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Jentadueto

"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"...

Jenadueto

CLINICAL PHARMACOLOGY

Mechanism Of Action

JENTADUETO

JENTADUETO combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus: linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin, a member of the biguanide class.

Linagliptin

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.

Metformin

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike SUs, metformin does not produce hypoglycemia in either patients with type 2 diabetes mellitus or normal subjects (except in special circumstances) [see WARNINGS AND PRECAUTIONS] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacodynamics

Linagliptin

Linagliptin binds to DPP-4 in a reversible manner and increases the concentrations of incretin hormones. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion, thus resulting in a better regulation of the glucose homeostasis. Linagliptin binds selectively to DPP-4 and selectively inhibits DPP-4, 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

JENTADUETO

The results of a bioequivalence study in healthy subjects demonstrated that JENTADUETO (linagliptin/metformin hydrochloride) 2.5 mg/500 mg, 2.5 mg/850 mg, and 2.5 mg/1000 mg combination tablets are bioequivalent to coadministration of corresponding doses of linagliptin and metformin as individual tablets. Administration of linagliptin 2.5 mg/metformin hydrochloride 1000 mg fixed-dose combination with food resulted in no change in overall exposure of linagliptin. There was no change in metformin AUC; however, mean peak serum concentration of metformin was decreased by 18% when administered with food. A delayed time-to-peak serum concentrations by 2 hours was observed for metformin under fed conditions. These changes are not likely to be clinically significant.

Absorption

Linagliptin

The absolute bioavailability of linagliptin is approximately 30%. Following oral administration, 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. However, the prolonged elimination 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. 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.

Metformin

The absolute bioavailability of a metformin hydrochloride 500-mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.

Distribution

Linagliptin

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% to 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.

Metformin

The apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin hydrochloride tablets 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins, in contrast to SUs, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin tablets, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally < 1 mcg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Metabolism

Linagliptin

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.

Metformin

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.

Excretion

Linagliptin

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.

Metformin

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

Specific Populations

Renal Impairment

JENTADUETO: Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of JENTADUETO in renally impaired patients have not been performed. Since metformin is contraindicated in patients with renal impairment, use of JENTADUETO is also contraindicated in patients with renal impairment (e.g., serum creatinine ≥ 1.5 mg/dL [males] or ≥ 1.4 mg/dL [females], or abnormal creatinine clearance) [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Linagliptin: 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 AUC by 42% and Cmax by 35%). For both type 2 diabetes mellitus groups, renal excretion was below 7% of the administered dose.

Metformin: In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Hepatic Impairment

JENTADUETO: Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of JENTADUETO in hepatically impaired patients have not been performed. However, use of metformin alone in patients with hepatic impairment has been associated with some cases of lactic acidosis. Therefore, use of JENTADUETO is not recommended in patients with hepatic impairment [see WARNINGS AND PRECAUTIONS].

Linagliptin: 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.

Metformin hydrochloride: No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.

Body Mass Index (BMI)/Weight

Linagliptin: BMI/Weight had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis.

Gender

Linagliptin: Gender had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis.

Metformin hydrochloride: Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females.

Geriatric

JENTADUETO: Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of JENTADUETO in geriatric patients have not been performed. Based on the metformin component, JENTADUETO treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

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

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

Pediatric

Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of JENTADUETO in pediatric patients have not yet been performed.

Race

Linagliptin: 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.

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

Drug Interactions

Pharmacokinetic drug interaction studies with JENTADUETO have not been performed; however, such studies have been conducted with the individual components of JENTADUETO (linagliptin and metformin hydrochloride).

Linagliptin

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 OCT. No dose adjustment of linagliptin 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 linagliptin when given with the following coadministered drugs:
Metformin 850 mg TID 10 mg QD 1.20 1.03
Glyburide 1.75 mg# 5 mg QD 1.02 1.01
Pioglitazone 45 mg QD 10 mg QD 1.13 1.07
Ritonavir 200 mg BID 5 mg# 2.01 2.96
The efficacy of JENTADUETO 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 [seeDRUG INTERACTIONS].
Rifampin 600 mg QD 5 mg 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 850 mg TID 10 mg QD metformin 1.01 0.89
Glyburide 1.75 mg# 5 mg QD glyburide 0.86 0.86
Pioglitazone 45 mg QD 10 mg 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

Metformin hydrochloride

Table 4 : Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

Coadministered Drug Dosing of Coadministered Drug* Dose of Metformin* Geometric Mean Ratio (ratio with/without coadministered drug) No effecf=1.0
  AUC† Cmax
No dosing adjustments required for the following coadministered drugs:
Furosemide 40 mg 850 mg metformin 1.09‡ 1.22‡
Nifedipine 10 mg 850 mg metformin 1.16 1.21
Propranolol 40 mg 850 mg metformin 0.90 0.94
Ibuprofen 400 mg 850 mg metformin 1.05‡ 1.07‡
Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination: use with caution [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Cimetidine 400 mg 850 mg metformin 1.40 1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis: use with caution [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Topiramate** 100 mg 500 mg metformin 1.25 1.17
* All metformin and coadministered drugs were given as single doses
† AUC = AUC(INF)
‡ Ratio of arithmetic means
**At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0-12h

