Liraglutide

Liraglutide is an Anti-diabetic Agent belonging to the pharmacological class of long-acting Glucagon-like peptide-1 receptor agonists (GLP-1 RA).

Liraglutide is approved to treat several medical conditions. It is primarily indicated for managing type 2 diabetes to improve blood sugar control. Additionally, it is used for chronic weight management in adults with obesity or those who are overweight and have at least one weight-related condition, like hypertension or high cholesterol.

When administered subcutaneously, it is primarily dispersed in adipose tissue before entering the circulation after absorption. Metabolic activity is controlled by endogenous enzyme degradation. Liraglutide is primarily excreted, broken down in the kidneys, and eliminated through urine.

Liraglutide's most common side effects are indigestion, constipation, gastrointestinal distress, nausea, vomiting, and diarrhoea. When used with other diabetic medications like sulphonylureas or insulin, it can also result in low blood sugar (hypoglycemia).

Liraglutide is available in the form of injectable solutions.

The molecule is available in the United States, Canada, the United Kingdom, France, Japan, Germany and Australia.

Liraglutide is an Anti-diabetic Agent belonging to the pharmacological class of long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RA)

Liraglutide has a 97% amino acid sequence similarity to natural human GLP-1(7-37). About 20% of the total circulating endogenous GLP-1 is GLP-1(7-37). Like GLP-1(7-37), Liraglutide stimulates the GLP-1 receptor, a membrane-bound cell-surface receptor connected to adenylyl cyclase via the stimulating G-protein, Gs, in pancreatic beta cells. Liraglutide raises intracellular cyclic AMP (cAMP) in increased glucose concentrations, which causes insulin release. This insulin release slows as blood glucose levels drop and become closer to euglycemia. Additionally, Liraglutide reduces glucagon production in a glucose-dependent way. A delay in stomach emptying is also a component of the blood-glucose-lowering process.

Neutral endopeptidases (NEP) and Dipeptidyl peptidase IV (DPP-IV) , two widely distributed endogenous enzymes, break down GLP-1(7-37), yielding it a half-life of 1.5–2 minutes. Liraglutide has a plasma half-life of 13 hours after subcutaneous dose, and unlike natural GLP-1, it is very stable against metabolic degradation by both peptidases. Liraglutide's pharmacokinetic profile qualifies it for once-daily dosing results from plasma protein binding, self-association that slows absorption, and stability against metabolic breakdown by DPP-IV and NEP.

Data duration of Liraglutide action typically lasts up to 24 hours after a single subcutaneous injection.

The Data of Tmax of Liraglutide approximately 9-15 hours post-injection.

The Data of Cmax of Liraglutide approximately 26-30 hours after subcutaneous injection.

Injectable solutions: To be administered parenterally, as applicable.

A prefilled multi-dose pen is used to dispense Liraglutide. Begin by visually checking for any flecks or discolouration. Clean the injection site on the upper arm, thigh, or belly. Subcutaneous injection, with the needle attached and the dosage adjusted. Hold for a short while before taking out the needle. Store the pen correctly and rotate the injection sites. Safely dispose of used needles.

• Liraglutide helps control blood sugar levels in adults with type 2 diabetes.
• It is used as an adjunct to a reduced-calorie diet and increased physical activity for weight management in those adults with obesity.
• Liraglutide has decreased the risk of major cardiovascular events in adult patients with type 2 diabetes and established cardiovascular disease.

In Treatment of Type 2 diabetes mellitus

Liraglutide helps lower the body's blood sugar levels, encourages weight reduction, and reduces the risk of cardiovascular events. Also, it maintains intact pancreatic beta-cell activity, which is crucial for insulin generation. It can aid those with type 2 diabetes to adequately manage their illness by enhancing blood sugar management throughout the day.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of any of the severe complications of diabetes, including kidney damage, eye damage, nerve problems, 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.

• It is indicated as an adjunct to exercise and diet in those people with type 2 diabetes who are at least ten years old to enhance glycemic control.
• To lower the risk of severe adverse cardiovascular events (cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke) in those individuals with type 2 diabetes mellitus and established cardiovascular disease
• Adjunctive treatment, in combination with a low-calorie diet and increased physical exercise, is used to treat chronic obesity in adolescents aged 12 or older who weigh more than 60 kg and have a body mass index (BMI) that, according to international cutoffs, is over the threshold for adult obesity (30 kg/m2).

