Skip to Content
Is it time for a new insulin treatment? Learn more >>

Insulin Degludec and Insulin Aspart

Pronunciation

(IN su lin de GLOO dek & IN soo lin AS part)

Index Terms

  • Insulin aspart and insulin degludec
  • Ryzodeg 70/30

Pharmacologic Category

  • Insulin, Combination

Pharmacology

Insulin acts via specific membrane-bound receptors on target tissues to regulate metabolism of carbohydrate, protein, and fats. Target organs for insulin include the liver, skeletal muscle, and adipose tissue.

Within the liver, insulin stimulates hepatic glycogen synthesis. Insulin promotes hepatic synthesis of fatty acids, which are released into the circulation as lipoproteins. Skeletal muscle effects of insulin include increased protein synthesis and increased glycogen synthesis. Within adipose tissue, insulin stimulates the processing of circulating lipoproteins to provide free fatty acids, facilitating triglyceride synthesis and storage by adipocytes; also directly inhibits the hydrolysis of triglycerides. In addition, insulin stimulates the cellular uptake of amino acids and increases cellular permeability to several ions, including potassium, magnesium, and phosphate. By activating sodium-potassium ATPases, insulin promotes the intracellular movement of potassium.

Normally secreted by the pancreas, insulin products are manufactured for pharmacologic use through recombinant DNA technology using either E. coli or Saccharomyces cerevisiae. Insulins are categorized based on the onset, peak, and duration of effect (eg, rapid-, short-, intermediate-, and long-acting insulin). Insulin degludec is a long-acting insulin analog and insulin aspart is a rapid-acting insulin analog.

Onset of Action

Insulin aspart: 14 minutes

Time to Peak

Insulin aspart: 72 minutes

Duration of Action

Insulin degludec: >24 hours

Half-Life Elimination

Insulin degludec: ~25 hours

Protein Binding

Insulin degludec: >99% (albumin); Insulin aspart: <10%

Use: Labeled Indications

Diabetes mellitus: To improve glycemic control in adults with diabetes mellitus

Contraindications

Hypersensitivity to insulin degludec, insulin aspart, or any component of the formulation; during episodes of hypoglycemia

Documentation of allergenic cross-reactivity for insulin is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Note: Insulin degludec is a long-acting insulin analog and insulin aspart is a rapid-acting insulin analog administered by SubQ injection. With combination insulin products, the proportion of short-acting to long-acting insulin is fixed; basal versus prandial dose adjustments cannot be made. Fixed-ratio insulins (such as insulin degludec and insulin aspart combination) are typically administered as 2 daily doses with each dose intended to cover two meals and a snack. Because of variability in the peak effect and individual patient variability in activities, meals, etc., it may be more difficult to achieve complete glycemic control using fixed combinations of insulins; frequent monitoring and close medical supervision may be necessary.

Diabetes mellitus, type 1: SubQ:

Insulin degludec and insulin aspart combination-specific dosing: Insulin-naive: Initial: Approximately one-third to one-half of the total daily insulin dose administered as insulin degludec and insulin aspart combination once or twice daily with any main meal; administer remainder of total daily insulin dose as short- or rapid-acting insulin divided between each daily meal. Titrate dose every 3 to 4 days.

Conversion from a once or twice daily premix or self-mix insulin: Initiate insulin degludec and insulin aspart combination at same dose and schedule as the premix or self-mix. Short- or rapid-acting mealtime insulins should be continued for meals not covered by insulin degludec and insulin aspart combination.

Conversion from basal insulin: Initiate insulin degludec and insulin aspart combination at same dose as basal insulin and administer once daily with main meal. Short- or rapid-acting mealtime insulins should be continued for meals not covered by insulin degludec and insulin aspart combination.

General insulin dosing:

Type 1: Note: Multiple daily doses or continuous subcutaneous infusions guided by blood glucose monitoring are the standard of diabetes care. Combinations of different insulin formulations are commonly used. The daily doses presented below are expressed as the total units/kg/day of all insulin formulations combined.

Initial total insulin dose: 0.2 to 0.6 units/kg/day in divided doses. Conservative initial doses of 0.2 to 0.4 units/kg/day are often recommended to avoid the potential for hypoglycemia. A rapid-acting insulin may be the only insulin formulation used initially.

