AHFS Class:

• Incretin Mimetics 68:20.06

Generic Name(s):

• Liraglutide

Liraglutide, a synthetic, long-acting human glucagon-like peptide-1 (GLP-1) receptor agonist (incretin mimetic), is an antidiabetic agent and antiobesity drug.1,24

Liraglutide (Victoza^®) is used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus1,2,18,19 and also is used to reduce the risk of major adverse cardiovascular events (i.e., cardiovascular death, nonfatal myocardial infarction [MI], nonfatal stroke) in patients with type 2 diabetes mellitus and established cardiovascular disease.1 Liraglutide in fixed combination with insulin degludec (insulin degludec/liraglutide; Xultophy^®) is used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.40,42,43,44

Liraglutide (Saxenda^®) is used for chronic weight management.24

Type 2 Diabetes Mellitus

Liraglutide is used as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients ≥10 years of age with type 2 diabetes mellitus.1,2,18,19 Liraglutide has been used alone or as add-on therapy with metformin, a sulfonylurea, insulin, or the combination of metformin and a sulfonylurea or thiazolidinedione.1,2,3,4,5,6,18,21 Various preparations of liraglutide are available; Victoza^® injection and the fixed-combination injection of liraglutide and insulin degludec (Xultophy^®) are specifically FDA-labeled for use in the management of diabetes mellitus.1,40

Glycemic Control

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).698,704,705 In patients with contraindications or intolerance to metformin (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, sodium-glucose cotransporter 2 [SGLT2] inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.698,704 Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another agent) may be appropriate in patients with an initial HbA_1c exceeding 7.5% or at least 1.5% above the target level.698,704 In metformin-intolerant patients with high initial HbA_1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic drug classes with complementary mechanisms of action. 698

Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.698,704 Patients who have inadequate glycemic control with initial (e.g., metformin) monotherapy should receive treatment with additional antidiabetic agents; data suggest that the addition of each noninsulin agent to initial therapy lowers HbA_1c by approximately 0.7-1%.704 In addition, early initiation of combination therapy may help more rapidly attain glycemic goals and extend the time to treatment failure.704

Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.698,699,704,705,706 When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.704 While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.698 Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698,704

Patients with type 2 diabetes mellitus who have established (or are at a high risk for) ASCVD, established kidney disease, or heart failure should receive a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular disease benefit.704,705 Experts state that therapy with a GLP-1 receptor agonist or SGLT2 inhibitor should be considered for patients with the aforementioned comorbidities independently of the patients' HbA_1c.704 GLP-1 receptor agonists and SGLT2 inhibitors appear to have effects on the kidneys independent of their glycemic effects, and some experts suggest that an agent from one of these classes of drugs be considered in patients with type 2 diabetes mellitus and chronic kidney disease (CKD). 698,704,706 In patients without established ASCVD or indicators of high ASCVD risk, heart failure, or CKD, the decision regarding the addition of other antidiabetic agents (e.g., GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, thiazolidinedione, sulfonylurea, basal insulin) to metformin therapy should be based on avoidance of adverse effects, cost, and individual patient factors.704

The manufacturer states that liraglutide or the fixed combination of insulin degludec and liraglutide (Xultophy^®) is not indicated for the treatment of type 1 diabetes mellitus.1,40

Liraglutide Monotherapy

When given as monotherapy for the management of type 2 diabetes mellitus, liraglutide improves glycemic control compared with glimepiride as evidenced by reductions from baseline in glycosylated hemoglobin (hemoglobin A_1c; HbA_1c) and fasting plasma glucose concentrations; liraglutide therapy also was associated with a reduction in body weight compared with an increase in body weight with glimepiride.1,2

Efficacy and safety of liraglutide as monotherapy in adults with type 2 diabetes mellitus have been established in a 52-week randomized, double-blind, active-controlled, double-dummy trial.1,2 In this trial, 746 patients with a mean baseline HbA_1c concentration of 8.2% received liraglutide 1.2 or 1.8 mg subcutaneously once daily or glimepiride 8 mg orally once daily.1,2 All patients randomized to liraglutide received an initial dosage of 0.6 mg once daily for 1 week; dosage subsequently was titrated in increments of 0.6 mg weekly to a dosage of either 1.2 or 1.8 mg once daily.1,2 All patients randomized to glimepiride received an initial dosage of 2 mg once daily for 2 weeks, followed by 4 mg once daily for 2 weeks, and then 8 mg once daily.1,2 The primary study end point was the change in HbA_1c concentration from baseline to week 52 (or the last value at time of early discontinuance of therapy).2 At week 52, HbA_1c was reduced from baseline by about 0.8, 1.1, or 0.5% with once-daily liraglutide 1.2 mg, liraglutide 1.8 mg, or glimepiride 8 mg, respectively.1,2 HbA_1c concentrations below 7% were achieved in 43, 51, or 28% of patients receiving once-daily liraglutide 1.2 mg, liraglutide 1.8 mg, or glimepiride 8 mg, respectively.2 Body weight was reduced from baseline by 2.1 or 2.5 kg with liraglutide 1.2 or 1.8 mg once daily, respectively, but was increased by 1.1 kg in patients receiving glimepiride 8 mg once daily.1

Combination Therapy

When given as add-on therapy to metformin and/or a sulfonylurea, metformin and a thiazolidinedione, or metformin and insulin detemir in clinical trials, liraglutide was more effective than placebo and at least as effective as add-on therapy with sitagliptin, glimepiride, or exenatide in improving glycemic control (as evidenced by reduction in HbA_1c concentrations).1,3,4,5,6,7,21

Efficacy and safety of liraglutide (1.2 or 1.8 mg subcutaneously once daily) as add-on therapy with maximally effective dosages of metformin, a sulfonylurea (e.g., glimepiride), or metformin in combination with a sulfonylurea or a thiazolidinedione were established in several studies of 26 weeks' duration.1,3,4,5,6,21 Combined therapy with subcutaneous liraglutide and these oral antidiabetic agents or regimens resulted in improved glycemic control (as indicated by a reduction in HbA_1c from baseline values) compared with that achieved with existing oral antidiabetic therapy.1,3,4,5,6,21

In a multicenter, randomized, open-label comparative study, adults with type 2 diabetes mellitus who received liraglutide 1.8 mg once daily in addition to their current therapy (metformin, a sulfonylurea, or both) experienced a greater reduction in HbA_1c than those who received exenatide 10 mcg twice daily in addition to current therapy (1.12 or 0.79% with liraglutide or exenatide, respectively).1,7 Mean reductions in weight were similar with liraglutide (3.24 kg) or exenatide (2.87 kg).7

In a 26-week, randomized, open-label comparative study, adults with type 2 diabetes mellitus who received liraglutide 1.2 or 1.8 mg once daily in addition to their current therapy (metformin hydrochloride at least 1.5 g daily) experienced a greater reduction in HbA_1c than those who received sitagliptin 100 mg once daily in addition to current therapy (HbA_1c reduction of 1.2, 1.5, or 0.9% with liraglutide 1.2 mg, liraglutide 1.8 mg, or sitagliptin 100 mg once daily, respectively).1

Safety and efficacy of liraglutide in combination with insulin (i.e., insulin detemir) were established in a study of 26 weeks' duration in adult patients receiving metformin hydrochloride (at least 1.5 g daily).1 Treatment with liraglutide 1.8 mg in addition to insulin detemir and metformin resulted in greater reduction in HbA_1c than treatment with liraglutide 1.8 mg in addition to metformin (HbA_1c reduction of 0.5% or 0, respectively).1

