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Levemir

Generic Name: Insulin Detemir
Class: Insulins
VA Class: HS501
Chemical Name: 29B-[N6-(Oxo-tetradecy)-l-lysine]-(1A-21A),(1B-29B)-insulin (human)
Molecular Formula: C267H402N64O76S6
CAS Number: 169148-63-4

Medically reviewed on December 4, 2017

Introduction

Antidiabetic agent; long acting human insulin analog synthesized using recombinant DNA technology in Saccharomyces cerevisiae then chemically modified.1 18

Uses for Levemir

Diabetes Mellitus

Treatment of type 1 diabetes mellitus in adults and children ≥2 years of age or type 2 diabetes mellitus in adults who require long-acting (basal) insulin to improve glycemic control.1 2 3 4 5 30 36

Not indicated for the treatment of diabetic ketoacidosis; short-acting IV insulins (e.g., regular insulin) are preferred.1 17 18 20

At least as effective for glycemic control in adults as isophane insulin human or insulin glargine.1 2 3 7 16 18

May be associated with less interindividual variability in fasting blood glucose concentration,2 7 10 16 17 22 23 lower risk for hypoglycemia,2 7 16 17 22 23 and a lower risk of weight gain1 2 7 16 17 22 than isophane insulin human.17 18 May provide advantages over isophane insulin human in patients who have had difficulty achieving adequate glycemic control without frequent hypoglycemic episodes and/or those at high risk of hypoglycemia, particularly nocturnal hypoglycemia.16 17 23

Levemir Dosage and Administration

Administration

Administer by sub-Q injection.1 18 Do not administer IV or IM or via insulin infusion pump.1 6 17

IV administration may cause severe hypoglycemia.1 17

Do not mix with any other insulin.1 6 7 17 18

Inspect visually prior to administration and use only if solution appears clear and colorless.1

Sub-Q Administration

Administer by sub-Q injection once or twice daily using a conventional insulin syringe or an injection pen (i.e., FlexTouch).1 8 Use FlexTouch device only with NovoFine, NovoFine Plus, or NovoTwist needles.8

Consult labeling accompanying the injection device for proper assembly, administration, and care of injection pen.1 8 18

Administer into thigh, abdominal wall, or upper arm.1 Follow a planned rotation of injection sites within an injection area.1

Once-daily regimen: Administer the daily dose with the evening meal or at bedtime.1 7 Has been administered once daily in the morning in patients with type 2 diabetes mellitus.18 21

Twice-daily regimen: Administer the first dose in the morning and the second dose after the evening meal, at bedtime, or 12 hours after the morning dose.1 3 7

Concomitant use with a glucagon-like peptide-1 (GLP-1) receptor agonist: Administer each drug as a separate injection (may inject into same body region but not adjacent to each other); do not mix.1

Dosage

Dosage of insulin detemir is expressed in terms of units.1

Individualize dosage based on blood glucose determinations to obtain optimum therapeutic effect.1 Glucose monitoring is recommended for all patients with diabetes mellitus.1

Closely monitor blood glucose concentrations during insulin initiations and transitions and in the initial weeks thereafter.1 Adjust dosage and timing of insulins and/or other concomitant antidiabetic agents as needed to achieve glycemic goals.1 18

Make any dosage change cautiously and only under medical supervision.1 If insulin therapy is changed (e.g., strength, timing of dosing, manufacturer, type, or method of administration), may require adjustments in dosage of insulin detemir or concomitant antidiabetic agents.1 2

May require insulin dosage adjustment if patient changes usual physical activity or meal plan, or during times of illness, emotional disturbances, or stress.1

Pediatric Patients

Diabetes Mellitus

Children ≥2 years of age: No specific dosage recommendations by manufacturer.1 When used with mealtime sub-Q insulin, basal insulin requirements (e.g., insulin detemir) should comprise approximately one-third of the total daily insulin dosage, with the remainder given preprandially as rapid- or short-acting insulin.1

Type 1
Sub-Q

Children ≥2 years of age: Initial total daily insulin dosages generally range from 0.2–1 unit/kg.

