Linagliptin (Tradjenta) - Uses, Dose, Side effects

Linagliptin belongs to the class of drugs called DPP-4 inhibitors. It is available in the international market as Tradjenta, Trajenta, and others. Linagliptin like other DPP-4 inhibitors is used as an adjunct to diet and exercise in the management of Diabetes Mellitus Type 2 (as monotherapy or in combination with metformin). Because linagliptin is excreted via the biliary tract, it is considered safe in patients with hepatic or renal impairment. Studies have compared it with other gliptins and found to be equally safe and an effective drug for the treatment of diabetes mellitus type 2. It has also been launched recently as a triple combination pill by the brand name of TRIJARDY XR. TRIJARDY XR is a combination of Empagliflozin, Linagliptin, and extended-release metformin.

Linagliptin Vs Sitagliptin (Januvia and Tradjenta):

 

Linagliptin

Sitagliptin

Brands

Tradjenta Januvia

Bioavailability

30% 87%

Half-life elimination

12 hours 12.4 hours

Time to peak serum concentration

1.5 hours 1 – 4 hours

Excretion

80% in the feces 87% in the urine

Safety in renal disease

Safe in renal disease. One study found an improvement in kidney function after the patients were switched from sitagliptin to linagliptin [Ref]. Requires dose adjustment if the eGFR is less than 45 ml/min

Usual dose

5 mg once daily 50 – 100 mg once daily

Efficacy

Same as sitagliptin. Same as linagliptin
However, one Chinese study found a greater improvement in the Fasting and postprandial glucose levels with linagliptin compared to sitagliptin or vildagliptin [Ref].

Effects on LDL-C and fatty liver

Significantly improved compared to sitagliptin [Ref]

Linagliptin dose in Adults

Linagliptin dose in the treatment of Type 2 Diabetes Mellitus:

  • 5 mg orally once a day.

Concomitant use of linagliptin with insulin and/or insulin secretagogues (like sulfonylureas):

    • Reduction in the dose of sulfonylurea and insulin may be required.

Dose in children:

It is not recommended for use in children.

Linagliptin use in pregnancy: C

  • Pregnancy is not recommended for Linagliptin.
  • An increased chance of adverse maternal and fetal outcomes is associated with uncontrolled diabetes during pregnancy. 
  • These include preeclampsia and diabetic ketoacidosis.
  • Before and during pregnancy, blood sugars should be within the target ranges.
  • Pregnancy is a time when insulin and metformin are the most preferred antidiabetic medications.

Use while breastfeeding

  • It is unknown whether linagliptin is excreted into breastmilk.
  • It is important to weigh the benefits and risks of drug use during lactation.

Dose in Renal disease:

Adjustment in the dose in not necessary in kidney disease.

Dose in liver disease:

Adjustment in the dose in not necessary in liver disease.

Linagliptin Side Effects:

  • Endocrine & metabolic:

    • Hypoglycemia
    • Increased uric acid
  • Gastrointestinal:

    • Increased serum lipase
  • Respiratory:

    • Nasopharyngitis
    • Cough
  • Dermatologic:

    • Urticaria
  • Neuromuscular & skeletal:

    • Myalgia
  • Respiratory:

    • Bronchoconstriction

Linagliptin Contraindications:

  • Exfoliative conditions, bronchial hyperreactivity, and urticaria may all be signs that you have severe allergic reactions.
  • Use for Type 1 diabetics

