Linagliptin Metformin is a combination is available as immediate-acting and extended-release tablets used to treat patients with Diabetes Mellitus Type 2. It is also available in combination with empagliflozin (Jardiance) as TriJardy and TriJardy XR that contains: Linagliptin, Empagliflozin, and Metformin extended-release.

Linagliptin Metformin Uses:

• Diabetes mellitus type 2:
  • When treatment with both linagliptin and metformin is necessary, it is used as an adjuvant therapy to diet and exercise to enhance glycemic control in adults with type 2 diabetes mellitus.

Linagliptin Metformin Dose in Adults:

Linagliptin Metformin Dose in the treatment of type 2 Diabetes mellitus:

• Initial oral doses ought to be calculated using the combined daily doses of metformin and linagliptin.
• Its dosage options include linagliptin 2.5 mg and metformin 1,000–2,000 mg once daily (immediate-release form) OR linagliptin 5 mg and metformin 1,000–2,000 mg twice day (immediate-release form) (extended-release). The recommended daily dose of linagliptin is 5 mg/2,000 mg of metformin.
• Patients currently on metformin:
  • Initial: 5 mg/day of linagliptin along with the recommended dose of metformin
• Patients not on metformin:
  • Initially: 5 mg of linagliptin and 1 mg of metformin every day.
• Conversion from immediate-release to an extended-release product:
  • It is possible to switch to an extended-release medication that contains the same amount of metformin (one dose per day) plus linagliptin (5 mg).
• Concomitant use with insulin and/or insulin secretagogues (eg, sulfonylureas):
  • When taken concurrently, the dosage of insulin and other secretagogues must be decreased.

Use in Children:

Not indicated.   

Pregnancy Category: Metformin (B), Linagliptin (C)

• Metformin crosses the placenta. For more information, refer to the individual monographs.

Breastfeeding: Metformin and Linagliptin are not recommended.

• It has been discovered that breast milk secretes metformin.
• The literature suggests that the decision to breastfeed while on therapy should be made taking into account the risks to infants, the benefits to the mother, and the benefits to the mother. 
• It is important to consider the risks and benefits of each option when deciding on your preference.

 Linagliptin Metformin Dose in Kidney disease:

• eGFR >45mL/minute/1.73m2
  • Dose adjustment is not required.
• eGFR 30 - 45 mL/minute/1.73m2
  • It is not recommended to be used for the initiation of therapy. Consider the benefits and risks of continuing therapy if eGFR drops below 45 mL/minute/1.73 m2. Metformin dosage reductions of 50% are recommended (maximum of 1 g/day), and monitoring of renal function every three months.
• eGFR 30mL/minute/1.73m2
  • It is not recommended to be used in this range.

Linagliptin Metformin Dose in Liver disease:

• Metformin should not be used as the liver disease can lead to lactic acidosis.
• Metformin continued use in diabetics with liver dysfunction (cirrhosis) has been proven to be beneficial and may even provide a survival advantage in some patients. 
• Patients at high risk of lactic acidosis, such as those with renal impairment or who have been drinking excessively, should not take metformin.

Reports of reactions or percentages with combination products; additionally see separate agents.

Side effects of Linagliptin Metformin:

• Dermatologic:
  • Pruritus
• Gastrointestinal:
  • Diarrhea
  • Decreased appetite
  • Nausea
  • Pancreatitis
  • Vomiting
• Hypersensitivity:
  • Hypersensitivity reaction
• Respiratory:
  • Nasopharyngitis
  • Cough

Contraindications to Linagliptin Metformin:

• According to US labeling
  • Anaphylaxis, angioedema and exfoliative skin conditions such as urticaria, anaphylaxis and angioedema can all be caused by hypersensitivity reactions to linagliptin or metformin.
  • Severe renal impairment (eGFR >30 mL/minute/1.73m2).
  • Chronic or acute metabolic acidosis, which includes diabetic ketoacidosis.