Limitations of Use:

• Not used in the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

• It has not been studied in combination with prandial insulin.

Parenterally: Liraglutide is available as an injection solution that can be administered parenterally. Liraglutide should be administered subcutaneously in the upper arm, thigh, or belly. To avoid irritation, rotate the injection location. Regardless of mealtimes, it can be taken once a day at any time. Never provide an intravenous or intramuscular injection. The dosage is unaffected by changes to the injection location or timing. Always check each dosage visually; only use the solution if it is still evident, colourless, and particle-free.

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

Injection solutions (multidose pen):

18mg/3mL (Victoza): It delivers doses of 0.6mg, 1.2mg, or 1.8mg

18mg/3mL (Saxenda); delivers doses of 0.6mg, 1.2mg, 1.8mg, 2.4mg, or 3mg

Liraglutide is available in the form of injection solutions.

Dose Adjustment in Adult Patients:

Diabetes Mellitus Type 2

Victoza only

0.6 mg SC, every day for the first week, then increase to 1.2 mg per day

If glycemic control is not established, the dose can be increased to 1.8 mg per day.

The initial dose of 0.6 mg SC qDay reduces GI side effects and does not affect glucose control.

Obesity

Saxenda only

Start with 0.6 mg SC qDay for the first week, then increase by 0.6 mg/day weekly until you reach 3 mg/day.

Consider postponing dosage escalation for one more week if patients cannot tolerate an increasing dose while on it.

If a patient cannot handle the 3-mg dose, stop using it since efficacy at lower doses (e.g., 0.6, 1.2, 1.8, 2.4 mg) has not been shown.

Sixteen weeks after initiating Saxenda, assess any weight changes.

Only use Saxenda if the patient gains at least 4% of their initial weight.

Dosing Considerations

Saxenda delays stomach emptying; it has not been examined in individuals with gastroparesis before taking it.

Limitations of use for Victoza

Not for managing type 1 diabetes or diabetic ketoacidosis (ineffective for these circumstances).

Combining prandial insulin has yet to be investigated.

Limitations of use for Saxenda

In the treatment of type 2 diabetes mellitus, it is not recommended.

Liraglutide is included in both Saxenda and Victoza. Hence, both medications shouldn't be combined with another GLP-1 receptor agonist.

It has yet to be shown if some weight loss items, such as prescription medications, over-the-counter medicines, and herbal remedies, are safe and effective when combined.

Liraglutide should be used in treating Type 2 Diabetes Mellitus, along with appropriate nutritional limits.

While taking Liraglutide, avoid large meals and maintain regular meals with balanced macronutrient content to help stabilize blood sugar levels.

Limit or avoid the intake of alcohol as it can interfere with blood sugar regulation.

Avoid high-calorie, high-fat meals as they may increase the risk of gastrointestinal side effects.

It is advised to stay hydrated, maintain a rich, balanced diet with appropriate carbohydrate intake, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.

Liraglutide may be contraindicated in the following conditions:-

• Hypersensitivity reaction to Liraglutide or any of its excipients,
• Medullary thyroid cancer (MTC) in the individual or the family
• Type 2 Multiple Endocrine Neoplasia (MEN-2)
• Only Saxenda: Pregnancy

• Even if the needle changes, prefilled liraglutide pens should never be shared between patients. Sharing needles or syringes is not permitted for patients using liraglutide vials. Transmitting blood-borne infections by sharing is unsafe.
• It has been reported that people with a history of pancreatitis can develop acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis. However, it is uncertain if these patients are more likely to develop pancreatitis in the future.
• Gallbladder investigations and the proper clinical follow-up are recommended if cholelithiasis is suspected. Acute occurrences of gallbladder illness, such as cholelithiasis or cholecystitis, have been described in GLP-1 receptor agonist trials and post-marketing.
• If serum calcitonin is elevated, further evaluate the patient. Patients with thyroid nodules shown on physical examination or neck imaging should also be assessed further. It may cause thyroid C-cell tumours (adenomas and/or carcinomas) at a clinically relevant exposures in both sexes of rats and mice.
• A renal impairment is linked to vomiting, diarrhoea, or dehydration and may occasionally call for hemodialysis. Use caution while starting or increasing dosages in these individuals; impaired renal function has been resolved in many recorded cases with supportive therapy and withdrawal of potentially causing drugs.
• Hypersensitivity: Post-marketing reports of severe hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue Liraglutide and promptly seek medical advice.

