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Liraglutide

Pronunciation

Class: Incretin Mimetics
Molecular Formula: C172H265N43O51
CAS Number: 204656-20-2
Brands: Victoza, Saxenda

Warning(s)

  • Risk of Thyroid C-Cell Tumors
  • Causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice.1 8 24 31

  • Unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as relevance to humans of such tumors in rodents has not been determined.1 8 24 31

  • Contraindicated in patients with a personal or family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).1 8 24 31

    Counsel patients regarding potential risk of MTC and inform them about symptoms of thyroid tumors.1 8 24 31 (See Advice to Patients.)

    Routine monitoring of serum calcitonin or use of thyroid ultrasound of uncertain value for early detection of MTC in patients receiving liraglutide.1 8 24 31

REMS:

FDA approved a REMS for liraglutide to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of liraglutide and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Antidiabetic and antiobesity agent; acylated glucagon-like peptide-1 (GLP-1) agonist (incretin mimetic).1 24

Uses for Liraglutide

Diabetes Mellitus

Used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1 2 18 19

Has been used in combination with metformin, a sulfonylurea, or the combination of metformin and a sulfonylurea as an adjunct to diet and exercise for the management of type 2 diabetes mellitus.1 2 3 4 5 6 7 21

Not recommended as first-line therapy for patients inadequately controlled on diet and exercise alone because of uncertain relevance of liraglutide-induced rodent C-cell tumors to humans.1 8 16 (See Risk of Thyroid C-Cell Tumors under Cautions.)

Safety and efficacy not established in patients with a history of pancreatitis; consider other antidiabetic agents in such patients.1 (See Pancreatitis and Pancreatic Precancerous Changes under Cautions.)

Safety and efficacy in combination with prandial insulin not demonstrated.1 8

Not indicated for use in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1

Victoza and Saxenda both contain liraglutide; do not use concomitantly.1 24

Obesity

Used as an adjunct to caloric restriction and increased physical activity for the long-term management of body weight.24 26 27 28

Used in patients who are obese (pretreatment body mass index [BMI] ≥;30 kg/m2); also used in overweight patients (pretreatment BMI ≥;27 kg/m2) in the presence of a weight-related condition (e.g., hypertension, type 2 diabetes mellitus, dyslipidemia).24

Safety and efficacy in combination with other weight-loss products (prescription or OTC drugs, dietary or herbal supplements) not established.24

Safety and efficacy not established in patients with a history of pancreatitis.24 (See Pancreatitis and Pancreatic Precancerous Changes under Cautions.)

Safety and efficacy in combination with insulin not established in the management of obesity; do not use with insulin for obesity management.24

Saxenda and Victoza both contain liraglutide; do not use concomitantly.1 24

Liraglutide Dosage and Administration

General

  • Perform regular monitoring (e.g., blood glucose determinations, HbA1c) to determine therapeutic response in patients with type 2 diabetes mellitus.1

  • When used for obesity, evaluate body weight after 16 weeks.24 Discontinue treatment in patients who do not experience a meaningful weight loss (≥4% baseline weight); such patients unlikely to achieve and sustain meaningful weight loss with continued liraglutide therapy.24

Administration

Administer by sub-Q injection using a prefilled injection pen;1 do not administer IV or IM.24

If a dose is missed, resume the regular schedule with the next scheduled dose; do not take an extra dose or increase the dose to replace a missed dose.1 24 If >3 days have elapsed since last dose, restart liraglutide at initial dosage and retitrate.1 24 (See Dosage under Dosage and Administration.)

Administer liraglutide and insulin as separate injections in patients receiving both drugs for diabetes mellitus; do not mix insulin and liraglutide.1 May inject liraglutide and insulin in the same body regions; however, do not administer injections adjacent to each other.1

Sub-Q Administration

Administer once daily without regard to meals.1 24

Administer into abdomen, thigh, or upper arm.1 24 29

Dosage

Adults

Diabetes Mellitus
Sub-Q

Initially, 0.6 mg daily.1 The 0.6 mg dosage is not effective for glycemic control; intended only as a starting dose to reduce GI intolerance.1

After 1 week, increase dosage to 1.2 mg daily.1 If needed, may increase dosage to 1.8 mg daily.1

If >3 days have elapsed since the last dose, reinitiate at 0.6 mg to minimize adverse GI effects and titrate dosage at the discretion of the clinician.1

Obesity
Sub-Q

Initially, 0.6 mg daily.1

Increase daily dosage by 0.6 mg at weekly intervals to maintenance dosage of 3 mg daily.24 (See Table 1.)

