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Insulin Glargine and Lixisenatide

Pronunciation

(IN soo lin GLAR jeen & lix i SEN a tide)

Index Terms

  • Glargine Insulin and Lixisenatide
  • Lixisenatide and Insulin Glargine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Pen-injector, Subcutaneous:

Soliqua: 100/33: Insulin glargine 100 units and lixisenatide 33 mcg per mL (3 mL) [contains metacresol]

Brand Names: U.S.

  • Soliqua

Pharmacologic Category

  • Antidiabetic Agent, Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist
  • Insulin, Long-Acting

Pharmacology

Refer to individual agents.

Use: Labeled Indications

Diabetes mellitus, type 2: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus inadequately controlled on basal insulin (<60 units daily) or lixisenatide

Contraindications

Hypersensitivity to insulin glargine, lixisenatide, or any component of the formulation; during episodes of hypoglycemia

Dosing: Adult

Note: Discontinue therapy with lixisenatide or basal insulin prior to initiation of therapy.

Diabetes mellitus, type 2: SubQ:

Patients inadequately controlled on less than 30 units of basal insulin or on lixisenatide: Initial: 15 units (insulin glargine 15 units/lixisenatide 5 mcg) once daily.

Patients inadequately controlled on 30 to 60 units of basal insulin: Initial: 30 units (insulin glargine 30 units/lixisenatide 10 mcg) once daily.

Dose titration: Titrate the dosage upwards or downwards by 2 to 4 units every week until the desired fasting plasma glucose is achieved; usual dosage range: 15 units (insulin glargine 15 units/lixisenatide 5 mcg) to 60 units (insulin glargine 60 units/lixisenatide 20 mcg)/day. Maximum dose: 60 units (insulin glargine 60 units/lixisenatide 20 mcg)/day

Missed dose: If a dose is missed, resume with the next scheduled dose. Do not double dose or increase the dose to make up for the missed dose.

Dosing: Geriatric

Refer to adult dosing; use with caution

Dosing: Renal Impairment

eGFR ≥15 mL/minute/1.73 m2 to <90 mL/minute/1.73 m2: There are no specific dosage adjustments provided in the manufacturer’s labeling for the combination product; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely. Limited data indicates lixisenatide exposure is increased in patients with severe impairment (eGFR <30 mL/minute/1.73 m2). Also refer to individual monographs.

eGFR <15 mL/minute/1.73 m2: Use is not recommended (has not been studied).

Dosing: Hepatic Impairment

There are no specific dosage adjustments provided in the manufacturer’s labeling for the combination product; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely. Also refer to individual monographs.

Administration

For SubQ use only. Do not administer IM, IV, or via an insulin pump. Cold injections should be avoided. Inject into the abdomen, thigh, or upper arm. Rotate injection sites for each dose; do not use the same site for each injection to avoid lipodystrophy. Administer within one hour before the first meal of the day, preferably the same meal each day. Solution should appear clear and colorless; do not use if particulate matter or coloration is seen. Do not split the dose. Do not mix or dilute with any other insulin or solution.

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy (ADA 2016b).

Storage

Prior to initial use, store pens refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze (discard if frozen). Protect from light. After initial use, store at room temperature <30°C (86°F) and use within 14 days. Replace the pen cap after each use, do not store with needle attached.

Drug Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Beta-Blockers: May enhance the hypoglycemic effect of Insulin. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Contraceptives (Estrogens): Lixisenatide may decrease the serum concentration of Contraceptives (Estrogens). Management: Administer oral contraceptives 1 hour before or at least 11 hours after administration of lixisenatide. Consider therapy modification

Contraceptives (Progestins): Lixisenatide may decrease the serum concentration of Contraceptives (Progestins). Management: Administer oral contraceptives 1 hour before or at least 11 hours after administration of lixisenatide. Consider therapy modification

DPP-IV Inhibitors: May enhance the hypoglycemic effect of Insulin. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulin. Monitor therapy

Edetate Disodium: May enhance the hypoglycemic effect of Insulin. Monitor therapy

GLP-1 Agonists: May enhance the hypoglycemic effect of Insulin. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Exceptions: Liraglutide. Consider therapy modification

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulin: GLP-1 Agonists may enhance the hypoglycemic effect of Insulin. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Consider therapy modification

Liraglutide: May enhance the hypoglycemic effect of Insulin. Management: If liraglutide is used for the treatment of diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided if liraglutide is used exclusively for weight loss (Saxenda). Consider therapy modification

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Metreleptin: May enhance the hypoglycemic effect of Insulin. Management: Insulin dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely. Consider therapy modification

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pioglitazone: May enhance the adverse/toxic effect of Insulin. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure. Consider therapy modification

Pramlintide: May enhance the hypoglycemic effect of Insulin. Management: Upon initiation of pramlintide, decrease mealtime insulin dose by 50% to reduce the risk of hypoglycemia. Monitor blood glucose frequently and individualize further insulin dose adjustments based on glycemic control. Consider therapy modification

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Rosiglitazone: Insulin may enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination. Avoid combination

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

SGLT2 Inhibitors: May enhance the hypoglycemic effect of Insulin. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Sulfonylureas: GLP-1 Agonists may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Adverse Reactions

Also see individual agents.