Table 5 : Effect of Metformin on Coadministered Drug Systemic Exposure

Coadministered Drug Dosing of Coadministered Drug* Dose of Metformin* Geometric Mean Ratio (ratio with/without metformin) No effect=1.0
  AUC† Cmax
No dosing adjustments required for the following coadministered drugs:
Glyburide 5 mg 500 mg§ glyburide 0.78‡ 0.63‡
Furosemide 40 mg 850 mg furosemide 0.87‡ 0.69‡
Nifedipine 10 mg 850 mg nifedipine 1.10§ 1.08
Propranolol 40 mg 850 mg propranolol 1.01§ 0.94
Ibuprofen 400 mg 850 mg ibuprofen 0.97¶ 1.01¶
* All metformin and coadministered drugs were given as single doses
† AUC = AUC(INF) unless otherwise noted
‡ Ratio of arithmetic means, p-value of difference < 0.05
§ AUC(0-24 hr) reported
¶ Ratio of arithmetic means

Clinical Studies

The coadministration of linagliptin and metformin has been studied in patients with type 2 diabetes mellitus inadequately controlled on diet and exercise and in combination with sulfonylurea.

There have been no clinical efficacy studies conducted with JENTADUETO; however, bioequivalence of JENTADUETO to linagliptin and metformin coadministered as individual tablets was demonstrated in healthy subjects.

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 linagliptin 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 linagliptin 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, Figure 1). 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 mg 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 linagliptin 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 linagliptin 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 Linagliptin 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 (%)] 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 linagliptin 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.

Figure 1 : Adjusted Mean Change from Baseline for A1C (%) over 24 Weeks with Linagliptin and Metformin, Alone and in Combination in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise -FAS completers.

Adjusted Mean Change from Baseline for A1C (%) over 24 Weeks with Linagliptin and Metformin, Alone and in Combination in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise -FAS completers - Illustration

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 linagliptin 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 2-week, 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 linagliptin 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, linagliptin provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo (Table 7). Rescue glycemic therapy was used in 7.8% of patients treated with linagliptin 5 mg and in 18.9% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.

Table 7 : Glycemic Parameters in Placebo-Controlled Study for Linagliptin in Combination with Metformin*

  Linagliptin 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
**Linagliptin 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.

Active-Controlled Study Vs Glimepiride In Combination With Metformin

The efficacy of linagliptin was evaluated in a 104-week double-blind, glimepiride-controlled non-inferiority study in type 2 diabetic patients 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 per 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 linagliptin 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 down-titration to prevent hypoglycemia.

After 52 weeks and 104 weeks, linagliptin and glimepiride both had reductions from baseline in A1C (52 weeks: -0.4% for linagliptin, -0.6% for glimepiride; 104 weeks: -0.2% for TRADJENTA, -0.4% for glimepiride) from a baseline mean of 7.7% (Table 8). 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 8 : Glycemic Parameters at 52 and 104 Weeks in Study Comparing Linagliptin to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin**

  Week 52 Week 104
Linagliptin 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 -2t -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 Metformin And A Sulfonylurea

A total of 1058 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of linagliptin 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 linagliptin 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 end points measured included A1C and FPG.

In combination with a sulfonylurea and metformin, linagliptin provided statistically significant improvements in A1C and FPG compared with placebo (Table 9). In the entire study population (patients on linagliptin in combination with a 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 linagliptin 5 mg and in 13% of patients treated with placebo. Change from baseline in body weight did not differ significantly between the groups.

Table 9 : Glycemic Parameters at Final Visit (24-Week Study) for Linagliptin in Combination with Metformin and Sulfonylurea*

  Linagliptin 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
**Linagliptin 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 linagliptin 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 linagliptin 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.

Linagliptin used in combination with insulin (with or without metformin and/or pioglitazone), provided statistically significant improvements in A1C and FPG compared to placebo (Table 10) after 24 weeks of treatment. The mean total daily insulin dose at baseline was 42 units for patients treated with linagliptin 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 linagliptin 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% linagliptin; 22.9% placebo) in the first 24 weeks of the study.

Table 10 : Glycemic Parameters in Placebo-Controlled Study for Linagliptin in Combination with Insulin*

  Linagliptin 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
**Linagliptin + 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 (eGRF ≥ 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 linagliptin 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, linagliptin 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: 6/5/2014
This monograph has been modified to include the generic and brand name in many instances.

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