In another study, pediatric patients at least 10 years of age (mean age: 14.6 years) with type 2 diabetes mellitus and a HbA_1c of 7-11% (if previously treated with diet and exercise alone) or a HbA_1c of 6.5-11% (if previously treated with metformin with or without insulin) were randomized to receive liraglutide or placebo once daily; all patients received metformin with or without basal insulin therapy.1,50 Liraglutide was initiated at a dosage of 0.6 mg subcutaneously once daily and increased by increments of 0.6 mg every week over the course of 2-3 weeks based on tolerability and fasting plasma glucose concentrations (goal fasting plasma glucose concentration: 110 mg/dL or less).1,50 Most patients did not receive the maximum dosage of liraglutide because fasting plasma glucose concentrations of 110 mg/dL or less were achieved with lower dosages.50 After 26 weeks of therapy, treatment with liraglutide was superior to placebo in reducing HbA_1c from baseline (reduction of 0.64% or increase of 0.42%, respectively).1 Additionally, a larger proportion of patients who received liraglutide therapy obtained a HbA_1c of less than 7% compared with those who received placebo (63.7 versus 36.5%, respectively).1,50

In a 26-week, randomized, double-blind, placebo-controlled study, adults with type 2 diabetes mellitus and moderate renal impairment (eGFR 30-59 mL/minute per 1.73 m²) who received liraglutide 1.8 mg once daily in addition to their current therapy (basal or premixed insulin and/or metformin, pioglitazone, or sulfonylurea) experienced a greater reduction in HbA_1c than those who received placebo in addition to their current therapy (reduction of 0.9 versus 0.4%, respectively).1,46 There was no worsening of renal function in those who received liraglutide therapy.46

If inadequate glycemic control or failure to achieve target glycemic control occurs with liraglutide, alternative antidiabetic therapy should be considered.22

Fixed-combination Therapy with Insulin Degludec and Liraglutide

Current data indicate that the fixed combination of insulin degludec and liraglutide (insulin degludec/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 adults with type 2 diabetes mellitus.41,42,43 Safety and efficacy of insulin degludec/liraglutide 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.40,41,42,43,44

In 2 clinical studies, the use of insulin degludec/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 basal insulin or GLP-1 receptor agonists.40 In the first study, all patients continued on prestudy treatment with metformin with or without pioglitazone.40 In addition to the prestudy treatment, patients also received insulin degludec/liraglutide (initial dosage: 10 units of insulin degludec and 0.36 mg liraglutide), liraglutide (initial dosage: 0.6 mg), or insulin degludec (initial dosage: 10 units) subcutaneously once daily.40 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.40 Patients in the liraglutide treatment group followed a fixed-escalation scheme with weekly dosage increases of 0.6 mg until the liraglutide maintenance dosage of 1.8 mg was achieved.40 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.40 In the second study, all patients continued on prestudy treatment with a sulfonylurea with or without metformin.40 In addition to the prestudy treatment, patients also received insulin degludec/liraglutide (initial dosage: 10 units of insulin degludec and 0.36 mg liraglutide) or placebo.40 Patients in the fixed-combination group had their dosage titrated twice weekly towards a target fasting plasma glucose concentration of 72-108 mg/dL.40 After 26 weeks, the reduction in HbA_1c from baseline was 1.42 or 0.62% in patients treated with insulin degludec/liraglutide or placebo, respectively.40

In another clinical 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 dose at baseline: 1.7 mg) continued to receive their pretrial therapy or had their therapy changed from liraglutide to insulin degludec/liraglutide.40,42 Oral antidiabetic agents were continued at pretrial dosages throughout the trial in both treatment groups.40 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).40,42 After 26 weeks, the reduction in HbA_1c from baseline was 1.31 or 0.36% with insulin degludec/liraglutide versus liraglutide, respectively.40,42 A mean weight gain from baseline of 2 kg was observed in patients receiving insulin degludec/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.42

In another trial comparing insulin degludec/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.40,43 In this trial, all basal insulins and oral antidiabetic drugs except for metformin hydrochloride (mean daily dose: 1984 mg) were discontinued at randomization; patients received a starting insulin degludec dosage of 16 units (given separately or in the fixed combination with liraglutide 0.58 mg) once daily, which was titrated biweekly based on fasting plasma glucose concentrations.43 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.40 The reductions in HbA_1c from baseline were superior with insulin degludec/liraglutide compared with insulin degludec treatment (reduction of 1.94 versus 1.05 %, respectively).40 There was no substantial difference between the 2 treatment groups with regard to hypoglycemia.43

In another trial comparing insulin degludec/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 therapy.40,44 Patients in this trial either continued treatment with insulin glargine or were switched to insulin degludec/liraglutide, both in conjunction with metformin.40,44 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 insulin degludec/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.44 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.44 The mean dosage of the fixed combination was insulin degludec 41 units and liraglutide 1.48 mg daily; mean dosage of insulin glargine was 66 units daily.40 The reductions in HbA_1c from baseline were substantially greater with insulin degludec/liraglutide compared with insulin glargine (reduction of 1.67 versus 1.16%, respectively).40

The manufacturer states that insulin degludec/liraglutide should not be used in combination with any other preparation containing liraglutide or another GLP-1 receptor agonist.40

Reduction in Risk of Major Adverse Cardiovascular Events

Liraglutide is used to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease.1,81 In addition to lowering blood glucose, GLP-1 receptor agonists appear to modify several nonglycemic cardiovascular risk factors, such as blood pressure, body weight, and lipid profile.80,81 GLP-1 receptor agonists also may have beneficial endothelial effects.80,81 The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) study was designed to assess the cardiovascular safety and efficacy of liraglutide in patients with type 2 diabetes mellitus at high risk for or with cardiovascular disease.1,51 This study included adults with type 2 diabetes mellitus who were at least 50 years of age (mean age: 64 years) with at least one coexisting cardiovascular condition (e.g., coronary heart disease, cerebrovascular disease, peripheral vascular disease, CKD of stage 3 or greater, chronic heart failure New York Heart Association [NYHA] class II or III) or at least 60 years of age with at least one cardiovascular risk factor (e.g., microalbuminuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, an ankle-branchial index of less than 0.9).1,51 In this study, patients were randomized to receive liraglutide (1.8 mg [or maximally tolerated dose]) or placebo subcutaneously once daily for a median duration of 3.5 years.1,51 During the study, antidiabetic and cardiovascular therapies were modified to achieve standard of care treatment targets with respect to blood glucose, lipids, and blood pressure.1 Concomitant use of other standard of care treatments for diabetes mellitus (excluding DPP-4 inhibitors or other GLP-1 receptor agonists) and ASCVD (nondiuretic antihypertensives [92.4%], diuretics [41.8%], statins [72.1%], antiplatelet agents [66.8%]) was permitted.1 The primary outcome was the composite of time to first occurrence of cardiovascular death, nonfatal MI, and nonfatal stroke.1,51 In these studies, patients who received treatment with liraglutide had substantially lower rates of the primary cardiovascular outcome compared with those who received placebo (event rate 13 versus 14.9%).1,51 Deaths from cardiovascular causes were substantially reduced in the liraglutide group compared with placebo (event rate 4.7 versus 6%).1,51

The manufacturer states that effects on cardiovascular morbidity and mortality have not been established in patients receiving liraglutide for management of obesity.24

