AHFS Class:

• Long-acting Insulins 68:20.08.16

Generic Name(s):

• Insulin Degludec

• Insulin Degludec and Liraglutide

Chemical Name:

• 29B-[ N ⁶-[ N -(15-carboxy-1-oxopentadecyl)-l-γ-glutamyl]-l-lysine]-(1A-21A) (1B-29B)-Insulin (human)

Molecular Formula:

• C₂₇₄H₄₁₁N₆₅O₈₁S₆

Insulin degludec is a biosynthetic (rDNA origin), long-acting human insulin analog.1,32

Diabetes Mellitus

Insulin degludec is used to improve glycemic control in the management of type 1 or type 2 diabetes mellitus in patients who require a long-acting insulin.1,2,3,4,5,6,7,8,9,10,20 Insulin degludec also is commercially available in fixed combination with liraglutide (Xultophy^®); the fixed combination is used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.36,38,39,40

Insulin degludec is not indicated for the treatment of diabetic ketoacidosis; a short-acting insulin (e.g., insulin human) is the preferred agent.1,31 Insulin degludec also is not recommended for use in pediatric patients who require less than 5 units of insulin degludec daily.1,32

Insulin Degludec

Insulin degludec appears to be at least as effective for glycemic control as insulin glargine or insulin detemir (as determined by glycosylated hemoglobin [hemoglobin A_1c, HbA_1c]) in adult and pediatric (1 year and older) patients with type 1 or type 2 diabetes mellitus and is more effective in adults with type 2 diabetes mellitus than the oral antidiabetic agent, sitagliptin.1,2,3,4,5,6,7,8,9,10,20 Current evidence suggests that the prolonged duration of action and low variability in insulin degludec concentrations over the dosing interval may contribute to potentially lower rates of hypoglycemia (particularly nocturnal hypoglycemia) compared with other basal insulins.1,2,3,5,9,12,14,18,19,21 The peakless pharmacokinetic profile of insulin degludec allows for the timing of a once-daily injection to be varied from day to day in adults (when required) without increasing the risk of hypoglycemia (see Description); this flexibility in dosing may make insulin therapy less demanding and more acceptable to some patients, potentially improving patient compliance and glycemic control.1,12,14,19,21,25 Some clinicians suggest that insulin degludec may be a more suitable option than other basal insulins (i.e., insulin detemir, insulin glargine) in individuals who are prone to hypoglycemia and in those who require twice-daily administration of a basal insulin for adequate glycemic control,15 as well as in patients who experience variability in glycemic control with other basal insulins.16,21

Type 1 Diabetes Mellitus

Safety and efficacy of insulin degludec for the treatment of type 1 diabetes mellitus has been demonstrated in comparisons with insulin detemir or insulin glargine in 3 randomized, open-label, noninferiority phase 3 trials of 26 or 52 weeks' duration in adults and a study in pediatric patients 1-17 years of a patients also received mealtime insulin aspart during these trials.1,2,3,4,13,35 In a phase 3 trial in adults with type 1 diabetes mellitus who had been treated with basal and rapid-acting (“bolus”) insulins for at least 1 year, patients received insulin degludec once daily with the evening meal or insulin glargine once daily at the same time each day, both in conjunction with mealtime insulin aspart.1,2 Basal insulin dosages were titrated based upon fasting plasma glucose concentrations.2 After 52 weeks of therapy, the decrease in HbA_1c from baseline was similar between treatment groups (average reduction in HbA_1c of 0.36 and 0.34% for insulin degludec and insulin glargine, respectively).1 The rate of nocturnal hypoglycemia (per patient-year of exposure) with insulin degludec in this trial was 25% lower than that with insulin glargine; however, the rate of severe hypoglycemic episodes did not differ substantially between the treatment groups.2 In another similar phase 3 trial, adults with type 1 diabetes mellitus received insulin degludec or insulin detemir once daily between the evening meal and bedtime, both in conjunction with mealtime insulin aspart.1,3 Patients who received insulin detemir were eligible to receive a second dose daily if there was inadequate glycemic control after at least 8 weeks of therapy.3 Basal insulin dosages were titrated based upon fasting blood glucose concentrations.3 After 26 weeks of therapy, the decrease in HbA_1c from baseline was similar between treatment groups (average reduction in HbA_1c of 0.71 and 0.61% for insulin degludec and insulin detemir treatment groups, respectively).1 Treatment with insulin degludec was associated with a substantially lower rate of nocturnal hypoglycemia than insulin detemir.3 In a third phase 3 trial, adults with type 1 diabetes mellitus received insulin degludec once daily (at the same time each day or at alternating times daily [minimum of 8 and maximum of 40 hours between doses]) or insulin glargine once daily, all in conjunction with mealtime insulin aspart.1,4 Basal insulin dosages were titrated based upon fasting plasma glucose concentrations.4 After 26 weeks of therapy, the treatment group that received insulin degludec at varying times of the day had similar reductions in HbA_1c as those patients who received insulin degludec or insulin glargine injections at the same time every day (average reduction in HbA_1c of 0.41, 0.4, and 0.57% for insulin degludec administered at the same time each day, insulin degludec administered at varying times, and insulin glargine treatment groups, respectively).1 The treatment group receiving insulin degludec at varying times of the day had lower rates of nocturnal hypoglycemia than the insulin glargine treatment group.4

In another study, pediatric patients 1-17 years of age (mean age: 10 years) with type 1 diabetes mellitus received insulin degludec once daily or insulin detemir once or twice daily, all in conjunction with mealtime insulin aspart.1,35 After 26 weeks of therapy, the mean decrease in HbA_1c from baseline did not differ substantially between treatment groups (reduction in HbA_1c of 0.19 and 0.34% for insulin degludec and insulin detemir treatment groups, respectively).1 At the conclusion of the additional 26-week extension period of this study, the observed mean decrease in HbA_1c remained similar between the 2 treatment groups; no substantial difference in the rates of hypoglycemia between groups was observed.35

Type 2 Diabetes Mellitus

Safety and efficacy of insulin degludec administered once daily in adults with type 2 diabetes mellitus have been established in 6 open-label, randomized clinical trials of 26 or 52 weeks' duration that compared insulin degludec with sitagliptin or with other basal insulins (i.e., insulin detemir or insulin glargine) in conjunction with oral antidiabetic agents or mealtime insulin.1,5,6,7,8,9,10 In a noninferiority trial in insulin-naive patients with type 2 diabetes mellitus who were inadequately controlled with oral antidiabetic therapy, once-daily therapy with insulin degludec or insulin glargine was added to existing therapy with metformin with or without a dipeptidyl peptidase-4 (DPP-4) inhibitor.1,5 Insulin degludec and insulin glargine provided similar improvements in glycemic control (as measured by HbA_1c, the primary clinical end point) in this trial.1,5 The proportion of patients attaining target HbA_1c values of less than 7% at trial end point was similar across treatment groups.1,5 The risk of nocturnal hypoglycemia was lower with insulin degludec compared with that observed with insulin glargine.5