Usual maintenance range: 0.5 to 1 units/kg/day in divided doses. An estimate of anticipated needs may be based on body weight and/or activity factors as follows:

Nonobese: 0.4 to 0.6 units/kg/day

Obese: 0.8 to 1.2 units/kg/day

Pubescent Children and Adolescents: During puberty, requirements may substantially increase to >1 unit/kg/day and in some cases up to 2 units/kg/day (IDF-ISPAD 2011).

Division of daily insulin requirement ("conventional therapy"): Generally, 50% to 75% of the total daily dose (TDD) is given as an intermediate-acting (eg, NPH) or a long-acting form of insulin (in 1 to 2 daily injections). The remaining portion of the TDD is then divided and administered before or at mealtimes (depending on the formulation) as a rapid-acting or short-acting form of insulin.

Division of daily insulin requirement ("intensive therapy"): Basal insulin delivery with 1 or 2 doses of intermediate- or long-acting insulin formulations superimposed with doses of short- or rapid-acting insulin (eg, insulin aspart) formulations 3 or more times daily.

Adjustment of dose: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Adjust dose to maintain premeal and bedtime glucose in target range. Because combinations of agents are frequently used, dosage adjustment must address the individual component of the insulin regimen that most directly influences the blood glucose value in question, based on the known onset and duration of the insulin component. Treatment and monitoring regimens must be individualized. Also see Additional Information or Pharmacotherapy Pearls.

Continuous SubQ insulin infusion (insulin pump): A combination of a "basal" continuous insulin infusion rate with preprogrammed, premeal bolus doses which are patient controlled. When converting from multiple daily SubQ doses of maintenance insulin, it is advisable to reduce the basal rate to less than the equivalent of the total daily units of the longer acting insulin (eg, NPH); divide the total number of units by 24 to get the basal rate in units/hour. Do not include the total units of regular insulin or other rapid-acting insulin formulations in this calculation. The same premeal regular insulin dosage may be used.

Diabetes mellitus, type 2: SubQ:

Insulin degludec and insulin aspart combination-specific dosing: Insulin-naive: Initial: 10 units once daily with a main meal.

Conversion from a once or twice daily premix or self-mix insulin: Initiate insulin degludec and insulin aspart combination at same dose and schedule as the premix or self-mix. Short- or rapid-acting mealtime insulins should be continued for meals not covered by insulin degludec and insulin aspart combination.

Conversion from basal insulin monotherapy: Initiate insulin degludec and insulin aspart combination with a main meal at same dose and frequency as the basal insulin.

Conversion from combination basal insulin and short- or rapid-acting insulin therapy: Initiate insulin degludec and insulin aspart combination at same dose and frequency as the basal insulin. Short- or rapid-acting mealtime insulins should be continued for meals not covered by insulin degludec and insulin aspart combination.

General considerations for insulin use in type 2 diabetes:

Timing of initiation: The goal of therapy is to achieve an HbA1c <7%. According to a position statement by the ADA and European Association for the Study of Diabetes (EASD), dual therapy (metformin + a second antihyperglycemic agent) is recommended in patients with type 2 diabetes who fail to achieve glycemic goals after ~3 months with lifestyle interventions and metformin monotherapy (unless contraindications to metformin exist). Preference is not given for adding insulin or a noninsulin agent as the second antihyperglycemic agent (drug choice should be individualized based on patient characteristics). However, insulin should be considered as part of a combination regimen when hyperglycemia is severe, particularly if patient is symptomatic or has catabolic features (eg, weight loss, ketosis). If insulin is selected, the addition of basal insulin (ie, a long-acting insulin such as glargine, degludec, or detemir) is recommended. If HbA1c target not achieved after ~3 months of dual therapy, may proceed to triple therapy (Inzucchi 2015).

Intensification of therapy: If HbA1c target has not been met, despite titrating basal insulin (ie, long-acting insulin) to provide acceptable fasting blood glucose concentrations, intensification of therapy should be considered to cover postprandial glucose excursions. Options include adding a mealtime insulin (1 to 3 injections of a rapid-acting insulin analog [lispro, aspart, glulisine]) or adding a GLP-1 receptor agonist (eg, exenatide, liraglutide). Alternatively, although less studied, may transition from basal insulin (ie, long-acting insulin) to a twice daily premixed (or biphasic) insulin analog (70/30 aspart mix, 75/25 or 50/50 lispro mix) (Inzucchi 2015).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.

