Get your patient on Linagliptin

Risk Summary

The limited data with linagliptin use in pregnant women are not sufficient to inform of drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations ].

In animal reproduction studies, no adverse developmental effects were observed when linagliptin was administered to pregnant rats during the period of organogenesis at doses similar to the maximum recommended clinical dose, based on exposure [see Data ] .

The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c>7 and has been reported to be as high as 20 to 25% in women with HbA1c>10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Data

Risk Summary

There is no information regarding the presence of linagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. However, linagliptin is present in rat milk. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for linagliptin tablets and any potential adverse effects on the breastfed child from linagliptin tablets or from the underlying maternal condition.

Hypoglycemia

Table 2 summarizes the incidence of hypoglycemia in placebo-controlled studies of linagliptin. The incidence of hypoglycemia increased when linagliptin was administered with sulfonylurea or insulin.

Use in Renal Impairment

Linagliptin was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with severe renal impairment (estimated GFR <30 mL/min). 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.

In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other linagliptin trials. The observed incidence of hypoglycemia was higher (linagliptin, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12 weeks when background glycemic therapies were kept stable. Ten linagliptin-treated patients (15%) and 11 placebo-treated patients (17%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying finger stick glucose ≤54 mg/dL). During the same time period, severe hypoglycemic events, defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 3 (4.4%) linagliptin-treated patients and 3 (4.6%) placebo-treated patients. Events that were considered life-threatening or required hospitalization were reported in 2 (2.9%) patients on linagliptin and 1 (1.5%) patient on placebo.

Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks' treatment compared to placebo.

Changes in laboratory findings were similar in patients treated with linagliptin 5 mg compared to patients treated with placebo.

Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the linagliptin group and > 1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the linagliptin group).

Increase in Lipase: In a placebo-controlled clinical trial with linagliptin in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the linagliptin arm compared to a mean decrease of 2% in the placebo arm. Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the linagliptin and placebo arms, respectively.

The clinical significance of elevations in lipase with linagliptin is unknown in the absence of potential signs and symptoms of pancreatitis [see Warnings and Precautions (5.1) ].

Vital Signs
No clinically meaningful changes in vital signs were observed in patients treated with linagliptin.

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.

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

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.

Elimination

Linagliptin has a terminal half-life of about 200 hours at steady-state, though the accumulation half-life is about 11 hours. Renal clearance at steady-state was approximately 70 mL/min.

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 (AUC _τ,ss by 71% and C _max 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 _τ,ss by 42% and C _max 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.

In patients with mild hepatic impairment (Child-Pugh class A), steady-state exposure (AUC _τ,ss ) of linagliptin was approximately 25% lower and C _max,ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUC _ss of linagliptin was about 14% lower and C _max,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 AUC _0-24 and approximately 23% lower C _max compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition.

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.

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.

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

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

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.

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.

Strong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations [see Drug Interactions (7) ] . 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).

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 linagliptin 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 linagliptin 5 mg; in the 24-week study, 167 patients were randomized to placebo and 336 to linagliptin 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 linagliptin 5 mg daily provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo (Table 5). In the 18-week study, 12% of patients receiving linagliptin 5 mg and 18% who received placebo required rescue therapy. In the 24-week study, 10.2% of patients receiving linagliptin 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 linagliptin 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 linagliptin, and 0.1% and 0.3%, respectively, for those given placebo. Change from baseline in body weight did not differ significantly between the groups.

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 1,500 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 1,500 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 6). 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.

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 1,000 mg of metformin twice daily, or 2.5 mg of linagliptin twice daily in combination with 500 mg or 1,000 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 7).

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 1,000 mg twice daily compared to metformin 1,000 twice daily; -1.1% (95% CI -1.4, -0.9; p<0.0001) for linagliptin 2.5 mg/metformin 1,000 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.

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 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 ≥1,500 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 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 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 linagliptin, -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.

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 linagliptin in combination with pioglitazone. Therapy was stopped in patients on oral antihyperglycemic therapy for a period of 6 weeks (4 weeks followed by a 2-week, open-label, placebo run-in period). Drug-naïve patients entered directly into the 2-week placebo run-in period. After the run-in period, patients were randomized to receive either linagliptin 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, linagliptin 5 mg provided statistically significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 9). Rescue therapy was used in 7.9% of patients treated with linagliptin 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 linagliptin 5 mg/pioglitazone 30 mg and placebo/pioglitazone 30 mg groups, respectively (p = 0.0141).

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 linagliptin 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 linagliptin 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, linagliptin provided statistically significant improvements in A1C compared with placebo following 18 weeks’ treatment; the improvements in FPG observed with linagliptin were not statistically significant compared with placebo (Table 10). Rescue therapy was used in 7.6% of patients treated with linagliptin 5 mg and 15.9% of patients treated with placebo. There was no significant difference between linagliptin and placebo in body weight.

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 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 endpoints 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 11). In the entire study population (patients on linagliptin 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 linagliptin 5 mg and in 13% of patients treated with placebo. Change from baseline in body weight did not differ significantly between the groups.

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 12) 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 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 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.