with type 2 diabetes participated in an 18-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with sulfonylurea (SU). Patients on sulfonylurea monotherapy (n = 142) were randomized after completing a 2-week, single-blind, placebo run-in period. Patients on a sulfonylurea plus one additional oral antihyperglycemic agent (n = 103) were randomized after a wash-out period of 4 weeks and a 2-week, single-blind, placebo run-in period. Patients were randomized to the addition of TRADJENTA 5 mg or to placebo, each administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured included A1C and FPG.

In combination with a sulfonylurea, TRADJENTA provided statistically significant improvements in A1C compared with placebo following 18 weeks' treatment; the improvements in FPG observed with TRADJENTA were not statistically significant compared with placebo (Table 9). Rescue therapy was used in 7.6% of patients treated with TRADJENTA 5 mg and 15.9% of patients treated with placebo. There was no significant difference between TRADJENTA and placebo in body weight.

Table 9: Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination with Sulfonylurea*

  TRADJENTA 5 mg + SU Placebo + SU
A1C (%)
Number of patients n = 158 n = 82
Baseline (mean) 8.6 8.6
Change from baseline (adjusted mean***) -0.5 -0.1
Difference from placebo + SU (adjusted mean) (95% CI) -0.5 (-0.7, -0.2) --
Patients [n (%)] achieving A1C < 7%** 23 (14.7) 3 (3.7)
FPG (mg/dL)
Number of patients n = 155 n = 78
Baseline (mean) 180 171
Change from baseline (adjusted mean***) -8 -2
Difference from placebo + SU (adjusted mean) (95% CI) -6 (-17, 4) --
SU= sulfonylurea
*Full analysis population using last observation on study
**TRADJENTA 5 mg + SU, n=156; Placebo + SU, n=82
***HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates

Add-On Combination Therapy with Metformin and a Sulfonylurea

A total of 1058 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with a sulfonylurea and metformin. The most common sulfonylureas used by patients in the study were: glimepiride (31%), glibenclamide (26%), and gliclazide (26%, not available in the United States). Patients on a sulfonylurea and metformin were randomized to receive TRADJENTA 5 mg or placebo, each administered once daily. Patients who failed to meet specific glycemic goals during the study were treated with pioglitazone rescue. Glycemic endpoints measured included A1C and FPG.

In combination with a sulfonylurea and metformin, TRADJENTA provided statistically significant improvements in A1C and FPG compared with placebo (Table 10). In the entire study population (patients on TRADJENTA in combination with sulfonylurea and metformin), a mean reduction from baseline relative to placebo in A1C of -0.6% and in FPG of -13 mg/dL was seen. Rescue therapy was used in 5.4% of patients treated with TRADJENTA 5 mg and in 13% of patients treated with placebo. Change from baseline in body weight did not differ significantly between the groups.

Table 10 :Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination with Metformin and Sulfonylurea*

  TRADJENTA 5 mg + Metformin + SU Placebo + Metformin + SU
A1C (%)
Number of patients n = 778 n = 262
Baseline (mean) 8.2 8.1
Change from baseline (adjusted mean***) -0.7 -0.1
Difference from placebo (adjusted mean) (95% CI) -0.6 (-0.7, -0.5) --
Patients [n (%)] achieving A1C < 7%** 217 (29.2) 20 (8.1)
FPG (mg/dL)
Number of patients n = 739 n = 248
Baseline (mean) 159 163
Change from baseline (adjusted mean***) -5 8
Difference from placebo (adjusted mean) (95% CI) -13(-18, -7) --
SU= sulfonylurea
*Full analysis population using last observation on study
**TRADJENTA 5 mg + Metformin + SU, n=742; Placebo + Metformin + SU, n=247
***HbA1c: ANCOVA model included treatment as class-effects and baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.