Transferring from Other Insulin Therapy
Sub-Q

Children ≥2 years of age, from combination therapy with intermediate- or long-acting insulin and short- or rapid-acting insulin: Initial dosage of insulin detemir is identical (unit-for-unit basis) to the dosage of the longer-acting insulin.1

Children ≥2 years of age, from basal insulin only: Initial dosage of insulin detemir is identical (unit-for-unit basis) to the dosage of basal insulin.1

Adults

Diabetes Mellitus

When used with mealtime sub-Q insulin, basal insulin requirements (e.g., insulin detemir) should comprise approximately one-third of the total daily insulin dosage, with the remainder given preprandially as rapid- or short-acting insulin.1

Insulin-naive Patients
Sub-Q

Type 1 diabetes mellitus: Initial total daily insulin dosages generally range from 0.2–1 unit/kg.

Type 2 diabetes mellitus inadequately controlled on oral antidiabetic agents: Initial dosage is 0.1–0.2 units/kg once daily in the evening or 10 units once daily in the evening or divided into a twice-daily regimen.1

Type 2 diabetes mellitus inadequately controlled with a GLP-1 receptor agonist: Initial dosage is 10 units given once daily in the evening.1 Dosage reduction or more conservative titration of insulin detemir may be required to minimize risk of hypoglycemia.1

Transferring from Other Insulin Therapy
Sub-Q

From combination therapy of intermediate- or long-acting and short- or rapid-acting insulin: Initial dosage of insulin detemir is identical (unit-for-unit basis) to the dosage of the longer-acting insulin.1

From basal insulin only: Initial dosage of insulin detemir is identical (unit-for-unit basis) to the dosage of the basal insulin.1

Some patients with type 2 diabetes mellitus may require a higher dosage of insulin detemir than of isophane insulin human.1 4

Special Populations

Hepatic Impairment

Dosage adjustment may be required ; carefully monitor blood glucose concentrations and adjust dosage as necessary.1 6 18 (See Hepatic Impairment under Cautions and also see Special Populations under Pharmacokinetics.)

Renal Impairment

Dosage adjustments may be required; carefully monitor blood glucose concentrations and adjust dosage as necessary.1 (See Renal Impairment under Cautions and also see Special Populations under Pharmacokinetics.)

Geriatric Patients

Conservative initial dosage, dose increments, and maintenance dosage recommended to avoid hypoglycemia.1 (See Geriatric Use under Cautions and also see Special Populations under Pharmacokinetics.)

Lactation

Dosage adjustments may be required.1 (See Specific Populations under Cautions.)

Cautions for Levemir

Contraindications

  • Known hypersensitivity to insulin detemir or any ingredient in the formulation.1

Warnings/Precautions

Hypoglycemia

Most common adverse effect of insulins.1 Blood glucose concentration monitoring is recommended for all diabetic patients.1 Hypoglycemic timing may differ among various insulin formulations, and may change when the treatment regimen or timing of dosing of the insulins is changed.1 Prolonged effect of sub-Q insulin detemir may delay recovery from hypoglycemia.1

Rapid changes in serum glucose concentrations may precipitate manifestations of hypoglycemia, regardless of glucose concentrations.

Use intensive insulin therapy with caution in patients with a history of hypoglycemic unawareness or recurrent, severe hypoglycemic episodes. Higher target blood glucose concentrations (e.g., fasting blood glucose concentrations of 140 mg/dL and 2-hour postprandial concentrations of 200–250 mg/dL) are advisable in these patients.

Some evidence suggests that insulin detemir may be associated with a lower risk of nocturnal hypoglycemia than isophane insulin human or insulin glargine.2 7 16 17 19 22 23

Sharing of Injection Pens

Do not share insulin detemir injection pens among patients, even if the needle has been changed; sharing poses risk for transmission of blood-borne pathogens.1

Metabolic Effects

May cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensive insulin therapy.1

Weight gain, attributable to the anabolic effect of insulin and the decrease in glucosuria, may occur with insulin therapy, including insulin detemir.1

Heart Failure

Peroxisome proliferator-activated receptor (PPAR)-γ agonists (e.g., thiazolidinediones) can cause dose-related fluid retention, particularly when used in conjunction with insulin; may lead to or exacerbate heart failure.1 32 33

Observe patients receiving insulin detemir and a PPAR-γ agonist for manifestations of heart failure (e.g., excessive/rapid weight gain, shortness of breath, edema); discontinue or reduce dose of PPAR-γ agonist if heart failure develops.1 32

