Lixisenatide (Monograph)

Brand names: Adlyxin, Soliqua 100/33 (combination)
Drug class: Incretin Mimetics

Medically reviewed by Drugs.com on Oct 16, 2023. Written by ASHP.

Introduction

Antidiabetic agent; synthetic, glucagon-like peptide-1 (GLP-1) receptor agonist (incretin mimetic).

Uses for Lixisenatide

Type 2 Diabetes Mellitus

Used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

Has been used as monotherapy or in combination with other antidiabetic agents, including metformin with or without a sulfonylurea; a sulfonylurea or thiazolidinedione with or without metformin; basal insulin (insulin glargine, insulin detemir, or isophane [NPH] insulin) with or without metformin or a sulfonylurea; or insulin glargine with or without metformin with or without a thiazolidinedione.

Commercially available in fixed combination with insulin glargine (Soliqua 100/33) for use as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).

In patients with metformin contraindications or intolerance (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a GLP-1 receptor agonist, sodium-glucose cotransporter 2 [SGLT2] inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.

May need to initiate therapy with 2 agents (e.g., metformin plus another drug) in patients with high initial HbA_1c (>7.5% or ≥1.5% above target). In such patients with metformin intolerance, some experts suggest initiation of therapy with 2 drugs from other antidiabetic drug classes with complementary mechanisms of action.

Consider early initiation of combination therapy for the treatment of type 2 diabetes mellitus to extend the time to treatment failure and more rapidly attain glycemic goals.

For patients with inadequate glycemic control on metformin monotherapy, consider patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preferences when selecting additional antidiabetic agents for combination therapy.

Consider early introduction of insulin for severe hyperglycemia (e.g., blood glucose ≥300 mg/dL or HbA_1c >9–10%), especially if accompanied by catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.

Safety and efficacy of lixisenatide or the fixed combination of insulin glargine and lixisenatide not established in patients with chronic pancreatitis or a history of unexplained pancreatitis; consider other antidiabetic agents in patients with a history of pancreatitis.

Lixisenatide alone or in combination with insulin glargine not indicated for treatment of type 1 diabetes mellitus.

Lixisenatide alone or in combination with insulin glargine not recommended for use in patients with gastroparesis.

Lixisenatide Dosage and Administration

General

Patient Monitoring

• Periodically monitor blood glucose and glycosylated hemoglobin (hemoglobin HbA_1c) to determine therapeutic response in patients with type 2 diabetes mellitus.

• Monitor renal function when initiating or escalating dosage in patients with renal impairment or those reporting severe adverse GI effects.

• Closely monitor patients with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist for allergic reactions during lixisenatide therapy.

• Observe patients carefully for signs and symptoms of pancreatitis.

Administration

Administer lixisenatide or the fixed combination of insulin glargine and lixisenatide by sub-Q injection using a prefilled injection pen; do not administer IV, IM, or via an insulin pump.

Sub-Q Administration

Administer sub-Q into abdomen, thigh, or upper arm; rotate sites within an area.

Lixisenatide: Administer within 1 hour before the first meal of the day, preferably the same meal each day (and at the same time each day). If a dose is missed, administer the dose within 1 hour before the next meal.

Fixed combination of insulin glargine and lixisenatide: Administer within 1 hour before the first meal of the day. If a dose is missed, resume the once-daily regimen with the next scheduled dose.

Consult drug labeling for additional details on administration.

Dosage

Dosage of fixed combination of insulin glargine and lixisenatide has been expressed in terms of the insulin glargine component; however, each mL of the fixed combination of insulin glargine and lixisenatide contains 100 units of insulin glargine and 33 mcg of lixisenatide.

If lixisenatide is used in combination with an insulin secretagogue (e.g., sulfonylurea) or basal insulin, reduction of sulfonylurea or basal insulin dosage may be required.

Adults

Type 2 Diabetes Mellitus

Lixisenatide

Sub-Q

Initially, 10 mcg once daily for 14 days. On day 15, increase to 20 mcg once daily.

Insulin Glargine/Lixisenatide Fixed-combination Therapy

Sub-Q

Patients who are naive to basal insulin or to a GLP-1 receptor agonist, currently on a GLP-1 receptor agonist, or inadequately controlled on <30 units of basal insulin daily: Initially, 15 units (15 units insulin glargine and 5 mcg lixisenatide) once daily.

