Linagliptin

Linagliptin is an Antidiabetic Agent belonging to the pharmacological class of Dipeptyl peptidase-4 (DPP-4) inhibitors.

Linagliptin is approved for treating type 2 diabetes mellitus. It is used to improve glycemic control by blocking the enzyme DPP-4. It helps to increase levels of incretin hormones like GLP-1 and GIP, which promote insulin release and limit glucagon secretion.

Linagliptin is widely distributed throughout the tissue and has an absolute bioavailability of about 30%. One inactive metabolite was found, suggesting a limited function for metabolism in its removal. Within four days, 85% of radioactivity is eliminated in urine (85%) or faeces (80%). About 70 ml/min is the steady-state renal clearance.

Linagliptin's most common side effect is hypoglycemia, characterized by lightheadedness, sweating, dizziness, and fainting.

Linagliptin is available in the form of Oral Tablets.

The molecule is available in India, the United States, Canada, the United Kingdom, Germany and Australia

Linagliptin is an Antidiabetic Agent belonging to the pharmacological class of Dipeptyl peptidase-IV inhibitors.

The incretin hormones GLP-1 and GIP (glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide) are inactivated by the enzyme DPP-4, which is inhibited by linagliptin (dipeptidyl peptidase 4, EC 3.4.14.5). The enzyme DPP-4 breaks down these hormones quickly. Incretin hormones work together to maintain glucose homeostasis physiologically. Throughout the day, incretin secretion is at a low baseline level; levels increase as soon as a meal is consumed. GLP-1 and GIP promote insulin production and secretion from pancreatic beta cells in normal and increased blood glucose levels.

Additionally, GLP-1 decreases glucagon release from pancreatic alpha cells, lowering the amount of glucose excreted from the liver. Linagliptin causes an extended rise and prolonging of active incretin levels by reversibly and highly effective binding to DPP-4. Linagliptin improves glucose homeostasis via glucose-dependently increasing insulin secretion and decreasing glucagon secretion.

In vitro, linagliptin binds to DPP-4 with a > 10,000-fold preference for DPP-8 or DPP-9 activity.

Linagliptin is available in tablets.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily, generally with or without a meal.

Linagliptin can be used to treat Diabetes mellitus type 2 treatment. It helps lower and control blood sugar levels in adults with this illness. This medicine may be used alone or in conjunction with other antidiabetic medications. It is often given together with a healthy diet and exercise regimen. It raises the body's levels of a group of naturally occurring compounds known as incretins, which encourage insulin release and lessen the amount of glucose the liver generates to help control blood sugar.

In Treatment of Type 2 diabetes mellitus

Linagliptin helps boost the amount of insulin your body generates following a meal and prevents excessive glucose (sugar) release into the blood. In doing so, it decreases your body's blood glucose levels. It often only causes a single frequent adverse effect and is taken once each day.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of developing any significant consequences of diabetes, including kidney damage, blindness, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.

Treatment of diabetes mellitus, type 2: As an adjunct to diet and exercise to improve glycemic control in people with type 2 diabetes. It can be taken alone or with other popular antidiabetic drugs, including metformin, sulfonylurea, pioglitazone, or insulin.

Orally: Linagliptin is available as a tablet that can be taken orally. Linagliptin should be taken on an empty stomach or with food. It is best to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

 Tablet: 5mg

Linagliptin is available in the form of Oral Tablets

Dose Adjustment in Adult Patients:

Type 2 Diabetes Mellitus: 5 mg PO qDay

Dosing Considerations

Patients with diabetes mellitus type 1 are not advised to use it since it would be ineffective.

It has not been investigated in individuals who have had Pancreatitis; it is unknown if those who have had it in the past are more likely to get it again while taking linagliptin.

Linagliptin should be used in treating Type 2 Diabetes Mellitus, along with appropriate dietary restrictions.

While taking Linagliptin, avoid consumption of a high-salt or high-sodium in the diet and be cautious of high-sodium processed foods.

Focus on limiting carbohydrate consumption, consuming high-fibre meals, and routinely checking blood sugar levels.

