Liraglutide

Mechanism of Action

Liraglutide is a human glucagon-like peptide-1 receptor agonist (GLP-1 RA) with 97% amino acid sequence homology to endogenous GLP-1. Liraglutide binds to GLP-1 receptors in the pancreatic β-cells, increasing intracellular cyclic AMP (cAMP) and triggering endogenous insulin release.[7] Insulin reduces blood glucose levels to reach euglycemia. GLP-1 receptor binding also leads to appetite suppression and decreased caloric intake.[3] In addition to enhancing insulin secretion, acute liraglutide treatment has been shown to suppress glucagon secretion and promote β-cell proliferation.[8][9] No elevations in insulin secretion or glucagon secretion suppression have been observed at normal or low glucose concentrations in patients receiving liraglutide therapy. 

GLP-1 receptors are found in several brain areas associated with appetite regulation, and endogenous GLP-1 regulates appetite and caloric intake.[1] Liraglutide has been shown to exert anorexigenic effects by increasing free leptin levels, thus reducing appetite.[10] Although the precise mechanism remains unclear, studies have demonstrated that liraglutide modulates brain activity in several regions.[11] The drug's unique amino acid sequence confers resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and neutral endopeptidase (NEP), prolonging its pharmacological activity.

Pharmacokinetics

Absorption: Liraglutide is absorbed into the bloodstream after subcutaneous injection. Peak concentration is achieved between 8 and 12 hours. The absolute bioavailability of liraglutide injection is 55%, and its maximum concentration increases proportionally with dose. There is no significant difference in absorption between an injection in the upper arm and abdomen. However, injection in the thigh may cause a 22% reduction in absorption.

Distribution: Liraglutide is almost entirely bound to plasma proteins (>98%). The approximate volume of distribution after a subcutaneous injection of 0.6 mg is 13 L. After intravenous administration, the mean volume of distribution is 0.07 L/kg.

Metabolism: Liraglutide is not metabolized by a specific organ; plasma protein degradation pathways endogenously metabolize it. The plasma half-life of liraglutide is 13 hours after injection.[12]

Elimination: Liraglutide is excreted through urine and feces. Studies have shown no trace of intact liraglutide in urine or feces. Partially-degraded liraglutide was found in urine and feces at 6% and 5%, respectively.[13]

Administration

Available Dosage Forms and Strengths

Liraglutide is available in a prefilled pen containing 3 mL of a clear and colorless 6 mg/mL solution. This solution may be injected subcutaneously into the abdomen, thigh, or upper arm. Solutions containing 1.2 mg, 1.8 mg, and 3 mg are also available, though the injection dose may vary based on indication and age.

Adult Dosage

For glycemic control: The recommended adult dose for glycemic control is 1.2 mg daily. Patients should start with an initial dose of 0.6 mg daily for the first week and increase to 1.2 mg daily at the beginning of week 2. Increasing the dose to 1.8 mg daily may be necessary if glucose levels remain uncontrolled. An outline of dosing for glycemic control is as follows:

• Week 1: 0.6 mg daily
• Week 2: 1.2 mg daily (if necessary)
• Week 3: 1.8 mg daily (if necessary)

For weight loss: The recommended adult dose is 3 mg daily. Patients should start with an initial dose of 0.6 mg daily for the first week and increase the dose by 0.6 mg every week until the target dose of 3 mg is achieved. An outline of the dosing schedule for weight loss is as follows:

• Week 1: 0.6 mg daily
• Week 2: 1.2 mg daily
• Week 3: 1.8 mg daily
• Week 4: 2.4 mg daily
• Week 5+: 3 mg daily

If a dose is missed, another should not be administered immediately. Patients should wait for the next scheduled injection and continue with regular dosing. If more than 3 days of injections have been missed, patients should reinitiate treatment at 0.6 mg daily and follow the original titration information used when therapy was initiated.

Specific Patient Populations

Patient with hepatic impairment: The safety and efficacy of liraglutide in patients with hepatic impairment have not been established. Patients should be closely monitored.