Add-On Combination Therapy with Insulin

A total of 1261 patients with type 2 diabetes inadequately controlled on basal insulin alone or basal insulin in combination with oral drugs participated in a randomized, double-blind placebo-controlled trial designed to evaluate the efficacy of TRADJENTA as add-on therapy to basal insulin over 24 weeks. Randomization was stratified by baseline HbA1c ( < 8.5% vs ≥ 8.5%), renal function impairment status (based on baseline eGFR), and concomitant use of oral antidiabetic drugs (none, metformin only, pioglitazone only, metformin + pioglitazone). Patients with a baseline A1C of > 7% and < 10% were included in the study including 709 patients with renal impairment (eGFR < 90 mL/min), most of whom (n=575) were categorized as mild renal impairment (eGFR 60 to < 90 mL/min). Patients entered a 2 week placebo run-in period on basal insulin (e.g., insulin glargine, insulin detemir, or NPH insulin) with or without metformin and/or pioglitazone background therapy. Following the run-in period, patients with inadequate glycemic control were randomized to the addition of either 5 mg of TRADJENTA or placebo, administered once daily. Patients were maintained on a stable dose of insulin prior to enrollment, during the run-in period, and during the first 24 weeks of treatment. Patients who failed to meet specific glycemic goals during the double-blind treatment period were rescued by increasing background insulin dose.

TRADJENTA used in combination with insulin (with or without metformin and/or pioglitazone), provided statistically significant improvements in A1C and FPG compared to placebo (Table 11) after 24 weeks of treatment. The mean total daily insulin dose at baseline was 42 units for patients treated with TRADJENTA and 40 units for patients treated with placebo. Background baseline diabetes therapy included use of: insulin alone (16.1%), insulin combined with metformin only (75.5%), insulin combined with metformin and pioglitazone (7.4%), and insulin combined with pioglitazone only (1%). The mean change from baseline to Week 24 in the daily dose of insulin was +1.3 IU in the placebo group and +0.6 IU in the TRADJENTA group. The mean change in body weight from baseline to Week 24 was similar in the two treatment groups. The rate of hypoglycemia, defined as all symptomatic or asymptomatic episodes with a self measured blood glucose was also similar in both groups (21.4% TRADJENTA; 22.9% placebo) in the first 24 weeks of the study.

Table 11 : Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination with Insulin*

  TRADJENTA 5 mg + Insulin Placebo + Insulin
A1C (%)
Number of patients n = 618 n = 617
Baseline(mean) 8.3 8.3
Change from baseline (adjusted mean***) -0.6 0.1
Difference from placebo (adjusted mean) (95% CI) -0.7 (-0.7, -0.6) --
Patients [n (%)] achieving A1C < 7%** 116 (19.5) 48 (8.1)
FPG (mg/dL)
Number of patients n = 613 n = 608
Baseline (mean) 147 151
Change from baseline (adjusted mean***) -8 3
Difference from placebo (adjusted mean) (95% CI) -11 (-16, -6) --
*Full analysis population using last observation carried forward (LOCF) method on study
**TRADJENTA + Insulin, n=595; Placebo + Insulin, n=593
***HbA1c: ANCOVA model included treatment, categorical renal function impairment status and concomitant OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment, categorical renal function impairment status and concomitant OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.

The difference between treatment with linagliptin and placebo in terms of adjusted mean change from baseline in HbA1c after 24 weeks was comparable for patients with no renal impairment (eGFR ≥ 90 mL/min, n=539), with mild renal impairment (eGFR 60 to < 90 mL/min, n= 565), or with moderate renal impairment (eGFR 30 to < 60 mL/min, n=124).

Renal Impairment

A total of 133 patients with type 2 diabetes participated in a 52 week, double-blind, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of TRADJENTA in patients with both type 2 diabetes and severe chronic renal impairment. Participants with an estimated (based on the four variables modified diet in renal disease [MDRD] equation) GFR value of < 30 mL/min were eligible to participate in the study. Randomization was stratified by baseline HbA1c ( ≤ 8% and > 8%) and background antidiabetic therapy (insulin or any combination with insulin, SU or glinides as monotherapy and pioglitazone or any other antidiabetics excluding any other DPP-4 inhibitors). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed. At baseline in this trial, 62.5% of patients were receiving insulin alone as background diabetes therapy, and 12.5% were receiving sulfonylurea alone.

After 12 weeks of treatment, TRADJENTA 5 mg provided statistically significant improvement in A1C compared to placebo, with an adjusted mean change of -0.6% compared to placebo (95% confidence interval -0.9, -0.3) based on the analysis using last observation carried forward (LOCF). With adjustments in antidiabetic background therapy after the initial 12 weeks, efficacy was maintained for 52 weeks, with an adjusted mean change from baseline in A1C of -0.7% compared to placebo (95% confidence interval -1.0, -0.4) based on analysis using LOCF.

Last reviewed on RxList: 6/9/2014
This monograph has been modified to include the generic and brand name in many instances.

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