In another noninferiority trial in insulin-naive Asian patients with type 2 diabetes mellitus who were inadequately controlled with oral antidiabetic therapy, once-daily therapy with insulin degludec or insulin glargine was added to existing therapy with 1 or more oral antidiabetic agents (metformin, a sulfonylurea, a meglitinide, or an alpha-glucosidase inhibitor).1,7 Patients receiving a glucagon-like peptide-1 (GLP-1) receptor agonist (exenatide or liraglutide) or a thiazolidinedione within 3 months of trial screening were excluded from the trial.1,7 All patients received an initial insulin degludec or insulin glargine dosage of 10 units subcutaneously once daily.1,7 Insulin dosages were titrated once weekly based on fasting plasma glucose concentrations.7 After 26 weeks of treatment, the observed mean HbA_1c and fasting plasma glucose concentrations were similar for insulin degludec and insulin glargine.1,7 Additionally, there was no substantial difference in the proportion of patients achieving an HbA_1c less than 7%.1,7

In a trial evaluating the safety and efficacy of varying the daily injection time of insulin degludec, adults with type 2 diabetes mellitus inadequately controlled on basal insulin, oral antidiabetic agents, or a combination of these agents received insulin degludec once daily with the evening meal, insulin degludec once daily at varying times, or insulin glargine once daily.1,8 Patients who received insulin degludec at varying times were given alternating morning and evening injections (minimum of 8 hours and maximum of 40 hours maintained between injections).8 Patients receiving once-daily basal insulin prior to the study were transitioned to insulin degludec or insulin glargine on a unit-for-unit basis.8 Insulin dosages were titrated individually once a week throughout the trial based upon fasting plasma glucose concentrations.8 Patients receiving oral antidiabetic agents were allowed to continue treatment with up to 3 oral antidiabetic agents (metformin, a sulfonylurea, a meglitinide, or a thiazolidinedione) during the trial.1 Overall, insulin degludec given at variable dosing intervals resulted in similar glycemic control, hypoglycemic risk, and weight gain compared with either insulin glargine or insulin degludec given at fixed dosing intervals.8 There was no substantial difference in HbA_1c between patients who received insulin degludec once daily, insulin degludec once daily at varying administration times, or insulin glargine once daily.1,8

In a noninferiority trial in adults with type 2 diabetes mellitus inadequately controlled on insulin and/or oral antidiabetic agents, no difference in overall glycemic control (as assessed by HbA_1c) was observed in patients receiving therapy with insulin degludec or insulin glargine;1,9 however, insulin degludec therapy was associated with a lower risk of hypoglycemia than insulin glargine.9 In this trial, patients received once-daily insulin degludec or once-daily insulin glargine, both in combination with mealtime insulin aspart, with or without oral antidiabetic agents (metformin, pioglitazone, or both).1,9 After 52 weeks of treatment, HbA_1c decreased by 1.1 and 1.2% in the insulin degludec and insulin glargine treatment groups, respectively.1,9 Rates of overall, nocturnal, and diurnal hypoglycemia were substantially lower in patients treated with insulin degludec versus insulin glargine.9

In a trial comparing the efficacy of insulin degludec with sitagliptin in insulin-naive adults with type 2 diabetes mellitus, insulin degludec improved glycemic control and was superior to sitagliptin in terms of lowering HbA_1c.1,10 Patients in this trial received add-on treatment with subcutaneous insulin degludec once daily at any time of the day (minimum of 8 hours and maximum of 40 hours between injections) or sitagliptin 100 mg orally once daily; all patients were receiving stable therapy with 1-2 oral antidiabetic agents (metformin, a meglitinide, a sulfonylurea, or pioglitazone) at baseline.1,10 The starting dosage of insulin degludec was 10 units once daily, which was titrated weekly based upon fasting plasma glucose concentrations.10 Sitagliptin was administered at a dosage of 100 mg orally once daily.10 After 26 weeks of treatment, HbA_1c was reduced by 1.52 and 1.09% in patients receiving insulin degludec and sitagliptin therapy, respectively.1,10 Patients receiving insulin degludec therapy also had a lower fasting blood glucose after 26 weeks of treatment compared with those receiving sitagliptin therapy (mean fasting glucose 112 versus 154 mg/dL, respectively).1,10

Insulin Degludec/Liraglutide Fixed-combination Therapy

Current data indicate that the fixed combination of insulin degludec and liraglutide is more effective than either drug (as add-on therapy to one or more oral antidiabetic agents) in improving glycemic control (as determined by reductions in HbA_1c) in patients with type 2 diabetes mellitus.37,38,39 Safety and efficacy of insulin degludec and liraglutide in fixed combination for the treatment of type 2 diabetes mellitus have been established in 5 parallel, randomized, active- or placebo-controlled phase 3 clinical trials of 26 weeks' duration in adults with type 2 diabetes mellitus.36,37,38,39,40

In 2 clinical studies, the use of the fixed combination of insulin degludec and liraglutide substantially improved glycemic control in adults with type 2 diabetes mellitus who had inadequate glycemic control with oral antidiabetic agents and who were naive to therapy with a basal insulin or GLP-1 receptor agonist.36 In the first study, all patients continued on prestudy treatment with metformin with or without pioglitazone.36 In addition to the prestudy treatment, patients also received insulin degludec and liraglutide in fixed combination (initially 10 units of insulin degludec and 0.36 mg liraglutide), liraglutide (initially 0.6 mg), or insulin degludec (initially 10 units) subcutaneously once daily.36 Patients in the fixed-combination group or the insulin degludec treatment group had their dosages titrated twice weekly towards a target fasting plasma glucose concentration of 72-90 mg/dL.36 Patients in the liraglutide treatment group followed a fixed-escalation scheme with weekly dosage increases of 0.6 mg until the maintenance dosage of 1.8 mg once daily was achieved.36 After 26 weeks, the reduction in HbA_1c from baseline was 1.81, 1.35, or 1.21% in patients treated with the fixed combination of insulin degludec and liraglutide, insulin degludec, or liraglutide, respectively.36 In the second study, all patients continued on prestudy treatment with a sulfonylurea with or without metformin.36 In addition to the prestudy treatment, patients also received insulin degludec and liraglutide in fixed combination (initially 10 units of insulin degludec and 0.36 mg liraglutide) or placebo once daily.36 Patients in the fixed-combination group had their dosage titrated twice weekly towards a target fasting plasma glucose concentration of 72-108 mg/dL.36 After 26 weeks, the reduction in HbA_1c from baseline was 1.42 or 0.62% in patients treated with the fixed combination of insulin degludec and liraglutide or placebo, respectively.36