Warnings & Precautions

  • Arthralgia
    • This can cause severe pain in the joints and arthralgia.
    • Arthralgias may develop within a matter of hours or for as long as two decades after treatment has been initiated.
    • The symptoms can disappear if the treatment is stopped but could return if the treatment is restarted.
  • Bullous pemphigoid
    • Liningriptin has been associated with bullous eruptions, bullous pemphigoid and other cases of bullous pemphigoid.
    • Patients should report any blisters or eruptions.
    • Patients should discontinue receiving treatment and see a dermatologist.
    • A discontinuation of a drug could lead to improvements.
  • Hypersensitivity reactions
    • Severe allergic reactions are possible.
    • Many patients experience allergic reactions within three to six months of receiving therapy.
    • Stop using the medication immediately if you experience an allergic reaction.
    • Patients with angioedema due to DPP-4 inhibitors need to be advised.
  • Pancreatitis
    • DPP-4 may cause pancreatitis.
    • Patients should be monitored closely for symptoms and signs of pancreatitis.
    • Patients with past pancreatitis should be cautious about using this drug.
  • Bariatric Surgery
    • Absorption modified:
      • Bariatric surgery can alter the absorption and transport processes of drugs.
    • Lininguliptin's therapeutic efficacy for bariatric surgery patients
      • DPP-4 Inhibitors have been well tolerated by patients with diabetes who have undergone bariatric surgery.
      • It is important to monitor for symptoms such as hypoglycemia and pancreatitis in patients.
      • The endogenous secretion of glucagon-like prostasterone-1 (GLP-1), may rise after gastric bypass or sleeve gastrectomy.
  • Cardiovascular disease
    • Heart Failure has been linked with DPP-4 inhibitors
    • Liningriptin safety was proven in the CARMELINA study in patients with atherosclerotic heart disease [ Refer].
    • The ADA recommends that patients with heart failure use DPP-4 inhibitors, but not Saxagliptin.

Linagliptin: Drug Interaction

Risk Factor C (Monitor therapy)

Alpha-Lipoic Acid

May strengthen an anti-diabetic agent's hypoglycemic impact.

Androgens

Can make blood glucose lowering medications more effective at lowering blood sugar. Danazol is an exception.

Angiotensin-Converting Enzyme Inhibitors

Dipeptidyl Peptidase-IV Inhibitors may make angiotensin-converting enzyme inhibitors more harmful or toxic. Particularly, there may be a higher incidence of angioedema.

Antihepaciviral Combination Products

May raise LinaGLIPtin's serum concentration.

Bosentan

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

CYP3A4 Inducers (Moderate)

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Deferasirox

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Direct Acting Antiviral Agents (HCV)

May strengthen an anti-diabetic agent's hypoglycemic impact.

Erdafitinib

May lower the serum level of CYP3A4 substrates (High risk with Inducers).

Erdafitinib

P-glycoprotein/ABCB1 Substrates serum levels can rise.

Guanethidine

May strengthen an anti-diabetic agent's hypoglycemic impact.

Hyperglycemia-Associated Agents

May reduce an anti-diabetic agent's therapeutic efficacy.

Hypoglycemia-Associated Agents

The hypoglycemic effect of hypoglycemia-associated agents may be strengthened by antidiabetic agents.

Ivosidenib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Maitake

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.

Monoamine Oxidase Inhibitors

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.

Pegvisomant

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.

P-glycoprotein/ABCB1 Inhibitors

Pglycoprotein/ABCB1 Substrates serum levels can rise. Additionally, p-glycoprotein inhibitors may improve the distribution of pglycoprotein substrates to particular cells, tissues, and organs where high levels of p-glycoprotein are present (e.g., brain, T-lymphocytes, testes, etc.).

Prothionamide

Can make blood glucose lowering medications more effective at lowering blood sugar.

Quinolones

Can make blood glucose lowering medications more effective at lowering blood sugar. Blood Glucose Lowering Agents' therapeutic impact may be lessened by quinolones. In particular, the use of quinolones may result in a loss of blood sugar control if an agent is being used to treat diabetes.

Ranolazine

P-glycoprotein/ABCB1 Substrates serum levels can rise.

Ritodrine

May reduce an anti-diabetic agent's therapeutic efficacy.

Ritonavir

May lower the serum level of CYP3A4 substrates (High risk with Inducers).

Salicylates

Can make blood glucose lowering medications more effective at lowering blood sugar.

Sarilumab

May lower the serum level of CYP3A4 substrates (High risk with Inducers).

Selective Serotonin Reuptake Inhibitors

Can make blood glucose lowering medications more effective at lowering blood sugar.

Siltuximab

May lower the serum level of CYP3A4 substrates (High risk with Inducers).

Thiazide and Thiazide-Like Diuretics

May reduce an anti-diabetic agent's therapeutic efficacy.

