Linagliptin

Linagliptin inhibits the enzyme DPP-4, which inactivates the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). Incretins are released at a low level throughout the day and rise immediately after a meal, and they take part in the normal regulation of glucose balance.

Mechanism of Action

• Incretin effect: GLP-1 and GIP increase insulin synthesis and secretion from pancreatic beta cells at normal and raised blood glucose. GLP-1 also lowers glucagon secretion from alpha cells, which reduces glucose output from the liver.
• DPP-4 inhibition: linagliptin binds DPP-4 very effectively and reversibly, which gives a sustained rise and prolongation of active incretin levels. Insulin secretion is increased and glucagon secretion lowered in a glucose-dependent way, improving overall glucose control.
• Selectivity: linagliptin binds selectively to DPP-4, with more than 10,000-fold selectivity over DPP-8 and DPP-9 activity in vitro.
• Extent of inhibition: a 5 mg oral dose is reported to inhibit DPP-4 by more than 80% for at least 24 hours.
• Clinical effect: in eight phase III trials (5,239 patients with type 2 diabetes, 3,319 of them on linagliptin), once-daily linagliptin produced clinically significant improvements in glycaemic control with no clinically relevant change in body weight.

Pharmacokinetics

• Absorption: rapid, with a median time to peak of 1.5 hours; absolute bioavailability is about 30%. A high-fat meal delayed the peak by 2 hours and lowered the peak concentration by 15% without changing total exposure, so linagliptin can be taken with or without food. Steady state is reached by the third dose, and exposure at steady state is about 33% higher than after the first dose.
• Non-linear exposure: because linagliptin binds to DPP-4 in a concentration-dependent way, total exposure rises less than in proportion to dose, while unbound exposure rises roughly in proportion.
• Distribution: the volume of distribution at steady state after a single 5 mg intravenous dose is about 1,110 litres, showing extensive tissue distribution. Plasma protein binding depends on concentration, falling from about 99% at 1 nmol/L to 75–89% at 30 nmol/L and above, as DPP-4 binding saturates. At high concentrations 70–80% is bound to plasma proteins other than DPP-4.
• Metabolism: metabolism plays a minor part in elimination. One main metabolite (13.3% of linagliptin exposure at steady state) is pharmacologically inactive.
• Elimination: plasma levels fall in three phases with a long terminal half-life (more than 100 hours) that reflects tight binding to DPP-4 and does not cause accumulation; the effective half-life for accumulation is about 12 hours. About 85% of a radiolabelled dose was recovered within 4 days, 80% in faeces and 5% in urine. Renal clearance at steady state is about 70 mL/min.
• Special populations: exposure is comparable to healthy subjects in mild renal impairment, about 1.7-fold higher in moderate impairment and about 1.4-fold higher in severe impairment in type 2 diabetes. Haemodialysis and peritoneal dialysis do not remove a therapeutically significant amount. In mild, moderate and severe hepatic impairment (Child-Pugh), mean exposure was similar to controls. Body mass index, sex, race and age (up to 80 years) have no clinically relevant effect. In children and adolescents aged 10 to 17 years, exposure was within the adult range.

Linagliptin is indicated in adults with type 2 diabetes mellitus, as an adjunct to diet and exercise, to improve glycaemic control:

• Monotherapy: when metformin is inappropriate because of intolerance, or contraindicated because of renal impairment.
• Combination therapy: with other medicinal products for diabetes, including insulin, when these do not provide adequate glycaemic control.

Linagliptin is also available in fixed-dose combinations with metformin (Jentadueto) and with empagliflozin (Glyxambi); these have their own product information.

• Hypersensitivity to linagliptin or to any of the excipients.

In pooled placebo-controlled trials, the overall rate of adverse events was similar with linagliptin 5 mg and placebo (59.1% versus 63.4%), and stopping treatment because of adverse events was slightly less frequent with linagliptin (3.4% versus 4.3%). The most frequently reported reaction was hypoglycaemia with the triple combination of linagliptin, metformin and a sulphonylurea (14.8% versus 7.6% with placebo). Across the placebo-controlled studies, 4.9% of patients on linagliptin had hypoglycaemia as an adverse reaction (4.0% mild, 0.9% moderate and 0.1% severe).

Very common (≥1/10): hypoglycaemia (seen in combination with metformin plus a sulphonylurea).

Common (≥1/100 to <1/10): raised lipase (based on increases above 3 times the upper limit of normal in clinical trials).

Uncommon (≥1/1,000 to <1/100): nasopharyngitis; hypersensitivity (for example bronchial hyperreactivity); cough; constipation (seen in combination with insulin); rash (post-marketing); raised amylase.

Rare (≥1/10,000 to <1/1,000): pancreatitis and bullous pemphigoid (both based on the CARMELINA cardiovascular and renal safety study); angioedema and urticaria (post-marketing).