In another trial, insulin-naive adults with type 2 diabetes mellitus who were inadequately controlled on metformin alone or in combination with pioglitazone and/or a sulfonylurea plus maximum-dose (or maximally tolerated) liraglutide (mean daily dosage at baseline: 1.7 mg) continued to receive their pretrial therapy or had their therapy converted from liraglutide to the fixed combination of insulin degludec and liraglutide.36,38 Oral antidiabetic agents were continued at pretrial dosages throughout the trial in both treatment groups.36 The starting dosage of the fixed combination was insulin degludec 16 units and liraglutide 0.58 mg once daily; dosage adjustments were performed twice weekly based on fasting blood glucose concentrations (end-of-trial dosage of the fixed combination: insulin degludec 44 units and liraglutide 1.58 mg daily).36,38 After 26 weeks, the reduction in HbA_1c from baseline was 1.31 or 0.36% with the fixed combination of insulin degludec and liraglutide versus liraglutide, respectively.36,38 A mean weight gain from baseline of 2 kg was observed in patients receiving the fixed combination of insulin degludec and liraglutide compared with a weight loss of 0.8 kg in those receiving liraglutide.38 A higher rate of hypoglycemia was observed in the fixed-combination treatment group.38

In another trial comparing the fixed combination of insulin degludec and liraglutide with insulin degludec therapy in adults with type 2 diabetes mellitus who were inadequately controlled with basal insulin and metformin with or without a sulfonylurea or a meglitinide, patients who received the fixed combination at equivalent insulin dosages achieved superior glycemic control.36,39 In this trial, all basal insulins and oral antidiabetic drugs except for metformin hydrochloride (mean daily dosage: 1984 mg) were discontinued at randomization; patients received a starting insulin degludec dosage of 16 units (given separately or in fixed combination with liraglutide 0.58 mg) once daily, which was titrated biweekly based on fasting plasma glucose concentrations.39 After 26 weeks, the mean daily dosage of insulin degludec was 46 units (with liraglutide 1.66 mg in the fixed combination) in both treatment groups.36 The reductions in HbA_1c from baseline were superior with the fixed combination of insulin degludec and liraglutide compared with insulin degludec treatment (reduction of 1.94 versus 1.05%, respectively).36 There was no substantial difference between the 2 treatment groups with regard to hypoglycemia.39

In another trial comparing the fixed combination of insulin degludec and liraglutide with insulin glargine therapy in adults with type 2 diabetes mellitus inadequately controlled on insulin glargine and metformin, patients who received the fixed combination of insulin degludec and liraglutide achieved substantially greater reductions in HbA_1c compared with those who received insulin glargine.36,40 Patients in this trial either continued treatment with insulin glargine or were switched to the fixed combination of insulin degludec and liraglutide, both in conjunction with metformin.36,40 The starting insulin degludec dosage was 16 units daily (with liraglutide 0.58 mg in the fixed combination), irrespective of the patient's previous daily dosage of insulin glargine (mean insulin glargine pretrial dosage: 31 units daily).40 Patients whose therapy was switched from insulin glargine to the fixed combination of insulin degludec and liraglutide showed no worsening of blood glucose control immediately following the switch, despite the initial reduction in insulin dosage for patients who received the fixed combination.40 Each treatment was titrated biweekly based on fasting blood glucose concentrations with no upper dosing limit in the insulin glargine group and a maximum daily dosage of 50 units of insulin degludec in the fixed-combination treatment group.40 The mean dosage of the fixed combination of insulin degludec and liraglutide or insulin glargine was 41 units insulin degludec and 1.48 mg liraglutide or 66 units of insulin glargine daily, respectively.36 The reductions in HbA_1c from baseline were substantially greater with the fixed combination of insulin degludec and liraglutide compared with insulin glargine (reduction of 1.67 versus 1.16 %, respectively).36

Insulin degludec and liraglutide in fixed combination should not be used for the treatment of diabetic ketoacidosis or for the treatment of type 1 diabetes mellitus.36 The fixed combination also should not be used with any other preparation containing liraglutide or another GLP-1 receptor agonist.36 Data are lacking on the use of the fixed combination of insulin degludec and liraglutide with prandial insulin.36

General

The dosage of insulin degludec is expressed in units.1 Each mL of insulin degludec injection contains 100 or 200 units of insulin degludec.1 Each mL of the fixed combination of insulin degludec and liraglutide contains 100 units of insulin degludec and 3.6 mg of liraglutide.36

Dosage of insulin degludec should be carefully individualized to obtain optimum therapeutic effect based on the patient's metabolic needs, blood glucose determinations, and glycemic control goals.1,36 Glucose monitoring is recommended for all patients with diabetes mellitus.1

Dosage adjustments of insulin degludec or the fixed combination of insulin degludec and liraglutide may be needed when used with other drugs or with intercurrent conditions (e.g., illness, stress, emotional disturbances), changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), or changes in weight or renal or hepatic function.1,36

The 100-units/mL and 200-units/mL formulations of insulin degludec are pharmacodynamically and pharmacokinetically bioequivalent and have shown similar effects on glycemic control at equivalent dosages in clinical trials.1,6,14 Dose conversions between the insulin degludec 100- and 200-units/mL FlexTouch^® injection pens based on differences in insulin concentration are not necessary and should not be performed.1,6 The dose window for the insulin degludec 100- and 200-units/mL FlexTouch^® injection pens displays the number of insulin degludec units to be delivered independent of insulin concentration, and no conversion is needed to calculate the dose using either injection pen.1,6

Administration

Insulin degludec is administered by subcutaneous injection once daily using a FlexTouch^® injection pen.1 Because of its delayed absorption and long duration of action, insulin degludec may be administered at any time of the day in adults.1,20 However, in pediatric patients, the drug should be administered once daily at the same time every day.1

The fixed combination of insulin degludec and liraglutide is administered by subcutaneous injection once daily at the same time each day without regard to meals in adults; the injection is administered using the Xultophy^® injection pen.36

Insulin degludec or the fixed combination of insulin degludec and liraglutide should not be given IV or IM, nor should it be given via an insulin infusion pump.1,36 (See Description.) Insulin degludec or the fixed combination with liraglutide should not be mixed with any other insulin preparations or solutions.1,36

Insulin degludec or the fixed combination of insulin degludec and liraglutide is administered subcutaneously into the thigh, abdomen, or upper arm.1,36 A planned rotation of sites within an area should be followed to reduce the risk of lipodystrophy.1

The accompanying labeling should be consulted for proper methods of administration and care of the FlexTouch^® or Xultophy^® injection pen.1,36 These injection pens are used with NovoFine^® or NovoTwist^® needles.1,36 Insulin degludec should not be transferred from the FlexTouch^® injection pen into a syringe for administration.1 (See Hypoglycemia: Hypoglycemia Due to Medication Errors under Warnings/Precautions, in Cautions.)