Administration

Subcutaneous: For subcutaneous administration into the thigh, upper arm, or abdomen; do not administer IM or IV, or in an insulin infusion pump. Rotate injection sites within the same region to reduce the risk of lipodystrophy. Do not dilute or mix insulin degludec/insulin aspart with any other insulin formulation or solution; do not transfer from the FlexTouch pen into a syringe for administration. Solution should be clear and colorless.

Dietary Considerations

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

Storage

Store not-in-use (unopened) pens at 2°C to 8°C (36°F to 46°F) until expiration date or at room temperature (below 30°C [86°F]) for up to 28 days (4 weeks). Do not freeze or use if solution has been frozen.

Store in-use (opened) pens at room temperature (below 30°C [86°F]) for up to 28 days (4 weeks); do not refrigerate; protect from direct heat and light.

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

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

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

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

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

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

Adverse Reactions

Frequency not always defined.

Cardiovascular: Peripheral edema (2%)

Central nervous system: Headache (6% to 10%)

Endocrine & metabolic: Severe hypoglycemia (13%, type 1 diabetics using combination insulin regimen; ≤3%, type 2 diabetes), hypoglycemia, weight gain

Immunologic: Antibody development

Infection: Influenza (7%, type 1 diabetes)

Local: Injection site reaction (2%; including hematoma, pain, hemorrhage, erythema, swelling, warmth, nodules, mass, discoloration, and pruritus), hypertrophy at injection site, lipoatrophy at injection site

Respiratory: Nasopharyngitis (11% to 25%), upper respiratory tract infection (6% to 9%)

<1% (Limited to important or life-threatening): Hypersensitivity, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity: Severe, life-threatening allergic reactions, including anaphylaxis, may occur. If hypersensitivity reactions occur, discontinue therapy.

• 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 degludec, insulin detemir, insulin glargine) 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.

Disease-related concerns:

• Diabetic ketoacidosis: Should not be used in patients with diabetic ketoacidosis (DKA); use of an IV rapid-acting or short-acting insulin is preferred.

• Hepatic impairment: Use with caution in patients with hepatic impairment. Dosage requirements may be reduced.

• Renal impairment: Use with caution in patients with renal impairment. Dosage requirements may be reduced.

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.

Special populations:

• Obesity: A decrease in glucose-lowering effect of insulin degludec with increasing body mass index (BMI) has been observed.

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:

• Administration: Insulin degludec and insulin aspart combination is a clear solution, but it is NOT intended for IV or IM administration or via an insulin pump.

• Appropriate use: Diabetes mellitus: The general objective of exogenous insulin therapy is to approximate the physiologic pattern of insulin secretion, which is characterized by two distinct phases. Phase 1 insulin secretion suppresses hepatic glucose production and phase 2 insulin secretion occurs in response to carbohydrate ingestion; therefore, exogenous insulin therapy may consist of basal insulin (eg, intermediate- or long-acting insulin, insulin administered via continuous subcutaneous insulin infusion [CSII]) and/or preprandial insulin (eg, short- or rapid-acting insulin) (see Related Information: Insulin Products). Patients with type 1 diabetes do not produce endogenous insulin; therefore, these patients require both basal and preprandial insulin administration. Patients with type 2 diabetes retain some beta-cell function in the early stages of their disease; however, as the disease progresses, phase 1 insulin secretion may become completely impaired and phase 2 insulin secretion becomes delayed and/or inadequate in response to meals. Therefore, patients with type 2 diabetes may be treated with oral antidiabetic agents, basal insulin, and/or preprandial insulin depending on the stage of disease and current glycemic control. Because treatment regimens often consist of multiple agents, dosage adjustments must address the specific phase of insulin release that is primarily contributing to the patient's impaired glycemic control. Treatment and monitoring regimens must be individualized.

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

Monitoring Parameters

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])

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies conducted with this combination, consistent with those observed using human insulin. 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 pharyngitis, rhinitis, headache, flu-like symptoms, or injection site irritation. Have patient report immediately to prescriber signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), vision changes, chills, severe dizziness, passing out, seizures, change in skin to thick or thin at injection site, mood changes, slurred speech, shortness of breath, excessive weight gain, or swelling of arms or legs (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.

Hide