Beneficial Effects on Renal Function

In several cardiovascular outcomes trials involving the use of GLP-1 receptor agonists (e.g., dulaglutide, liraglutide, semaglutide) in patients with type 2 diabetes mellitus at high risk for cardiovascular disease or with existing cardiovascular disease, beneficial effects on renal function have been observed as a secondary outcome.52,704,706 Some experts state that in patients with type 2 diabetes mellitus and CKD who are at increased risk for cardiovascular events, use of a GLP-1 receptor agonist may reduce risk of progression of albuminuria, cardiovascular events, or both.706 In the LEADER study, liraglutide reduced the risk of new or worsening nephropathy (a composite of persistent macroalbuminuria, doubling of serum creatinine, end-stage renal disease, or death from end-stage renal disease)† by 22%.52,706

Chronic Weight Management

Liraglutide is used as an adjunct to a reduced-calorie diet and increased physical activity for the long-term management of body weight in adults who are obese (pretreatment body mass index [BMI] of 30 kg/m² or greater) or, in those who are overweight (pretreatment BMI of 27 kg/m² or greater) and have an underlying weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, dyslipidemia).24,26,27,28 Liraglutide also is used as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in pediatric patients ≥12 years of age with body weight >60 kg and an initial BMI corresponding to 30 kg/m² for adults (obese) by international cut-offs.24

Various preparations of liraglutide are available; Saxenda^® injection is specifically FDA-labeled for use in chronic weight management.24

The manufacturer states that the Saxenda^® preparation of liraglutide is not intended for use in the treatment of type 2 diabetes mellitus.24 In addition, Saxenda^® should not be used in combination with any other GLP-1 receptor agonist or with insulin.24

Safety and efficacy of liraglutide in combination with other products used to promote weight loss, including prescription and nonprescription (OTC) drugs and dietary or herbal supplements, have not been established.24

When used in conjunction with a reduced-calorie diet and increased exercise, liraglutide substantially decreases body weight compared with placebo in obese and overweight diabetic and nondiabetic patients.24,26,27,28 In clinical trials, weight loss with liraglutide therapy has been maintained over 56 weeks.24,26,27,28

Efficacy and safety of liraglutide for the management of body weight in adults were evaluated in 3 randomized, double-blind, placebo-controlled studies of 56 weeks' duration (studies 1, 2, and 3) in a total of 4788 patients who were obese (defined as a BMI of 30 kg/m² or greater) or overweight (defined as a BMI of 27-29.9 kg/m²) with at least one weight-related comorbid condition such as hypertension or dyslipidemia.24,26,28 All patients received instruction regarding a reduced-calorie diet (approximately 500 kcal/day deficit) and exercise counseling (recommended increased physical activity for at least 150 minutes per week) initially and throughout the study.24,27,28 In all 3 studies, liraglutide was initiated at 0.6 mg subcutaneously once daily and titrated over 4 weeks to a dosage of 3 mg once daily.24,26,28 Across all 3 studies, 27% of patients in the liraglutide group and 35% of patients in the placebo group discontinued treatment.24 Approximately 10 or 4% of patients treated with liraglutide or placebo, respectively, discontinued treatment due to an adverse reaction; most such discontinuances occurred during the first few months of treatment.24

Study 1 compared liraglutide with placebo in addition to caloric restriction and increased physical activity in 3731 obese or overweight nondiabetic patients.24,26 The mean baseline body weight for both treatment groups was 106.2 kg and mean BMI was 38.3 kg/m².24,26 Other baseline characteristics were similar between groups; mean age was 45 years, 79% were female, 85% Caucasian, 10% African American, and 11% Hispanic or Latino.24,26 Principal measures of efficacy were mean percent change in body weight from baseline, the proportion of patients who lost at least 5% of their baseline body weight, and the proportion who lost at least 10% of their baseline body weight.24,26 At 56 weeks, liraglutide 3 mg daily reduced body weight by a greater percentage from baseline than placebo (a mean reduction of 7.4% versus 3%, respectively).24 A substantially greater proportion of patients receiving liraglutide lost 5% or more of their baseline body weight compared with patients receiving placebo (62.3 versus 34.4%, respectively).24,26 Similarly, more patients receiving liraglutide lost 10% or more of their baseline body weight compared with patients receiving placebo (33.9 versus 15.4%, respectively).24,26 In a subset of patients who had abnormal blood glucose concentrations at randomization (prediabetes),47 a substantially greater proportion of patients receiving liraglutide lost 5% or more of their baseline body weight at week 56, 160, or both 56 and 160 weeks compared with patients receiving placebo (56, 28, or 26 versus 25, 14, or 10%, respectively).24 More patients in the liraglutide treatment group regressed from prediabetes to normoglycemia by week 160 than those patients who received placebo.47 In addition, liraglutide was superior to placebo on several secondary measures of efficacy: deceased BMI, waist circumference, systolic and diastolic blood pressure, total cholesterol and triglyceride concentrations, and measures of glycemic control (glycosylated hemoglobin [HbA_1c], fasting glucose, fasting insulin).24,26

Study 2 compared liraglutide with placebo in addition to caloric restriction and increased physical activity in 635 obese or overweight patients with type 2 diabetes mellitus.24,27 Patients had baseline HbA_1c 7-10% and were treated with 1-3 oral antidiabetic agents (metformin, a sulfonylurea, a thiazolidinedione) or with diet and exercise alone.24,27 The mean baseline body weight was 105.9 kg and mean BMI was 37.1 kg/m²; mean age was 55 years, 50% were female, 83% Caucasian, 12% African American, and 10% Hispanic or Latino.24 Principal measures of efficacy were identical to those in study 1.24 At 56 weeks, liraglutide 3 mg daily reduced body weight by a greater percentage from baseline than placebo (a mean reduction of 5.4% versus 1.7%, respectively).24 More patients receiving liraglutide lost 5% or more (49%) or 10% or more (22.4%) of their baseline body weight compared with patients receiving placebo (16.4 or 5.5%, respectively).24 Liraglutide also improved several secondary measures of efficacy: waist circumference, systolic and diastolic blood pressure, total cholesterol and triglyceride concentrations, and measures of glycemic control (HbA_1c, fasting glucose).24,27

Study 3 evaluated the effect of liraglutide or placebo in 422 obese or overweight nondiabetic patients who had lost at least 5% of their baseline body weight with diet and exercise.24,28 In this study, patients were initially treated with a low-calorie diet (total daily energy intake 1200-1400 kcal) and recommended physical activity of at least 150 minutes per week for up to 12 weeks.24,28 Patients who lost at least 5% of their baseline body weight received liraglutide 3 mg daily or placebo for 56 weeks in addition to a continued reduced-calorie diet (approximately 500 kcal/day deficit) and exercise counseling.24,28 The mean baseline body weight was 99.6 kg and mean BMI was 35.6 kg/m²; mean age was 46 years, 81% were female, 84% Caucasian, 13% African American, and 7% Hispanic or Latino.24 Principal measures of efficacy in this study were mean percent change in body weight from time of randomization, the proportion of patients that maintained their original weight loss (i.e., not gaining more than 0.5% body weight from time of randomization), and the proportion of patients who lost 5% or more of body weight after randomization.24,28 Liraglutide was superior to placebo on all primary efficacy end points at 56 weeks; liraglutide-treated patients experienced a weight loss of 4.9% of body weight at randomization compared with a weight gain of 0.3% in placebo recipients.24,28 A greater proportion of liraglutide-treated patients did not gain back more than 0.5% of their weight at randomization compared with placebo recipients, and more liraglutide-treated patients lost an additional 5% or more of their body weight at randomization compared with those who received placebo (44.2 versus 21.7%, respectively).24,28 Furthermore, a substantially greater proportion of patients receiving liraglutide lost 10% or more of their body weight at randomization compared with patients receiving placebo (25.4 versus 6.9%, respectively).24,28

