Liraglutide (Saxenda, Victoza) is a GLP-1 (Glucagon-like Peptide) receptor agonist that is also called an incretin mimetic, is used to treat diabetes mellitus type 2 as an adjunct to diet and exercise. It may be used as monotherapy or with metformin/ other diabetes medications. It is also available in combination with insulin degludec (ultra-long-acting insulin) by the brand name of Xultophy. It stimulates glucose-dependent insulin-release and inhibits glucagon secretion. It also delays gastric emptying and inhibits the replication of beta cells of the pancreas.

Liraglutide (Saxenda, Victoza) Uses:

• Chronic weight management (Saxenda):

  • It is used as an adjunct therapy to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with a BMI of more than 30 kg/m (obese) or more than 27 kg/m² (overweight) in the presence of at least one weight-related comorbid condition (eg, hypertension, type 2 diabetes mellitus, dyslipidemia).

• Diabetes mellitus, type 2 (Victoza):

  • It can be used as an adjunct to diet and exercise to improve glycemic control in children of more than 10 years of age, adolescents, and adults with type 2 diabetes mellitus.
  • The risk reduction of major cardiovascular events like cardiovascular death, nonfatal myocardial infarction, and non-fatal stroke, in adults with type 2 diabetes mellitus and established cardiovascular disease.

Liraglutide (Saxenda, Victoza) Dose in Adults:

It is noteworthy that its usage in conjunction with a dipeptidyl peptidase-4 (DPP4) inhibitor like sitagliptin should be avoided due to the absence of additive glycemic benefit.

Liraglutide (Saxenda, Victoza) Dose in the treatment of type 2 Diabetes mellitus:

For some patients, particularly those who fail initial therapy with lifestyle changes and metformin or who are unable to take metformin, it may be used as an adjuvant drug or as an alternative to metformin monotherapy.

In patients with atherosclerotic cardiovascular disease or in people whose HbA1c levels are much over the target range (i.e., when their HbA1c is >9% and type 1 diabetes is not anticipated), liraglutide may be recommended as an extra anti-diabetic medication or alternative first-line medication.
 

• SubQ: Initially administered as 0.6 mg once daily for 1 week, then increase to 1.2 mg once daily.
• If the optimal glycemic response is not achieved after an additional week of treatment, it can be increased further to 1.8 mg once a day.
• It is important to highlight that the goal of the lower first dose (0.6 mg per day) is to lessen GI problems. However, it does not offer reliable glycemic control.

• Concomitant use with insulin and/or insulin secretagogues (eg, sulfonylurea):

  • Insulin and other secretagogues' dose reduction is required if used concomitantly.

Liraglutide (Saxenda, Victoza) Dose in the treatment of Obesity and select overweight patients:

For use in obese or overweight individuals with more than one weight-related comorbidity as a supplement to diet and exercise (eg, hypertension, dyslipidemia).

First, think about a preferred pharmacologic weight-loss strategy for type 2 diabetes mellitus patients who are obese and overweight, especially for those who have atherosclerotic cardiovascular disease.

• SubQ: Initially administered as 0.6 mg once daily for a week, and then upped to a target dosage of 3 mg once daily by adding 0.6 mg daily at weekly intervals.
• Consider postponing dosage titration for an extra week if the patient is unable to accept an enhanced dose during dose escalation.
• The company claims that at dosages greater than 3 mg/day, effectiveness has not yet been shown.
• Few doctors would, however, keep a patient on the highest tolerable dose (even if it is just 3 mg/day) if the dose results in the desired weight reduction.

Note: Change in body weight should be evaluated after 12 weeks at the maximum tolerated dose or 16 weeks after initiation of therapy. Stop the drug if at least 4% to 5% of baseline body weight loss has not been achieved.

• Missed doses:

  • The once-daily regimen can be restarted with the following planned dose in the case of a missed dose.

  • It is not advised to attempt an additional dosage or to raise the subsequent dose. If it has been more than 3 days since the last liraglutide dosage, start the medication again at 0.6 mg/day to prevent GI symptoms and titrate using clinical judgment while taking prior GI tolerability into account.