In the CARMELINA study (3,494 patients on linagliptin and 3,485 on placebo, with increased cardiovascular risk), overall and serious adverse events were similar in both groups. Severe hypoglycaemia needing assistance occurred in 3.0% and 3.1% of patients; among sulphonylurea users in 2.0% and 1.7%, and among insulin users in 4.4% and 4.9%. Adjudicated acute pancreatitis was reported in 0.3% of patients on linagliptin and 0.1% on placebo, and bullous pemphigoid in 0.2% and none. In children and adolescents aged 10 to 17 years with type 2 diabetes, the safety profile was similar to that in adults.

The risk of clinically meaningful interactions is low. In vitro, linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP3A4, does not inhibit other CYP enzymes and is not an inducer. It is a P-glycoprotein substrate and inhibits P-glycoprotein-mediated digoxin transport only weakly.

• Rifampicin (a potent inducer of P-glycoprotein and CYP3A4): linagliptin exposure fell by about 40% (steady-state AUC down 39.6%, peak down 43.8%) and trough DPP-4 inhibition by about 30%. Full efficacy with strong P-glycoprotein inducers may not be reached, particularly with long-term use. Other potent inducers such as carbamazepine, phenobarbital and phenytoin have not been studied.
• Ritonavir (a potent inhibitor of P-glycoprotein and CYP3A4): linagliptin exposure rose about twofold (AUC) and threefold (peak), and unbound concentrations 4–5-fold, without more accumulation. These changes were not considered clinically relevant, and relevant interactions are not expected with other P-glycoprotein or CYP3A4 inhibitors.
• Metformin and glibenclamide did not meaningfully change linagliptin exposure.
• Effect of linagliptin on other medicines: no clinically relevant effect on metformin, glibenclamide, simvastatin, warfarin, digoxin or oral contraceptives (levonorgestrel and ethinylestradiol). Glibenclamide exposure fell by 14% (not relevant), and similar sulphonylureas (glipizide, tolbutamide, glimepiride) are not expected to interact. With a supratherapeutic 10 mg linagliptin dose, simvastatin exposure rose by 34% and its peak by 10%.
• Sulphonylureas and insulin: they cause hypoglycaemia, so a lower dose of the sulphonylurea or insulin may be considered when linagliptin is added.
• Alcohol: excessive or chronic alcohol use should be avoided, as it can raise the risk of serious side effects.

Linagliptin is a once-daily tablet taken by mouth, with or without a meal and at any time of day.

Recommended Dose

• 5 mg once daily.
• Added to metformin: the metformin dose is kept and linagliptin is given at the same time.
• With a sulphonylurea or insulin: a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia.

Special Populations

• Renal impairment: no dose adjustment.
• Hepatic impairment: pharmacokinetic studies suggest no dose adjustment is needed, but clinical experience in these patients is lacking.
• Elderly: no dose adjustment based on age.
• Children and adolescents: a clinical trial did not establish efficacy in patients 10 to 17 years of age, so treatment of children and adolescents is not recommended. Linagliptin has not been studied below 10 years.

Missed Dose

Take it as soon as it is remembered. Do not take a double dose on the same day.

Type 1 Diabetes and Ketoacidosis

Linagliptin must not be used in patients with type 1 diabetes or to treat diabetic ketoacidosis.

Hypoglycaemia

Linagliptin alone had a hypoglycaemia rate comparable to placebo, and the rate was similar to placebo when it was added to metformin. When it was added to a sulphonylurea (on a background of metformin), hypoglycaemia was more frequent than with placebo. Sulphonylureas and insulin are known to cause hypoglycaemia, so care is needed with the combinations and a dose reduction may be considered.

Acute Pancreatitis

Use of DPP-4 inhibitors has been associated with a risk of acute pancreatitis, and it has been seen in patients taking linagliptin. Patients should be told the characteristic symptoms. If pancreatitis is suspected, treatment should be stopped; if it is confirmed, linagliptin should not be restarted. Caution is needed in patients with a history of pancreatitis.

Bullous Pemphigoid

Bullous pemphigoid has been seen in patients taking linagliptin. Treatment should be stopped if it is suspected.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: linagliptin has not been studied in pregnant women. Animal studies show no direct or indirect harm to reproduction. As a precaution, it is preferable to avoid linagliptin in pregnancy.
• Breastfeeding: animal data show that linagliptin or its metabolites pass into milk, and a risk to the breast-fed child cannot be excluded. A decision must be made whether to stop breastfeeding or to stop or avoid linagliptin, weighing the benefit of breastfeeding for the child against the benefit of treatment for the mother.
• Fertility: no human fertility studies have been done; animal studies show no direct or indirect harm.

Effect on Driving

Linagliptin has no or negligible influence on the ability to drive and use machines. Patients should be warned of the risk of hypoglycaemia, especially when it is combined with a sulphonylurea or insulin.

Trajenta tablets need no special storage conditions. They are supplied in perforated aluminium unit-dose blisters. Keep out of the sight and reach of children.

3 years.

Prescription only (Rx): a medicinal product subject to medical prescription. The tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.