Liraglutide

Dosage for Liraglutide is highly individualized and depends on the specific condition being treated. A "start low and go slow" titration (gradual increase) schedule is utilized to minimize gastrointestinal side effects.

For Type 2 Diabetes (Victoza)

• Initial Dose: 0.6 mg injected subcutaneously once daily for one week. This starting dose is intended to reduce gastrointestinal symptoms and is not effective for glycemic control.
• Maintenance Dose: After one week, the dose is increased to 1.2 mg once daily. If the target blood sugar (HbA1c) is not reached, the dose may be further increased to 1.8 mg once daily.
• Maximum Dose: 1.8 mg once daily.

For Chronic Weight Management (Saxenda)

• Week 1: 0.6 mg once daily.
• Week 2: 1.2 mg once daily.
• Week 3: 1.8 mg once daily.
• Week 4: 2.4 mg once daily.
• Week 5 and beyond: 3.0 mg once daily.
• Evaluation: If a patient has not lost at least 4% of their baseline body weight after 16 weeks on the 3.0 mg dose, the medication is typically discontinued as it is unlikely the patient will achieve clinically meaningful weight loss.

Type 2 Diabetes (Ages 10-17)

• The titration schedule is identical to the adult schedule for Victoza, starting at 0.6 mg and titrating up to a maximum of 1.8 mg daily.

Chronic Weight Management (Ages 12-17)

• For pediatric patients weighing more than 60 kg, the titration follows the adult Saxenda schedule up to the 3.0 mg maintenance dose. If the 3.0 mg dose is not tolerated, the dose may be reduced to 2.4 mg.

Renal Impairment

No dose adjustment is recommended for patients with mild, moderate, or severe renal (kidney) impairment. However, because gastrointestinal side effects can lead to dehydration, which may worsen kidney function, healthcare providers monitor renal function closely during titration.

Hepatic Impairment

No dose adjustment is recommended for patients with hepatic (liver) impairment. Clinical data in patients with severe hepatic impairment is limited, so caution is advised.

Elderly Patients

No overall differences in safety or effectiveness have been observed between patients 65 years and older and younger patients, but greater sensitivity in some older individuals cannot be ruled out.

1. 1Timing: Inject Liraglutide once daily at any time of day, regardless of meal timing. It is best to choose a time that is easy to remember.
2. 2Injection Technique: Rotate injection sites within the same region (abdomen, thigh, or upper arm) each day to reduce the risk of lipodystrophy (skin thickening or pitting). Do not inject into areas where the skin is tender, bruised, red, or hard.
3. 3Pen Care: Always use a new needle for each injection to prevent contamination and needle blockage. Never share your pen with another person, even if the needle has been changed.
4. 4Storage: Store new, unused pens in the refrigerator (36°F to 46°F). After the first use, the pen can be stored at room temperature (up to 86°F) or in the refrigerator for up to 30 days. Do not freeze.

If you miss a dose, take it as soon as you remember. However, if it has been more than 12 hours since your scheduled time, skip the missed dose and take the next dose at the regular time. Do not take an extra dose or increase the dose to make up for a missed one. If you miss more than three days of Liraglutide, call your doctor to discuss whether you should restart the medication at the 0.6 mg dose to avoid gastrointestinal upset.

Signs of a Liraglutide overdose may include severe nausea, severe vomiting, and severe hypoglycemia (if used with other diabetes medications). If an overdose is suspected, contact a Poison Control Center (1-800-222-1222) or seek emergency medical attention immediately. Treatment is supportive, focusing on hydration and monitoring blood glucose levels.

> Important: Follow your healthcare provider's dosing instructions precisely. Do not adjust your dose or stop the medication without medical guidance.

The most frequent side effects associated with Liraglutide involve the gastrointestinal system. These are typically most severe during the first few weeks of treatment or when the dose is increased.

• Nausea: Affecting up to 40% of patients, this is the most common reason for discontinuation. It usually diminishes over time.
• Diarrhea: Loose or watery stools may occur as the body adjusts to the slowed gastric emptying.
• Vomiting: Frequent during the titration phase; persistent vomiting can lead to dehydration.
• Constipation: Due to slowed gut motility, some patients experience difficulty with bowel movements.
• Hypoglycemia: Low blood sugar is common when Liraglutide is used in combination with sulfonylureas or insulin.

• Dyspepsia (Indigestion): A feeling of fullness, bloating, or heartburn.
• Abdominal Pain: General discomfort in the stomach area.
• Fatigue: An unusual feeling of tiredness or lack of energy.
• Dizziness: Often related to changes in blood sugar or hydration levels.
• Increased Lipase: Elevated levels of pancreatic enzymes may be noted on blood tests, even without symptoms of pancreatitis.