It is unsafe to consume Liraglutide with alcohol.

There is no sufficient scientific evidence traceable regarding the use and safety of Liraglutide in breastfeeding.

Safe to use during pregnancy only if the possible benefit outweighs the potential risk to the foetus. Use caution.

Limit Alcohol and avoid fatty or high-calorie meals.

The adverse reactions related to Liraglutide can be categorized as:

• Common Adverse Effects: Nausea, diarrhoea, vomiting, constipation, headache and abdominal pain.
• Less Common Adverse Effects: Hypoglycemia (when used with insulin or sulfonylurea), dizziness, or headache.
• Rare Adverse Effects: Hypersensitivity, sometimes severe (e.g., severe urticaria, systemic rash, facial oedema, lip swelling), pancreatitis, kidney problems, or thyroid cancer.

Reports on Post-marketing

Vomiting, nausea, and diarrhoea-related dehydration

An increased blood creatinine level, acute renal failure, and increasing chronic renal failure that may occasionally need hemodialysis

Anaphylactic and angiopathic responses to allergens

Rash, itching, and other allergic symptoms

Acute pancreatitis, such as necrotizing or hemorrhagic pancreatitis, may be lethal.

A breast cancer

Colorectal tumours

Cutaneous amyloidosis is a condition of the skin and subcutaneous tissues.

Hyperbilirubinemia, elevated liver enzymes, cholestasis, hepatitis, cholecystitis, and cholelithiasis necessitating cholecystectomy are signs of hepatobiliary diseases.

Ileus

The clinically relevant drug interactions of Liraglutide are briefly summarized here.

• Warfarin: Liraglutide may increase the risk of bleeding when used with anticoagulants like warfarin. Frequent monitoring of INR (International Normalized Ratio) is essential.
• Insulin and Sulfonylureas: Combining Liraglutide with insulin or sulfonylureas may increase the risk of hypoglycemia (low blood sugar). Adjustments in insulin or sulfonylurea doses may be necessary.
• Orlistat: Liraglutide may affect the absorption of fat-soluble vitamins. Patients using orlistat, a weight loss medication, should take vitamin supplements separately.
• Thyroid Hormones: Liraglutide may affect the absorption of oral thyroid hormones. Monitoring thyroid function is essential if these medications are used together.
• Dulaglutide and Exenatide: Combining Liraglutide with other GLP-1 receptor agonists may increase the risk of adverse effects. The combination should be used with caution.
• Digoxin: Liraglutide can affect the absorption of digoxin, a heart medication. Monitor digoxin levels and adjust the dose as needed.

The most common side effects of Liraglutide include:

• Constipation
• A decreased appetite
• Diarrhoea
• Nausea
• Vomiting
• Pain in the stomach
• Dyspepsia
• Flatulence
• Nasopharyngitis, or throat and nasal passage inflammation

• Pregnancy

Victoza

Pregnancy Category C. Use with caution if the benefits outweigh the risks.

According to research on animal reproduction, exposure during pregnancy may pose dangers to the foetus. There are no adequate and well-controlled studies of Victoza in pregnant women.

Use only if the possible benefit outweighs the potential harm to the foetus when pregnant.

Animal data

Studies on animal reproduction found that exposure during pregnancy led to more unfavourable developmental outcomes.

In pregnant rats given Liraglutide during organogenesis at doses that resemble clinical exposures at the maximum advised human dosage (MRHD) of 1.8 mg/day, liraglutide exposure was linked to early embryonic mortality and an imbalance in several foetal malformations.

Liraglutide was administered to pregnant rabbits throughout organogenesis, and at doses below human exposure levels at the MRHD, lower foetal weight and an increased incidence of foetal severe malformations were seen.