Efficacy and safety of liraglutide for weight management in pediatric patients 12 years of age or older with obesity were evaluated in a 56-week, double-blind, randomized, placebo-controlled trial in 251 pubertal patients with BMI corresponding to 30 kg/m² or greater for adults by international cut-off points and BMI of 95th percentile or greater for age and sex.24 The mean age of patients was 14.5 years; 40.6% were male, 87.6% were white. 0.8% were Asian, 8% were Black or African American, and 22.3% were of Hispanic or Latino ethnicity.24 The mean baseline body weight was 100.8 kg and mean BMI was 35.6 kg/m².24 The primary endpoint was change in BMI standard deviation score (SDS).24 Mean BMI SDS at baseline was 3.14 in the liraglutide group and 3.2 in the placebo group.24 The observed mean change in BMI SDS from baseline to week 56 was -0.23 in the liraglutide group and -0 in the placebo group (estimated treatment difference of -0.22 between liraglutide and placebo).24 Liraglutide treatment also resulted in beneficial effects on waist circumference and cardiometabolic parameters.24

The STEP 8 trial was a 68-week, open-label, multicenter trial that compared once-weekly subcutaneous semaglutide 2.4 mg with once-daily subcutaneous liraglutide 3 mg in adults with BMI ≥30 kg/m² or BMI ≥ 27 kg/m² with 1 or more weight-related comorbidities (except diabetes).32 All patients received counseling to adhere to diet and physical activity recommendations.32 The study showed that weight loss with semaglutide was significantly greater than with liraglutide.32 The mean weight change from baseline at 68 weeks was -15.8% with semaglutide compared with -6.4% with liraglutide (difference of -9.4 percentage points).32

Clinical Perspective

Clinical practice guidelines recommend treatment for obesity in patients with excess body weight and associated health risks.33,34 A comprehensive lifestyle intervention is an essential component of therapy and should be provided to all patients; pharmacologic therapy may be considered as an adjunct to behavioral modification in patients who fail to achieve or sustain clinically meaningful weight loss (generally defined as a loss of more than 4-5% of total body weight).33,34 Response to drug therapy should be evaluated after 3-4 months of treatment; if clinically meaningful weight loss is not achieved, it is generally recommended that a new treatment plan be considered because the patient is likely not responding to the drug.33,34

General

Patient Monitoring

• Patients receiving liraglutide for the management of type 2 diabetes mellitus should be monitored regularly (e.g., blood glucose determinations, HbA_1c) to determine therapeutic response.1
• When used for chronic weight management, evaluate body weight after 16 weeks (in adults) and after 12 weeks (in pediatric patients).24 Discontinue treatment in adults who do not experience a meaningful weight loss (≥4% baseline weight); discontinue treatment in pediatric patients who do not experience a reduction in BMI of ≥1% from baseline.24
• Observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting).1

Administration

Liraglutide or the fixed combination of insulin degludec and liraglutide (insulin degludec/liraglutide) is administered by subcutaneous injection into the abdomen, thigh, or upper arm using a prefilled injection pen;1,24,40 the drug must not be administered IV or IM.24,40

Liraglutide is administered once daily at any time of day, without regard to meals.1,24 The injection site and timing can be changed without dosage adjustment.1,24 Rotate injection sites within the same region to reduce the risk of cutaneous amyloidosis.1

The fixed combination of insulin degludec/liraglutide is administered by subcutaneous injection once daily at the same time each day without regard to meals.40

If a dose of liraglutide or insulin degludec/liraglutide is missed, the regular schedule should be resumed with the next scheduled dose; an extra dose or increase in dose should not be taken to replace a missed dose.1,24,40 If more than 3 days have elapsed since the last dose of liraglutide or insulin degludec/liraglutide, the initial dosage should be restarted and retitrated.1,24,40

When using liraglutide in combination with insulin for the management of type 2 diabetes mellitus, the drugs should be administered as separate injections; insulin and liraglutide should never be mixed.1 Liraglutide and insulin may be injected in the same body regions; however, the injections should not be adjacent to each other.1 Liraglutide in fixed combination with insulin degludec is commercially available as Xultophy^®.40 The fixed combination of insulin degludec and liraglutide should not be mixed with any other insulin preparations or solutions.40

Dosage

Type 2 Diabetes Mellitus

The recommended initial dosage of liraglutide for the management of type 2 diabetes mellitus in adults is 0.6 mg subcutaneously once daily.1 The 0.6-mg daily dosage of liraglutide is not effective for glycemic control and is intended only as a starting dosage to reduce GI intolerance.1 After one week, the dosage of liraglutide should be increased to 1.2 mg daily.1 If additional glycemic control is required, dosage may be increased to 1.8 mg daily after at least one week of treatment with the 1.2-mg daily dose.1

The recommended initial dosage of liraglutide for the management of type 2 diabetes mellitus in children and adolescents ≥10 years of age is 0.6 mg subcutaneously once daily.1 After at least one week, the dosage may be increased by 0.6 mg increments.1 The maximum recommended dosage is 1.8 mg once daily.1

If a dose is missed and more than 3 days have elapsed since the last dose of liraglutide, patients should be advised to reinitiate liraglutide at 0.6 mg subcutaneously once daily to minimize any adverse GI effects.1 Upon reinitiation, liraglutide should be titrated at the discretion of the clinician.1

Fixed Combination of Insulin Degludec and Liraglutide (Xultophy®)

Dosage of the fixed combination of insulin degludec and liraglutide (insulin degludec/liraglutide) is expressed in terms of units of insulin degludec on the dose counter display of the Xultophy^® injection pen; each dosage unit delivers 1 unit of insulin degludec and 0.036 mg of liraglutide.40

The dosage of insulin degludec/liraglutide is based on the results of blood glucose determinations and should be carefully individualized to obtain optimum therapeutic effect.40 Dosage adjustments may be needed during acute illness or when used with other drugs or with changes in physical activity, meal patterns (i.e., macronutrient content or timing of food intake), or renal or hepatic function.40

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 insulin degludec/liraglutide is 10 units (10 units of insulin degludec and 0.36 mg of liraglutide) once daily.40

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/liraglutide.40 The recommended initial dosage of insulin degludec/liraglutide in these patients is 16 units (16 units of insulin degludec and 0.58 mg of liraglutide) once daily.40

The 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.40 The fixed combination preparation should not be administered more than once daily.40 Adjustments in concomitant oral antidiabetic therapy may be needed.40 The maximum daily dosage of insulin degludec in the fixed combination with liraglutide is 50 units (50 units of insulin degludec and 1.8 mg of liraglutide).40

Chronic Weight Management

The recommended maintenance dosage of liraglutide for the management of body weight in adults and pediatric patients ≥12 years of age is 3 mg subcutaneously once daily.24 To minimize adverse GI effects, dosage should be initiated at 0.6 mg daily for 1 week and then increased at weekly intervals until the maintenance dosage is reached.24 (See Table 1.)