For adults who miss a dose of insulin degludec, the missed dose should be injected as soon as remembered during waking hours if at least 8 hours have elapsed between consecutive doses.1 If a pediatric patient misses a dose of insulin degludec, the patient or a parent or caregiver should be instructed to contact the child's clinician for guidance about dosing and monitoring blood glucose concentrations more frequently until the next scheduled insulin degludec dose.1 Patients who miss a dose of the fixed combination of insulin degludec and liraglutide should be instructed to resume the once-daily regimen as prescribed with the next scheduled dose; however, if more than 3 days have elapsed since the last dose, the fixed combination of insulin degludec and liraglutide should be reinitiated at the starting dose to mitigate GI symptoms related to the liraglutide component.36

Unopened injection pens containing insulin degludec or the fixed combination of insulin degludec and liraglutide should be stored at 2-8°C until the expiration date.1,36 Alternatively, unopened insulin degludec injection pens may be stored at room temperature (up to 30°C) for up to 56 days.1 Injection pens containing insulin degludec or the fixed combination of insulin degludec and liraglutide should not be subjected to freezing; if freezing has occurred, the pen should not be used.1,36 In-use insulin degludec pens may be stored at room temperature (up to 30°C) or under refrigeration (2-8°C) away from direct heat and light for up to 56 days.1 In-use pens containing the fixed combination of insulin degludec and liraglutide may be stored at room temperature (15-30°C) or under refrigeration (2-8°C) away from heat or light for up to 21 days.36

Dosage

Insulin Degludec Therapy

Dosage of insulin degludec may be increased every 3-4 days as needed.1

Insulin-Naive Patients

In patients with type 1 diabetes mellitus, insulin degludec should be administered once daily concomitantly with a prandial, shorter-acting (“bolus”) insulin to provide more optimal postprandial glycemic control.1,14,19 In patients with type 2 diabetes mellitus, insulin degludec can be administered alone or concomitantly with oral antidiabetic agents or with a shorter-acting insulin.1,14,19 When used in a meal-related subcutaneous insulin regimen in patients with type 1 diabetes mellitus, an initial insulin degludec dosage usually comprises one-third to one-half of the total daily insulin dosage, with the remainder given preprandially in divided doses as a rapid- or short-acting insulin.1 An initial total daily dosage of insulin (total combined dosages of basal and rapid- or short-acting insulins) of 0.2-0.4 units/kg generally is recommended for insulin-naive patients with type 1 diabetes mellitus.1 The dosage of insulin degludec should be titrated based upon the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal.1

In insulin-naive adult and pediatric patients with type 2 diabetes mellitus, the recommended initial dosage of insulin degludec is 10 units once daily, with subsequent dosage adjustments to achieve glycemic goals.1,32

Transferring from Therapy with Other Insulins

When insulin degludec is substituted for another intermediate- or long-acting insulin in adults with type 1 or type 2 diabetes mellitus, the manufacturer states that the initial dosage of insulin degludec for adults can be identical (on a unit-for-unit basis) to the total daily dosage of the previous longer-acting insulin.1 The dosage and timing of concurrent short- or rapid-acting insulins or other concomitant antidiabetic agents may need to be adjusted with the initiation of insulin degludec therapy.1,19

For pediatric patients 1 year of age and older with type 1 or type 2 diabetes mellitus, the manufacturer recommends initiating insulin degludec at 80% of the previous total daily intermediate- or long-acting insulin dose to reduce the risk of hypoglycemia.1 The dosage of insulin degludec should then be adjusted according to blood glucose determinations to achieve glycemic goals.1 Close monitoring of blood glucose concentrations is recommended during the transition to insulin degludec from other insulin therapies.1,19 Additionally, adjustments to the dose and timing of concurrent short- or rapid-acting insulin or other glucose-lowering treatments (e.g., oral antidiabetic agents) may also be required.1,19

For additional information on monitoring and management of insulin therapy, see Dosage: Considerations in Monitoring Insulin Therapy, in Dosage and Administration in the Insulins General Statement 68:20.08.

Insulin Degludec/Liraglutide Fixed-combination Therapy

In adults with type 2 diabetes mellitus who are naive to basal insulin or a glucagon-like peptide-1 (GLP-1) receptor agonist, the recommended initial dosage of the fixed combination of insulin degludec and liraglutide (Xultophy^®) is 10 units (10 units of insulin degludec and 0.36 mg of liraglutide) once daily.36

In adults with type 2 diabetes mellitus who are currently receiving basal insulin or a GLP-1 receptor agonist (e.g., liraglutide), such therapy must be discontinued prior to initiation of the fixed combination of insulin degludec and liraglutide.36 The recommended initial dosage of the fixed combination in these patients is 16 units (16 units of insulin degludec and 0.58 mg of liraglutide) once daily.36

Dosage of insulin degludec in the fixed combination with liraglutide may be increased or decreased by 2 units (2 units of insulin degludec and 0.072 mg of liraglutide) every 3-4 days as needed.36 The fixed combination of insulin degludec and liraglutide should not be administered more than once daily.36 Adjustments in concomitant oral antidiabetic therapy may be needed.36

The maximum daily dosage of insulin degludec in fixed combination with liraglutide is 50 units (50 units of insulin degludec and 1.8 mg of liraglutide).36

Special Populations

Hepatic Impairment

As with all insulin preparations, glucose monitoring should be intensified and the dosage of insulin degludec adjusted on an individual basis in patients with hepatic impairment.1,27 Safety and efficacy of the fixed combination of insulin degludec and liraglutide have not been established in patients with hepatic impairment.36

Renal Impairment

As with all insulin preparations (including combination preparations), glucose monitoring should be intensified and the dosage of insulin degludec adjusted on an individual basis in patients with renal impairment.1,26,36 Safety and efficacy of the fixed combination of insulin degludec and liraglutide have not been established in patients with renal impairment.36

Geriatric Patients

In geriatric patients, the initial dosage, dose increments, and maintenance dosage of insulin degludec or the fixed combination of insulin degludec and liraglutide should be conservative in order to avoid hypoglycemia.1,36

Contraindications

Insulin degludec alone or in fixed combination with liraglutide is contraindicated in patients with known hypersensitivity to insulin degludec or to any ingredient in the formulation.1,36 Insulin degludec alone or in fixed combination with liraglutide also is contraindicated during episodes of hypoglycemia.1,36