Table 1. Dosage Escalation Schedule for the Treatment of Obesity24

Week

Daily Dose

1

0.6 mg

2

1.2 mg

3

1.8 mg

4

2.4 mg

5 and onward

3 mg

If dosage increase not tolerated (e.g., adverse GI effects), may delay dosage escalation for approximately 1 week.24 If 3-mg daily dosage not tolerated, discontinue therapy; efficacy not established at dosages <3 mg daily.24

If >3 days have elapsed since the last dose, reinitiate at 0.6 mg to minimize adverse GI effects; retitrate to maintenance dosage of 3 mg once daily.1

Special Populations

No special population dosage recommendations.1 24

Use caution when initiating liraglutide or escalating dosage in patients with renal impairment.1 24 (See Renal Effects under Cautions.)

Cautions for Liraglutide

Contraindications

  • Personal or family history of MTC.1 8 16 24

  • MEN 2.1 8 16 24

  • Prior serious hypersensitivity to liraglutide or any component in the formulation.1 24

  • Pregnancy (when used for obesity management).24 (See Pregnancy under Cautions.)

Warnings/Precautions

Warnings

Risk of Thyroid C-Cell Tumors

Dose-dependent and treatment-duration-dependent thyroid C-cell tumors found at clinically relevant exposures in rats and mice.1 8 24 31 Cases of MTC reported in patients receiving liraglutide during postmarketing experience; data insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans.1 Unknown whether liraglutide causes thyroid C-cell tumors, including MTC, in humans; relevance to humans could not be ruled out by clinical or nonclinical studies.1 8 16 24 31 Therefore, do not use as first-line treatment for diabetes mellitus until additional studies completed.1 16

Very elevated serum calcitonin values may suggest MTC; such values generally exceed 50 ng/L in patients with MTC.1 24 Uncertain value of routine monitoring of serum calcitonin or thyroid ultrasound examinations; further evaluate patients if serum calcitonin is elevated or thyroid nodules noted on physical examination or neck imaging.1 8 24 31

To specifically evaluate the risk of MTC, manufacturer is required to establish a cancer registry to monitor the rate of this type of cancer in the US over a period of 15 years.16 17

Sensitivity Reactions

Hypersensitivity Reactions

Serious hypersensitivity reactions (anaphylaxis, angioedema) reported.1 24 Discontinue liraglutide and other suspect medications and promptly seek medical advice if hypersensitivity reaction occurs.1 24 Use with caution in patients with a history of angioedema with another GLP-1 receptor agonist.1 24

Other Warnings and Precautions

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, reported during postmarketing experience.1 24 31 Pancreatitis also reported during clinical trials.1 24 31 FDA has been evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous cellular changes in patients with type 2 diabetes mellitus receiving incretin mimetics.36 37 FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete or when the agency has additional information to report.36

FDA has recommended that clinicians continue to follow the recommendations in the prescribing information for incretin mimetics.36 Observe patients carefully for manifestations of pancreatitis after drug initiation and dosage increases.1 24 31 36 Contact clinician promptly if symptoms of pancreatitis occur, including persistent severe abdominal pain that sometimes radiates to the back and that may or may not be accompanied by vomiting.1 24 Manufacturer states that if pancreatitis is suspected, promptly discontinue liraglutide and initiate appropriate management.1 8 24 If pancreatitis is confirmed, do not restart liraglutide.1 8 24

Safety and efficacy not established in patients with a history of pancreatitis;24 31 consider other antidiabetic agent in such patients.1 8

Acute Gallbladder Disease

May increase the risk of acute gallbladder disease.24 Cholelithiasis and cholecystitis reported in clinical trials of obesity management; most cases required cholecystectomy.24

Although substantial or rapid weight loss can increase risk of cholelithiasis, the incidence of acute gallbladder disease was greater with liraglutide than with placebo in obesity clinical trials, even after accounting for the degree of weight loss.24 If cholelithiasis suspected, gallbladder studies and appropriate clinical follow-up are recommended.24