If an increase in dosage is not tolerated (e.g., adverse GI effects) in adults, dosage escalation may be delayed for approximately 1 week.24 However, if a dosage of 3 mg daily is not tolerated, liraglutide should be discontinued, as efficacy has not been established at dosages lower than 3 mg daily.24 If pediatric patients do not tolerate an increased dose during dose escalation, the dose may be lowered to the previous level.24 Dose escalation for pediatric patients may take up to 8 weeks.24 In pediatric patients who do not tolerate a dosage of 3 mg daily, the maintenance dosage may be reduced to 2.4 mg daily; therapy should be discontinued if the patient cannot tolerate the 2.4 mg dose.24

If a dose is missed and more than 3 days have elapsed since the last dose of liraglutide, the drug should be reinitiated at a dosage of 0.6 mg subcutaneously once daily to minimize any adverse GI effects; the dosage should then be retitrated to a maintenance dosage of 3 mg once daily.24

Body weight should be evaluated 16 weeks after initiating liraglutide in adults.24 Treatment should be discontinued in patients who do not experience a meaningful reduction in weight (at least 4% of baseline body weight) after 16 weeks since such patients are unlikely to achieve and sustain meaningful weight loss with continued liraglutide therapy.24

The change in BMI should be evaluated in pediatric patients after 12 weeks on the maintenance liraglutide dosage and treatment should be discontinued if the patient has not had a reduction in BMI of at least 1% from baseline, since it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.24

Special Populations

No adjustment of liraglutide dosage is recommended in patients with renal or hepatic impairment or based solely on age or sex.1,24 However, clinicians should use caution when initiating liraglutide or escalating dosage in patients with renal impairment.1,24 Data are lacking on the use of the fixed combination of insulin degludec and liraglutide in patients with hepatic impairment.40 There is limited experience with the use of the fixed combination of insulin degludec and liraglutide in patients with mild or moderate renal impairment; glucose monitoring should be intensified and the dosage of the fixed combination individualized as required.40

Contraindications

Liraglutide alone or in fixed combination with insulin degludec (Xultophy^®) is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).1,16,24,40

Liraglutide alone or in fixed combination with insulin degludec also is contraindicated in patients with a history of serious hypersensitivity to liraglutide or to any of the product components.1,24,40

The fixed combination of insulin degludec and liraglutide is contraindicated during episodes of hypoglycemia.40

Liraglutide is contraindicated for chronic weight management in women who are pregnant.24

Warnings/Precautions

Warnings

Risk of Thyroid C-Cell Tumors

Liraglutide causes dose-dependent and treatment duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice.1,24,40 Cases of MTC have been reported in patients receiving liraglutide during postmarketing experience; data from these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans.1 It is also unknown whether liraglutide causes thyroid C-cell tumors in humans, as relevance to humans of such tumors in rodents has not been determined.1,16,24,40 For this reason, liraglutide or the fixed combination of insulin degludec and liraglutide is contraindicated in patients with a history of MTC and in patients with MEN 2.1,16,24,40 In addition, liraglutide should not be used as first-line treatment for diabetes mellitus until additional studies are completed that support expanded use.1,16

In clinical trials of diabetes mellitus treatment, adjusted mean serum calcitonin concentrations were higher in liraglutide-treated patients than in placebo-treated patients but not higher than in patients receiving an active comparator drug.1 Adjusted mean serum calcitonin concentrations were also higher in liraglutide-treated patients than in placebo-treated patients in clinical trials of obesity management.24 Very elevated serum calcitonin values may be indicative of MTC; patients with MTC usually have serum calcitonin values exceeding 50 ng/L.1,24 Although routine monitoring of serum calcitonin concentrations or thyroid ultrasounds for the purpose of early detection of MTC in patients receiving liraglutide is of uncertain value and may increase the risk of unnecessary procedures, patients should be further evaluated if serum calcitonin is measured and found to be elevated or thyroid nodules are noted on physical examination or neck imaging.1,24

To specifically evaluate the risk of MTC, the FDA has required the manufacturer 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

Serious hypersensitivity reactions (anaphylaxis, angioedema) have been reported in patients receiving liraglutide.1,24 Asthma,24 bronchial hyperreactivity,24 bronchospasm,24 oropharyngeal swelling,24 facial swelling,24 pharyngeal edema,24 and type IV hypersensitivity reactions24 also have been reported with liraglutide therapy. Anaphylactic reactions with additional symptoms (e.g., hypotension, palpitations, dyspnea, edema) have been reported; anaphylactic reactions may be potentially life-threatening.24 If a hypersensitivity reaction occurs, patients should discontinue liraglutide-containing therapy and other suspect drugs and promptly seek medical advice.1,24,40

Liraglutide should be used with caution in patients with a history of anaphylaxis or angioedema with another glucagon-like peptide-1 (GLP-1) receptor agonist, as it is unknown whether such patients will be predisposed to angioedema with liraglutide.1,24

Other Warnings and Precautions

Use of Fixed Combinations

When liraglutide is used in fixed combination with other drugs (e.g., insulin degludec), cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) should be considered in addition to those associated with insulin degludec.40

Risks During General Anesthesia and Deep Sedation

GLP-1 agonists are associated with adverse GI effects such as nausea, vomiting, and delayed gastric emptying; such effects are likely a result of rapid tachyphlaxis at the level of vagal nerve activation.90 Delayed gastric emptying from GLP-1 agonists can increase the risk of regurgitation and pulmonary aspiration of gastric contents during general anesthesia and deep sedation.90 Given these concerns, the American Society of Anesthesiologists (ASA) Task Force on Preoperative Fasting has issued a consensus-based guidance for the management of GLP-1 receptor agonists prior to elective surgery.90 The task force suggests that for patients on daily GLP-1 agonist dosing (irrespective of indication, dose, or type of surgery), consider holding the drug on the day of the procedure/surgery.90 For patients on weekly dosing (irrespective of indication, dose, or type of surgery), consider holding the GLP-1 agonist a week prior to the procedure/surgery.90 If GLP-1 agonists prescribed for diabetes management are held for longer than the dosing schedule, consider consulting an endocrinologist for bridging the antidiabetic therapy to avoid hyperglycemia.90 These recommendations are based on limited evidence only (case reports).90 For patients requiring urgent or emergent procedures, the task force states to proceed and treat the patient as ‘full stomach' and manage accordingly.90

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been reported during postmarketing experience with liraglutide.1,24,40

In clinical trials with liraglutide in type 2 diabetes mellitus, there were 13 cases of pancreatitis (9 acute, 4 chronic) among liraglutide-treated patients compared with 1 case in a glimepiride-treated patient (2.7 versus 0.5 cases per 1000 patient-years, respectively).1 One case of pancreatitis with necrosis was fatal, though clinical causality could not be established.1 Some patients had other risk factors for pancreatitis, including a history of cholelithiasis or alcohol abuse.1 In clinical trials in adults with liraglutide for chronic weight management, acute pancreatitis was confirmed in 0.3% of liraglutide-treated patients (9 of 3291 patients) compared with 0.1% of patients who received placebo (1 of 1843 patients).24 In addition, there were 2 cases of acute pancreatitis in liraglutide-treated patients who withdrew prematurely from the clinical trials; these cases occurred 74 and 124 days after the last dose of liraglutide.24 Two additional cases of acute pancreatitis were reported during a follow-up period; one case occurred within 2 weeks of discontinuing liraglutide and the other occurred 106 days after completing treatment with liraglutide.24 In a clinical trial in pediatric patients receiving liraglutide for chronic weight management, pancreatitis was not independently adjudicated; pancreatitis was reported in 1 (0.8%) liraglutide-treated patient and resulted in treatment discontinuation.24

Observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting).24 If pancreatitis is suspected, liraglutide or the fixed combination of insulin degludec and liraglutide should be discontinued promptly and appropriate management initiated.1,24,40 If pancreatitis is confirmed, liraglutide or the fixed combination of insulin degludec and liraglutide should not be restarted.1,24,40

Efficacy and safety of liraglutide or the fixed combination of insulin degludec and liraglutide have not been established in patients with a history of pancreatitis, and it is not known whether such patients would have an increased risk of pancreatitis while taking liraglutide.1,40 Liraglutide has been evaluated in a limited number of adults with a history of pancreatitis in clinical trials of the drug for chronic weight management; it is not known if patients with a history of pancreatitis are at increased risk for pancreatitis while receiving liraglutide.24

Acute Gallbladder Disease

Liraglutide may increase the risk of acute gallbladder disease (e.g., cholelithiasis, cholecystitis).24 In clinical trials for obesity management, cholelithiasis was reported in 2.2% of patients receiving liraglutide and in 0.8% of placebo recipients, and cholecystitis occurred in 0.8% of liraglutide-treated patients compared with 0.4% of placebo recipients.24 Cholecystectomy was required in most liraglutide-treated patients experiencing cholelithiasis and cholecystitis.24 In the LEADER study, gallbladder disease (e.g., cholelithiasis or cholecystitis) occurred in 3.1% of liraglutide-treated patients compared with 1.9% of placebo recipients.1 Cholecystectomy or hospitalization was required in most liraglutide-treated patients experiencing gallbladder disease.1

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

Sharing of Injection Pens

Injection pens containing liraglutide (Victoza^®, Saxenda^®) or the fixed combination of insulin degludec and liraglutide (Xultophy^®) must never be shared among patients, even if the needle has been changed.1,24,40 Sharing of injection pens poses a risk for transmission of blood-borne pathogens.1,24,40

Hypoglycemia

Patients receiving liraglutide in combination with an insulin secretagogue (e.g., a sulfonylurea) or insulin may have an increased risk of hypoglycemia.1,24 In 5 clinical trials of liraglutide for the treatment of diabetes mellitus, hypoglycemia requiring the assistance of another person for treatment occurred in 8 patients receiving liraglutide, and 7 of these patients were concomitantly receiving a sulfonylurea antidiabetic agent.1

In pediatric patients 10 years of age or older with type 2 diabetes mellitus, the risk of hypoglycemia was higher with liraglutide regardless of concomitant antidiabetic therapies.1 In a clinical study in pediatric patients (mean age: 14.6 years) with type 2 diabetes mellitus, 21.2% of liraglutide-treated patients experienced hypoglycemia (blood glucose concentration less than 54 mg/dL) with or without symptoms.1 None of the patients experienced severe hypoglycemia (i.e., a hypoglycemic episode requiring assistance of another person).1

In clinical trials of chronic weight management in adults without type 2 diabetes mellitus, spontaneously reported symptomatic episodes of unconfirmed hypoglycemia were reported by 1.6 or 1.1% of adults receiving liraglutide or placebo, respectively.24 The manufacturer states that in patients with type 2 diabetes mellitus receiving liraglutide for chronic weight management, blood glucose parameters should be monitored prior to starting and during treatment.24 If needed, dosage of coadministered antidiabetic drugs should be adjusted based on results of glucose monitoring and risk of hypoglycemia.24

In a clinical trial of chronic weight management in pediatric patients without type 2 diabetes mellitus in which blood glucose meters were provided, 15.2% of liraglutide-treated patients had hypoglycemia with a blood glucose less than 70 mg/dL with symptoms compared to 4% of placebo-treated patients.24 No severe hypoglycemic episodes, defined as requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, occurred in patients receiving liraglutide.24

When initiating liraglutide in patients taking insulin secretagogues (e.g., a sulfonylurea) or insulin, the risk of hypoglycemia may be reduced by decreasing the dosage of the concomitant insulin secretagogue (e.g., by 50% in patients receiving the drug for obesity)24 or insulin.1,24 The manufacturer states that insulin should not be used concomitantly in patients receiving liraglutide for the management of obesity.24 Patients with type 2 diabetes mellitus should be monitored for an increase in blood glucose when liraglutide is discontinued.24

Elevated Heart Rate

Liraglutide has been associated with increases in heart rate in patients receiving the drug for the management of type 2 diabetes mellitus or obesity.1,24 In clinical trials in such patients, liraglutide was associated with a mean increase in resting heart rate of 2-3 beats per minute compared with placebo.1,24 In a clinical pharmacology study in patients receiving liraglutide for management of obesity, liraglutide therapy was associated with an increase in heart rate of 4-9 beats per minute compared with placebo.24 Heart rate increases of more than 10 or 20 beats per minute at 2 consecutive study visits were reported in 34 or 5% of patients receiving liraglutide, respectively, compared with 19 or 2% of patients receiving placebo, respectively, in clinical studies of obesity management.24 At least one occurrence of resting heart rate exceeding 100 beats per minute was reported in 6% of liraglutide-treated patients compared with 4% of placebo recipients, and such heart rate increases occurred at 2 consecutive visits in 0.9 or 0.3% of liraglutide- or placebo-treated patients, respectively.24 Tachycardia was reported as an adverse effect in 0.6% of patients receiving liraglutide for management of obesity versus 0.1% of those receiving placebo.24 The clinical importance of elevated heart rate is unclear, especially in patients with cardiovascular or cerebrovascular disease who had limited exposure to the drug in clinical trials of obesity management.24 Heart rate should be monitored regularly in patients receiving liraglutide; the drug should be discontinued in patients who experience a sustained increase in resting heart rate.24

Renal Effects

Acute renal failure and worsening of chronic renal failure, sometimes requiring hemodialysis, have been reported with GLP-1 receptor agonists, including liraglutide.1,24,40 Some of these events occurred in patients without known underlying renal disease.1 Most of these events occurred in patients experiencing nausea, vomiting, diarrhea, or dehydration.1,24 Some of these events occurred in patients receiving liraglutide in combination with one or more agents known to affect renal function or hydration status.1,24

Liraglutide has not been found to be directly nephrotoxic in preclinical or clinical studies.1 Renal effects usually have been reversible with supportive treatment and discontinuance of potentially causative agents, including liraglutide.1,24

Suicidality

Suicidal ideation was reported in 9 patients (0.3%) receiving liraglutide in clinical trials for chronic weight management and in 2 patients (0.1%) receiving placebo; suicide attempt was reported in one of these patients.24 Patients receiving liraglutide should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.24 If a patient experiences suicidal thoughts or behaviors while receiving liraglutide, the drug should be discontinued.24 Liraglutide should be avoided in patients with a history of suicidal attempts or active suicidal ideation.24

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity with liraglutide or the fixed combination of insulin degludec and liraglutide.1,40 In 5 double-blind clinical studies in patients with type 2 diabetes mellitus, antibodies to liraglutide were assessed in 50-70% of liraglutide-treated patients at the end of treatment (week 26 or greater).1 Low titers of anti-liraglutide antibodies were detected in 8.6% of these liraglutide-treated patients.1 Anti-liraglutide antibodies were detected at a post-baseline assessment in 42 (2.8%) of 1505 patients receiving liraglutide for management of obesity.24 Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 18 (1.2%) of 1505 liraglutide-treated patients.24 The presence of antibodies may be associated with a higher incidence of injection site reactions and reports of low blood glucose.24 In clinical trials, these events were usually classified as mild and resolved while patients continued on treatment.24 The development of cross-reacting anti-liraglutide antibodies to native GLP-1 peptide also has occurred; however, the potential for clinically important neutralization of native GLP-1 has not been assessed.1 Antibody formation has not been associated with reduced efficacy of liraglutide or an increase in adverse events potentially related to immunogenicity (e.g., urticaria, angioedema).1 In a clinical study in pediatric patients 10-17 years of age, anti-liraglutide antibodies were detected in 1.5% of liraglutide-treated patients after 26 weeks of treatment and 8.5% of liraglutide-treated patients after 53 weeks of treatment.1 None of these patients developed cross-reactive antibodies to native GLP-1 or had neutralizing antibodies.1