Concomitant use of rosiglitazone and insulin therapy not recommended.33

Immunogenicity

Potential risk of immunogenicity.1 Insulin antibodies may increase or decrease the efficacy of insulin; dosage adjustments may be required.1 Antibody development observed in phase 3 clinical trials of insulin detemir with no apparent impact on glycemic control.1

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

Lipodystrophy may occur at sites of insulin injections and may delay insulin absorption;1 7 18 rotate injection sites to reduce or prevent these effects.1 Possible localized allergic reactions (e.g., pruritus, erythema, swelling, urticaria) at injection site.1 4 12 13 14 15 Usually resolves within a few days to a few weeks; 1 14 15 but, rarely, may require discontinuance of insulin detemir.1 12 13 May be related to other factors (e.g., irritants in skin cleansing agents, poor injection technique).1 Injection site rotation within an area may reduce or prevent these effects in some patients.1 13

Generalized hypersensitivity reactions (e.g., whole-body rash, pruritus, shortness of breath, wheezing, hypotension, tachycardia, diaphoresis, anaphylaxis) reported less frequently than localized reactions, but may be life-threatening. 1

Specific Populations

Pregnancy

Category B.1

In an open-label clinical study of pregnant women with type 1 diabetes mellitus, insulin detemir therapy did not increase the risk of fetal abnormalities compared with isophane (NPH) insulin human.1 38 No difference in pregnancy outcomes or the health of the fetus and newborn with insulin detemir use.1

Studies in rats and rabbits indicate that insulin detemir and human insulin have similar embryotoxic and teratogenic effects which may be attributable to maternal hypoglycemia.1

Lactation

Not known whether insulin detemir is distributed into milk; use caution in nursing women.1 (See Lactation under Dosage and Administration.)

Pediatric Use

Safety and efficacy not established in children <2 years of age with type 1 diabetes mellitus or in pediatric patients with type 2 diabetes mellitus.1

Geriatric Use

Response in patients ≥65 years of age does not appear to differ from that in younger adults; but increased sensitivity cannot be ruled out.1 Hypoglycemia may be difficult to recognize in geriatric patients.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Monitor blood glucose concentrations closely; dosage adjustment may be necessary.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Monitor blood glucose concentrations closely; dosage adjustment may be necessary.1 (See Renal Impairment under Dosage and Administration)

Common Adverse Effects

Hypoglycemia,1 2 3 5 11 allergic reactions,1 pruritus,1 5 rash,1 5 injection site reactions,1 5 11 lipodystrophy,1 peripheral edema,1 weight gain.1 5 11

Adults with type 1 or type 2 diabetes mellitus: Upper respiratory tract infection,1 headache,1 pharyngitis,1 influenza-like illness,1 abdominal pain,1 back pain,1 gastroenteritis,1 bronchitis.1

Pregnant women with type 1 diabetes mellitus: nasopharyngitis,1 headache,1 anemia,1 diarrhea,1 preeclampsia,1 urinary tract infection,1 gastroenteritis,1 upper abdominal pain,1 vomiting,1 spontaneous abortion,1 abdominal pain,1 oropharyngeal pain.1

Children and adolescents with type 1 diabetes mellitus: Upper respiratory tract infection,1 headache,1 pharyngitis,1 gastroenteritis,1 influenza-like illness,1 abdominal pain,1 pyrexia,1 cough,1 viral infection,1 nausea,1 rhinitis,1 vomiting.1

Interactions for Levemir

Many drugs affect glucose metabolism; if such drugs are used concomitantly, may require insulin dosage adjustment and careful monitoring.1

Specific Drugs

Drugs That May Potentiate Hypoglycemic Effects

ACE inhibitors1 18

Disopyramide1 18

Fibrate derivatives1 18

Fluoxetine1 18

MAO inhibitors1 18

Oral antidiabetic agents1 18

Pentoxifylline1

Pramlintide1

Propoxyphene1 18

Salicylates1 18

Somatostatin analogs (e.g., octreotide)1 18

Sulfonamide anti-infectives1 18

Drugs that May Antagonize Hypoglycemic Effects

Atypical antipsychotics (e.g., olanzapine, clozapine)1

Corticosteroids1 16

Danazol1

Diuretics1 16

Estrogens or progestins (e.g., oral contraceptives)1

Glucagon1

Isoniazid1

Niacin26

Phenothiazines1

Protease inhibitors1

Somatropin1

Sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline)1

Thyroid hormones1 18

Drugs that May Have a Variable Effect on Glycemic Control

Alcohol1

β-Adrenergic blocking agents (β-Blockers)1 16

Clonidine1

Lithium salts1

Pentamidine1

Drugs That may Reduce or Eliminate Signs of Hypoglycemia (Sympatholytic Agents)