Patients inadequately controlled on 30–60 units of basal insulin daily with or without a GLP-1 receptor agonist: Initially, 30 units (30 units insulin glargine and 10 mcg lixisenatide) once daily.

Titrate dosage by 2–4 units every week based on the patient's metabolic needs, blood glucose concentrations, and glycemic control goal until desired fasting plasma glucose concentration is obtained. Recommended dosage of the fixed combination of insulin glargine and lixisenatide is 15–60 units (15–60 units insulin glargine and 5–20 mcg lixisenatide) once daily.

Special Populations

Hepatic Impairment

Dosage adjustments of lixisenatide not likely required.

Frequent glucose monitoring and dosage adjustments may be required for patients with hepatic impairment receiving the fixed combination of insulin glargine and lixisenatide.

Renal Impairment

Mild or moderate renal impairment (eGFR 30–89 mL/minute per 1.73 m²): Dosage adjustment of lixisenatide not required. Monitor for changes in renal function and for adverse effects (e.g., hypoglycemia, nausea, vomiting) when initiating or escalating dosage. May require frequent glucose monitoring and dosage adjustments for patients receiving the fixed combination of insulin glargine and lixisenatide.

Severe renal impairment (eGFR 15 to <30 mL/minute per 1.73 m²): Limited experience with use of lixisenatide in patients with severe renal impairment; closely monitor for the occurrence of adverse GI effects and changes in renal function. May require frequent glucose monitoring and dosage adjustments for patients receiving the fixed combination of insulin glargine and lixisenatide.

End-stage renal disease (ESRD; eGFR <15 mL/minute per 1.73 m²): Data and experience lacking on use of lixisenatide or the fixed combination of insulin glargine and lixisenatide in patients with ESRD; not recommended in such patients.

Cautions for Lixisenatide

Contraindications

Known severe hypersensitivity to lixisenatide or any ingredient in the formulation.

Fixed combination of insulin glargine and lixisenatide also contraindicated during episodes of hypoglycemia.

Warnings/Precautions

Risks During General Anesthesia and Deep Sedation

GLP-1 agonists are associated with adverse GI effects such as nausea, vomiting, and delayed gastric emptying.

Delayed gastric emptying from GLP-1 agonists can increase the risk of regurgitation and pulmonary aspiration of gastric contents during general anesthesia and deep sedation.

The American Society of Anesthesiologists (ASA) Task Force on Preoperative Fasting has issued a consensus-based guidance for management of GLP-1 receptor agonists prior to elective surgery. The task force suggests that for patients on daily GLP-1 agonist dosing (irrespective of indication, dose, or type of surgery), consider holding the drug on the day of procedure/surgery. For patients on weekly dosing (irrespective of indication, dose, or type of surgery), consider holding the GLP-1 agonist a week prior to procedure/surgery. If GLP-1 agonists prescribed for diabetes management are held for longer than the dosing schedule, consider consulting an endocrinologist for bridging the antidiabetic therapy to avoid hyperglycemia.

For patients requiring urgent or emergent procedures, the task force states to proceed and treat the patient as ‘full stomach’ and manage accordingly.

Pancreatitis

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, reported during postmarketing experience in patients treated with GLP-1 receptor agonists.

Observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting).

If pancreatitis is suspected, promptly discontinue lixisenatide or the fixed combination of insulin glargine and lixisenatide and initiate appropriate management. If pancreatitis is confirmed, do not restart therapy.

Safety and efficacy of lixisenatide not established in patients with chronic pancreatitis or a history of unexplained pancreatitis; consider other antidiabetic therapies in patients with a history of pancreatitis.

Sharing of Injection Pens

Do not share injection pens of lixisenatide or the fixed combination of insulin glargine and lixisenatide among patients, even if the needle has been changed; sharing poses risk for transmission of blood-borne pathogens.

Use with Drugs Known to Cause Hypoglycemia

Risk of hypoglycemia increased when lixisenatide used in combination with an insulin secretagogue (e.g., sulfonylurea) or basal insulin; may require reduction in sulfonylurea (or other insulin secretagogue) or insulin dosage.