The fixed combination of insulin degludec and liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with multiple endocrine neoplasia type 2 (MEN 2).36

Warnings/Precautions

Use of Fixed Combinations

When insulin degludec is used in fixed combination with liraglutide or other drugs, the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) should be considered in addition to those associated with insulin degludec.36

Hypoglycemia

Hypoglycemia is the most common adverse effect of insulins, including insulin degludec, and monitoring of blood glucose concentrations is recommended for all patients with diabetes mellitus.1,36 Severe hypoglycemia can cause seizures, may be life-threatening, or cause death.1,36 The onset of hypoglycemia depends on the action profile of the insulin used and may change when the treatment regimen or timing of dosing of the insulin is changed.1 (See Transferring from Therapy with Other Insulins under Dosage: Insulin Degludec Therapy, in Dosage and Administration.) As with all insulin preparations, the time course of the glucose-lowering effect of insulin degludec or the fixed combination of insulin degludec and liraglutide may vary among different individuals or at different times in the same individual and depends on many conditions (e.g., the area of injection, the injection site blood supply and temperature).1,36 The risk of hypoglycemia generally increases with the intensity of glycemic control.1,36 Other factors that may increase a patient's risk of hypoglycemia include changes in meal patterns, changes in level of physical activity, or changes to concomitant drug therapy.1 Patients with renal or hepatic impairment may be at higher risk of hypoglycemia.1,36 (See Renal Impairment and also see Hepatic Impairment under Dosage and Administration: Special Populations.) Some evidence suggests that insulin degludec may be associated with a lower risk of hypoglycemia, particularly nocturnal hypoglycemia, than insulin glargine and insulin detemir.2,3,5,9,12,14,18,19,21 (For more information on the symptoms associated with hypoglycemia, see Hypoglycemia under Cautions: Endocrine and Metabolic Effects, in the Insulins General Statement 68:20.08.)

Hypoglycemia Due to Medication Errors

Confusion between basal insulin preparations and other insulins, particularly rapid-acting insulins, has caused medication errors.1 To avoid such errors, patients should be advised to check the label on all insulin preparations to confirm the correct formulation and strength prior to administration.1,36 Insulin degludec should not be transferred from the FlexTouch^® injection pen into an insulin syrin the insulin syringe will not measure the dose correctly, and may cause an overdose and severe hypoglycemia.1

Formulation Considerations

Any change in insulin should be made cautiously and only under medical supervision.1,19,36 Insulin degludec should not be diluted or mixed with any other insulins or solutions.1 Changes in insulin type, manufacturer, and/or method of administration may predispose patients to hypoglycemia or hyperglycemia.1 The frequency of blood glucose monitoring should be increased when changing a patient's insulin regimen.1,36 Adjustments to the dosage and timing of concurrent short- or rapid-acting insulin or other glucose-lowering treatments (e.g., oral antidiabetic agents) may be required.1,19,36 (See Transferring from Therapy with Other Insulins under Dosage: Insulin Degludec Therapy, in Dosage and Administration.)

Sharing of Injection Pens

Injection pens containing insulin degludec or the fixed combination of insulin degludec and liraglutide must never be shared among patients, even if the needle has been changed.1,36 Sharing of injection pens poses a risk for transmission of blood-borne pathogens.1,36

Hypokalemia

All insulin preparations, including insulin degludec, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia.1,36 Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death.1,36 Serum potassium concentrations should be monitored in patients at risk for hypokalemia (e.g., patients receiving potassium-lowering drugs, patients taking drugs with effects sensitive to serum potassium concentrations).1,36

Metabolic Effects

Insulin therapy may cause sodium retention and edema.1,36 Insulin therapy, including insulin degludec, also may cause weight gain attributable to the anabolic effects of insulin.1

Heart Failure

Peroxisome proliferator-activated receptor (PPAR)-γ agonists (e.g., thiazolidinediones) can cause dose-related fluid retention, particularly when used in combination with insulin.1,23,24,36 Fluid retention may lead to or exacerbate heart failure.1,23,24 Patients treated with insulins, including insulin degludec, and a PPAR-γ agonist should be observed for manifestations of heart failure (e.g., excessive/rapid weight gain, shortness of breath, edema).1,23,36 If heart failure develops, it should be managed according to current standards of care and discontinuance or reduction of the dosage of the PPAR-γ agonist must be considered.1,23,36 Concomitant use of rosiglitazone and insulin therapy is not recommended.24

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity with insulin degludec or the fixed combination of insulin degludec and liraglutide.1,36 In studies in patients with type 1 and type 2 diabetes mellitus, anti-insulin antibodies were detected in patients receiving insulin degludec therapy, including some patients who had anti-insulin antibodies at baseline.1 The presence of antibodies that affect clinical efficacy may require dosage adjustments to correct for tendencies toward hyperglycemia or hypoglycemia.1 The incidence of anti-insulin degludec antibodies has not been established.1

Antiliraglutide antibodies have been found in patients who received the fixed combination of insulin degludec and liraglutide; however, this antibody formation has not been associated with reduced efficacy of the fixed combination.36

Sensitivity Reactions

Dermatologic and Hypersensitivity Reactions

As with any insulin therapy, lipodystrophy may occur at sites of insulin injections and may affect insulin absorption.1,36 Injection site rotation may reduce the risk of lipodystrophy.1 Localized allergic reactions (e.g., pruritus, erythema, swelling) at the injection site may develop in patients receiving insulin, including insulin degludec.1,36 Pain,1,36 hematoma,1,36 hemorrhage,1,36 discoloration,1,36 warmth,1,36 injection site mass,1,36 and nodules at the injection site of insulin degludec or the fixed combination of insulin degludec and liraglutide also have been reported.1,36

Severe, life-threatening, generalized allergic reactions, including anaphylaxis, angioedema, bronchospasm, hypotension, and shock, may occur with insulin preparations, including insulin degludec.1,36 If hypersensitivity reactions occur, insulin degludec therapy or the fixed combination of insulin degludec and liraglutide should be discontinued and appropriate treatment initiated; patients should be monitored until the hypersensitivity reaction resolves.1,36

Specific Populations

Pregnancy

Data are lacking on the use of insulin degludec in pregnant women.1 In reproduction studies in animals, insulin degludec caused pre- and post-implantation loss and visceral/skeletal abnormalities in the offspring of pregnant rats and rabbits at maternal plasma concentrations 5-10 times higher than those achieved with a subcutaneous human dosage of 0.75 units/kg per day.1,20 The manufacturer states that these effects are probably secondary to maternal hypoglycemia.1 Insulin degludec should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.1

Data are lacking on the use of the fixed combination of insulin degludec and liraglutide in pregnant women.36 Animal studies suggest that there may be risks to the fetus from exposure to liraglutide during pregnancy.36 The fixed combination of insulin degludec and liraglutide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.36

Lactation

Insulin degludec is distributed into milk in rats; it is not known whether the drug is distributed into human milk.1 The benefits of breast-feeding and the importance of insulin degludec to the woman should be considered along with any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1

Pediatric Use

Safety and efficacy of insulin degludec have not been established in pediatric patients younger than 1 year of age.1 Insulin degludec is not recommended for pediatric patients who require less than 5 units of insulin degludec daily; in clinical trials, pediatric patients receiving less than 5 units daily had their dosages titrated in 0.5-unit increments, which cannot be measured accurately with the commercially available FlexTouch^® injection pen.1,32 In pediatric patients whose therapy is being transferred from another long- or intermediate-acting insulin to insulin degludec, the drug should be initiated at a reduced dosage to minimize the risk of hypoglycemia.1 (See Transferring from Therapy with Other Insulins under Dosage: Insulin Degludec Therapy, in Dosage and Administration.)

