Levemir® efficacy and safety for adult patients

Tresiba® (insulin degludec injection) 100 U/mL, 200 U/mL

Another long-acting insulin from Novo Nordisk

Once-daily Tresiba®: Provide proven A1C control for your patients with diabetes.1

Levemir® A1C reductions across multiple clinical trials in adults with type 2 diabetes2-5

Levemir® A1C reductions across multiple clinical trials in adult patients with type 2 diabetes
Levemir® A1C reductions across multiple clinical trials in adult patients with type 2 diabetes
Levemir® A1C reductions across multiple clinical trials in adult patients with type 2 diabetes

aLevemir® can be dosed once or twice daily.6
*Estimated treatment difference between the Levemir® group and the comparator group.

24-hour action

Levemir® has a 24-hour action profile similar to insulin glargine U‑1007


  • Insulin action profiles of once-dailya Levemir® and insulin glargine U-100 were similar at clinically relevant doses7
  • Levemir® once dailya demonstrated a similar glucose-lowering effect over 24 hours compared with insulin glargine U-1008

FPG reductions across multiple trials in adults with type 2 diabetes2-5

Levemir® FPG reductions across multiple clinical trials in adult patients with type 2 diabetes
Levemir® FPG reductions across multiple clinical trials in adult patients with type 2 diabetes
Levemir® FPG reductions across multiple clinical trials in adult patients with type 2 diabetes

*Estimated treatment difference between the Levemir® group and the comparator group.


Levemir® safety results

✔ Safety results


TITRATE2

  • Nearly all hypoglycemic events were minor or symptoms onlyb
  • A single major hypoglycemic event was reported in the 70-90 mg/dL group; no major hypoglycemic events in the 80-110 mg/dL group
  • Minor hypoglycemia rates were 5.09 (70-90 mg/dL) and 3.16 (80-110 mg/dL) per patient-year

TRANSITION4

  • Low rates of minor hypoglycemia in patients being treated with metformin + sitagliptin + Levemir®b,c
  • There were no major hypoglycemic events in either treatment group

DeVries et al5

  • Low rates of hypoglycemia over 26 weeks in patients being treated with metformin + liraglutide + Levemir®c-e

bMinor=self-measured plasma glucose (SMPG) <56 mg/dL and not requiring third-party assistance; symptoms only=SMPG ≥56 mg/dL or no measurement; major=requiring third-party assistance.

cLow rates defined as <1 episode/year.

dDuring the main treatment period.

eOne patient in the metformin + liraglutide arm was excluded due to the 25 hypoglycemic episodes that the patient was able to self-treat. This patient had a history of frequent hypoglycemia prior to the study.

Levemir® and pregnancy

No difference in pregnancy outcomes or the health of the fetus and newborn were seen with Levemir® use6


  • Comparable A1C reductions vs NPH insulin6,9
  • Similar rates of hypoglycemia vs NPH insulin6,f

fNon-severe=PG <56 mg/dL (BG <50 mg/dL) with or without symptoms (patient able to self-treat). Severe=PG <56 mg/dL (BG <50 mg/dL) with symptoms consistent with hypoglycemia or reversal of symptoms after food intake, glucagon, or intravenous glucose (patient unable to self-treat).

Study designs

TITRATE2
A 20-week, randomized, controlled, multicenter, open-label, parallel-group, treat-to-target trial using a physician-directed self-titration algorithm in insulin-naïve patients with type 2 diabetes, A1C ≥7% and ≤9% on oral antidiabetic drug (OAD) therapy, randomized to once-dailya Levemir® (insulin detemir [rDNA origin] injection) and OAD (1:1) to 2 different fasting plasma glucose (FPG) titration targets (70-90 mg/dL [n=122] or 80-110 mg/dL [n=122]).

Philis-Tsimkas et al3
A 20-week, randomized, multicenter, open-label, parallel-group trial in insulin-naïve patients with type 2 diabetes who were uncontrolled on 1 or 2 OADs. Patients were randomized to once-dailya Levemir® AM administration (n=168), once-daily Levemir® PM administration (n=170), or NPH insulin (n=166).

TRANSITION4
A 26-week, open-label, randomized, parallel-group study in patients with type 2 diabetes. Insulin-naïve patients concomitantly treated with metformin +/– a second OAD were randomized to receive either once-dailya Levemir® + sitagliptin + metformin (n=111; metformin continued while all other OADs discontinued) or sitagliptin + metformin +/– sulfonylurea (SU) (n=111; metformin and SU continued while all other OADs discontinued. SU was allowed to be discontinued at the discretion of the investigator.) The primary study end point was A1C after 26 weeks.