It is advised to stay hydrated, maintain a rich, balanced diet low in saturated fats and cholesterol, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.

The dietary restriction should be individualized as per patient requirements.

Linagliptin may be contraindicated in the following conditions:-

• Type 1 diabetes mellitus
• Hypersensitivity (such as anaphylaxis, angioedema, exfoliative skin disorders, urticaria, or bronchial hyperreactivity)
• Diabetic ketoacidosis

Pancreatitis: Examine for signs and symptoms of Pancreatitis, including in patients with a history of the condition, as there have been postmarketing reports of acute Pancreatitis, including fatal cases, associated with linagliptin use. If pancreatitis is suspected, discontinue linagliptin.

Insulin and Insulin Secretagogues Combined with Hypoglycemia: A lower insulin secretagogue or insulin dosage may be required to lower the risk of hypoglycemia when combined with Linagliptin.

Hypersensitivity Reactions: Serious hypersensitivity responses, including anaphylaxis, angioedema, and skin disorders that exfoliate, have been established. Other DPP-4 (dipeptidyl peptidase-4) inhibitors have also been linked to angioedema. It is uncertain if individuals who have already experienced angioedema from another DPP-4 inhibitor would be more susceptible to experiencing it with Linagliptin. Thus, proceed with caution in such patients.

Severe and Disabling Arthralgia: Patients on DPP-4 inhibitors have reported experiencing Severe and disabling arthralgia; as a potential cause of excruciating joints, consider discontinuing the treatment if necessary.

Heart Failure: Consider the risks and advantages of empagliflozin in patients with heart failure risk factors; two additional DPP-4 inhibitors have been linked to heart failure; observe for symptoms and indications. If heart failure occurs, treat it as necessary and consider withdrawing the medication.

Bullous Pemphigoid: Patients should report the development of blisters or erosions, stop DPP-4 therapy, and consult a dermatologist if bullous pemphigoid is suspected. Bullous pemphigoid was reported with DPP-4 inhibitor use, requiring hospitalization. Patients in confirmed instances recovered with topical or systemic immunosuppressive therapy and the cessation of DPP-4 inhibitor.

It is unsafe to consume Linagliptin with alcohol.

There is insufficient scientific evidence regarding the use and safety of Linagliptin for pregnant populations.

The adverse reactions related to Linagliptin can be categorized as

• Common Adverse Effects: Hypoglycemia, Upper respiratory tract infection, nasopharyngitis, and headache

• Less Common Adverse Effects: Hypersensitivity reactions like angioedema or skin reactions.

• Rare Adverse Effects: Elevated liver enzymes, Pancreatitis or severe joint pain.

Reports on Postmarketing

Acute Pancreatitis, including fatal acute Pancreatitis

Anaphylaxis, oedema, and exfoliative skin disorders are manifestations of hypersensitivity responses.

Severe and debilitating arthralgia

Pemphigoid bullous

Rash

Stomatitis and mouth ulceration

Rhabdomyolysis

Failure of the heart

Hypoglycemia with concurrent use of insulin and insulin secretagogues

The clinically relevant drug interactions of Linagliptin are briefly summarized here

• Inducers of P-glycoprotein or CYP3A4 Enzymes: Given that rifampin lowered linagliptin exposure, Linagliptin effectiveness will be diminished when combined with a potent P-gp or CYP3A4 inducer. Therefore, it is strongly advised to seek alternate therapies when linagliptin and a potent P-gp or CYP3A4 inducer are provided.

• Insulin Secretagogues or Insulin: It is well known that insulin and insulin secretagogues can lead to hypoglycemia. When linagliptin is used with an insulin secretagogue (such as a sulfonylurea) or insulin, the risk of hypoglycemia increases. To lessen the risk of hypoglycemia, coadministration of linagliptin with an insulin secretagogue (such as a sulfonylurea) or insulin might be required for lower dosages of those medications.