Saxenda

Pregnancy Category X;

Losing weight is not advised during pregnancy as it might damage the foetus and has no possible benefits for the pregnant mother.

No data is available on pregnant women to indicate a drug's risk for severe birth abnormalities and miscarriage.

Treatment should be stopped if the patient wants or becomes pregnant.

Due to the essential weight growth in maternal tissues during pregnancy, a minimum weight gain is advised for all pregnant women, including those already overweight or obese.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly managed diabetes during pregnancy raises the risk of diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm birth, and delivery complications for the mother.

Poorly managed diabetes increases the chance of significant birth abnormalities, stillbirths, and macrosomia-related morbidity in foetuses.

• Nursing mothers:

There are no data on the presence of Liraglutide in human milk, the effects on breastfed infants, or the impact on milk production. Liraglutide was found in the milk of nursing rats.

In addition to the mother's clinical requirement for Liraglutide and any possible adverse effects on the breastfed newborn from Liraglutide or the underlying maternal disease, it is essential to consider the developmental and health advantages of breastfeeding.

Data

In lactating rats, Liraglutide was present unchanged in milk at approximately 50% of maternal plasma concentrations.

• Pediatric Use

Liraglutide is safe and effective in paediatric patients ten years of age and older, using adjunct diet and exercise to enhance glycemic control in type 2 diabetes mellitus. Studies conducted in adult patients with type 2 diabetes mellitus, a paediatric pharmacokinetic analysis, and a 26-week placebo-controlled clinical trial in 134 paediatric patients aged 10-17 with type 2 diabetes mellitus all support using Liraglutide for this indication. Regardless of whether insulin or metformin was used, the risk of hypoglycemia with Liraglutide increased in paediatric patients.

Paediatric children under ten have not yet been subjected to Liraglutide safety and efficacy studies.

Dose Adjustment in Pediatric Patients:

Type 2 Diabetes Mellitus

Victoza only

<10 years: Safety and efficacy not studied

≥10 years 6.8 mg SC per day

If extra glycemic control is needed after at least a week at 0.6 mg/qDay, the dosage may be increased to 1.2 mg/day.

After at least a week from the 1.2 mg qDay dose, the dosage may be increased to 1.8 mg qDay if extra glycemic control is necessary.

Obesity

Saxenda only

Start with 0.6 mg SC qDay for one week, then gradually increase by 0.6 mg/day until you reach 3 mg/day.

The recommended maintenance dose is 3 mg/day; if this is not tolerated, it may be reduced to 2.4 mg/day; if 2.4 mg is not accepted, cease use.

Paediatric patients' dose escalation may take up to 8 weeks if they cannot tolerate the increasing dose during the dose escalation process.

BMI should be assessed 12 weeks after starting a maintenance dosage.

If the patient's BMI has stayed the same by at least 1% from baseline, discontinue Saxenda since it is uncertain that further therapy would result in clinically significant weight reduction for the patient.

Dosing Considerations

Saxenda delays stomach emptying; it has not been examined in individuals with gastroparesis before taking it.

Victoza restrictions on usage

Not for managing type 1 diabetes or diabetic ketoacidosis (ineffective for these circumstances).

It has not been investigated when combined with postprandial insulin

• Geriatric Use

In the glycemic control studies' VICTOZA treatment groups, a total of 832 (19.3%) patients were 65 to 74 years old, and 145 (3.4%) were 75 years of age or older [see Clinical Studies (14.1)]. At baseline, there were a total of 1738 (37.2%) patients in the VICTOZA treatment arm of the LEADER study [see Clinical Studies (14.3)], 401 (8.6%) patients in the age range of 75 to 84, and 17 (0.4%) patients in the 85+ age range.

Between the patients 65 years of age and older and younger patients, no variations in VICTOZA's general safety or efficacy have been found.

Dose Adjustment in Kidney Impairment Patients:

Victoza

Mild to severe: No dosage adjustment is necessary

Patients with end-stage renal disease (ESRD): Limited experience; post-marketing reports of acute renal failure and worsening of the chronic renal failure, which may occasionally require hemodialysis; use cautiously in patients who develop dehydration.