DeVries et al5
A multinational, open-label study of 988 insulin-naïve adults with type 2 diabetes (aged 18 to 80 years) who were uncontrolled on metformin ≥1500 mg/day +/– SU. All patients underwent a 12-week run-in with metformin and liraglutide once daily, titrated to 1.8 mg. At the end of the run-in period, if patients achieved A1C <7%, they continued treatment in a nonrandomized, observational arm (50% of patients from run-in). If A1C was ≥7% at the end of run-in, patients were randomized to 26 weeks of once-dailya Levemir® as add-on therapy or to continued, unchanged treatment with liraglutide 1.8 mg and metformin.

Klein et al7
A 24-hour, randomized, double-blind, parallel group comparison of the pharmacodynamic properties of Levemir® and insulin glargine U-100 in patients with type 2 diabetes under glucose clamp conditions (n=27). 0.4, 0.8, and 1.4 units/kg doses were studied in this trial, with no observed differences in pharmacodynamic profile.

King8
A 24-hour, randomized, double-blind, crossover study of 29 patients with type 2 diabetes to evaluate whether Levemir® and insulin glargine U-100 once daily yield similar 24-hour glycemic control. Patients were randomized to a single daily injection of Levemir® or insulin glargine U-100 at 8 PM. Insulin dose was titrated to achieve blood glucose goals of 70-120 mg/dL, with <5% of the readings <70 mg/dL between 12 AM and 6 AM. Patients were switched after 2 consecutive days at goal.

Mathiesen et al9
An open-label, randomized, parallel-group, multinational study in women with type 1 diabetes who were on insulin for at least 12 months before randomization and who were planning to become pregnant or already pregnant at gestational weeks (GWs) 8 to 12. Patients could enroll in the study with intention to become pregnant. Patients were withdrawn from the trial if they did not become pregnant within 1 year. Patients were separated at randomization as pregnant and nonpregnant and all were required to have A1C ≤8% at confirmation of pregnancy. Patients were randomized 1:1 to Levemir® (n=152) or NPH insulin (n=158). Both groups used NovoLog® (insulin aspart injection) 100 U/mL as mealtime insulin. Approximately 50% of the women also received Levemir® or NPH insulin prior to conception and in the first 8 weeks of gestation. Regimen was followed from randomization until termination/6 weeks post delivery.

Selected Important Safety Information for Levemir® (insulin detemir [rDNA origin] injection)

Contraindications

  • Levemir® is contraindicated in patients with hypersensitivity to Levemir® or any of its excipients.

Warnings and Precautions

  • Never Share a Levemir® FlexTouch® Between Patients, even if the needle is changed. Sharing poses a risk for transmission of blood-borne pathogens.
  • Dosage adjustment and monitoring: Monitor blood glucose in all patients treated with insulin. Insulin regimens should be modified cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in insulin dose or an adjustment of concomitant anti-diabetic treatment.
  • Administration: Do not dilute or mix with any other insulin or solution. Do not administer subcutaneously via an insulin pump, intramuscularly, or intravenously because severe hypoglycemia can occur.

Levemir® (insulin detemir [rDNA origin] injection) Indications and Usage

  • Levemir® (insulin detemir [rDNA origin] injection) is indicated to improve glycemic control in adults and children with diabetes mellitus.

Important Limitations of Use

  • Levemir® is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting or short-acting insulin is the preferred treatment for this condition.

Important Safety Information

Contraindications

  • Levemir® is contraindicated in patients with hypersensitivity to Levemir® or any of its excipients.

Warnings and Precautions

  • Never Share a Levemir® FlexTouch® Between Patients, even if the needle is changed. Sharing poses a risk for transmission of blood-borne pathogens.
  • Dosage adjustment and monitoring: Monitor blood glucose in all patients treated with insulin. Insulin regimens should be modified cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in the insulin dose or an adjustment of concomitant anti-diabetic treatment.
  • Administration: Do not dilute or mix with any other insulin or solution. Do not administer subcutaneously via an insulin pump, intramuscularly, or intravenously because severe hypoglycemia can occur.

  • Hypoglycemia: Hypoglycemia is the most common adverse reaction of insulin therapy and may be life-threatening. When a GLP-1 receptor agonist is used in combination with Levemir®, the Levemir® dose may need to be lowered or more conservatively titrated to minimize the risk of hypoglycemia.

  • Hypersensitivity and allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Levemir®.