Canadian labeling

• Hypersensitivity to metformin, linagliptin, or any other ingredient of the formulation is a definite contraindication.
• It is unknown how well the kidneys are functioning.
• It is possible to have renal disease or kidney dysfunction, which can also be brought on by situations like cardiovascular collapse, acute coronary infarction, or septicemia (serum creatinine >=136 mg/L for men and >=124 mg/L for women), as well as abnormal creatinine clearance (60 mL/minute).
• Severe hepatic dysfunction.
• Type 1 diabetes mellitus: Unstable or insulin-dependent.
• Chronic or acute metabolic acidosis including diabetic ketoacidosis.
• History of lactic acidosis, regardless of precipitating factors.
• A high level of alcohol intake, whether it is acute or chronic.
• Hyperlactic-acidemia is often associated with cardiovascular collapse and other diseases that are associated with hypoxemia, such as cardiorespiratory failure.
• Stress conditions (eg severe infection, trauma, surgery and the postoperative recovery phase).
• Severe dehydration.
• Pregnancy and breastfeeding

Warnings and precautions

• Arthralgia
  • DPP-4 inhibitors have been linked to severe and disabling arthritis. 
  • The onset of the condition can occur as soon as treatment is initiated. It may resolve by stopping therapy.
  • DPP4 inhibitor therapy may be reintroduced for some patients who experience a relapse.
  • If severe joint pain is caused by DPP-4 inhibitor therapy, discontinue use
• Bullous pemphigoid
  • Bullous pemphigoid has been linked to DPP-4 inhibitor therapy. 
  • Most cases can be resolved by discontinuing DPP-4 inhibitor therapy and applying topical or systemic immunosuppressive treatment.
  • Patients should be advised to notify you if they develop blisters or other erosions.
  • If bullous pemphigoid symptoms are suspected, withhold treatment and refer to a dermatologist.
• Hypersensitivity reactions
  • Patients treated with linagliptin have reported rare hypersensitivity reactions such as anaphylaxis, exfoliative skin conditions, and angioedema. If you notice signs or symptoms of hypersensitivity reactions, do not hesitate to contact us.
  • Generally, events are noted within the first three months of therapy. They may also occur after the initial dose.
  • If the patient has had angioedema from other DPP-4 inhibitors, caution is advised.
• Lactic acidosis: [US Boxed Warning]
  • Metformin-associated lactosis has been linked to death, hypothermia and hypotension in post-marketing cases.
  • The symptoms that may accompany the onset of anemia are often subtle and can include myalgias or respiratory distress, nausea, abdominal pain, sleepiness, somnolence, and malaise. Blood lactate levels above 5 mmol/L can also be elevated. 
  • There might be anion gap acidosis without any indication of ketonuria. The ratios of lactate and pyruvate rise. Plasma levels of metformin are often greater than 5 mg/mL.
  • Risk factors for lactic acidosis include patients with renal impairment, concurrent use of specific medications (such as carbonic anhydrase inhibitors like topiramate), being older than 65, having a radiologic scan with contrast, surgery, and other operations.
  • If lactic acidosis suspects, immediately withhold the drug. It is recommended to immediately undergo hemodialysis.
  • Patients with diabetes who are receiving metformin should suspect lactic acidosis if they have signs of acidosis, but not ketoacidosis.
  • Patients with hypoperfusion, hypoperfusion, sepsis or dehydration should be stopped using this product.
  • Patients with limited food intake and fluid intake may temporarily stop therapy.
  • With impairment in renal function, the risk of lactic acidosis and accumulation increases.
• Pancreatitis
  • Liningriptin has been linked to fatal cases of acute pancreatitis.
  • You should be aware of signs and symptoms that could indicate pancreatitis. 
  • If pancreatitis suspicion is raised, stop using the medication immediately and seek appropriate treatment.
  • Patients with a history or pancreatitis should be cautious. It is not known if they are at higher risk.
• Concentrations of Vitamin B-12:
  • Vitamin B-12 deficiency is a common side effect of long-term metformin treatment. Long-term therapy requires monitoring of vitamin B serum levels.
  • Patients receiving metformin should monitor their serum vitamin B-12 levels, especially those suffering from peripheral neuropathy or anemia.
• Bariatric surgery
  • Absorption altered:
    • It is recommended to use immediate-release tablets following surgery
    • Gastric bypass and Sleeve Gastrectomy can cause changes in absorption.
    • Extended tablets can have a decreased effect after gastric bypass. This is due to either a direct bypass of stomach and proximal bowel with gastric bypass, or a faster gastric emptying and transit with sleeve-gastrectomy.
    • Administration of IR tablets after gastric bypass (Rouxen-Y gastric bypass [RYGB]) led to improved absorption (AUC elevated by 21%; increased 50% in bioavailability).
    • After gastric bypass, lactate levels decrease whether or not metformin is used (RYGB).
    • As long as normal renal function remains intact, it is not necessary to reduce metformin doses after gastric bypass.
  • Exposure to Glucagon-like peptide-1 and its therapeutic efficacy
    • Monitor your pancreatitis symptoms and signs carefully.
    • Endogenous secretion may be increased by gastric bypass or sleeve-gastrectomy.
    • One placebo-controlled, single-dose study evaluated short-term sitagliptin therapy for 4 weeks in patients undergoing gastric bypass.
    • It was found to be well tolerated and resulted in a modest but significant drop in blood glucose postprandially.
• Heart Failure:
  • Metformin can be used for patients with stable or refractory heart disease (HF). Metformin should not be used in patients who are unstable or hospitalized with heart failure.
  • Hypoperfusion may increase the risk of developing lactic acidosis.
  • The American Heart Association has stated that metformin may be an agent that can exacerbate myocardial dysfunction.
  • Metformin may reduce mortality and hospital readmissions in patients with HF.
  • In cardiovascular outcomes trials involving individuals with type 2 diabetes and atherosclerotic cardiomyopathy, DPP-4 inhibitor therapy was linked to elevated blood pressure.
  • Patients with type 2 diabetes and high cardiovascular risk were compared with placebo in a double-blind, placebo-controlled, randomised study to see if linagliptin had any impact on the primary composite cardiovascular outcome.
  • Non-fatal MI, stroke, cardiovascular mortality, and cardiovascular death were all included.
  • Additionally, in patients with preexisting illnesses, hospitalisations for HF were no different from a placebo.
  • The average follow-up time was 2.2 years.
• Hepatic impairment
  • Metformin should not be used in patients with hepatic impairment because of the possibility of lactic acidosis.
  • Metformin may have a survival benefit for patients with diabetes and liver dysfunction. However, this is only true in a small number of patients.
• Renal impairment
  • The kidney excretes a large amount of Metformin. Before starting therapy, assess the renal function and then periodically use estimated glomerular filter rate (eGFR).
  • With increasing renal impairment, the risk of metformin accumulation or lactic acidosis is higher.
  • Patients with an eGFR of 30mL/minute/1.73m2 are not advised to use this medication.
  • Metformin is a medication that can be used to treat patients who have a eGFR of 30 to 45 mL/minute/1.73m2. If metformin is used, it is recommended to reduce the dose.
  • Metformin disposition may be affected by concomitant medication that can affect renal function (ie tubular secretion).
  • Patients with prerenal azotemia and dehydration should not take metformin.
• Stress-related disorders:
  • It can be required to cease giving metformin and start giving insulin if the patient is experiencing stress, such as a fever, trauma, or surgery.