Medication Errors

Administration of the fixed combination of insulin glargine and lixisenatide in a dose >60 units (of insulin glargine component) may result in overdose of the lixisenatide component. Do not exceed maximum lixisenatide dosage of 20 mcg daily; do not use the fixed combination of insulin glargine and lixisenatide in combination with another GLP-1 receptor agonist.

Renal Effects

Deterioration of renal function (e.g., acute kidney injury and worsening of chronic renal failure, sometimes requiring hemodialysis) reported with GLP-1 receptor agonists during postmarketing experience. Some patients did not have known underlying renal disease. Other factors (nausea, vomiting, diarrhea, or dehydration) were present in most patients.

Monitor renal function closely during initiation or escalation of lixisenatide or the fixed combination of insulin glargine and lixisenatide dosage in patients with renal impairment and in those with severe GI adverse effects.

Immunogenicity

Development of antibodies to lixisenatide reported. Development of antibodies to lixisenatide and insulin glargine also reported with the fixed combination of insulin glargine and lixisenatide. Attenuated glycemic response reported in some patients with high (>100 nmol/L) antibody concentrations.

If worsening glycemic control, failure to achieve targeted glycemic control, or clinically important injection-site or allergic reactions occur, consider alternative antidiabetic therapy.

Acute Gallbladder Disease

Acute events of gallbladder disease such as cholelithiasis or cholecystitis reported in clinical trials with GLP-1 receptor agonists and during postmarketing experience. If cholelithiasis suspected, gallbladder studies and appropriate clinical follow-up are indicated.

Sensitivity Reactions

Serious hypersensitivity reactions (anaphylaxis, angioedema) reported. Discontinue lixisenatide or the fixed combination of insulin glargine and lixisenatide and promptly seek medical attention if hypersensitivity reaction occurs. Use with caution in patients with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist.

Specific Populations

Pregnancy

Data are lacking on the use of lixisenatide or the fixed combination of insulin glargine and lixisenatide in pregnant women. Lixisenatide has been associated with visceral and skeletal defects in animal reproduction studies. Lixisenatide or the fixed combination of insulin glargine and lixisenatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

Lixisenatide is distributed into milk in rats; not known whether distributed into milk in humans. Consider the benefits of breast-feeding and the importance of lixisenatide to the woman along with any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

Pediatric Use

Safety and efficacy of lixisenatide or the fixed combination of insulin glargine and lixisenatide not established in patients <18 years of age.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults. Use caution when administering the fixed combination of insulin glargine and lixisenatide to geriatric patients since hypoglycemia may be difficult to recognize; initial dosing, dose increments, and maintenance dosage should be conservative to prevent hypoglycemia.

Hepatic Impairment

Data lacking on use of lixisenatide in patients with acute or chronic hepatic impairment. Because lixisenatide is presumed to be cleared principally by the kidney, hepatic dysfunction not expected to affect pharmacokinetics; manufacturer makes no specific dosage recommendations for patients with hepatic impairment.

Effect of hepatic impairment on pharmacokinetics of the fixed combination of insulin glargine and lixisenatide not evaluated. Frequent glucose monitoring and dosage adjustments may be necessary in patients with hepatic impairment receiving the fixed combination.

Renal Impairment

Lixisenatide or the fixed combination of insulin glargine and lixisenatide not recommended in patients with ESRD.

In patients with mild, moderate, or severe renal impairment, lixisenatide plasma concentrations and systemic exposure were increased by 60, 42, or 83% and 34, 69, or 124%, respectively. No dosage adjustments recommended for patients with mild, moderate, or severe renal impairment receiving lixisenatide; however, closely monitor renal function of such patients and observe for adverse effects when initiating or escalating lixisenatide dosage.

Frequent glucose monitoring and dosage adjustments may be necessary in patients with renal impairment receiving the fixed combination of insulin glargine and lixisenatide.

Patients with Gastroparesis

Lixisenatide slows gastric emptying and may affect absorption of concomitantly administered oral drugs. Data lacking on use of lixisenatide or the fixed combination of insulin glargine and lixisenatide in patients with preexisting gastroparesis.

Common Adverse Effects

Lixisenatide: Nausea, vomiting, headache, diarrhea, dizziness, hypoglycemia.

Fixed combination of insulin glargine and lixisenatide: Hypoglycemia, nausea, nasopharyngitis, diarrhea, upper respiratory tract infection, headache.