Liraglutide (Saxenda, Victoza) Dose in Children:

Liraglutide Dose in the treatment of Diabetes mellitus, type 2; adjunct to diet and exercise:

• Children ≥10 years and Adolescents: Victoza:

  • SubQ: For at least a week, it is first administered as 0.6 mg once day.
  • To establish glycemic control, it can be raised in 0.6 mg/day steps at weekly intervals. (week 2: increase to 1.2 mg once daily; week 3: increase to 1.8 mg once daily).
  • The daily dosage cap is set at 1.8 mg.
  • Missed doses:
    • Therapy should be restarted at the starting dose (0.6 mg/day) and re-titrated if more than 3 days of treatment are missed in order to prevent GI problems.

Liraglutide (Saxenda, Victoza) Dose in the treatment of Obesity; adjunct to strict lifestyle interventions:

• Children ≥12 years and Adolescents ≤17 years:

  • SubQ: At first, 0.6 mg once per day.

  • Then, up until the goal dose of 3 mg once per day, increase in weekly intervals by 0.6 mg/day increments.

• Adolescents ≥18 years: Saxenda:

  • SubQ:
    • It is first administered as 0.6 mg once daily for a week, and then the dose is increased at weekly intervals by 0.6 mg/day increments until the goal dose of 3 mg once daily is reached.
    • Consider postponing dosage escalation for an extra week if the patient is unable to tolerate an enhanced dose.
    • As its usage effectiveness has not been proven at lower levels, withhold the medication if the 3 mg daily dose is not tolerated.
    • Evaluate your body weight 16 weeks into therapy. Stop therapy if the patient has not lost more than 4% of their initial body weight since liraglutide is unlikely to produce significant and long-lasting benefits.
  • Missed doses:
    • To prevent GI problems, medication should be restarted at the starting dose (0.6 mg/day) if more than 3 days of treatment are missed.

Liraglutide (Saxenda, Victoza) Pregnancy Category: C

• Pregnant women should not use liraglutide to manage chronic weight because of the potential harm to their fetus and the lack of benefit.
• Obesity is associated with a higher risk of adverse maternal or fetal outcomes. 
• Pregnancy and conception are not the best times to take weight loss medication.
• Poor glycemic control in pregnancy can lead to adverse maternal and fetal outcomes including preeclampsia and preterm birth, preterm delivery, complications, and major birth defects.
• Preventing adverse outcomes by keeping maternal blood glucose and HbA1c as close to the target levels as possible before conception and throughout pregnancy.
• However, it is important to avoid significant hypoglycemia.
• Agents other than liraglutide in pregnant women are preferred.

Use of Liraglutide during breastfeeding

• It is not yet known if breast milk contains it.
• When prescribing liraglutide, a doctor should weigh the clinical benefits against the risk to lactating mothers.

Dose in Kidney Disease:

No dosage adjustment is required in kidney disease but caution is advised with severe renal impairment.

Dose in Liver disease:

it should be prescribed cautiously in patients with liver disease as study data is not sufficient.

Obesity:

Common Side Effects of Liraglutide (Saxenda, Victoza):

• Cardiovascular:

  • Increased heart rate

• Endocrine & metabolic:

  • Hypoglycemia

• Central nervous system:

  • Headache

• Local:

  • Injection site reaction

• Gastrointestinal:

  • Nausea
  • Vomiting
  • Diarrhea
  • Constipation

Less Common Side Effects of Liraglutide (Saxenda, Victoza):

• Neuromuscular & skeletal:

  • Asthenia

• Cardiovascular:

  • Tachycardia

• Dermatologic:

  • Injection site pruritus
  • Rash at injection site

• Central nervous system:

  • Fatigue
  • Dizziness

• Endocrine & metabolic:

  • Altered hormone level

• Gastrointestinal:

  • Abdominal distension
  • Abdominal pain
  • Decreased appetite
  • Dyspepsia
  • Eructation
  • Gastroenteritis
  • Increased serum lipase
  • Flatulence
  • Gastroesophageal reflux disease
  • Upper abdominal pain
  • Viral gastroenteritis
  • Cholelithiasis
  • Xerostomia

• Immunologic:

  • Antibody development

• Genitourinary:

  • Urinary tract infection

• Local:

  • Erythema at injection site

Type 2 diabetes mellitus: Incidence reported with adult patients in monotherapy trials unless otherwise specified.