Saxenda

Patients with end-stage renal disease (ESRD), as well as mild to severe: Limited knowledge

Liraglutide has been linked to post-marketing reports of acute renal failure and worsening chronic renal failure, which may occasionally need hemodialysis in these individuals.

Dose Adjustment in Hepatic Impairment Patients:

Mild to severe: Exercise cautious; limited knowledge

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Liraglutide.

Overconsumption of Liraglutide may include non-severe hypoglycemia and mild to moderate gastrointestinal events (e.g., nausea and vomiting).

Management

There is no specific antidote or treatment for excessive intake of Liraglutide. However, immediate medical attention is essential. Liraglutide should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

Management typically involves supportive measures like intravenous fluids, fluid replacement to prevent dehydration, and symptomatic treatment such as antiemetic medications for nausea and vomiting.

If hypoglycemia (low blood sugar) occurs, appropriate measures should be taken to raise blood glucose levels, such as administering glucose or high-sugar foods and beverages.

Hospitalization and intravenous (IV) glucose administration may be required in severe cases.

Maintain a healthy lifestyle through proper nutritional diet, regular physical activity, and stress management. These factors can help improve blood sugar control and reduce the risk of hypoglycemia.

Pharmacodynamics:

A once-daily GLP-1 derivative called Liraglutide is used to treat type 2 diabetes. Liraglutide functions over a more extended period of time by attaching a fatty acid molecule to the GLP-1 molecule at position 26. This allows it to reversibly bind to albumin in subcutaneous tissue and the circulation and release it gradually over time. Compared to GLP-1, binding with albumin causes Liraglutide to degrade more slowly and be removed from the bloodstream by the kidneys. Liraglutide has the effect of causing an increase in insulin secretion and a reduction in glucagon production in response to glucose, as well as a delayed rate of stomach emptying. Liraglutide does not negatively impact glucagon secretion in response to low blood sugar.

Pharmacokinetics:

Absorption

Maximum liraglutide concentrations are attained 8 to 12 hours after subcutaneous injection. For a subcutaneous single dosage of 0.6 mg of Liraglutide, the mean peak (Cmax) and total (AUC) exposures were 35 ng/mL and 960 ng/mL, respectively. Liraglutide's Cmax and AUC rose proportionately across the therapeutic dosage range of 0.6 mg to 1.8 mg after subcutaneous single-dose administrations. The average steady-state concentration of Liraglutide over 24 hours at 1.8 mg was around 128 ng/mL. AUC0 was the same between the upper arm, thigh, upper arm, and abdomen. AUC0- from the thigh was 22% lower than that from the abdomen. However, liraglutide doses at these three subcutaneous injection locations were thought to be equivalent. Following subcutaneous injection, Liraglutide has about 55% absolute bioavailability.

Peak plasma time: 11 hr (Saxenda)

Peak plasma concentration: 35 ng/mL (Victoza)

AUC: 960 ng·hr/mL (Victoza)

Average steady-state concentration over 24 hr: 128 ng/mL (at 1.8 mg dose)

Absolute bioavailability: 55%

Distribution

Following the subcutaneous dose of Liraglutide 0.6 mg, the mean apparent volume of distribution is about 13 L. Liraglutide is administered intravenously, and the typical volume of distribution is 0.07 L/kg. Over 98% of Liraglutide is effectively linked to plasma protein.

Protein-bound: Less than 98%

Vd: 13 L (Victoza); 20 to 25 L (Saxenda); 0.07 L/kg (IV)

Metabolism

Liraglutide is metabolised by neutral endopeptidase and dipeptidyl peptidase-4 more slowly than endogenous GLP-1 to various smaller polypeptides, not all structurally characterised. Liraglutide may break down into carbon dioxide and water in one body area.

They are endogenously metabolized to large proteins without a specific organ route.

Elimination

Liraglutide has an elimination half-life of around 13 hours and a mean apparent clearance of 1.2 L/h after subcutaneous administration of a single dosage.

Half-life: 13 hr

Mean apparent clearance: 1.2 L/hr (Victoza); 0.9 to 1.4 L/hr (Saxenda)

Excretion (metabolites): 5% feces, 6% urine

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