Monitoring parameters:

• Patients who are stable in their glycemic control, and have met treatment goals, should have HbA1c measured at least twice per year. It should be performed quarterly .
• Plasma glucose
• Annual hemoglobin, hemoglobin, and red blood cell indexes are all important parameters in the hematology field.
• Hepatic functions.
• Before starting therapy, it is recommended that you check your renal functions at least once a year or more often if needed If patients are not achieving their therapeutic objectives or changing their therapy.
• When megaloblastic aemia is detected, vitamin B12 levels (regularly, long-term treatment) and folate levels are advised.
• Signs and symptoms of pancreatitis.
• Heart failure symptoms and signs

How to administer Linagliptin Metformin?

• You should take it orally along with your daily meals. 

Extended-release tablets:

• Take the tablet whole.
• Do not crush, break, dissolve or chew.   

Mechanism of action of Linagliptin and metformin:

Linagliptin

• inhibits dipeptidyl peptidase 4 (DPP-4) enzymes, leading in high quantities of active incretin.
• Incretin hormones, such as glucagon-like propeptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), control glucose homeostasis by increasing insulin synthesis and release by pancreatic beta cells and reducing glucagon production by pancreatic alpha cells.
• Hepatic sugar synthesis is reduced when glucagon secretion declines.
• The intestine releases incretin hormones continuously throughout the day under normal physiological conditions.
• Levels increase in response to meals; DPP-4 enzymes rapidly activate incretin hormones.

Metformin

• It decreases the hepatic glucose output, reduces intestinal absorption, and increases insulin sensitivity (increases peripheral sugar uptake and utilization).
• Contact individual agents (Linagliptin and metformin).   

International Brand Names of Linagliptin and metformin:

• Jentadueto
• Jentadueto XR
• Controgliptin
• Gliptalina
• Jentadueto
• Trajenta Duo
• Trajentamet
• Trayebta Duo
• Trayenta Duo

Linagliptin and metformin Brand Names in Pakistan:

No Brands Available in Pakistan.