Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Boehringer Ingelheim International GmbH, Binger Str. 173, D-55216 Ingelheim am Rhein, Germany
Pharmacotherapeutic group: Drugs used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors
ATC code: A10BH05
Linagliptin is an inhibitor of the enzyme DPP-4 (dipeptidyl peptidase 4, EC 3.4.14.5) an enzyme which is involved in the inactivation of the incretin hormones GLP-1 and GIP (glucagon-like peptide1, glucose-dependent insulinotropic polypeptide). These hormones are rapidly degraded by the enzyme DPP-4. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretins 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. Linagliptin binds very effectively to DPP-4 in a reversible manner and thus leads to a sustained increase and a prolongation of active incretin levels. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion thus resulting in an overall improvement in the glucose homeostasis. Linagliptin binds selectively to DPP-4 and exhibits a > 10,000 fold selectivity versus DPP-8 or DPP-9 activity in vitro.
8 phase III randomised controlled trials involving 5,239 patients with type 2 diabetes, of which 3,319 were treated with linagliptin were conducted to evaluate efficacy and safety. These studies had 929 patients of 65 years and over who were on linagliptin. There were also 1,238 patients with mild renal impairment, and 143 patients with moderate renal impairment on linagliptin. Linagliptin once daily produced clinically significant improvements in glycaemic control, with no clinically relevant change in body weight. The reductions in glycosylated haemoglobin A1c (HbA1c) were similar across different subgroups including gender, age, renal impairment and body mass index (BMI). Higher baseline HbA1c was associated with a greater reduction in HbA1c. There was a significant difference in reduction in HbA1c between Asian patients (0.8%) and White patients (0.5%) in the pooled studies.
The efficacy and safety of linagliptin monotherapy was evaluated in a double-blind placebo-controlled study of 24 weeks duration. Treatment with once daily linagliptin at 5 mg provided a significant improvement in HbA1c (-0.69% change compared to placebo), in patients with baseline HbA1c of approximately 8%. Linagliptin also showed significant improvements in fasting plasma glucose (FPG), and 2-hour post-prandial glucose (PPG) compared to placebo. The observed incidence of hypoglycaemia in patients treated with linagliptin was similar to placebo.
The efficacy and safety of linagliptin monotherapy was also evaluated in patients for whom metformin therapy is inappropriate, due to intolerability or contraindicated due to renal impairment, in a double-blind placebo-controlled study of 18 weeks duration. Linagliptin provided significant improvements in HbA1c, (-0.57% change compared to placebo), from a mean baseline HbA1c of 8.09%. Linagliptin also showed significant improvements in fasting plasma glucose (FPG) compared to placebo. The observed incidence of hypoglycaemia in patients treated with linagliptin was similar to placebo.
The efficacy and safety of linagliptin in combination with metformin was evaluated in a double-blind placebo-controlled study of 24 weeks duration. Linagliptin provided significant improvements in HbA1c, (-0.64% change compared to placebo), from a mean baseline HbA1c of 8%. Linagliptin also showed significant improvements in fasting plasma glucose (FPG), and 2-hour post-prandial glucose (PPG) compared to placebo. The observed incidence of hypoglycaemia in patients treated with linagliptin was similar to placebo.
A placebo-controlled study of 24 weeks in duration was conducted to evaluate the efficacy and safety of linagliptin 5 mg to placebo, in patients not sufficiently treated with a combination with metformin and a sulphonylurea. Linagliptin provided significant improvements in HbA1c (-0.62% change compared to placebo), from a mean baseline HbA1c of 8.14%. Linagliptin also showed significant improvements in patients fasting plasma glucose (FPG), and 2-hour post-prandial glucose (PPG), compared to placebo.
In patients inadequately controlled with metformin and empagliflozin (10 mg (n=247) or 25 mg (n=217)), 24-weeks treatment with add-on therapy of linagliptin 5 mg provided adjusted mean HbA1c reductions from baseline by -0.53% (significant difference to add-on placebo -0.32% (95% CI -0.52, -0.13) and -0.58% (significant difference to add-on placebo -0.47% (95% CI -0.66; -0.28), respectively. A statistically significant greater proportion of patients with a baseline HbA1c ≥7.0% and treated with linagliptin 5 mg achieved a target HbA1c of <7% compared to placebo.
The efficacy and safety of the addition of linagliptin 5 mg to insulin alone or in combination with metformin and/or pioglitazone has been evaluated in a double-blind placebo-controlled study of 24 weeks duration. Linagliptin provided significant improvements in HbA1c (-0.65% compared to placebo) from a mean baseline HbA1c of 8.3%. Linagliptin also provided significant improvements in fasting plasma glucose (FPG), and a greater proportion of patients achieved a target HbA1c of <7.0%, compared to placebo. This was achieved with a stable insulin dose (40.1 IU). Body weight did not differ significantly between the groups. Effects on plasma lipids were negligible. The observed incidence of hypoglycaemia in patients treated with linagliptin was similar to placebo (22.2% linagliptin; 21.2% placebo).
