Linagliptin

Generic Name: Linagliptin

Drug Class: Dipeptidyl Peptidase-4 (DPP-4) Inhibitor

Pharmacological Class: Oral antihyperglycemic agent

ATC Code: A10BH05

Regulatory Status: Prescription-only (Rx)

Common Brand Names: Tradjenta (US), Trajenta (EU/International)

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Mechanism of Action

Linagliptin is a selective, reversible DPP-4 enzyme inhibitor that enhances the body’s own ability to regulate blood glucose by increasing incretin levels. DPP-4 rapidly degrades incretin hormones such as:

• Glucagon-like peptide-1 (GLP-1)

• Glucose-dependent insulinotropic peptide (GIP)

By inhibiting DPP-4, linagliptin:

• Increases endogenous GLP-1 and GIP concentrations

• Enhances glucose-dependent insulin secretion

• Suppresses glucagon release

• Improves postprandial and fasting blood glucose control

Unlike sulfonylureas, linagliptin does not cause insulin release in a glucose-independent manner, and therefore has minimal hypoglycemia risk when used as monotherapy.

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Therapeutic Indications

1. Type 2 Diabetes Mellitus (T2DM):

   • Adjunct to diet and exercise to improve glycemic control in adults

   • Can be used as:

     • Monotherapy (if metformin is inappropriate)

     • Dual therapy (with metformin, sulfonylurea, or SGLT2 inhibitor)

     • Triple therapy (with metformin and sulfonylurea)

     • In combination with insulin or basal insulin + metformin

2. No established role in Type 1 Diabetes or Diabetic Ketoacidosis (contraindicated)

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Formulations and Strengths

• Film-coated tablets:

  • 5 mg linagliptin (standard dose)

• Fixed-dose combinations:

  • Linagliptin + Metformin (e.g., Jentadueto): 2.5 mg/500 mg, 2.5 mg/850 mg, 2.5 mg/1000 mg

  • Linagliptin + Empagliflozin (e.g., Glyxambi): 5 mg/10 mg, 5 mg/25 mg

  • Linagliptin + Metformin + Empagliflozin (e.g., Trijardy XR)

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Dosage and Administration

Adults (T2DM):

• Standard dose: 5 mg once daily orally

• Can be taken with or without food, at any time of day

No dosage adjustment required in:

• Renal impairment (all stages, including dialysis)

• Hepatic impairment

• Elderly patients

Pediatric use:

• Not approved for use in children or adolescents (<18 years) as safety and efficacy are not established

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Pharmacokinetics

• Absorption: Rapid; Tmax ~1.5 hours

• Bioavailability: ~30% (due to extensive enterohepatic cycling and binding)

• Distribution: Large volume of distribution; ~99% plasma protein bound

• Metabolism: Minimal; largely excreted unchanged

• Half-life: Terminal half-life ~100–120 hours, but effective half-life ~12 hours

• Elimination:

  • ~80% via bile and gut (feces)

  • <5% renally excreted

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Contraindications

• Hypersensitivity to linagliptin or any component of the formulation

• Type 1 diabetes mellitus

• Diabetic ketoacidosis

• Pregnancy and lactation (not recommended due to insufficient data)

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Special Warnings and Precautions

1. Pancreatitis:

   • Cases of acute pancreatitis (including hemorrhagic and necrotizing) reported

   • Discontinue if pancreatitis suspected or confirmed

   • Use caution in patients with a history of pancreatitis

2. Heart Failure Risk (Class Effect):

   • Unlike saxagliptin or alogliptin, linagliptin has not demonstrated increased risk in trials

   • The CARMELINA trial confirmed cardiovascular safety in high-risk patients

3. Arthralgia:

   • Severe joint pain has been reported; resolves upon discontinuation

4. Hypoglycemia:

   • Low risk as monotherapy or with metformin/SGLT2i

   • Increased risk when used with sulfonylureas or insulin

5. Bullous Pemphigoid:

   • Rare autoimmune blistering skin disorder associated with DPP-4 inhibitors

   • Discontinue if suspected and refer to dermatologist

6. Immune-Mediated Reactions:

   • Rare reports of angioedema, urticaria, hypersensitivity reactions

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Adverse Effects

Common (≥1%):

• Nasopharyngitis

• Upper respiratory tract infection

• Cough

• Headache

• Diarrhea (especially in combinations with metformin)

Less Common to Rare (<1%):

• Pancreatitis

• Urticaria, rash

• Arthralgia

• Edema

• Elevated amylase or lipase

• Hepatic enzyme elevations

• Hypoglycemia (mainly with insulin or sulfonylurea)

Very Rare:

• Bullous pemphigoid

• Angioedema

• Anaphylaxis

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Drug Interactions

• P-glycoprotein/CYP3A4 inducers (e.g., rifampin): May reduce linagliptin plasma levels and efficacy

• No significant interaction with:

  • Metformin

  • Sulfonylureas

  • Insulin

  • SGLT2 inhibitors

  • Statins

  • Warfarin

• Low potential for drug-drug interactions due to minimal CYP involvement and non-renal clearance

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Monitoring Parameters

• Fasting and postprandial blood glucose

• HbA1c every 3 months during dose titration, then every 6 months

• Renal function: not required for dosing but monitored routinely in T2DM

• Signs of pancreatitis: epigastric pain, nausea, vomiting

• Skin inspection for bullous disorders

• Signs of hypersensitivity

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Pregnancy and Lactation

Pregnancy:

• Category C (US FDA); use only if benefits justify potential fetal risk

• No adequate human studies available

• Discontinue if pregnancy is detected

Lactation:

• Unknown if excreted in human milk; not recommended while breastfeeding

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Clinical Trials and Efficacy

1. CARMELINA Trial (2019):

   • Assessed cardiovascular and renal safety in high-risk patients

   • Linagliptin was non-inferior to placebo for major adverse CV events

   • No increased risk of heart failure hospitalization

2. CAROLINA Trial (2019):

   • Compared linagliptin to glimepiride

   • Similar cardiovascular outcomes

   • Lower hypoglycemia risk and less weight gain with linagliptin

3. MARLINA-T2D:

   • Demonstrated modest reduction in albuminuria in patients with T2DM and kidney disease

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Comparison with Other DPP-4 Inhibitors

Drug	Renal Adjustment	Half-life	CYP Metabolism	CV Safety
Linagliptin	No	~12 hrs (functional)	Minimal (non-CYP)	Proven safe (CARMELINA)
Sitagliptin	Yes	~12 hrs	Minimal	Proven safe
Saxagliptin	Yes	~2.5 hrs	CYP3A4	Linked to ↑ HF hospitalization
Alogliptin	Yes	~21 hrs	Minimal	Linked to ↑ HF hospitalization

Patient Counseling Points

• Take once daily, with or without food

• Do not miss doses; take at the same time each day

• Watch for signs of pancreatitis (persistent severe abdominal pain)

• Low risk of hypoglycemia unless taken with insulin or sulfonylureas

• Tell your doctor before starting new medications (esp. rifampin or anticonvulsants)

• Maintain regular HbA1c monitoring

• Store at room temperature away from heat and moisture

• Discontinue and seek help if skin blistering or allergic reactions occur

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Storage

• Store at 20–25°C (68–77°F)

• Protect from excessive heat, moisture, and direct light

• Keep out of reach of children