Common Side Effects of Liraglutide (Saxenda, Victoza):

• Respiratory:

  • Upper respiratory tract infection

• Central nervous system:

  • Headache

• Gastrointestinal:

  • Gastrointestinal disease
  • Nausea
  • Diarrhea

• Endocrine & metabolic:

  • Hypoglycemia

• Infection:

  • Infection

Less Common Side Effects of Liraglutide (Saxenda, Victoza):

• Dermatologic:

  • Rash at the injection site

• Gastrointestinal:

  • Cholecystitis
  • Increased amylase
  • Decreased appetite
  • Dyspepsia
  • Constipation
  • Vomiting
  • Increased serum lipase
  • Cholelithiasis

• Hepatic:

  • Hyperbilirubinemia

• Local:

  • Injection site reaction
  • Erythema at the injection site

• Immunologic:

  • Antibody development

• Neuromuscular & skeletal:

  • Back pain

• Respiratory:

  • Nasopharyngitis

Contraindications to Liraglutide (Saxenda, Victoza):

• An absolute contraindication is any prior serious hypersensitivity to liraglutide, or any component of its formulation.
• MTC family history or history
• Multiple endocrine disorders neoplasia patients 2 (MEN2)
• Pregnancy (Saxenda).

Canadian labeling includes additional contraindications that aren't present in US labeling

• Pregnancy (Saxenda and Victoza).
• Breastfeeding

Warnings and precautions

• Formation of antibodies:

  • Its use could be linked to the creation of anti-liraglutide antibody.
  • However, antibody formation was not associated to a decrease in efficacy. 
  • Patients with high titers anti-liraglutide antibody levels had the greatest HbA1c reductions.

• Cardiovascular effects

  • Monitoring is necessary periodically to ensure that the resting heart rate does not increase.
  • Patients who experience an increase in their resting heart rate should be withheld.

• Gallbladder disease

  • GLP-1 agonists can increase the risk of gallbladder or bile duct diseases.
  • Patients treated with liraglutide have had cholecystitis and cholelithiasis, with most patients needing hospitalization or cholecystectomy.

• GI symptoms

  • The GI system is the most common cause of reactions.
  • These symptoms can be dose-related. They may decrease in severity and frequency with continued use and gradual titration.
  • If volume depletion occurs (eg, because of nausea, vomiting, diarrhea), you should stop using it

• Hypersensitivity reactions

  • It has been associated with serious hypersensitivity reactions such as anaphylactic reactions or angioedema. In the event of hypersensitivity reactions, discontinue use.
  • Patients with an allergy or history of angioedema to GLP-1 receptor agonists should be cautious.
  • Cross-sensitivity is possible but not guaranteed.

• Pancreatitis

  • Trials have shown cases of acute and chronic pancreatitis, including fatal and non-fatal hemorhagic and necrotizing pancreatitis.
  • You should be aware of signs and symptoms such as persistent abdominal pain that radiates to the back or is accompanied by vomiting.
  • If you suspect pancreatitis, stop taking the drug.
  • If you are not sure, do not restart the pancreas unless another cause is identified.
  • There is no evidence to suggest that patients who have had pancreatitis before may be at increased risk of developing it.

• Psychiatric effects

  • Patients treated for obesity have reported suicidal behavior and one attempt at suicide.
  • Monitor for depression and suicidal thoughts, behavior, or unusual mood changes.
  • If suicidal thoughts or behavior occur, stop using it.
  • Patients with active suicidal thoughts or a history of suicide attempts should not be given this medication.

• Effects on the renal system:

  • There have been reports of acute renal failure and chronic kidney failure exacerbation, as well as severe cases that required hemodialysis. 
  • The majority of incidents have not affected patients who do not already have a renal illness.
  • The most probable patients to have reported these occurrences were those who had nausea, vomiting, or diarrhea.
  • Renal impairment can be treated well and even reversed.
  • Patients who concurrently use drugs that alter hydration or renal function may be at higher risk.