The most common side effects of Linagliptin include:

• Low blood glucose, or hypoglycemia

• Nasopharyngitis, or throat and nasal passage inflammation

• Cough

• Vomiting

• Diarrhoea

• Constipation

• Pregnancy

Pregnancy Category B; Could be acceptable. Either no danger has been shown by animal research, but human studies have yet to be conducted, or some risk has been shown by animal studies but not by human studies.

Drugs can increase the chance of miscarriage and significant birth abnormalities, but there are also hazards to the mother and foetus associated with poorly managed diabetes during pregnancy. In investigations on animal reproduction, administration of linagliptin to pregnant rats throughout the organogenesis phase at dosages equivalent to the maximum recommended clinical dose, depending on exposure, did not result in any negative developmental consequences.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Pregnant women with poorly managed diabetes are more likely to have diabetic ketoacidosis, pre-eclampsia, and delivery problems; similarly, pregnant women with poorly controlled diabetes are more likely to have stillbirths, significant birth abnormalities, and macrosomia-related morbidity.

Animal Data

When linagliptin was given to pregnant Wistar Han rats and Himalayan rabbits during

the process of organogenesis at dosages up to 240 mg/kg/day and 150 mg/kg/day, respectively, no detrimental developmental outcomes were seen. Based on

exposure, these doses correspond to roughly 943 and 1,943 times, respectively, the maximum therapeutic dosage of 5 mg for rats and rabbits. Following injection of linagliptin to Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49 times the maximum advised human dose, depending on exposure, no unfavourable functional, behavioural, or reproductive effects were observed in offspring.

Following oral administration to pregnant rats and rabbits, linagliptin passes the

placenta into the foetus.

• Nursing Mothers

However, as linagliptin is found in rat milk, it is crucial to consider the developmental and health benefits associated with breastfeeding, the mother's clinical requirement for medication, and any potential side effects on the breastfed kid from therapy or an underlying maternal health condition. There is no information on linagliptin's presence in human milk, its effects on breastfed children, or milk production.

• Pediatric Use

As per FDA, safety and effectiveness in the pediatric population have not been established.

• Geriatric Use

In trials using linagliptin, 131 patients who were 75 years or older and 1,085 patients who were 65 years or older received treatment. There were no general differences between elderly patients and younger adult patients in these linagliptin studies regarding the safety or effectiveness of Linagliptin.

Dose Adjustment in Kidney Impairment Patient:

Hepatic impairment: No dosage adjustment necessary.

Dose Adjustment in Hepatic Patients:

Renal impairment: No dosage adjustment is necessary

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Linagliptin. Overconsumption of Linagliptin could lead to symptoms such as low blood sugar (hypoglycemia), gastrointestinal discomfort, headache, fatigue, elevated blood pressure, and heart rhythm irregularities.

Management

There is no specific antidote or treatment for excessive intake of Linagliptin. However, immediate medical attention is essential.

Linagliptin should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Management typically involves supportive measures and symptomatic treatment.

Monitor the patient's vital signs, correct any electrolyte imbalances, especially blood glucose levels, and administer intravenous glucose if necessary.

Because linagliptin is widely distributed throughout the body, removing it using hemodialysis or peritoneal dialysis is unlikely to be effective.

Pharmacodynamics:

The concentration of incretin hormones increases due to the ligand's reversible binding to DPP-4. Optimal control of glucose homeostasis is achieved by linagliptin's glucose-dependent increase in insulin secretion and decrease in glucagon secretion. Linagliptin binds specifically to DPP-4 and suppresses DPP-4 activity in vitro at doses close to those used in therapeutic exposures but not DPP-8 or DPP-9.

Cardiac Electrophysiology

In a randomized, placebo-controlled, active-comparator, four-way crossover research, 36 healthy participants received one oral administration of linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. The prescribed amount of 5 mg or 100 mg did not increase QTc. When given in doses of 100 mg, linagliptin plasma concentrations peaked at a rate that was about 38 times greater than when given in quantities of 5 mg.

Pharmacokinetics:

Absorption

Linagliptin has an estimated 30% absolute bioavailability. A high-fat meal co-administered with linagliptin resulted in a 2-hour delay in reaching Cmax and a 15% reduction in Cmax, but no effect on AUC 0-72h was seen. Lintagliptin can be taken with or without food because there shouldn't be any clinically significant effects from Cmax and Tmax variations.