Safety and efficacy of insulin degludec in pediatric patients 1 year of age and older are based on a noninferiority clinical study of 12 months' duration in patients 1-17 years of age with type 1 diabetes mellitus, a pharmacokinetic study that included approximately 200 patients 1-17 years of age with type 1 diabetes mellitus, and data from clinical trials conducted in adults with type 2 diabetes mellitus.1,35 In the noninferiority study, insulin degludec and insulin detemir provided similar glycemic control (as determined by glycosylated hemoglobin [hemoglobin A_1c, HbA_1c]).1,35 Adverse effects reported in pediatric patients with type 1 diabetes mellitus who were receiving insulin degludec therapy were similar to those reported in adults.1

Safety and efficacy of the fixed combination of insulin degludec and liraglutide have not been established in pediatric patients.36

Geriatric Use

No substantial differences in safety and efficacy of insulin degludec or the fixed combination of insulin degludec and liraglutide have been observed in geriatric patients relative to younger patients; however, increased sensitivity of some older patients cannot be ruled out.1,36 Data indicate that the pharmacokinetic and pharmacodynamic properties of insulin degludec at steady sate are similar in younger adults and geriatric patients; however, greater variability has been observed among geriatric patients.1 Initial dosage, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia.1,36 Hypoglycemia may be difficult to recognize in geriatric patients.1,36

Renal Impairment

In a pharmacokinetic study in patients with or without renal impairment (including some patients with end-stage renal disease) who received a single subcutaneous dose of insulin degludec, there was no clinically relevant difference in the pharmacokinetic parameters in the renally impaired patients compared with healthy individuals.1,25,26 Blood glucose concentrations should be monitored closely; adjustment of insulin degludec dosage may be necessary.1

Experience with the fixed combination of insulin degludec and liraglutide in patients with mild, moderate, or severe renal impairment is limited; the drug should be used with caution in such patients.36 (See Dosage and Administration: Special Populations.)

Hepatic Impairment

In a pharmacokinetic study in patients with or without hepatic impairment (mild to severe hepatic impairment) who received a single subcutaneous dose of insulin degludec, there was no clinically relevant difference in the pharmacokinetic parameters in the hepatically impaired patients compared with healthy individuals.1,25,27 Blood glucose concentrations should be monitored closely; adjustment of insulin degludec dosage may be necessary.1

Experience with the fixed combination of insulin degludec and liraglutide in patients with mild, moderate, or severe hepatic impairment is lacking.36 (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Common adverse effects associated with insulin degludec during clinical trials include hypoglycemia,1,2,3,14 allergic reactions,1 injection site reactions,1,3,14 lipodystrophy,1 pruritus,1 rash,1 edema,1 and weight gain.1,2,3 Adverse effects occurring in at least 5% of patients with type 1 or type 2 diabetes mellitus who received insulin degludec during clinical trials include nasopharyngitis,1,14 headache,1,14 and upper respiratory tract infection.1,14 Sinusitis and gastroenteritis also were reported in at least 5% of patients with type 1 diabetes mellitus who received insulin degludec during clinical trials.1 Diarrhea was reported in at least 5% of patients with type 2 diabetes mellitus who received insulin degludec during clinical trials.1,14

Adverse effects occurring in at least 5% of patients with type 2 diabetes mellitus who received the fixed combination of insulin degludec and liraglutide include nasopharyngitis,36,38 headache,36,38 nausea,36,38 diarrhea,36 increased lipase concentrations,36,38 and upper respiratory tract infection.36,38

Drugs Affecting Glycemic Control

Drugs that May Potentiate Hypoglycemic Effects

Angiotensin-converting enzyme (ACE) inhibitors,1,14 angiotensin II receptor antagonists,1 antidiabetic agents,1,14 dipeptidyl peptidase-4 (DPP-4) inhibitors,1 disopyramide,1 fibrate derivatives,1 fluoxetine,1 glucagon-like peptide-1 (GLP-1) receptor agonists,1,14 monoamine oxidase (MAO) inhibitors,1,14 pentoxifylline,1 pramlintide,1 propoxyphene (no longer commercially available in US),1 salicylates,1,14 sodium-glucose cotransporter 2 (SGLT2) inhibitors,1 somatostatin analogs (e.g., octreotide),1 sulfonamide anti-infectives.1,14 Dosage reductions and increased frequency of glucose monitoring may be required if insulin degludec or the fixed combination of insulin degludec and liraglutide is used concomitantly with these drugs.1

Drugs that May Antagonize Hypoglycemic Effects

Atypical antipsychotics (e.g., olanzapine, clozapine),1 corticosteroids,1,14 danazol,1,14 diuretics (e.g., thiazides),1,14 estrogens or progestins (e.g., oral contraceptives),1,14 glucagon,1 niacin,1 phenothiazines,1 protease inhibitors,1 somatropin,1 sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline),1,14 thyroid hormones.1,14 Insulin degludec dosage increases and increased frequency of glucose monitoring may be required if insulin degludec is used concomitantly with these drugs.1

Drugs With a Variable Effect on Glycemic Control

Alcohol,1β-adrenergic blocking agents (β-blockers),1 clonidine,1 lithium salts,1 pentamidine.1 Adjustments of insulin degludec dosage and increased frequency of glucose monitoring may be required if insulin degludec is used concomitantly with these drugs.1

Sympatholytic Agents

May decrease or eliminate the signs and symptoms of hypoglycemia in patients receiving insulin degludec concomitantly with these drugs (e.g., β-blockers, clonidine, guanethidine, reserpine).1,14 Increased frequency of glucose monitoring may be required if insulin degludec is used concomitantly with these drugs.1