Patient with renal impairment: The safety and efficacy of liraglutide have not been established in patients with renal impairment. However, postmarketing surveillance has shown that acute renal failure and worsening of chronic renal failure have been reported in patients taking liraglutide. Patients with renal impairment should be closely monitored while taking liraglutide.

Pregnancy: Liraglutide (for glycemic control) should be used with caution during pregnancy. Animal studies have shown that liraglutide is associated with an increased risk of fetal death and fetal abnormalities.[14] However, poorly controlled diabetes increases the morbidity and mortality of both the mother and the fetus during pregnancy. Clinicians should administer liraglutide based on the patient's glycemic control. According to the American Diabetes Association, alternate medicines are preferred over liraglutide for patients who are pregnant.[15] Liraglutide should never be used for weight loss during pregnancy.

Breastfeeding: Liraglutide is safe for breastfeeding mothers. In clinical studies, liraglutide was not detected in human milk.[16] However, it was detected in the milk of rats at 50% of the maternal plasma concentration.

Pediatric patients: Liraglutide is safe for children aged 10 and older for glycemic control and children aged 12 and older for weight loss.[17] Pediatric patients should be administered liraglutide for glycemic control according to the same dosing schedule as adults. Adequate control may be established by administering 0.6 mg daily; these patients should be closely monitored. Pediatric dosing for weight loss is the same as adult dosing. If a dose increase is not tolerated, the patient should remain at the lower dose for another week and attempt to increase the following week. To increase the dose to 3 mg after consecutive weeks, a target dose of 2.4 mg daily is sufficient. Clinical trials showed that liraglutide increased the risk of hypoglycemia and resting heart rate by 3 to 7 beats per minute in pediatric patients. Liraglutide has not been studied in children younger than 10 years old.

Older patients: Liraglutide is safe for use in patients 65 and older. Clinical studies have shown that using liraglutide in these populations does not increase the risk of adverse effects or decrease the effectiveness of the drug.[12]

Adverse Effects

The most common adverse reactions associated with liraglutide administration include nausea, diarrhea, vomiting, decreased appetite, dyspepsia, and constipation. Immunogenic-related events have been reported in less than 0.8% of patients.

The most severe adverse effects include the following:

• Risk of C-cell tumors: Reports of patients developing medullary thyroid cancer (MTC) and C-cell tumors have been documented. Animal studies showed that liraglutide causes dose- and duration-dependent thyroid C-cell tumors in mice and rats of both sexes.[18] Patients with a personal or family history of MTC or C-cell tumors should avoid liraglutide.[1]
• Acute pancreatitis: Pancreatitis is a rare but severe adverse effect. Fewer than 0.4% of patients experience pancreatitis. If pancreatitis is suspected, patients should stop injections immediately, call their doctor, and seek emergency care.[1]
• Acute gallbladder disease: Cholelithiasis, or “gallstones,” is a rare but urgent side effect of liraglutide injection. This adverse effect was observed in 2.2% of patients. If symptoms of gallstone disease arise (eg, pain in the right upper quadrant after meals), patients should stop injections immediately, call their doctor, and seek emergency care.[1]
• Hypoglycemia: The risk of hypoglycemia is elevated in patients receiving liraglutide with other diabetic medications, including insulin or insulin secretagogues (eg, sulfonylureas). Symptoms of hypoglycemia include sweating, shaking, and dizziness.[1]
• Elevated heart rate: Liraglutide may increase the resting heart rate by 4 to 9 bpm. Reports of heart rates exceeding 100 bpm have been documented.[1]
• Renal impairment: Liraglutide may cause acute renal failure or exacerbate kidney decline in patients with chronic renal failure. Reports of patients’ renal function declining to the point of dialysis have been documented. Patients with a history of kidney disease should discuss the risks and benefits of starting liraglutide with their physician.[1]
• Hypersensitivity reactions: Anaphylaxis and angioedema have been reported during the use of liraglutide. If a patient experiences acute-onset breathing difficulties, hives, or swelling in the face or hands, they should immediately seek emergency medical care.[1]
• Suicidal behavior and ideation: Suicidal thoughts and behaviors were reported in 0.3% of patients during clinical studies. Liraglutide should not be administered to patients with a history of suicidal thoughts or behaviors, which may be exacerbated. Suicidal thoughts were increased in pediatric patients receiving liraglutide, amounting to 0.8% of the patients.[1]