β-Blockers1

Clonidine1

Guanethidine1

Reserpine1

Drug

Interaction

Comments

GLP-1 receptor agonists (e.g., liraglutide)

No pharmacokinetic interaction observed following administration of single-dose sub-Q injections of insulin detemir in patients on steady-state liraglutide;1 however, risk of hypoglycemia35

May require dosage reduction or more conservative titration of insulin detemir1

PPAR-γ agonists (e.g., thiazolidinediones)

Increased risk of heart failure1 23 24

Monitor patients for manifestations of heart failure;1 23 concomitant use of rosiglitazone not recommended24

Protein bound drugs

No clinically relevant in vivo or in vitro interaction1 18

Levemir Pharmacokinetics

Absorption

Bioavailability

Following sub-Q injection, insulin detemir self-associates and binds to albumin, resulting in slow systemic absorption from injection site and a prolonged duration of action.1 2 3 5 6 7 18

Following sub-Q injection, absolute bioavailability is 60%.1

Interindividual and intraindividual variation may occur based on site of injection, tissue blood supply, temperature, and physical activity.1

Absorption occurs with less variability than with other basal insulins.2 3 7

Atrophy or hypertrophy of subcutaneous fat tissue at the injection site may affect insulin absorption.1

Duration

Dose dependent; ≤24 hours;1 37 >50% of maximum effect occurs within 3–14 hours of administration.1

Special Populations

Children 6–12 years of age: slightly increased AUC and maximum serum concentration (increased by 10 and 24%, respectively) compared with adults.1

Adolescents 13–17 years of age: No pharmacokinetic differences compared with adults.1

In geriatric patients, increased AUC.1 (See Special Populations under Elimination.)

In severe hepatic dysfunction in nondiabetics, decreased AUC.1 (See Special Populations under Dosage and Administration and also see Hepatic Impairment under Cautions.)

Distribution

Extent

Not known whether insulin detemir is distributed into milk.1

Plasma Protein Binding

>98% (albumin).1

Elimination

Half-life

Terminal half-life: Dose dependent; 5–7 hours.1

Special Populations

In geriatric patients, clearance is decreased.1 (See Special Populations under Absorption.)

In renal impairment, no difference in pharmacokinetic parameters.1 However, clearance of human insulin is decreased in renally impaired patients.1 (See Special Populations under Dosage and Administration and see Renal Impairment under Cautions.)

Stability

Storage

Parenteral

Injection

Unopened vials, and FlexTouch injection pens: 2–8°C; store in carton to protect from light.1 Do not store directly adjacent to refrigerator cooling element and do not freeze; discard if freezing occurs.1 May keep at <30°C for ≤42 days.1

Opened (in-use) vials: 2 to <30°C for ≤42 days.1 Protect from direct heat and light.1

Opened (in-use) FlexTouch injection pens: <30°C for ≤42 days.1 Do not refrigerate; do not store with needle in place.1 Protect from direct heat and sunlight.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

For information on systemic interactions resulting from concomitant use, see Interactions.

Do not mix with any other insulin or solutions.1 6 7 17 18

Actions

  • Regulates glucose metabolism.1

  • Binds insulin receptors to lower blood glucose by increasing cellular uptake of glucose into skeletal muscle and fat; inhibits hepatic glucose production, lipolysis and proteolysis and increases protein synthesis.1

  • Longer duration of action and less intrapatient variability in blood glucose concentrations than with isophane insulin human.1 2 4 5 7 9 11

Advice to Patients

  • Provide copy of manufacturer’s patient information.1

  • Importance of informing patients that they should never share an insulin detemir injection pen with another person, even if needle is changed; sharing of pen may pose a risk of transmission of infection.1

  • Importance of informing patients that changes to insulin regimens should be made cautiously and only under medical supervision.1