Sharing of Injection Pens

Do not share liraglutide (Victoza, Saxenda) injection pens among patients, even if the needle has been changed; sharing poses risk for transmission of blood-borne pathogens.1 23 24 25

Use with Drugs Known to Cause Hypoglycemia

Patients receiving liraglutide in combination with an insulin secretagogue (e.g., a sulfonylurea) or insulin may have an increased risk of hypoglycemia; reduction in sulfonylurea or insulin dosage may be necessary.1 24

Manufacturer states that insulin should not be used concomitantly in patients receiving liraglutide for the management of obesity.24

Monitor patients with type 2 diabetes mellitus for an increase in blood glucose when liraglutide is discontinued.24

Elevated Heart Rate

Increases in heart rate observed with liraglutide therapy for obesity management.24 Resting heart rate >100 bpm reported.24 Clinical importance of elevated heart rate unknown, especially in patients with cardiovascular or cerebrovascular disease who had limited exposure to liraglutide in obesity clinical trials.24

Monitor heart rate regularly; if sustained increase in resting heart rate occurs during therapy, discontinue liraglutide.24

Renal Effects

Acute renal failure and worsening of chronic renal failure (sometimes requiring hemodialysis) reported with GLP-1 receptor agonists, including liraglutide, during postmarketing experience.1 24 Some patients did not have known underlying renal disease.1 24 Other factors (nausea, vomiting, diarrhea, or dehydration) were present in most patients.1 24 Some patients received liraglutide in combination with one or more agents known to affect renal function or hydration status.1 24

Not found to be directly nephrotoxic in preclinical or clinical studies.1

Renal effects usually reversible with supportive treatment and discontinuance of potentially causative agents, including liraglutide.1 24 Use caution when initiating liraglutide or escalating dosage in patients with renal impairment.1 24

Suicidality

Suicidal ideation observed in clinical trials for obesity; suicide attempt reported in 1 patient.24

Monitor patients receiving liraglutide for emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.24 Discontinue in patients who experience suicidal thoughts or behaviors.24

Avoid use in patients with a history of suicidal attempts or active suicidal ideation.24

Macrovascular Outcomes

Evidence of macrovascular risk reduction with liraglutide or any other antidiabetic agent has not been conclusively demonstrated in controlled clinical trials.1

Effects on cardiovascular morbidity and mortality in patients receiving the drug for obesity management not established.24

Specific Populations

Pregnancy

Victoza: Category C.1

Saxenda: Category X.24

Weight loss offers no potential benefit to pregnant women and may result in fetal harm.24 Manufacturer states that liraglutide is contraindicated for the management of obesity in pregnant women.24 Discontinue liraglutide for obesity management if patient is or plans to become pregnant.24

Lactation

Liraglutide is distributed into milk in rats; not known whether distributed into milk in humans.1 24 Discontinue nursing or the drug, taking into account the importance of the drug to the woman.1 24

Pediatric Use

Safety and efficacy not established in children or adolescents younger than 18 years of age.1 24

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out. 1 24

Hepatic Impairment

Limited experience in patients with hepatic impairment; use caution.1 12 24

Renal Impairment

Limited experience in patients with renal impairment, including end-stage renal disease; use caution.1 11 24

Patients with Gastroparesis

Slows gastric emptying and potentially may affect absorption of concomitantly administered oral drugs. 1 (See Orally Administered Drugs under Interactions.) Has not been studied in patients with preexisting gastroparesis. 1 24

Common Adverse Effects

Management of type 2 diabetes mellitus: nausea,1 2 diarrhea,1 2 vomiting,1 2 constipation,1 2 upper respiratory tract infection,1 2 headache,1 2 influenza,1 2 urinary tract infection,1 2 dizziness,1 2 sinusitis,1 2 nasopharyngitis,1 2 back pain.1 2

Management of obesity: nausea,24 hypoglycemia (in patients with obesity and type 2 diabetes mellitus),24 diarrhea,24 constipation,24 vomiting,24 headache,24 decreased appetite,24 dyspepsia,24 fatigue,24 dizziness,24 abdominal pain,24 increased lipase concentrations,24 GERD,24 gastroenteritis,24 abdominal distention,24 eructation,24 urinary tract infection,24 flatulence,24 viral gastroenteritis,24 injection site erythema,24 injection site reaction,24 insomnia,24 dry mouth,24 asthenia,24 anxiety.24