Drug-Drug Interactions

• Absorption of oral medications may be affected due to delayed gastric emptying.
• Liraglutide has limited potential for interactions with drugs that utilize the cytochrome P450 system or plasma-binding proteins.
• Drugs administered concomitantly with liraglutide:
• Digoxin (1 mg): The area under the curve (AUC) was reduced by 16%, and the maximum concentration (Cmax) was reduced by 31%.
• Lisinopril (20 mg): The AUC was reduced by 15%, and the Cmax was reduced by 27%.
• Atorvastatin (40 mg): The AUC was unchanged, and the Cmax was reduced by 38%.
• Acetaminophen (1000 mg): The AUC was unchanged, and the Cmax was reduced by 31%.
• Griseofulvin (500 mg): The AUC was unchanged, and the Cmax was increased by 37%.
• Oral contraceptives (0.03 mg ethinylestradiol/0.15 mg levonorgestrel): The AUC was unchanged for ethinylestradiol and was increased by 18% for levonorgestrel; the Cmax was reduced for both drugs by approximately 12%.
• Insulin: No change in concentration has been observed. However, the hypoglycemic effects may be enhanced, so clinicians should consider reducing the dose of liraglutide.

Contraindications

Box Warnings

Liraglutide has been shown to cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in rats and mice of both sexes. It is unknown whether liraglutide causes thyroid C-cell tumors, including 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, or with a family history of, MTC or MEN2.

Warnings and Precautions

Liraglutide should not be combined with insulin as a mixture for injection.

Monitoring

The patient's thyroid function and symptoms are monitored closely. Thyroid abnormalities (eg, nodules, dysphagia, dyspnea, hoarseness, new neck masses) should be investigated immediately. Serum calcitonin levels or a neck ultrasound are performed in such cases. Clinicians should regularly assess plasma glucose levels, heart rate, renal function, changes in behavior, suicidal thoughts or behavior, worsening depression, triglycerides, signs and symptoms of pancreatitis, signs and symptoms of gallbladder disease, and body weight (if receiving liraglutide for chronic weight management). The patient's HbA1c levels should be obtained quarterly in patients whose treatment goals have not been met or with any change in medicines. HbA1c levels should be obtained at least twice a year in patients with stable glycemic control who are meeting treatment goals.

Toxicity

Severe nausea, vomiting, or hypoglycemia may indicate an overdose of liraglutide, which is treated with symptom management. There is no rescue drug for a liraglutide overdose.

Enhancing Healthcare Team Outcomes

Diagnosing and treating type 2 diabetes requires regular collaboration within the healthcare team. Prescribers and pharmacists work together to ensure patients receive their medication at a reasonable cost and within an appropriate time frame. Continuous monitoring of patients' glucose levels assesses the effect of liraglutide on glycemic control. Primary care physicians and advanced-level providers diagnose and treat T2D and manage weight loss. In severe cases where glycemic control is not achieved with first- or second-line treatments, an endocrinologist may be consulted to further evaluate the patient's endocrine dysfunction. For weight loss, patients may require medications such as liraglutide to increase metabolism and reduce appetite. Pharmacists and prescribers communicate with patients to navigate insurance challenges, explore patient assistance programs, and consider alternative payment options to improve access to these medications. Nurses ensure patients understand safe and precise dose administration and drug interactions and educate patients on lifestyle and diet modifications when indicated. Patients taking liraglutide should follow up with their providers every 3 to 6 months to evaluate glycemic control or weight loss progress. Patients with diabetes require close surveillance due to severe complications such as irreversible diabetic neuropathy. Patients taking liraglutide maintain regular appointments and monitor their blood glucose levels. Clinicians, pharmacists, and dieticians work collaboratively to ensure optimal use of liraglutide to treat obesity and T2D.