  • Advise patients of the potential adverse effects of insulin therapy (e.g., hypoglycemia, weight gain, lipodystrophy [and the need to rotate injection sites], allergic reactions).1

  • Inform patients that 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 Advise patients who experience frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.1

  • Inform patients to always check the label on insulin vial or injection pen prior to each injection; medication errors involving confusion between insulin detemir and other insulins (e.g., short-acting insulins) have occurred.1

  • Provide instructions regarding self-monitoring of blood glucose concentrations, injection technique, and management of hypoglycemia or hyperglycemia.1

  • Importance of not mixing insulin detemir with other insulins or solutions.1 Importance of using insulin detemir only if solution is clear and colorless with no visible particles.1

  • 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, inadvertent administration of an incorrect dose, inadequate food intake, or skipped meals.1

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

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

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

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Insulin Detemir (Recombinant DNA Origin)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

100 units/mL

Levemir (available as FlexTouch prefilled pens and 10-mL vials)

Novo Nordisk

AHFS DI Essentials. © Copyright 2018, Selected Revisions December 4, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Novo Nordisk. Levemir (insulin detemir) injection prescribing information. Plainsboro, NJ; 2015 Feb.

2. Russell-Jones D, Simpson R, Hylleberg B et al. Effects of QD insulin detemir or neutral protamine hagedorn on blood glucose control in patients with type 1 diabetes mellitus using a basal-bolus regimen. Clin Ther. 2004; 26:724-36.

3. Home P, Bartley P, Russell-Jones D et al. Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes. Diabetes Care. 2004; 27:1081-7. http://www.ncbi.nlm.nih.gov/pubmed/15111525?dopt=AbstractPlus

4. Misbin RI. Insulin detemir injection, Levemir: Medical review, FDA approval package. NDA number: 21-536. Rockville, MD: US Food and Drug Administration; 2005 Jun 16. (IDIS 453559)

5. Raslova K, Bogoev M, Raz I et al. Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes. Diabetes Res Clin Pract. 2004; 66:193-201. http://www.ncbi.nlm.nih.gov/pubmed/15533587?dopt=AbstractPlus

6. Wei X. Insulin detemir injection, Levemir. Clinical pharmacology and biopharmaceutics review, FDA approval package. NDA number: 21-536. Rockville, MD: US Food and Drug Administration; 2005 Jun 16.

7. Chapman TM, Perry CM. Insulin detemir: a review of its use in the management of type 1 and 2 diabetes mellitus. Drugs. 2004; 64:2577-95. http://www.ncbi.nlm.nih.gov/pubmed/15516157?dopt=AbstractPlus

8. Novo Nordisk. Levemir FlexTouch Pen: Instructions for use. Plainsboro, NJ; 2015 Feb.

9. Plank J, Bedenlenz M, Sinner F et al. A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care. 2005; 28:1107-1112. http://www.ncbi.nlm.nih.gov/pubmed/15855574?dopt=AbstractPlus

10. Robertson K, Schoenle E, Gucev Z et al. Insulin detemir compared with NPH insuln in children and adolescents with type 1 diabetes. Diabet Med. 2007; 24:27-34. http://www.ncbi.nlm.nih.gov/pubmed/17227321?dopt=AbstractPlus

11. Hernamsen K, Davies M, Derezinski T et al. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care. 2006; 29:1269-74. http://www.ncbi.nlm.nih.gov/pubmed/16732007?dopt=AbstractPlus

12. Darmon P, Castera V, Koeppel MC et al. Type III allergy to insulin detemir. Diabetes Care. 2005; 28:2980. Letter. http://www.ncbi.nlm.nih.gov/pubmed/16306568?dopt=AbstractPlus

13. Blumer I. Severe injection site reaction to insulin detemir. Diabetes Care. 2006; 29:946. Letter. http://www.ncbi.nlm.nih.gov/pubmed/16567849?dopt=AbstractPlus

14. Stechemesser L, Hofmann M, Hawranek T et al. Type III allergy to insulin detemir. Diabetes Care. 2006; 29:2758. Letter. http://www.ncbi.nlm.nih.gov/pubmed/17130222?dopt=AbstractPlus

15. Sola-Gazagnes A, Pecquet C, M’Bemba J et al. Type I and type IV allergy to the insulin analogue detemir. Lancet. 2007; 369:637-8. Letter.