Interactions for Liraglutide

Low potential for pharmacokinetic interactions related to CYP metabolism.1

Orally Administered Drugs

Possible decreased rate and extent of absorption of concomitantly administered oral drugs; use caution with concomitantly administered oral drugs.1 24

Specific Drugs

Drug

Interaction

Comments

Acetaminophen

Potential decreased peak plasma acetaminophen concentration and absorption rate; no change in overall AUC1 24

Atorvastatin

Potential decreased peak plasma atorvastatin concentration and absorption rate; no change in overall AUC1 24

Digoxin

Decreased peak plasma digoxin concentration and absorption rate following single digoxin dose1 24

Griseofulvin

Increased peak plasma griseofulvin concentration following single griseofulvin dose1 24

Hormonal contraceptives, oral

Potential reduced peak plasma concentrations and rates of absorption of ethinyl estradiol and levonorgestrel; increased AUC of levonorgestrel but no effect on ethinyl estradiol AUC1 24

Insulin detemir

No pharmacokinetic interaction observed following administration of separate sub-Q injections of insulin detemir and liraglutide1 24

Lisinopril

Decreased peak plasma lisinopril concentration, AUC, and absorption rate following single lisinopril dose1 24

Liraglutide Pharmacokinetics

Absorption

Bioavailability

Absolute: Approximately 55% after sub-Q administration.1 10 24

Peak plasma concentration achieved in 11 hours1 24 (range: 8-12 hours) following sub-Q administration.9 10 13 15 20

Duration

Sustained glucose-lowering activity for 24 hours after a dose of liraglutide at steady state.20

Distribution

Plasma Protein Binding

>98%.1 24

Elimination

Metabolism

Endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination.1 13 24 Dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP) likely involved in its degradation.13

Elimination Route

Only a minor portion of liraglutide-related metabolites excreted in urine (6%) or feces (5%).1 13 24

Half-life

13 hours after sub-Q administration.1 9 10 15 24

Stability

Storage

Parenteral

Solution for Injection

Before use, 2–8°C.1 24 After first use, can be stored at 15–30ºC or 2–8°C.1 24 Do not freeze and do not use if frozen; protect from heat and light.1 24 Discard injection pen 30 days after first use.1 24

Actions

  • An acylated long-acting human glucagon-like peptide-1 (GLP-1) receptor agonist; synthetic (recombinant DNA origin) peptide precursor has 97% amino acid sequence homology to endogenous human GLP-1(7-37).1 10

    Activates the GLP-1 receptor in pancreatic β cells.1 14

  • Increases intracellular cyclic AMP (cAMP) leading to insulin release in the presence of elevated glucose concentrations.1 9 14 20 24 This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia.1

  • Suppresses glucagon secretion in a glucose-dependent manner but does not impair normal glucagon response to hypoglycemia.1 9 14 20 24

  • Delays gastric emptying, reducing the rate at which postprandial glucose appears in the circulation.1 9

  • Effectively reduces fasting and postprandial plasma glucose concentrations in patients with type 2 diabetes.2 3 4 5 6 7 9 18 20

  • GLP-1 is a physiological regulator of appetite.24 Weight loss effects of liraglutide are mediated by decreased calorie intake; drug does not increase energy expenditure.24

Advice to Patients

  • Importance of reading manufacturer’s medication guide and the injection pen's patient instructions for use before starting liraglutide therapy and of reviewing this information each time the prescription is renewed.1 23 24 25 29 30

  • Importance of informing patients that liraglutide causes benign and malignant thyroid C-cell tumors in mice and rats and that relevance of this finding to humans is unknown.1 23 24 25 Importance of counseling patients to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia, dyspnea) or a personal or family history of thyroid cancer, including MTC or MEN 2, to their clinician.1 23 24 25

  • Importance of informing patients of potential risk of acute pancreatitis, which may be severe or fatal, with liraglutide therapy.1 23 24 25 Importance of patient informing clinicians about a history of pancreatitis, gallstones, alcoholism, or high triglyceride levels.1 23 24 25 Importance of informing patients about signs and symptoms of pancreatitis, including persistent severe abdominal pain sometimes radiating to the back that may or may not be accompanied by vomiting.1 23 24 25 Importance of instructing patients to discontinue liraglutide promptly and contact their clinician if persistent, severe abdominal pain occurs.1 23 24 25