Specific Populations

Pregnancy

Data are lacking on the use of liraglutide (Victoza^®) in pregnant women.1 Reproduction studies in rats using liraglutide at dosages resulting in systemic exposures 0.8 times the exposure from the maximum recommended human dosage (1.8 mg daily) have shown teratogenic effects.1,24 Studies in rabbits have shown reduced growth and major abnormalities at systemic exposures below the maximum recommended human dosage.1 Liraglutide for the management of diabetes mellitus should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1

The manufacturer states that liraglutide (Saxenda^®) is contraindicated for the management of obesity in women who are pregnant because weight loss offers no potential benefit to pregnant women and may result in fetal harm.24 If a woman taking liraglutide for the management of obesity becomes pregnant or plans to become pregnant, the drug should be discontinued.24

Lactation

Liraglutide is distributed into milk in rats.1,24 It is not known whether liraglutide is distributed into milk in humans; a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1,24

Pediatric Use

Safety and efficacy of liraglutide for the management of type 2 diabetes mellitus have not been established in children or adolescents younger than 10 years of age.1,50 Safety and efficacy of liraglutide for chronic weight management have not been established in children or adolescents younger than 18 years of age, and the manufacturer of Saxenda^® states that the drug is not recommended for use in pediatric patients.24

Safety and efficacy of the fixed combination of insulin degludec and liraglutide have not been established in pediatric patients.40

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults have been observed with liraglutide or the fixed combination of insulin degludec and liraglutide, but increased sensitivity of some older patients cannot be ruled out. 1,24,40 Hypoglycemia may be difficult to recognize in geriatric patients.40

Hepatic Impairment

Experience in patients with mild, moderate, or severe hepatic impairment is limited; liraglutide (as Victoza^®or Saxenda^®) or the fixed combination of insulin degludec and liraglutide should be used with caution in such patients.1,12,24,40

Renal Impairment

In a clinical study of 26 weeks' duration, patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-59 mL/minute per 1.73m²) who received liraglutide 1.8 mg once daily had no worsening of renal function.1,46 Data regarding the use of liraglutide in patients with severe renal impairment are lacking.1 Caution should be used when initiating or escalating doses of liraglutide in patients with renal impairment.1,24 Experience with the fixed combination of insulin degludec and liraglutide in patients with mild, moderate, or severe renal impairment is limited; the combination should be used with caution in such patients.40

The manufacturer states that there is limited experience with liraglutide (as Saxenda^®) in patients with mild, moderate, and severe renal impairment, including in patients with end-stage renal disease; Saxenda^® should be used with caution in this patient population.24

Patients with Gastroparesis

Liraglutide slows gastric emptying and potentially may affect absorption of concomitantly administered oral drugs.1,24 Liraglutide has not been studied in patients with preexisting gastroparesis.1,24

Common Adverse Effects

Adverse effects reported in at least 5% of patients receiving liraglutide monotherapy for the management of type 2 diabetes mellitus in clinical trials include nausea,1,2 diarrhea,1,2 vomiting,1,2 constipation,1,2 and headache.1,2

Adverse effects reported in at least 2% of patients receiving liraglutide for the management of obesity and more frequently than with placebo include nausea,24 hypoglycemia (in patients with both obesity and type 2 diabetes mellitus),24 headache,24 diarrhea,24 constipation,24 dizziness,24 fatigue,24 vomiting,24 gastroenteritis,24 abdominal pain,24 urinary tract infection,24 abdominal distention,24 dyspepsia,24 upper abdominal pain,24 flatulence,24 decreased appetite,24 increased lipase,24 gastroesophageal reflux disease,24 insomnia,24 anxiety,24 viral gastroenteritis,24 dry mouth,24 asthenia,24 injection site reaction,24 eructation,24 and injection site erythema.24

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,40,40 headache,40,42 nausea,40 diarrhea,40,42 increased lipase concentrations,40,42 and upper respiratory tract infection.40,42

Effects on GI Absorption of Other Drugs

Potential pharmacokinetic interaction (altered absorption because of liraglutide-induced slowing of gastric emptying).1,24 In clinical trials, liraglutide did not affect the absorption of concomitantly administered oral drugs to any clinically relevant degree.1 However, caution should be exercised when liraglutide is administered concomitantly with oral drugs.1,24

Acetaminophen

Potential pharmacokinetic interaction (decreased acetaminophen peak plasma concentration and rate of absorption following a single dose of acetaminophen); no change in overall acetaminophen exposure (area under the serum concentration-time curve [AUC]).1

Antidiabetic Agents

The risk of serious hypoglycemia is increased when liraglutide is used in conjunction with an insulin secretagogue (e.g., sulfonylurea) or basal insulin; patients receiving liraglutide concomitantly with such agents may require a reduction in the dosage of the insulin secretagogue or insulin.1

No pharmacokinetic interaction has been observed following administration of separate subcutaneous injections of insulin detemir (single dose of 0.5 units/kg) and liraglutide (1.8 mg at steady state) in patients with type 2 diabetes mellitus.1

Atorvastatin

Potential pharmacokinetic interaction (decreased atorvastatin peak plasma concentration and rate of absorption following a single dose of atorvastatin); no change in overall atorvastatin exposure (AUC).1

Digoxin

Potential pharmacokinetic interaction (decreased digoxin peak plasma concentration, AUC, and rate of absorption following a single dose of digoxin).1

Griseofulvin

Potential pharmacokinetic interaction (increased griseofulvin peak plasma concentration following a single dose of griseofulvin); no change in overall griseofulvin exposure (AUC).1

Lisinopril

Potential pharmacokinetic interaction (decreased lisinopril peak plasma concentration, AUC, and rate of absorption following a single dose of lisinopril).1

Oral Contraceptives

Potential pharmacokinetic interaction (decreased peak plasma concentrations and rates of absorption of ethinyl estradiol and levonorgestrel; increased AUC of levonorgestrel but no effect on AUC of ethinyl estradiol).1

Description

Liraglutide is an acylated, long-acting, human glucagon-like peptide-1 (GLP-1) receptor agonist; the synthetic (recombinant DNA origin) peptide precursor of liraglutide has 97% amino acid sequence homology to endogenous human GLP-1-(7-37).1,10,24 Liraglutide is prepared by substituting arginine for lysine at position 34 and attaching palmitic acid with a glutamic acid spacer on the remaining lysine residue at position 26 of the peptide precursor.1,38 GLP-1-(7-37) represents less than 20% of total circulating endogenous GLP-1. 1,14 Like GLP-1-(7-37), liraglutide binds to and activates the GLP-1 receptor in pancreatic β cells.1,14,24 Liraglutide also increases intracellular cyclic 3',5'-adenosine monophosphate (cAMP) leading to insulin release in the presence of elevated glucose concentrations.1,20,24 This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia.1 In addition, liraglutide suppresses glucagon secretion in a glucose-dependent manner but does not impair normal glucagon response to hypoglycemia.1,9,20,24 Liraglutide delays gastric emptying, reducing the rate at which postprandial glucose appears in the circulation.1,9 As a result of these actions resulting in increased insulin secretion, suppression of glucagon secretion, and delays in gastric emptying, liraglutide effectively reduces fasting and postprandial plasma glucose concentrations in patients with type 2 diabetes mellitus.2,3,4,5,6,7,9,18,20

