Insulin Glargine and Lixisenatide

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]

Pharmacology

Mechanism of Action

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

Contraindications

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

Dosage and Administration

Dosing: Adult

Diabetes mellitus, type 2: SubQ: Note: Discontinue therapy with basal insulin or a GLP-1 agonist prior to initiation of therapy.

Initial:

Patients naive to basal insulin or a GLP-1 agonist, or currently on a GLP-1 agonist or <30 units of basal insulin/day: 15 units (insulin glargine 15 units/lixisenatide 5 mcg) once daily

Patients currently on 30 to 60 units of basal insulin/day, with or without a GLP-1 agonist: 30 units (insulin glargine 30 units/lixisenatide 10 mcg) once daily

Dose titration: Titrate the dosage upwards or downwards by 2 to 4 units (insulin glargine 2 to 4 units/lixisenatide 0.66 to 1.32 mcg) 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

Administration

SubQ: 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 or localized cutaneous amyloidosis. Rotating from an injection site where lipodystrophy/cutaneous amyloidosis is present to an unaffected site may increase risk of hypoglycemia. 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. Prefilled pen dials in 1-unit increments.

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 <25°C (<77°F) and use within 28 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 Insulins. Exceptions: Levobunolol; Metipranolol. Monitor therapy

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

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

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

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

Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Insulins. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. 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

Insulins: Glucagon-Like Peptide-1 Agonists may enhance the hypoglycemic effect of Insulins. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Consider therapy modification

Liraglutide: May enhance the hypoglycemic effect of Insulins. 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

Macimorelin: Insulins may diminish the diagnostic effect of Macimorelin. Avoid combination

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

Metreleptin: May enhance the hypoglycemic effect of Insulins. 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

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

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

Pioglitazone: May enhance the adverse/toxic effect of Insulins. 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 Insulins. 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

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

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

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones 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

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Rosiglitazone: Insulins 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

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Consider therapy modification

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: May enhance the hypoglycemic effect of Insulins. 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: Glucagon-Like Peptide-1 Agonists may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. 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 (8% 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%), vomiting (3%)

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%, postmarketing, and/or case reports: Abdominal distention, abdominal pain, constipation, decreased appetite, dyspepsia, flatulence, gastritis, gastroesophageal reflux disease

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:

• Bariatric surgery:

– Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy, and closely monitor the patient for the duration of therapy; acute and chronic kidney failure exacerbation may occur. A majority of cases occurred in patients with nausea, vomiting, diarrhea, and/or dehydration. Nausea is common and fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2013).

– Excessive glucagon-like peptide-1 exposure: Closely monitor for efficacy and assess for signs and symptoms of pancreatitis if therapy is initiated after surgery; gastric bypass and sleeve gastrectomy (but not gastric band) significantly increase endogenous postprandial glucagon-like peptide-1 (GLP-1) concentrations (Korner 2009; Peterli 2012). Administration of exogenous GLP-1 agonists may be redundant to surgery effects.

– Type 2 diabetes, hypoglycemia: Closely monitor insulin dose requirement throughout active weight loss with a goal of eliminating antidiabetic therapy or transitioning to agents without hypoglycemic potential; hypoglycemia after gastric bypass, sleeve gastrectomy, and gastric band may occur (Mechanick 2013). Insulin secretion and sensitivity may be partially or completely restored early after these procedures (gastric bypass is most effective, followed by sleeve and finally band) (Korner 2009; Peterli 2012). Monitoring of hospital insulin requirements is recommended to guide discharge insulin dose. Rates and timing of type 2 diabetes improvement and resolution vary widely by patient; insulin dose reduction of 75% has been suggested after gastric bypass for patients without severe β-cell failure (fasting c-peptide <0.3 nmol/L) (Cruijsen 2014).

– Weight gain: Evaluate risk versus benefit and consider alternative therapy after gastric bypass, sleeve gastrectomy, and gastric banding; weight gain may occur (Apovian 2015).

• Cardiac disease: Concurrent use with peroxisome proliferator-activated receptor (PPAR)-gamma agonists, including thiazolidinediones (TZDs) may cause dose-related fluid retention and lead to or exacerbate heart failure, particularly when used in combination with insulin. If PPAR-gamma agonists are prescribed, monitor for signs and symptoms of heart failure. If heart failure develops, consider PPAR-gamma agonist dosage reduction or therapy discontinuation.
• 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 (typically before meals and snacks and at bedtime; occasionally additional monitoring may be required), electrolytes, HbA_1c (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 2019]), hepatic function, weight; 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

Gestational diabetes mellitus: Blood glucose 4 times daily (1 fasting and 3 postprandial) until well controlled, then as appropriate (ACOG 190 2018).

Pregnancy

Pregnancy Considerations

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

Patient Education

What is this drug used for?

• It is used to lower blood sugar in patients with high blood sugar (diabetes).

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Diarrhea
• Constipation
• Abdominal pain
• Passing gas
• Lack of appetite
• Nose irritation
• Throat irritation
• Common cold symptoms
• Headache
• Weight gain
• Injection site irritation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat
• Vision changes
• Dizziness
• Passing out
• Seizures
• Injection site thick skin, pits, or lumps
• Shortness of breath
• Excessive weight gain
• Swelling in the arms or legs
• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating.
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

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