In a study comparing the efficacy and safety of the addition of linagliptin 5 mg or glimepiride (mean dose 3 mg) in patients with inadequate glycaemic control on metformin monotherapy, mean reductions in HbA1c were -0.16% with linagliptin (mean baseline HbA1c 7.69%) and -0.36% with glimepiride (mean baseline HbA1c 7.69%.) with a mean treatment difference of 0.20% (97.5% CI: 0.09, 0.299). The incidence of hypoglycaemia in the linagliptin group (7.5%) was significantly lower than that in the glimepiride group (36.1%). Patients treated with linagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glimepiride (-1.39 vs +1.29 kg).
The efficacy and safety of linagliptin was also evaluated in type 2 diabetes patients with severe renal impairment in a double-blind study versus placebo for 12 weeks duration, during which background glycaemic therapies were kept stable. Most patients (80.5%) received insulin as background therapy, alone or in combination with other oral anti-diabetics such as sulphonylurea, glinide and pioglitazone. There was a further follow up 40 week treatment period during which dose adjustments in antidiabetes background therapies were allowed.
Linagliptin provided significant improvements in HbA1c (-0.59% change compared to placebo after 12 weeks), from a mean baseline HbA1c of 8.2%. The observed difference in HbA1c over placebo was -0.72% after 52 weeks.
Body weight did not differ significantly between the groups. The observed incidence of hypoglycaemia in patients treated with linagliptin was higher than placebo, due to an increase in asymptomatic hypoglycaemic events. There was no difference between groups in severe hypoglycaemic events.
The efficacy and safety of linagliptin in elderly (age ≥70 years) with type 2 diabetes was evaluated in a double-blind study of 24 weeks duration. Patients received metformin and/or sulphonylurea and/or insulin as background therapy. Doses of background antidiabetic medicinal products were kept stable during the first 12 weeks, after which adjustments were permitted. Linagliptin provided significant improvements in HbA1c (-0.64% change compared to placebo after 24 weeks), from a mean baseline HbA1c of 7.8%. Linagliptin also showed significant improvements in fasting plasma glucose (FPG) compared to placebo. Body weight did not differ significantly between the groups.
In a prospective meta-analysis of independently adjudicated CV events from 19 clinical studies (ranging from 18 weeks to 24 months duration) involving 9,459 patients with type 2 diabetes, linagliptin treatment was not associated with an increase in CV risk. The primary endpoint, the composite of: the occurrence or time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina, was non-significantly lower for linagliptin versus combined active and placebo comparators [Hazard ratio 0.78 (95% confidence interval 0.55;1.12)]. In total there were 60 primary events on linagliptin and 62 on comparators. To date there is no evidence for an increased CV risk but the number of events in the clinical studies precludes firm conclusions. However, CV events were similar between linagliptin and placebo (1.03% with linagliptin vs 1.35% with placebo).
The European Medicines Agency has deferred the obligation to submit the results of studies with linagliptin in one or more subsets of the paediatric population in Type 2 diabetes (see section 4.2 for information on paediatric use).
The pharmacokinetics of linagliptin has been extensively characterised in healthy subjects and patients with type 2 diabetes. After oral administration of a 5 mg dose to healthy volunteers or patients, linagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1.5 hours post-dose.
Plasma concentrations of linagliptin decline in a triphasic manner with a long terminal half-life (terminal half-life for linagliptin more than 100 hours), that is mostly related to the saturable, tight binding of linagliptin to DPP-4 and does not contribute to the accumulation of the medicinal product. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of 5 mg linagliptin, is approximately 12 hours. After once daily dosing of 5 mg linagliptin, steady-state plasma concentrations are reached by the third dose. Plasma AUC of linagliptin increased approximately 33% following 5 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Due to the concentration dependent binding of linagliptin to DPP-4, the pharmacokinetics of linagliptin based on total exposure is not linear; indeed total plasma AUC of linagliptin increased in a less than dose-proportional manner while unbound AUC increases in a roughly dose-proportional manner. The pharmacokinetics of linagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.
The absolute bioavailability of linagliptin is approximately 30%. Co-administration of a high-fat meal with linagliptin prolonged the time to reach Cmax by 2 hours and lowered Cmax by 15% but no influence on AUC 0-72h was observed. No clinically relevant effect of Cmax and Tmax changes is expected; therefore linagliptin may be administered with or without food.
Dh3. istribution
As a result of tissue binding, the mean apparent volume of distribution at steady-state following a single 5 mg intravenous dose of linagliptin to healthy subjects is approximately 1,110 litres, 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, 70-80% of linagliptin was bound to other plasma proteins than DPP-4, hence 30-20% were unbound in plasma.