GLP-1 is a physiological regulator of appetite and caloric intake.24 The GLP-1 receptor is located in several areas of the brain involved in appetite regulation.24 Weight loss effects of liraglutide are mediated by decreased calorie intake; the drug does not increase 24-hour energy expenditure.24

Peak plasma liraglutide concentration is achieved an average of 11 hours1,24 (range: 8-12 hours) following subcutaneous administration.1,9,10,13,15 The average liraglutide steady-state concentration following administration of liraglutide in obese (body mass index [BMI] 30-40 kg/m²) individuals was approximately 116 ng/mL.24 Glucose-lowering activity is sustained for 24 hours after a dose of liraglutide at steady state.20 Liraglutide exposure increases proportionally in the dosage range of 0.6-3 mg; exposures were similar following subcutaneous injection into the upper arm, abdomen, or thigh.24 Absolute bioavailability following subcutaneous administration is approximately 55%.1,10,24 The mean apparent volume of distribution after subcutaneous administration of liraglutide 3 mg is 20-25 L (for an individual weighing approximately 100 kg).24 Liraglutide is extensively (greater than 98%) bound to plasma proteins.1,24 Liraglutide is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination.1,13,24 The endogenous enzymes dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP) are likely to be involved in degradation of the drug.13 The average terminal half-life of liraglutide is 13 hours following subcutaneous administration, making the drug suitable for once-daily administration.1,9,10,15,24 Following a dose of radiolabeled liraglutide, intact liraglutide was not detected in urine or feces, and only a minor amount of administered radioactivity was excreted as liraglutide-related metabolites in urine or feces (6 or 5%, respectively).1,13,24

In a study of the effect of liraglutide on cardiac repolarization in healthy individuals, steady-state liraglutide concentrations attained with daily dosages of up to 1.8 mg did not produce QT_c (QT interval corrected for rate, Bazett's formula) prolongation.1,24 The manufacturer states that maximum plasma liraglutide concentrations in overweight or obese individuals receiving liraglutide 3 mg daily are similar to those observed in the QT_c study in healthy individuals.24

Advice to Patients

When liraglutide is used in fixed combination with other drugs, importance of informing patients of important cautionary information about the concomitant agents.40

Importance of reading manufacturer's medication guide and the injection pen's patient instructions for use before starting therapy with liraglutide or the fixed combination of insulin degludec and liraglutide and of reviewing this information each time the prescription is renewed.1,24,40 Importance of clinicians instructing patients in proper injection technique to reduce administration errors (e.g., needle sticks, incomplete dosing).24

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.1,24,40 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 medullary thyroid cancer (MTC) or multiple endocrine neoplasia type 2 (MEN 2), to their clinician.1,24,40

Importance of informing patients of the potential risk of acute pancreatitis, which may be severe or fatal, with liraglutide therapy.1,24,40 Importance of patient informing clinicians about a history of pancreatitis.1,24 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.1,24,40 Importance of instructing patients to discontinue liraglutide or the fixed combination of insulin degludec and liraglutide promptly and contact their clinician if persistent, severe abdominal pain occurs.1,24,40

Importance of informing patients of the risk of gallbladder disease, which can require cholecystectomy.1,24 Importance of informing patients that substantial or rapid weight loss increases the risk of cholelithiasis; however, cholelithiasis can occur in the absence of weight loss.24 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

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

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

Importance of informing patients of possibility of risk of dehydration due to adverse GI reactions; patients should be advised to take precautions to avoid fluid depletion.1,40 Importance of informing patients of potential risk of worsening renal function, including renal failure that may require dialysis in some cases.1,40

Importance of informing patients of possibility of serious hypersensitivity reactions.1,38,40 Patients should be instructed to discontinue liraglutide or the fixed combination of insulin degludec and liraglutide and promptly seek medical advice if symptoms of hypersensitivity occur.1,38,40

Potential risk of suicidality; importance of patients being alert to and immediately reporting emergence or worsening of depression, suicidal thoughts or behavior, and/or unusual changes in mood or behavior.24 Importance of patient discontinuing liraglutide if suicidal thoughts or behaviors are experienced.24

Importance of informing patients that they should never share an injection pen containing liraglutide 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.1,24,40

Importance of instructing patients with diabetes mellitus regarding self-monitoring of blood glucose, periodic glycosylated hemoglobin (hemoglobin A_1c, HbA_1c) monitoring, adherence to meal planning, and regular physical exercise.1

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

Importance of cautioning patients not to take an extra dose of liraglutide or the fixed combination of insulin degludec and liraglutide to make up for a missed dose.1,40 If a dose is missed, patients should resume the once-daily regimen with the next scheduled dose.1,40

Importance of informing patients that if more than 3 days have passed since the last dose of liraglutide, the drug should be reinitiated at a dosage of 0.6 mg once daily to mitigate GI symptoms associated with reinitiation of treatment, then retitrated.1

Importance of informing patients that if more than 3 days have passed since the last dose of the fixed combination of insulin degludec and liraglutide, the drug should be reinitiated at the starting dose to mitigate GI symptoms due to the liraglutide component.40

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

Response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA_1c levels, with a goal of decreasing these levels towards the normal range.1

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

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).1,24

Inform patients of other important precautionary information.1,24

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Novo Nordisk. Victoza^® [liraglutide (rDNA origin) injection] solution for injection prescribing information. Plainsboro, NJ; 2023 Jul.

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 randomized, parallel-group, multinational, open-label trial (LEAD-6). Lancet . 2009; 374:39-47. [PubMed 19515413]

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]

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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]

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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, Buse JB, Davidson MB et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care . 2009; 32:193-203. [PubMed 18945920]

24. Novo Nordisk. Saxenda^® [liraglutide (rDNA origin) injection] solution for injection prescribing information. Plainsboro, NJ; 2023 Apr.

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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]

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33. Bray GA, Frühbeck G, Ryan DH, Wilding JP. Management of obesity. Lancet. 2016 May 7;387(10031):1947-56. doi: 10.1016/S0140-6736(16)00271-3. Epub 2016 Feb 10. PMID: 26868660.

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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]

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

40. Novo Nordisk. Xultophy^® (insulin degludec and liraglutide) injection prescribing information. Plainsboro, NJ; 2023 Jul.

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42. 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]

43. 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]

44. 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]

46. Davies MJ, Bain SC, Atkin SL et al. Efficacy and Safety of Liraglutide Versus Placebo as Add-on to Glucose-Lowering Therapy in Patients With Type 2 Diabetes and Moderate Renal Impairment (LIRA-RENAL): A Randomized Clinical Trial. Diabetes Care . 2016; 39:222-30. [PubMed 26681713]

47. le Roux CW, Astrup A, Fujioka K et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet . 2017; 389:1399-1409. [PubMed 28237263]

50. Tamborlane WV, Barrientos-Pérez M, Fainberg U et al. Liraglutide in children and adolescents with type 2 diabetes. N Engl J Med . 2019; [PubMed 31034184]

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