• Urticaria (Hives): An itchy, red skin rash.
• Delayed Gastric Emptying: In rare cases, the slowing of the stomach can become severe (gastroparesis).
• Altered Taste: Some patients report a metallic or different taste in the mouth.

> Warning: Stop taking Liraglutide and call your doctor immediately if you experience any of these serious conditions.

• Pancreatitis (Inflammation of the Pancreas): Characterized by severe, persistent abdominal pain that may radiate to the back, with or without vomiting. This can be life-threatening.
• Gallbladder Disease: Liraglutide can cause gallstones (cholelithiasis) or inflammation of the gallbladder (cholecystitis). Symptoms include upper stomach pain, fever, and yellowing of the skin or eyes (jaundice).
• Kidney Impairment: Severe nausea and vomiting can lead to dehydration, which may cause acute kidney injury. Symptoms include decreased urination or swelling in the legs and ankles.
• Serious Allergic Reactions: Signs include swelling of the face, lips, tongue, or throat; problems breathing or swallowing; severe rash or itching; and very rapid heartbeat.
• Suicidal Thoughts or Behavior: Especially with the weight-loss indication (Saxenda), patients should be monitored for mood changes, depression, or suicidal ideation.

With prolonged use, Liraglutide has been associated with a potential increase in heart rate (tachycardia). Patients should have their heart rate monitored regularly. Additionally, there is ongoing research regarding the long-term impact on bone density and muscle mass, particularly in patients losing significant weight rapidly.

Risk of Thyroid C-cell Tumors: In animal studies (rats and mice), Liraglutide caused dose-dependent and treatment-duration-dependent thyroid C-cell tumors, including medullary thyroid carcinoma (MTC). It is unknown whether Liraglutide causes MTC in humans. Liraglutide is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Patients should be instructed to report any symptoms of a thyroid tumor, such as a lump in the neck, difficulty swallowing, hoarseness, or shortness of breath.

Report any unusual symptoms to your healthcare provider. You may also report side effects to the FDA at 1-800-FDA-1088.

Liraglutide is a powerful metabolic modifier that requires careful monitoring. Patients must be aware of the risk of pancreatitis and gallbladder disease. It is essential to maintain adequate fluid intake to prevent dehydration, which is a leading cause of secondary kidney complications associated with this drug class.

WARNING: RISK OF THYROID C-CELL TUMORS

• Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of Liraglutide-induced rodent thyroid C-cell tumors has not been determined.
• Liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
• Counsel patients regarding the potential risk for MTC with the use of Liraglutide and inform them of symptoms of thyroid tumors (e.g. a lump in the neck, hoarseness, difficulty swallowing, or shortness of breath). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Liraglutide.

• Pancreatitis: Cases of fatal and non-fatal hemorrhagic or necrotizing pancreatitis have been reported. If pancreatitis is suspected, Liraglutide should be discontinued promptly. Patients with a history of pancreatitis should use Liraglutide with extreme caution.
• Acute Gallbladder Disease: Substantial weight loss can increase the risk of cholelithiasis (gallstones). If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.
• Hypoglycemia with Concomitant Use: When used with insulin secretagogues (e.g., sulfonylureas) or insulin, the risk of hypoglycemia is increased. A reduction in the dose of the insulin secretagogue or insulin may be necessary.
• Renal Impairment: Acute kidney injury and worsening of chronic renal failure, sometimes requiring hemodialysis, have been reported. This is often associated with dehydration from gastrointestinal side effects.
• Hypersensitivity: Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. If these occur, discontinue Liraglutide and seek immediate medical help.

Healthcare providers typically monitor the following:

• Blood Glucose and HbA1c: To assess the efficacy of treatment in diabetes.
• Weight: To assess efficacy in chronic weight management.
• Renal Function: Especially in patients reporting severe gastrointestinal distress.
• Heart Rate: Monitoring for increases in resting heart rate.
• Mental Status: Monitoring for the emergence or worsening of depression or suicidal thoughts (specifically for Saxenda).

Liraglutide generally does not affect the ability to drive. However, if used in combination with other diabetes medications that cause hypoglycemia, dizziness or lack of concentration may occur. Use caution until you know how Liraglutide affects you.

Alcohol can affect blood glucose levels. While there is no direct chemical interaction between Liraglutide and alcohol, excessive alcohol consumption can increase the risk of hypoglycemia and may worsen gastrointestinal side effects or increase the risk of pancreatitis.

Liraglutide does not typically require a tapering schedule. However, if discontinued, blood glucose levels may rise, and weight regain is common if dietary and exercise changes are not maintained. If you experience severe side effects, your doctor may advise immediate discontinuation.