Peroxisome Proliferator-activated Receptor- Agonists

Peroxisome proliferator-activated receptor (PPAR)-γ agonists (e.g., thiazolidinediones) can cause dose related fluid retention, particularly when used in combination with insulin.1,23,24 Fluid retention may lead to or exacerbate heart failure.1,23,24 Patients treated with insulin, including insulin degludec, and a PPAR-γ agonist should be observed for manifestations of heart failure (e.g., excessive/rapid weight gain, shortness of breath, edema).1,23 (See Heart Failure under Cautions: Warnings/Precautions.) Concomitant use of rosiglitazone and insulin therapy is not recommended.24

Protein-bound Drugs

No clinically relevant interaction suggested by in vitro binding studies with other protein-bound drugs.1,32

Description

Insulin degludec is a biosynthetic (rDNA origin), long-acting insulin human analog that is prepared using a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification.1 Insulin degludec differs structurally from insulin human by the deletion of threonine at position 30 on the B chain and by the acylation of lysine at position 29 on the B chain with hexadecandioic acid, a 16-carbon fatty acid, via a glutamic acid spacer.1,14,19,22

Insulin degludec has pharmacologic effects comparable to those of insulin human.21 (See the Insulins General Statement 68:20.08.) The prolonged duration of action of insulin degludec is dependent in part on slow systemic absorption, predominantly due to the formation of a depot of soluble multihexamer chains after subcutaneous injection and to a lesser extent due to binding of insulin degludec to circulating albumin.1,14,15,19,21 The fatty acid side chain modification of insulin degludec favors the formation of stable dihexamers while in solution at a neutral pH in the presence of phenol and zinc.14,15,18,19,21,25 After subcutaneous injection, these dihexamers assemble into long multihexamers; the large molecular weight of these multihexamers slows absorption, which creates a subcutaneous depot of insulin degludec from which monomers slowly dissociate in circulation.18,25 Insulin degludec has a long, flat, stable glucose lowering-profile, with a duration of action exceeding 42 hours and a terminal elimination half-life of approximately 25 hours.1,14,18,19 Due to the prolonged pharmacodynamics of insulin degludec, under steady state conditions the overlapping effect of daily injections results in less variability in glucose-lowering effect.19 Total exposure (in terms of area under the concentration-time curve [AUC]) and glucose-lowering effect of insulin degludec have been shown to be more evenly distributed than other basal insulins across a 24-hour dosing interval (i.e., peakless) in patients with type 1 or type 2 diabetes mellitus.19,21,25 Insulin degludec has a longer duration of action than insulin detemir and insulin glargine, and insulin degludec therapy is associated with less pharmacodynamic variability than other basal insulins.3,14,18,25 Insulin degludec has been associated with a fourfold lower within-patient day-to-day variability with regard to total glucose lowering effect compared to insulin glargine.21,32,33

Advice to Patients

When insulin degludec is used in fixed combination with other drugs, importance of informing patients of important cautionary information about the concomitant agents.1,36

Importance of providing patient a copy of manufacturer's patient information.1,36 Importance of advising patient to read the manufacturer's medication guide before beginning treatment with insulin degludec in fixed combination with liraglutide and of reviewing this information each time the prescription is refilled.36,41

Importance of instructing patients not to administer the fixed combination of insulin degludec and liraglutide concurrently with other glucagon-like peptide-1 (GLP-1) receptor agonists.36 Importance of advising patients that dosages of insulin degludec exceeding 50 units daily given as the fixed combination with liraglutide can result in an overdose of the liraglutide component.36

Importance of informing patients that serious hypersensitivity reactions have been reported with insulin degludec or the fixed combination of insulin degludec and liraglutide; importance of instructing patients to stop taking insulin degludec or the fixed combination and seek prompt medical attention if such adverse reactions occur.1,36

Importance of advising patients to refer to patient information for additional information about the potential side effects of insulin therapy, including lipodystrophy (and the need to rotate injection sites within the same body region), weight gain, allergic reactions, and hypoglycemia.1

Importance of informing patients that they should never share an injection pen containing insulin degludec or the fixed combination of insulin degludec and liraglutide with another person, even if the needle is changed; sharing of the pen may pose a risk of transmission of infection.1,36

Importance of informing patients that hypoglycemia is the most common adverse effect of insulin.1,36 Importance of informing patients of the symptoms of hypoglycemia; the ability to concentrate and react may be impaired as a result of hypoglycemia, which may pose a risk in situations where these abilities are especially important (e.g., driving, operating machinery).1,36 Importance of advising patients who experience frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.1,36

Importance of advising patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia.1,36 Importance of changing insulin dosage with caution and only under medical supervision.1,36

Discuss potential for alterations in insulin requirements in special situations (e.g., illness, emotional disturbances, other stresses).1 Discuss potential for alterations in insulin requirements as a result of inadequate or skipped doses, or inadvertent administration of an incorrect dose.1

Importance of advising patients regarding what to do in the event of missed or delayed doses.1 (See Dosage and Administration: Administration.)

Importance of not mixing insulin degludec or the fixed combination of insulin degludec and liraglutide with other insulins or solutions.1,36 Importance of using insulin degludec or the fixed combination of insulin degludec and liraglutide only if the solution is clear and colorless with no visible particles.1,36

Importance of informing patients to always check the insulin label prior to each injection;1,36 insulin degludec is available in concentrations of 100 and 200 units/mL.1 Importance of informing patients that the dose window of the insulin degludec FlexTouch^® injection pen displays the number of units to be injected independent of insulin concentration; no recalculation of the dose is required to convert between different concentrations of insulin degludec.1 Importance of informing patients that the dose window of the injection pen containing the fixed combination of insulin degludec and liraglutide shows the number of units of insulin degludec to be injected; with each unit of insulin degludec, the pen also delivers 0.036 mg of liraglutide.36

Provide instructions regarding self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia.1

Provide instructions to patient regarding use of the subcutaneous injection devices containing insulin degludec or the fixed combination of insulin degludec and liraglutide.1,36 Patients should be cautioned against reuse of needles.1 Importance of advising patients to never use a syringe to remove insulin degludec from the FlexTouch^® injection pen.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1,36

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,36

Importance of informing patients of other important precautionary information.1,36 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Novo Nordisk. Tresiba^® (insulin degludec) injection prescribing information. Plainsboro, NJ; 2016 Dec.