16. Jones MC, Patel M. Insulin detemir: a long-acting insulin product. AJHP. 2006; 63(Dec 15):2466-72. http://www.ncbi.nlm.nih.gov/pubmed/17158694?dopt=AbstractPlus

17. Reviewers’ comments (personal observations).

18. Novo Nordisk, Princeton, NJ: Personal communication.

19. Pieber TR, Treichel HC, Hompesch B et al. Comparison of insulin detemir and insulin glargine in subjects with type 1 diabetes using intensive insulin therapy. Diabet Med. 2007; 24:635-42. http://www.ncbi.nlm.nih.gov/pubmed/17381500?dopt=AbstractPlus

20. Kitabchi AE, Umpierrez GE, Murphy MB et al. Hyperglycemic crises in adult patients with diabetes mellitus: a consensus statement from the American Diabetes Association. Diabetes Care. 2006; 29:2739-48. http://www.ncbi.nlm.nih.gov/pubmed/17130218?dopt=AbstractPlus

21. Philis-Tsimikas A, Charpentier G, 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 mellitus. Clin Ther. 2006; 28:1569-81.

22. Vague P, Selam JL, Skeie S et al. Insulin detemir is associated with more preducatable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal-blous regimen with premeal insulin aspart. Diabetes Car. 2003; 26:590-6.

23. Kolendorf K, Ross GP, Pavlic-Renart I et al. Insulin detemir lowers the risk of hypoglycemia and provides more consistent plasma glucose levels compared with NPH insulin in type 1 diabetes. Diabet Med. 2006; 23:729-35. http://www.ncbi.nlm.nih.gov/pubmed/16842476?dopt=AbstractPlus

24. Heise T, Nosek L, Ronn BB et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004; 53:1614-20. http://www.ncbi.nlm.nih.gov/pubmed/15161770?dopt=AbstractPlus

25. Bartley PC, Boroev M, Larsen J et al. Superior glycaemic control, less nocturnal hypoglycemia and less weight gain with insulin detemir relative to NPH insulin in subjects with T1DM treated for 24 months using a treat-to-target concept. Paper presented at the 43rd EASD annual meeting. Amsterdam: 2007 September 17–21. Abstract 222.

26. Abbott. Niaspan (niacin extended-release tablets) prescribing information. North Chicago, IL; 2007 Sep.

30. Thalange N, Bereket A, Larsen J et al. Insulin analogues in children with Type 1 diabetes: a 52-week randomized clinical trial. Diabet Med. 2013; 30:216-25. http://www.ncbi.nlm.nih.gov/pubmed/23094597?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3579233&blobtype=pdf

31. 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; 35:1446-54. http://www.ncbi.nlm.nih.gov/pubmed/22584132?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3379583&blobtype=pdf

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

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

34. Keating GM. Insulin detemir: a review of its use in the management of diabetes mellitus. Drugs. 2012; 72:2255-87. http://www.ncbi.nlm.nih.gov/pubmed/23110609?dopt=AbstractPlus

35. Morrow L, Hompesch M, Guthrie H et al. Co-administration of liraglutide with insulin detemir demonstrates additive pharmacodynamic effects with no pharmacokinetic interaction. Diabetes Obes Metab. 2011; 13:75-80. http://www.ncbi.nlm.nih.gov/pubmed/21114606?dopt=AbstractPlus

36. Thalange N, Bereket A, Larsen J et al. Treatment with insulin detemir or NPH insulin in children aged 2-5 yr with type 1 diabetes mellitus. Pediatr Diabetes. 2011; 12:632-41. http://www.ncbi.nlm.nih.gov/pubmed/21418455?dopt=AbstractPlus

37. Morales J. Defining the role of insulin detemir in Basal insulin therapy. Drugs. 2007; 67:2557-84. http://www.ncbi.nlm.nih.gov/pubmed/18034591?dopt=AbstractPlus

38. Hod M, Mathiesen ER, Jovanovic L et al. A randomized trial comparing perinatal outcomes using insulin detemir or neutral protamine Hagedorn in type 1 diabetes. J Matern Fetal Neonatal Med. 2014; 27:7-13. http://www.ncbi.nlm.nih.gov/pubmed/23617228?dopt=AbstractPlus

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