> Important: Discuss all your medical conditions, especially history of pancreatitis, gallbladder issues, or kidney disease, with your healthcare provider before starting Liraglutide.

• Other GLP-1 Receptor Agonists: Liraglutide should not be used in combination with other drugs in the same class (e.g., semaglutide, dulaglutide, exenatide). Combining these increases the risk of severe gastrointestinal side effects and overdose without providing additional therapeutic benefit.

• Insulin and Sulfonylureas: Drugs like glimepiride, glipizide, and various insulin formulations have a synergistic effect with Liraglutide. This significantly increases the risk of severe hypoglycemia. Management: A dose reduction of the insulin or sulfonylurea is often required when starting Liraglutide.
• Narrow Therapeutic Index Oral Medications: Because Liraglutide slows gastric emptying, it can potentially delay the absorption of oral medications that require rapid onset or have a narrow therapeutic window (e.g., Digoxin, Warfarin). Management: Monitor clinical effects or drug levels of these medications more frequently when starting or changing the dose of Liraglutide.

• Oral Contraceptives: While studies have shown that Liraglutide does not clinically reduce the overall absorption (AUC) of oral contraceptives, the peak concentration (Cmax) may be slightly delayed. Most clinicians do not consider this interaction to be clinically significant, but patients should be aware.
• Acetaminophen: The absorption of acetaminophen may be delayed, but the total amount absorbed is generally not affected.

• High-Fat Meals: While Liraglutide can be taken with or without food, high-fat meals may exacerbate the nausea and bloating associated with the medication.
• Hydration: It is critical to consume plenty of non-caffeinated fluids. Dehydration caused by vomiting or diarrhea can interact with the drug's effect on the kidneys, leading to acute injury.

• Hypoglycemic Herbs: Supplements such as bitter melon, fenugreek, gymnema, and alpha-lipoic acid may have blood-sugar-lowering effects. Combining these with Liraglutide may increase the risk of hypoglycemia.
• St. John's Wort: While no direct metabolic interaction exists via CYP enzymes, St. John's Wort can affect mood, which may complicate the monitoring of psychiatric side effects in patients taking Saxenda for weight loss.

• Calcitonin: Liraglutide may cause elevations in serum calcitonin. While this is used as a marker for Medullary Thyroid Carcinoma (MTC), the clinical significance of modest elevations in patients on Liraglutide is unclear.
• Amylase and Lipase: Liraglutide can cause increases in these enzymes. This can make the diagnosis of acute pancreatitis more complex, as elevations can occur even in the absence of disease.

Interaction Mechanisms

1. 1Pharmacodynamic Interaction: The most common interaction with Liraglutide is the additive effect on blood glucose lowering when combined with other antidiabetic agents.
2. 2Gastric Emptying Delay: This is the primary mechanism by which Liraglutide affects the pharmacokinetics of other oral drugs. By slowing the rate at which the stomach empties into the small intestine (the primary site of drug absorption), the time to reach peak plasma concentration (Tmax) of other drugs is often increased.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including over-the-counter pain relievers and cold medicines.

Conditions where Liraglutide must NEVER be used include:

• Personal or Family History of Medullary Thyroid Carcinoma (MTC): Because Liraglutide has been shown to cause C-cell tumors in rodents, and MTC is a C-cell tumor, the risk in humans cannot be ruled out. This is a strict contraindication.
• Multiple Endocrine Neoplasia Syndrome Type 2 (MEN 2): This is a genetic condition that predisposes individuals to MTC and other endocrine tumors. Use of Liraglutide in these patients poses an unacceptable risk.
• Hypersensitivity: Patients with a known serious hypersensitivity to Liraglutide or any of the product's excipients (such as phenol or propylene glycol) should not use the drug. Reactions can include anaphylaxis or angioedema.
• Pregnancy (Saxenda): Weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. Therefore, Saxenda is contraindicated during pregnancy.

Conditions requiring careful risk-benefit analysis include:

• History of Pancreatitis: Since Liraglutide is associated with an increased risk of pancreatitis, patients with a prior history of this condition are generally advised to seek alternative therapies unless the benefits clearly outweigh the risks.
• Severe Gastrointestinal Disease: Patients with gastroparesis (paralysis of the stomach) or inflammatory bowel disease (IBD) may find their symptoms significantly worsened by Liraglutide's effect on gut motility.
• History of Suicidal Ideation: For the weight loss indication, patients with a history of major depressive disorder or suicidal attempts should be screened and monitored very closely, as weight-loss drugs can sometimes exacerbate these issues.