Following a [14C] linagliptin oral 10 mg dose, approximately 5% of the radioactivity was excreted in urine. Metabolism plays a subordinate role in the elimination of linagliptin. One main metabolite with a relative exposure of 13.3% of linagliptin at steady-state was detected which was found to be pharmacologically inactive and thus does not contribute to the plasma DPP-4 inhibitory activity of linagliptin.
Following administration of an oral [14C] linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated in faeces (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady-state was approximately 70 ml/min.
A multiple-dose, open-label study was conducted to evaluate the pharmacokinetics of linagliptin (5 mg dose) in patients with varying degrees of chronic renal insufficiency compared to normal healthy control subjects. The study included patients with renal insufficiency classified on the basis of creatinine clearance as mild (50 to <80 ml/min), moderate (30 to <50 ml/min), and severe (<30 ml/min), as well as patients with ESRD on hemodialysis. In addition patients with T2DM and severe renal impairment (<30 ml/min) were compared to T2DM patients with 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. CrCl = (140–age) x weight/72 x serum creatinine [x 0.85 for females], where age is in years, weight in kg, and serum creatinine is in mg/dl. Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects. In moderate renal impairment, a moderate increase in exposure of about 1.7 fold was observed compared with control. Exposure in T2DM patients with severe RI was increased by about 1.4 fold compared to T2DM patients with normal renal function. Steady-state predictions for AUC of linagliptin in patients with ESRD indicated comparable exposure to that of patients with moderate or severe renal impairment. In addition, linagliptin is not expected to be eliminated to a therapeutically significant degree by hemodialysis or peritoneal dialysis. Therefore, no dosage adjustment of linagliptin is necessary in patients with any degree of renal insufficiency.
In non-diabetic patients with mild moderate and severe hepatic insufficiency (according to the Child- Pugh classification), mean AUC and Cmax of linagliptin were similar to healthy matched controls following administration of multiple 5 mg doses of linagliptin. No dosage adjustment for linagliptin is proposed for diabetic patients with mild, moderate or severe hepatic impairment.
No dosage adjustment is necessary based on BMI. BMI had no clinically relevant effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data. The clinical trials before marketing authorisation have been performed up to a BMI equal to 40 kg/m².
No dosage adjustment is necessary based on gender. Gender had no clinically relevant effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data.
No dosage adjustment is required based on age up to 80 years, as age did not have a clinically relevant impact on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data. Older subjects (65 to 80, oldest patient was 78 years) had comparable plasma concentrations of linagliptin compared to younger subjects.
A paediatric Phase 2 study examined the pharmacokinetics and pharmacodynamics of 1 mg and 5 mg linagliptin in children and adolescents ≥10 to <18 years of age with type 2 diabetes mellitus. The observed pharmacokinetic and pharmacodynamic responses were consistent with those found in adult subjects. Linagliptin 5 mg showed superiority over 1 mg with regard to trough DPP-4 inhibition (72% vs 32%, p=0.0050) and a numerically larger reduction with regard to adjusted mean change from baseline in HbA1c (-0.63% vs -0.48%, n.s.). Due to the limited nature of the data set the results should be interpreted cautiously.
No dosage adjustment is necessary based on race. Race had no obvious effect on the plasma concentrations of linagliptin based on a composite analysis of available pharmacokinetic data, including patients of Caucasian, Hispanic, African, and Asian origin. In addition the pharmacokinetic characteristics of linagliptin were found to be similar in dedicated phase I studies in Japanese, Chinese and Caucasian healthy volunteers.
Liver, kidneys and gastrointestinal tract are the principal target organs of toxicity in mice and rats at repeat doses of linagliptin of more than 300 times the human exposure. In rats effects on reproductive organs, thyroid and the lymphoid organs were seen at more than 1,500 times human exposure. Strong pseudo-allergic reactions were observed in dogs at medium doses, secondarily causing cardiovascular changes, which were considered dog-specific. Liver, kidneys, stomach, reproductive organs, thymus, spleen, and lymph nodes were target organs of toxicity in Cynomolgus monkeys at more than 450 times human exposure. At more than 100 times human exposure, irritation of the stomach was the major finding in these monkeys.
Linagliptin and its main metabolite did not show a genotoxic potential. Oral 2 year carcinogenicity studies in rats and mice revealed no evidence of carcinogenicity in rats or male mice. A significantly higher incidence of malignant lymphomas only in female mice at the highest dose (>200 times human exposure) is not considered relevant for humans (explanation: non-treatment related but due to highly variable background incidence). Based on these studies there is no concern for carcinogenicity in humans.
The NOAEL for fertility, early embryonic development and teratogenicity in rats was set at >900 times the human exposure. The NOAEL for maternal-, embryo-fetal-, and offspring toxicity in rats was 49 times human exposure. No teratogenic effects were observed in rabbits at >1,000 times human exposure. A NOAEL of 78 times human exposure was derived for embryo-fetal toxicity in rabbits, and for maternal toxicity the NOAEL was 2.1 times human exposure. Therefore, it is considered unlikely that linagliptin affects reproduction at therapeutic exposures in humans.
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