Drug Interactions

In vitro, lixisenatide is neither an inducer nor an inhibitor of CYP isoenzymes; lixisenatide is not metabolized by CYP isoenzymes.

Effects on GI Absorption of Other Drugs

Possible decreased rate and extent of absorption of concomitantly administered oral drugs; use caution with oral drugs that have a narrow therapeutic index or require careful clinical monitoring.

With oral drugs for which efficacy depends on threshold concentrations or for which delay in effect would be undesirable, administer ≥1 hour before lixisenatide or the fixed combination of insulin glargine and lixisenatide. If such drugs need to be administered with food, administer them with a meal or snack at a time when lixisenatide is not administered.

Specific Drugs

Lixisenatide Pharmacokinetics

Absorption

Bioavailability

Following sub-Q administration of lixisenatide, peak plasma concentration usually attained in 1–3.5 hours.

Absorption of lixisenatide is similar when injected into abdomen, thigh, or arm.

Special Populations

Peak plasma concentrations increased 60, 42, or 83% and AUC increased approximately 34, 69, or 124% in patients with mild, moderate, or severe renal impairment, respectively.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

Elimination

Metabolism

Principally glomerular filtration and proteolytic degradation.

Half-life

Approximately 3 hours.

Special Populations

Manufacturer states pharmacokinetics are independent of age, body weight, sex, and race.

Stability

Storage

Parenteral

Injection

Lixisenatide: Before use, 2–8°C in original carton. After first use, <30ºC. Do not freeze; protect from light. Discard pen 14 days after first use.

Fixed combination of insulin glargine and lixisenatide: Before use, 2–8°C in original carton. After first use, <25ºC. Do not freeze; protect from light. Discard pen 28 days after first use.

Actions

• Lixisenatide, a synthetic analog of a naturally occurring peptide (exendin-4) isolated from the saliva of Heloderma suspectum (Gila monster), is a GLP-1 receptor agonist (incretin mimetic).

• Stimulates insulin release in the presence of elevated glucose concentrations, suppresses glucose-dependent glucagon release, and slows gastric emptying, resulting in lower fasting and postprandial blood glucose concentrations and, potentially, weight loss in patients with type 2 diabetes mellitus.

• Long-acting GLP-1 agonists induce marked reductions in fasting plasma glucose (by stimulating insulin secretion) and modest reductions in postprandial glucose, while short-acting GLP-1 agonists (e.g., lixisenatide), have less of an effect on fasting plasma glucose concentrations and more of an effect on reducing postprandial glucose concentrations (by slowing gastric emptying and inhibiting glucagon secretion).

• Does not appear to be associated with clinically important prolongation of the corrected QT interval (QT_c, Bazett's formula).

Advice to Patients

• Importance of patient reading medication guide and the injection pen instructions for use before initiating therapy and each time drug is dispensed.

• Importance of instructing patient and caregivers on preparation and use of injection pen prior to first use; training should include a practice injection.

• Importance of not mixing or diluting the fixed combination of insulin glargine and lixisenatide with any other insulin or solution.

• Importance of informing patients of possibility of serious hypersensitivity reactions (e.g., anaphylaxis); instruct patients to discontinue lixisenatide or the fixed combination of insulin glargine and lixisenatide and promptly seek medical advice if hypersensitivity symptoms occur.

• Importance of informing patient of the potential risk of acute pancreatitis. Importance of patient informing clinicians about a history of pancreatitis, gallstones, or alcoholism. Importance of informing patients about signs and symptoms of pancreatitis, including persistent severe abdominal pain sometimes radiating to the back that may or may not be accompanied by vomiting; importance of patient discontinuing lixisenatide or the fixed combination of insulin glargine and lixisenatide and promptly notifying clinician if such signs or symptoms occur.

• Importance of informing patients that injection pens should not be shared with another person, even if the needle has been changed. Such sharing may pose a risk of transmitting or acquiring infection.

• Importance of informing patients of the risk of hypoglycemia, particularly if concomitant therapy with an insulin secretagogue (e.g., sulfonylurea) or insulin is used.

• Importance of informing patients of the potential risk of dehydration due to adverse GI effects; importance of advising patients to take precautions to avoid fluid depletion. Importance of informing patients of the potential risk for worsening renal function, which in some cases may require dialysis.

• Importance of informing patients of the potential risk of cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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