There is a potential for cross-sensitivity among GLP-1 receptor agonists. If a patient has had a severe allergic reaction to semaglutide (Ozempic/Wegovy) or dulaglutide (Trulicity), they should not be started on Liraglutide without specialist consultation and possible allergy testing.

> Important: Your healthcare provider will evaluate your complete medical history, including your family history of cancer, before prescribing Liraglutide.

• Type 2 Diabetes (Victoza): Liraglutide is classified as Pregnancy Category C by the older FDA system. Data from clinical trials are insufficient to determine a drug-associated risk for major birth defects or miscarriage. However, poorly controlled diabetes in pregnancy poses significant risks to both the mother and the fetus. Most guidelines recommend transitioning to insulin during pregnancy.
• Weight Management (Saxenda): Contraindicated in pregnancy. If a patient becomes pregnant while taking Saxenda, the medication should be discontinued immediately.
• Animal Data: Studies in rats and rabbits have shown reproductive toxicity, including reduced fetal growth and skeletal abnormalities at doses higher than the human clinical dose.

It is not known whether Liraglutide is excreted in human milk. In animal studies, Liraglutide was present in the milk of lactating rats at low concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

• Victoza: Approved for children 10 years and older with type 2 diabetes. The safety profile was found to be similar to that in adults.
• Saxenda: Approved for children 12 years and older with obesity. Clinical trials showed that Liraglutide, in combination with lifestyle changes, significantly reduced BMI compared to placebo. Long-term effects on growth and pubertal development are still being monitored, though no negative signals have emerged to date.

In clinical trials, no overall differences in safety or effectiveness were observed between patients 65 years and older and younger patients. However, elderly patients may be more prone to gastrointestinal side effects and subsequent dehydration. Renal function should be monitored closely in this population, especially during the titration phase.

Liraglutide can be used in patients with renal impairment, including those with end-stage renal disease (ESRD). However, there is limited experience in these populations. Because most renal issues reported with Liraglutide are secondary to dehydration from GI side effects, patients with existing kidney disease must be exceptionally vigilant about maintaining hydration.

No dose adjustment is required for patients with mild, moderate, or severe hepatic impairment. Liraglutide is not metabolized by the liver in a way that is affected by liver enzyme changes, but clinical data for patients with severe cirrhosis (Child-Pugh score >9) is limited.

> Important: Special populations require individualized medical assessment and more frequent follow-up with a healthcare team.

Liraglutide is an acylated human Glucagon-Like Peptide-1 (GLP-1) receptor agonist. It is produced using recombinant DNA technology in Saccharomyces cerevisiae. The primary molecular modification is the attachment of a C16 fatty acid (palmitic acid) to the lysine residue at position 26. This fatty acid chain allows Liraglutide to bind non-covalently to albumin, protecting the molecule from rapid degradation by dipeptidyl peptidase-4 (DPP-4) and reducing renal filtration.

Once bound to the GLP-1 receptor, Liraglutide activates the adenylyl cyclase pathway, increasing intracellular cyclic AMP (cAMP). In the pancreas, this leads to insulin release from beta cells in a glucose-dependent manner. It also suppresses glucagon secretion. In the brain, it activates receptors in the arcuate nucleus of the hypothalamus, promoting satiety and reducing caloric intake.

Liraglutide lowers fasting and postprandial (after-meal) blood glucose. The insulin secretion effect is strictly glucose-dependent; as blood glucose concentrations decrease toward euglycemia (normal levels), insulin secretion diminishes. It also causes a minor delay in gastric emptying, which reduces the rate at which postprandial glucose appears in the circulation.

| Parameter | Value |

|---|---|

| Bioavailability | ~55% (Subcutaneous) |

| Protein Binding | >98% (Primarily Albumin) |

| Half-life | ~13 hours |

| Tmax | 8 to 12 hours |

| Metabolism | Endogenous proteolysis (No specific CYP enzymes) |

| Excretion | Minimal renal/fecal (primarily as metabolites) |

• Molecular Formula: C172H265N43O51
• Molecular Weight: 3751.2 Daltons
• Solubility: Highly soluble in water and physiological buffers.
• Structure: A 31-amino acid peptide with 97% homology to human GLP-1(7-37). The substitution of Lys34 with Arg34 and the addition of the palmitoyl group are the key structural features.

Liraglutide is a member of the GLP-1 Receptor Agonist [EPC] class. It is categorized as a "long-acting" GLP-1 agonist, distinct from "short-acting" agents like Exenatide (Byetta). Other medications in this therapeutic class include Semaglutide (Ozempic), Dulaglutide (Trulicity), and Tirzepatide (Mounjaro - which is a dual GIP/GLP-1 agonist).