Tocilizumab

May lower the serum level of CYP3A4 substrates (High risk with Inducers).

Risk Factor D (Consider therapy modification)

CYP3A4 Inducers (Strong)

May lower the level of LinaGLIPtin in the serum. Treatment: When administering a powerful CYP3A4 inducer to patients receiving linagliptin, strongly consider utilising an alternative. If this combination is utilised, keep a watchful eye on the patients for signs of diminished linagliptin effectiveness.

Dabrafenib

May lower the serum level of CYP3A4 substrates (High risk with Inducers). Management: When possible, look for substitutes for the CYP3A4 substrate. If concurrent therapy cannot be avoided, pay special attention to the substrate's clinical consequences (particularly therapeutic effects).

Enzalutamide

May lower the serum level of CYP3A4 substrates (High risk with Inducers). Treatment: Enzalutamide should not be used concurrently with CYP3A4 substrates that have a limited therapeutic index. Enzalutamide use, like with the use of any other CYP3A4 substrate, should be done cautiously and under close observation.

Insulins

Dipeptidyl Peptidase-IV Inhibitors may improve insulin's ability to lower blood sugar. When starting treatment with a dipeptidyl peptidase-IV inhibitor, take into account lowering the insulin dosage and keep an eye out for hypoglycemia in the patients.

Lorlatinib

May lower the serum level of CYP3A4 substrates (High risk with Inducers). Management: Avoid taking lorlatinib at the same time as any CYP3A4 substrates for which even a small drop in serum levels of the substrate could result in therapeutic failure and negative clinical outcomes.

Mitotane

May lower the serum level of CYP3A4 substrates (High risk with Inducers). Treatment: When administered in individuals receiving mitotane, doses of CYP3A4 substrates may need to be significantly modified.

P-glycoprotein/ABCB1 Inducers

May lower the level of LinaGLIPtin in the serum. Treatment: If a patient is receiving linagliptin, strongly consider utilising an alternate to any strong P-glycoprotein inducer. If this combination is utilised, keep a watchful eye on the patients for signs of diminished linagliptin effectiveness.

Sulfonylureas

Dipeptidyl Peptidase-IV Inhibitors might make sulfonylureas' hypoglycemia effect stronger. When starting treatment with a dipeptidyl peptidase-IV inhibitor, take into account lowering the dose of sulfonylurea and keep an eye out for hypoglycemia in the patients.

Risk Factor X (Avoid combination)

Lasmiditan

P-glycoprotein/ABCB1 Substrates serum levels can rise.

 

Monitor:

  • Patients with low glycemic control should be monitored every three months.
  • Monitor your glucose
  • Be aware of signs and symptoms.
  • Check your heart for signs or symptoms of heart disease.

How to administer Linagliptin (Tradjenta)?

It may be taken with or without food.

Linagliptin (Tradjenta) Mechanism of action:

  • It inhibits dipeptidyl protease 4 (DPP-4). The DPP-4 enzymes activate insulin hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent, insulinotropic peptide[GIP].
  • Though hormones called Incretin are released throughout a day, they rise after meals.
  • DPP-4 inhibition results in an increase in active incretin. 
  • They also reduce glucagon secretion from pancreatic alpha cells.
  • A decrease in glucagon causes a decrease of glucose hepatic sugar production.
  • You can resell 70% to 80% off the drug.

Protein-boundIs concentration dependent? It isn't widely used.MetabolizedIt has a bioavailability of approximately 30% The half-life of the drug is approximately 12 hours TheTime to reach maximum serum concentrationIt takes approximately 1.5 hours. Feces excrete 80% from the drug.

Linagliptin Brands Names (International):

  • Tradjenta
  • Glitin
  • Glucoliptin
  • Ligatin
  • Linajenta
  • Linax
  • Lino
  • Prevaglip
  • Tradjenta
  • Trajenta
  • Traneta
  • Trayenta
  • Trazenta

Each 5 mg tablet of Tradjenta (linagliptin) costs: $ 18.49

Linagliptin brand names in Pakistan:

It is not currently available in Pakistan.