>10%:

Endocrine & metabolic: Hypoglycemia (26% to 40%)

Immunologic: Antibody development (21% to 26%)

1% to 10%:

Central nervous system: Headache (5%)

Endocrine & metabolic: Severe hypoglycemia (≤1%)

Gastrointestinal: Nausea (10%), diarrhea (7%)

Local: Injection site reaction (2%)

Respiratory: Nasopharyngitis (7%), upper respiratory tract infection (6%)

Frequency not defined: Local: Hypertrophy at injection site, lipoatrophy at injection site

<1% (Limited to important or life-threatening): Abdominal distention, abdominal pain, constipation, decreased appetite, dyspepsia, flatulence, gastritis, gastroesophageal reflux disease, vomiting

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: Development of antibodies to insulin and lixisenatide may occur; in clinical trials with lixisenatide, high titers were observed in 2.4% of patients and were associated with an attenuated glycemic response. Allergic reactions and injection site reactions were more frequent in antibody positive patients; consider alternative antidiabetic therapy in patients not achieving targeted glycemic control or with worsening glycemic control and/or significant allergic or injection site reactions.

• Hypersensitivity: Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with lixisenatide and with insulin glargine; discontinue use if hypersensitivity reactions occur and treat promptly as indicated. It is not known if patients with a history of hypersensitivity to other GLP-1 agonists are at increased risk for hypersensitivity reactions with lixisenatide; patients with prior serious reactions to similar agents should be monitored closely.

• Hypoglycemia: The most common adverse effect of insulin is hypoglycemia. The timing of hypoglycemia differs among various insulin formulations. Hypoglycemia may result from increased work or exercise without eating; use of long-acting insulin preparations (eg, insulin detemir, insulin glargine, insulin degludec) may delay recovery from hypoglycemia. Profound and prolonged episodes of hypoglycemia may result in convulsions, unconsciousness, temporary or permanent brain damage, or even death. Insulin requirements may be altered during illness, emotional disturbances, or other stressors. Instruct patients to use caution with ethanol; may increase risk of hypoglycemia.

• Hypokalemia: Insulin (especially IV insulin) causes a shift of potassium from the extracellular space to the intracellular space, possibly producing hypokalemia. If left untreated, hypokalemia may result in respiratory paralysis, ventricular arrhythmia and even death. Use with caution in patients at risk for hypokalemia (eg, loop diuretic use). Monitor serum potassium and supplement potassium when necessary.

• Pancreatitis: Cases of acute pancreatitis (including hemorrhagic and necrotizing with some fatalities) have been reported with GLP-1 receptor agonists; monitor for signs and symptoms of pancreatitis (eg, persistent severe abdominal pain which may radiate to the back, and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue use. Do not resume unless an alternative etiology of pancreatitis is confirmed. Consider alternative antidiabetic therapy in patients with a history of pancreatitis (has not been studied).

Disease-related concerns:

• Gastroparesis: Lixisenatide slows gastric emptying and is not recommended for use in patients with gastroparesis (has not been studied); do not initiate therapy in patients with severe gastroparesis.

• Renal impairment: Use with caution in patients with renal impairment. Dosage adjustments may be necessary. Patients with mild to moderate renal impairment (eGFR ≥30 to 89 mL/minute/1.73 m2) may be at increased risk of adverse effects (eg, diarrhea, nausea, vomiting) which may lead to dehydration, acute kidney injury, and worsening of chronic renal failure. There is limited experience with severe impairment (eGFR 15 to <30 mL/minute/1.73 m2); lixisenatide exposure may be increased in these patients. Monitor all patients with renal impairment closely for decreasing renal function. Use is not recommended in patients with end-stage renal disease (eGFR <15 mL/minute/1.73 m2) (has not been studied).

• Hepatic impairment: Use with caution in patients with hepatic impairment. Dosage adjustments may be necessary.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Multiple dose injection pens: According to the Centers for Disease Control and Prevention (CDC), pen-shaped injection devices should never be used for more than one person (even when the needle is changed) because of the risk of infection. The injection device should be clearly labeled with individual patient information to ensure that the correct pen is used (CDC 2012).

Other warnings/precautions:

• Appropriate use: Not approved for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus (insulin-dependent, IDDM).

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

Monitoring Parameters

Diabetes mellitus: Plasma glucose, electrolytes, HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016a]), potassium (in patients at risk for hypokalemia; renal function, signs/symptoms of pancreatitis; signs/symptoms of adverse GI effects (diarrhea, nausea, vomiting); signs/symptoms of hypersensitivity

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Refer to individual monographs.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, constipation, abdominal pain, flatulence, lack of appetite, rhinitis, pharyngitis, common cold symptoms, headache, weight gain, or injection site irritation. Have patient report immediately to prescriber signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), difficulty swallowing, vision changes, dizziness, passing out, seizures, change in skin to thick or thin at injection site, shortness of breath, excessive weight gain, swelling in the arms or legs, or signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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