  • Importance of informing patients receiving liraglutide for obesity management of the risk of gallbladder disease, which can require cholecystectomy.24 Substantial or rapid weight loss increases the risk of cholelithiasis; however, cholelithiasis can occur in the absence of weight loss.24 25 Patients should be instructed to contact their clinician if they experience symptoms of gallbladder disease (e.g., abdominal pain, fever, jaundice, clay-colored stools).24 25

  • Importance of informing patient of risk of hypoglycemia, particularly if concomitant therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin is used.1 Importance of reviewing signs, symptoms, and management of hypoglycemia.1 23

  • Risk of increased resting heart rate; importance of advising patients that their heart rate should be measured periodically during therapy.24 25 Patients should be instructed to contact their clinician if they experience sustained palpitations or tachycardia at rest.24 25

  • Importance of informing patients of risk of dehydration because of adverse GI reactions; advise patients to take precautions to avoid fluid depletion.1 23 Importance of informing patients of potential risk of worsening renal function, which may require dialysis in some cases.1 23

  • Importance of informing patients of possibility of serious hypersensitivity reactions; instruct patients to discontinue liraglutide and promptly seek medical advice if hypersensitivity symptoms occur.1 23

  • Potential risk of suicidality; importance of patients being alert to and immediately reporting emergence of suicidality, worsening depression, or unusual changes in mood or behavior.24 25

  • Importance of informing patients that they should never share a liraglutide pen with another person, even if the needle is changed; sharing of the pen may pose a risk of transmission of infection.1 23 24 25

  • Importance of informing patients of the potential risks and benefits of liraglutide and of alternative therapies. 1 23

  • Importance of instructing patients with diabetes mellitus regarding self-monitoring of blood glucose, periodic HbA1c monitoring, adherence to meal planning, and regular physical exercise.1 23

  • Importance of informing patients of the most common side effects, including headache, nausea, and diarrhea.1 23 24 Nausea is most common when first starting liraglutide, but decreases over time in most patients and does not typically require discontinuance of the drug.1 23 24

  • Importance of reading manufacturer’s patient information (e.g., medication guide) and the injection pen user manual before starting liraglutide therapy and of reviewing this information each time the prescription is renewed.1 23

  • Importance of cautioning patients not to take an extra dose of liraglutide to make up for a missed dose.1 23 If a dose is missed, patients should resume the once-daily regimen with the next scheduled dose.1 23

  • Importance of informing patients that if >3 days have passed since the last dose, liraglutide should be reinitiated at dosage of 0.6 mg once daily to mitigate GI symptoms associated with reinitiation of treatment, then retitrated.1 23 24 (See Dosage under Dosage and Administration.)

  • Importance of instructing patients to discontinue use of liraglutide for the management of obesity if 4% weight loss not achieved after 16 weeks of therapy.24

  • Response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing these levels towards the normal range.1 23

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 23 24

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., gallstones, hypertension, pancreatitis, history of alcoholism, high triglyceride concentrations, digestion problems, severe kidney disease, kidney transplant).1 23 24

  • Importance of informing patients of other important precautionary information.1 24 (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.

Liraglutide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

6 mg/mL

Victoza (available as prefilled cartridge pen)

Novo Nordisk

6 mg/mL

Saxenda (available as prefilled cartridge pen)

Novo Nordisk

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Novo Nordisk. Victoza [liraglutide (rDNA origin) injection] solution for injection prescribing information and patient information. Plainsboro, NJ; 2015 Mar.