Peak Plasma Time: 1.5 hr

Peak Plasma Concentration: 8.9 nmol/L

AUC: 139 nmol h/L

Distribution

A single 5 mg intravenous dosage of linagliptin causes about 1,110 litres of mean apparent volume of distribution at steady-state in healthy people due to tissue binding, demonstrating linagliptin's broad tissue distribution. With increasing linagliptin concentration, the plasma protein binding of linagliptin decreases, from 99% at one nmol/l to 75-89% at 30 nmol/l, showing saturation of binding to DPP-4. When DPP-4 is wholly saturated at high doses, 70–80% of linagliptin is bound to proteins other than DPP-4 in the plasma, allowing 30–20% unbound.

Vd: 1,110 L

Metabolism

A 10 mg oral dosage of [14C] linagliptin eliminated 5% of the radioactivity in urine. The metabolism only has a little impact on how quickly linagliptin is excreted. One major metabolite was shown to be pharmacologically inactive. It hence did not contribute to the plasma DPP-4 inhibitory action of linagliptin, although at steady-state having a relative exposure of 13.3% of linagliptin.

Excretion

Within four days after administering an oral dosage of [14C] linagliptin, 85% of the radioactivity was removed, with the remaining 15% passing through urine or faeces.

An average of 70 ml/min of renal clearance was measured at a steady state.

Half-Life: 12 hr

Terminal Half-Life: >100 hr

Enterohepatic system (80%), urine (5%)

• McGill, Janet B. “Linagliptin for type 2 diabetes mellitus: a review of the pivotal clinical trials.” Therapeutic advances in endocrinology and metabolism vol. 3,4 (2012): 113-24. doi:10.1177/2042018812449406
• Freeman, Maisha Kelly. “Efficacy and safety of linagliptin (tradjenta) in adults with type-2 diabetes mellitus.” P & T: a peer-reviewed journal for formulary management vol. 36,12 (2011): 807-42.
• Markku Laakso, Julio Rosenstock, Per-Henrik Groop, Anthony H. Barnett, Baptist Gallwitz, Uwe Hehnke, Ilkka Tamminen, Sanjay Patel, Maximilian von Eynatten, Hans-Juergen Woerle; Treatment With Dipeptidyl Peptidase-4 Inhibitor Linagliptin or Placebo Followed by Glimepiride in Patients With Type 2 Diabetes With Moderate to Severe Renal Impairment: A 52-Week, Randomized, Double-Blind Clinical Trial. Diabetes Care 1 February 2015; 38 (2): e15–e17. https://doi.org/10.2337/dc14-1684
• Rosenstock J, Perkovic V, et al. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial. JAMA. 2019;321(1):69–79. doi:10.1001/jama.2018.18269

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year trial, linagliptin at 6, 18, and 60 mg/kg dosages did not affect the tumour frequency in male and female rats. The maximum dosage of 60 mg/kg is almost 418 times the therapeutic dose of 5 mg/day based on AUC exposure. Linagliptin did not increase the frequency of tumours in mice throughout 2-year research at doses up to 80 mg/kg (for males) and 25 mg/kg (for females), or around 35 and 270 times the therapeutic dosage based on AUC exposure. Based on AUC exposure, higher linagliptin dosages (80 mg/kg) in female mice led to an estimated 215-fold increase in the incidence of lymphoma.

In the chromosomal aberration test in human cells, the in vivo micronucleus assay, and the Ames bacterial mutagenicity assay, linagliptin was neither mutagenic nor clastogenic with or without metabolic activation.

In rat fertility tests, linagliptin exhibited no adverse effects on fertility, early embryonic development, mating, or giving birth to live young up to the maximum dose of 240 mg/kg (about 943 times the therapeutic dose based on AUC exposure).

https://www.ncbi.nlm.nih.gov/books/NBK548554/

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm

https://www.ema.europa.eu/en/documents/product-information/

https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020850s032lbl.pdf

https://www.nhs.uk/medicines/linagliptin/