• Thyroid tumors: [US Boxed Warning]

  • In animal studies, thyroid C cell tumors that are dose-dependent or treatment duration-dependent have been identified in thyroid C cells.
  • However, it is not known if liraglutide can cause thyroid C-cell cancers in humans. The human relevance of rodent thyroid C–cell tumors has not yet been established.
  • Patients should be told that taking liraglutide may increase their chance of developing MTC.
  • It is advised against using this drug in those who have a history of multiple endocrine neoplasia type 2 (MEN2) or MTC.
  • Liraglutide-treated individuals have experienced a relatively small number of MTC instances.
  • Patients should see a specialist if they have thyroid nodules or increased calcitonin levels that were found on scans or during physical examinations.
  • Liraglutide patients shouldn't be frequently observed or have thyroid ultrasound surveillance performed to look for MTC early symptoms.

• Bariatric surgery

  • Dehydration

    • Before starting treatment with liraglutide, it is important to properly assess and hydrate the patient. An exacerbation of acute or chronic kidney disease may occur.
    • Most cases were experienced by patients suffering from nausea, vomiting, diarrhea, or dehydration. Patients with nausea are common. Fluid intake may be more difficult following gastric bypass, gastric band, or sleeve gastrectomy.

  • Excessive glucagon-like peptide-1:

    • If therapy is started after surgery, closely monitor the effectiveness of the treatment and look out for signs and symptoms such as pancreatitis.
    • Endogenous postprandial glucagon-like peptide-1 (GLP-1) concentrations are significantly increased by gastric bypass and sleeve gastrectomy (but excluding the gastric band).
    • Exogenous GLP-1 agonists can be used in lieu of surgery.

• Gastroparesis

  • It slows down gastric motility.

• Hepatic impairment

  • Patients with hepatic impairment should exercise caution.

• Renal impairment

  • RFTs should always be evaluated during dose titration and initiation.

Liraglutide: Drug Interaction

Monitoring parameters:

• Plasma glucose and HbA1c levels should be tested at least twice a year in patients whose glycemic control is stable and who are achieving their treatment objectives.
• Patients who are not completing their treatment objectives or undergoing modifications in therapy should have it done every three months.
• Renal functions
• Signs and symptoms of pancreatitis.
• Triglycerides.
• Gallbladder disease symptoms and signs
• The appearance of depression or suicidal thoughts, behavior, or behavior changes.
• Heart rate
• If you are using chronic weight management, your bodyweight is at week 16.

How to administer Liraglutide (Saxenda, Victoza)?

SubQ:

• Subcutaneously inject beneath the arm, the thigh, or the belly.
• You shouldn't administer intramuscular or intravenous injections.
• Do not eat or use any other time during the day. 
• For each administration, change the needle.
• Only use clear, uncolored, and non-particulate matter pens. 
• Even if you change the needle, do not share pens among patients.

• Use insulin simultaneously. Never mix.

• It can be injected in the same location as insulin, but not simultaneously.

Mechanism of action of Liraglutide (Saxenda, Victoza):

• Liraglutide, a long-acting analog to human glucagonlike peptide-1, (GLP-1), is an incretinhormone that increases glucose-dependent insulin, decreases inappropriate, glucagon, increases B-cell proliferation, slows down gastric emptying, and reduces food intake.
• The hemoglobin A1c level drops by about 1% when Liraglutide is administered.

Notification: The pharmacokinetic data for type 2 diabetes mellitus children (ages 10-17 years) are similar to that of adult patients.

Protein binding:

• More than 98%

Metabolism:

• Endogenously metabolized with dipeptidyl Peptase IV, (DPP-IV), and endogenous endopeptidases.
• The metabolism is slower than native GLP-1

Bioavailability:

• SubQ: 55%

Elimination, half-life:

• 13 hours

Plasma peak time:

• SubQ: 8-12 hours

Excretion:

• Urine (6% as metabolites).
• Via feces (5% as metabolites).

International Brand Names of Liraglutide:

• Saxenda
• Victoza

Liraglutide Brand Names in Pakistan:

Victoza 1.2 mg, 1.8 mg: NovoNordisk