2. Garber A, Henry R, Ratner R et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomized, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009; 373:473-81. [PubMed 18819705]

3. Nauck M, Frid A, Hermansen K et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009; 32:84-90. [PubMed 18931095]

4. Marre M, Shaw J, Brändle M et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med. 2009; 26:268-78. [PubMed 19317822]

5. Zinman B, Gerich J, Buse JB et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care. 2009; 32:1224-30. [PubMed 19289857]

6. Russell-Jones D, Vaag A, Schmitz O et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomized controlled trial. Diabetologia. 2009; 52:2046-55. [PubMed 19688338]

7. Buse JB, Rosenstock J, Sesti G et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009; 374:39-47. [PubMed 19515413]

8. Victoza (liraglutide [rDNA origin]) injection risk evaluation and mitigation strategy (REMS). From FDA website.

9. Juhl CB, Hollingdal M, Sturis J et al. Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. Diabetes. 2002; 51:424-9. [PubMed 11812750]

10. Elbrønd B, Jakobsen G, Larsen S et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects. Diabetes Care. 2002; 25:1398-404. [PubMed 12145241]

11. Jacobsen LV, Hindsberger C, Robson R et al. Effect of renal impairment on the pharmacokinetics of the GLP-1 analogue liraglutide. Br J Clin Pharmacol. 2009; 68:898-905. [PubMed 20002084]

12. Flint A, Nazzal K, Jagielski P, Hindsberger C and Zdravkovic, M. Influence of hepatic impairment on pharmacokinetics of the human GLP-1 analogue, liraglutide. Br J Clin Pharmacol. 2010;70:807–814.

13. Malm-Erjefält M, Bjørnsdottir I, Vanggaard J et al. Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Drug Metab Dispos. 2010; 38:1944-53. [PubMed 20709939]

14. Vahl TP, Paty BW, Fuller BD et al. Effects of GLP-1-(7-36)NH2, GLP-1-(7-37), and GLP-1- (9-36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans. J Clin Endocrinol Metab. 2003; 88:1772-9. [PubMed 12679472]

15. Agersø H, Jensen LB, Elbrønd B et al. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia. 2002; 45:195-202. [PubMed 11935150]

16. Food and Drug Administration. FDA News Release: FDA approves new treatment for type 2 diabetes. 2009 Jan 25. Accessed 2010 Dec 6.

17. Parks M, Rosebraugh C. Weighing risks and benefits of liraglutide--the FDA’s review of a new antidiabetic therapy. N Engl J Med. 2010; 362:774-7. [PubMed 20164475]

18. Vilsbøll T, Zdravkovic M, Le-Thi T et al. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care. 2007; 30:1608-10. [PubMed 17372153]

19. Madsbad S, Schmitz O, Ranstam J et al. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004; 27:1335-42. [PubMed 15161785]

20. Degn KB, Juhl CB, Sturis J et al. One week’s treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004; 53:1187-94. [PubMed 15111485]

21. Pratley RE, Nauck M, Bailey T et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomized, parallel-group, open-label trial. Lancet. 2010; 375:1447-56. [PubMed 20417856]

22. Nathan DM, Holman RR, Buse JB et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. 2009;32:193-203.

23. Novo Nordisk. Victoza [liraglutide (rDNA origin) injection] solution for injection medication guide. Plainsboro, NJ; 2015 Jan.

24. Novo Nordisk. Saxenda [liraglutide (rDNA origin) injection] solution for injection prescribing information. Plainsboro, NJ; 2015 Jan.

25. Novo Nordisk. Saxenda [liraglutide (rDNA origin) injection] solution for injection medication guide. Plainsboro, NJ; 2015 Jan.

26. Pi-Sunyer X, Astrup A, Fujioka K et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med. 2015; 373:11-22. [PubMed 26132939]

27. Davies MJ, Bergenstal R, Bode B, et al. Liraglutide 3.0 mg for weight management in obese/overweight adults with type 2 diabetes: SCALE diabetes 56-week randomized, double-blind, placebo-controlled trial. Presented at EASD annual meeting. Vienna: 2014 Sep 16. Abstract 39-OR.

28. Wadden TA, Hollander P, Klein S et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2013; 37:1443-51. [PubMed 23812094]

29. Novo Nordisk. Victoza [liraglutide (rDNA origin) injection] solution for injection patient instructions for use. Plainsboro, NJ; 2015 Mar.

30. Novo Nordisk. Saxenda [liraglutide (rDNA origin) injection] solution for injection patient instructions for use. Plainsboro, NJ; 2014 Dec.

31. Saxenda (liraglutide [rDNA origin]) injection risk evaluation and mitigation strategy (REMS). From FDA website.

36. Food and Drug Administration. Early communication: reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas. Silver Spring, MD; 2013 Mar 14. From FDA website.

37. Singh S, Chang HY, Richards TM et al. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013; 173:534-9. [PubMed 23440284]

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