  • Renal and hepatic impairment: Careful glucose monitoring and dose adjustments of insulin, including Levemir®, may be necessary in patients with renal or hepatic impairment.
  • Drug interactions: Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia or hyperglycemia.
  • Fluid retention and heart failure with concomitant use of PPAR-gamma agonists: Fluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin, including Levemir®. Patients should be observed for signs and symptoms of heart failure. If heart failure occurs, dosage reduction or discontinuation of the TZD must be considered.

Adverse Reactions

  • Adverse reactions associated with Levemir® include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, rash, pruritus, and if taken with a GLP-1 receptor agonist, diarrhea.

Use in Specific Populations

  • Levemir® has not been studied in children with type 2 diabetes or in children with type 1 diabetes who are younger than 2 years of age.

  • The background risk of birth defects, pregnancy loss, or other adverse events that exists for all pregnancies is increased in pregnancies complicated by hyperglycemia.

Please click here for Levemir® Prescribing Information.

 

Tresiba® (insulin degludec injection) is indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus.

Limitations of Use

Tresiba® is not recommended for treating diabetic ketoacidosis or for pediatric patients requiring less than 5 units of Tresiba®.

Important Safety Information

Contraindications

  • Tresiba® is contraindicated during episodes of hypoglycemia and in patients with hypersensitivity to Tresiba® or one of its excipients

Warnings and Precautions

  • Never Share a Tresiba® FlexTouch® Pen Between Patients, even if the needle is changed. Sharing poses a risk for transmission of blood-borne pathogens
  • Monitor blood glucose in all patients treated with insulin. Changes in insulin may affect glycemic control. These changes should be made cautiously and under medical supervision. Adjustments in concomitant anti-diabetic treatment may be needed
  • Hypoglycemia is the most common adverse reaction of insulin, including Tresiba®, and may be life-threatening. Increase monitoring with changes to: insulin dose, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with hypoglycemia unawareness or renal or hepatic impairment
  • Accidental mix-ups between basal insulin products and other insulins, particularly rapid-acting insulins, have been reported. To avoid medication errors, always instruct patients to check the insulin label before each injection
  • Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Tresiba®
  • As with all insulins, Tresiba® use can lead to life-threatening hypokalemia, which then may cause respiratory paralysis, ventricular arrhythmia, and death. Closely monitor potassium levels in patients at risk of hypokalemia and treat if indicated
  • Fluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin, including Tresiba®. Patients should be observed for signs and symptoms of heart failure. If heart failure occurs, dosage reduction or discontinuation of the TZD must be considered

Adverse Reactions

  • Adverse reactions commonly associated with Tresiba® are hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema, and weight gain

Drug Interactions

There are certain drugs that may cause clinically significant drug interactions with Tresiba®.

  • Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors
  • Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones
  • Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine
  • Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine

Please click here for Tresiba® Prescribing Information.

 

References:

  1. Tresiba [package insert]. Plainsboro, NJ: Novo Nordisk Inc; August 2018.
  2. Blonde L, Merilainen M, Karwe V, Raskin P; TITRATE Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets—the TITRATE study. Diabetes Obes Metab. 2009;11(6):623-631.
  3. Philis-Tsimikas A, Charpentier C, Clauson P, et al. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther. 2006;28(10):1569-1581.
  4. Hollander P, Raslova K, Skjøth TV, Råstam J, Liukus JF. Efficacy and safety of insulin detemir once daily in combination with sitagliptin and metformin: the TRANSITION randomized controlled trial. Diabetes Obes Metab. 2011;13(3):268-275.
  5. DeVries JH, Bain SC, Rodbard HW, et al. Sequential intensification of metformin treatment in type 2 diabetes with liraglutide followed by randomized addition of basal insulin prompted by A1C targets. Diabetes Care. 2012;35(7):1446-1454.
  6. Levemir [package insert]. Plainsboro, NJ: Novo Nordisk Inc; February 2015.
  7. Klein O, Lynge J, Endhal L, Damholt B, Nosek L, Heise T. Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes Obes Metab. 2007;9(3):290-299.
  8. King AB. Once-daily insulin detemir is comparable to once-daily insulin glargine in providing glycaemic control over 24 h in patients with type 2 diabetes: a double-blind, randomized, crossover study. Diabetes Obes Metab. 2009;11(1):69-71.
  9. Mathiesen ER, Hod M, Ivanisevic M, et al; Detemir in Pregnancy Study Group. Maternal efficacy and safety outcomes in a randomized, controlled trial comparing insulin detemir with NPH insulin in 310 pregnant women with type 1 diabetes. Diabetes Care. 2012;35(10):2012-2017.