2. Heller S, Buse J, Fisher M et al. Insulin degludec, an ultra-long acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet . 2012; 379:1489-97. [PubMed 22521071]

3. Davies MJ, Gross JL, Ono Y et al. Efficacy and safety of insulin degludec given as part of basal-bolus treatment with mealtime insulin aspart in type 1 diabetes: a 26-week randomized, open-label, treat-to-target non-inferiority trial. Diabetes Obes Metab . 2014; 16:922-30. [PubMed 24702700]

4. Mathieu C, Hollander P, Miranda-Palma B et al. Efficacy and safety of insulin degludec in a flexible dosing regimen vs insulin glargine in patients with type 1 diabetes (BEGIN: Flex T1): a 26-week randomized, treat-to-target trial with a 26-week extension. J Clin Endocrinol Metab . 2013; 98:1154-62. [PubMed 23393185]

5. Zinman B, Philis-Tsimikas A, Cariou B et al. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN Once Long). Diabetes Care . 2012; 35:2464-71. [PubMed 23043166]

6. Gough SC, Bhargava A, Jain R et al. Low-volume insulin degludec 200 units/ml once daily improves glycemic control similarly to insulin glargine with a low risk of hypoglycemia in insulin-naive patients with type 2 diabetes: a 26-week, randomized, controlled, multinational, treat-to-target trial: the BEGIN LOW VOLUME trial. Diabetes Care . 2013; 36:2536-42. [PubMed 23715753]

7. Onishi Y, Iwamoto Y, Yoo SJ et al. Insulin degludec compared with insulin glargine in insulin-naïve patients with type 2 diabetes: A 26-week, randomized, controlled, Pan-Asian, treat-to-target trial. J Diabetes Investig . 2013; 4:605-12. [PubMed 24843715]

8. Meneghini L, Atkin SL, Gough SC et al. The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes. Diabetes Care . 2013; 36:858-64. [PubMed 23340894]

9. Garber AJ, King AB, Del Prato S et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet . 2012; 379:1498-507. [PubMed 22521072]

10. Philis-Tsimikas A, Del Prato S, Satman I et al. Effect of insulin degludec versus sitagliptin in patients with type 2 diabetes uncontrolled on oral antidiabetic agents. Diabetes Obes Metab . 2013; 15:760-6. [PubMed 23577643]

11. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 203313Orig1s000/203314Orig1s000: summary review. From FDA website. [Web]

12. Khunti K, Cos X, Rutten G. Insulin degludec--the impact of a new basal insulin on care in type 2 diabetes. Prim Care Diabetes . 2014; 8:119-25. [PubMed 24207030]

13. US Food and Drug Administration. FDA News Release: FDA approves two new drug treatments for diabetes mellitus. 2015 Sep 25. Accessed 2016 Aug 10. [Web]

14. Keating GM. Insulin degludec and insulin degludec/insulin aspart: a review of their use in the management of diabetes mellitus. Drugs . 2013; 73:575-93. [PubMed 23620200]

15. Drab SR, Philis-Tsimikas A. A new option for glycemic control: insulin degludec, a new-generation basal insulin with an ultralong duration of action. Pharmacotherapy . 2014; 34:291-302. [PubMed 24132869]

16. Kalra S, Gupta Y. Clinical use of Insulin Degludec: Practical Experience and Pragmatic Suggestions. N Am J Med Sci . 2015; 7:81-5. [PubMed 25838998]

18. Atkin S, Javed Z, Fulcher G. Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus. Ther Adv Chronic Dis . 2015; 6:375-88. [PubMed 26568812]

19. Vora J, Cariou B, Evans M et al. Clinical use of insulin degludec. Diabetes Res Clin Pract . 2015; 109:19-31. [PubMed 25963320]

20. . Insulin degludec (Tresiba)--a new long-acting insulin for diabetes. Med Lett Drugs Ther . 2015; 57:163-4. [PubMed 26633683]

21. Kalra S. Insulin degludec: a significant advancement in ultralong-acting Basal insulin. Diabetes Ther . 2013; 4:167-73. [PubMed 24254338]

22. Jonassen I, Havelund S, Hoeg-Jensen T et al. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res . 2012; 29:2104-14. [PubMed 22485010]

23. Takeda Pharmaceuticals America, Inc. Actos^® (pioglitazone) tablets prescribing information. Deerfield, IL; 2013 Nov.

24. GlaxoSmithKline. Avandia^® (rosiglitazone maleate) tablets prescribing information. Research Triangle Park, NC; 2014 May.

25. Haahr H, Heise T. A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin Pharmacokinet . 2014; 53:787-800. [PubMed 25179915]

26. Kiss I, Arold G, Roepstorff C et al. Insulin degludec: pharmacokinetics in patients with renal impairment. Clin Pharmacokinet . 2014; 53:175-83. [PubMed 24163264]

27. Kupcová V, Arold G, Roepstorff C et al. Insulin degludec: pharmacokinetic properties in subjects with hepatic impairment. Clin Drug Investig . 2014; 34:127-33. [PubMed 24277680]

28. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 203313Orig1s000/203314Orig1s000: medical review(s). From FDA website. [Web]

29. US Food and Drug Administration. FDA briefing document from the endocrinologic and metabolic drugs advisory committee meeting, November 8, 2012. From FDA website [Web]

30. Standl E, Owen DR. New Long-Acting Basal Insulins: Does Benefit Outweigh Cost?. Diabetes Care . 2016; 39 Suppl 2:S172-9. [PubMed 27440830]

31. Kitabchi AE, Umpierrez GE, Miles JM et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care . 2009; 32:1335-43. [PubMed 19564476]

32. Novo Nordisk, Plainsboro, NJ: Personal communication.

33. Heise T, Hermanski L, Nosek L et al. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes Metab . 2012; 14:859-64. [PubMed 22594461]

35. Thalange N, Deeb L, Iotova V et al. Insulin degludec in combination with bolus insulin aspart is safe and effective in children and adolescents with type 1 diabetes. Pediatr Diabetes . 2015; 16:164-76. [PubMed 25683037]

36. Novo Nordisk. Xultophy^® (insulin degludec and liraglutide) injection prescribing information. Plainsboro, NJ; 2019 Feb.

37. . Drugs for type 2 diabetes. Med Lett Drugs Ther . 2017; 59:9-18. [PubMed 28076339]

38. Linjawi S, Bode BW, Chaykin LB et al. The Efficacy of IDegLira (Insulin Degludec/Liraglutide Combination) in Adults with Type 2 Diabetes Inadequately Controlled with a GLP-1 Receptor Agonist and Oral Therapy: DUAL III Randomized Clinical Trial. Diabetes Ther . 2017; 8:101-114. [PubMed 27943107]

39. Buse JB, Vilsbøll T, Thurman J et al. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care . 2014; 37:2926-33. [PubMed 25114296]

40. Lingvay I, Pérez Manghi F, García-Hernández P et al. Effect of Insulin Glargine Up-titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients With Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial. JAMA . 2016; 315:898-907. [PubMed 26934259]

41. Novo Nordisk. Xultophy^® (insulin degludec and liraglutide) injection medication guide. Plainsboro, NJ; 2016 Nov.