By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The glucagon-like peptide (GLP-1) receptor agonist, liraglutide is now approved for weight management in adults. The drug is also approved for the treatment of diabetes (Victoza®) but at a lower dose. Liraglutide is marketed by Novo Nordisk as Saxenda® for the weight-loss indication.
Liraglutide is indicated as an adjunct to a reduced-caloric diet and increased physical activity for chronic weight management in adults with initial body mass index (BMI) ≥ 30 kg/m2 (obese) and BMI of 27 kg/m2 (overweight) with at least one weight-related comorbidity such as hypertension, type 2 diabetes, or dyslipidemia.1
DOSAGE
The recommended dose is 3 mg subcutaneously daily. The dose is initiated at 0.6 mg daily and titrated on a weekly basis until 3 mg is reached. Liraglutide is available as a 6mg/mL (3 mL) pre-filled, multi-dose pen that delivers 0.6 mg, 1.2 mg, 1.8 mg, or 3 mg.
POTENTIAL ADVANTAGES
Liraglutide provides another treatment option with a different mechanism of action for weight management.
POTENTIAL DISADVANTAGES
Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma.1 It should not be used in patients taking insulin or any other GLP-1 receptor agonist. Most frequent adverse events are nausea, diarrhea, constipation, vomiting, hypoglycemia, and decreased appetite.1 Acute pancreatitis (fatal and nonfatal) has been observed in postmarking surveillance. Less frequent adverse events include suicidal ideation (0.2%), cholelithiasis (1.5%), and cholecystitis (0.2%).
COMMENTS
The safety and efficacy of liraglutide were studied in three 56-week, randomized, double-blind, placebo-controlled clinical trials. Subjects were randomized to liraglutide 3 mg or placebo. All patients were instructed on a reduced-calorie diet and received exercise counseling throughout the trial. The primary efficacy endpoints were mean percent change in body weight and the percentage of patients achieving ≥ 5% and 10% weight loss from baseline to week 56. Study 1 included obese subjects or overweight subjects with hypertension or dyslipidemia. Study 2 included obese and overweight type 2 diabetics. The mean baseline weights were 106 kg. Least square percent mean change from baseline were -7.4% for liraglutide compared to -3.0% for study 1 (difference -4.5%; 95% confidence interval [CI], -5.2% to -3.8%) and -5.4% vs -1.7% for study 2, difference of -3.7% (-4.7%; -2.7%). The percentage of patients losing 5% of body weight compared to placebo was 62.3% vs 34.4% (study 1) and 49% vs 16.4% (study 2), and for losing 10% of body weight, 24% vs 15% (study 1) and 22% vs 6% (study 2). Difference (in ≥ 5% or weight loss) from placebo was 28% and 33% for the two studies. All these were statistically significant. Study 3 included subjects who achieved weight loss of at least 5% of their screening body weight in the run-in period of 4-12 weeks while on liraglutide. These subjects were then randomized to liraglutide or placebo for 56 weeks. Those randomized to liraglutide showed additional mean weight loss from placebo of 5.2 kg with 44% losing ≥ 5% compared to 22% for placebo (difference 23%; 95% CI, 14%; 31%) and for weight loss of ≥ 10%, 25% vs 7%. Improvements in some cardiovascular disease-risk factors were also observed (HbA1c, fasting plasma glucose, fasting insulin, systolic blood pressure). In a 2-year extension study, the prevalence of prediabetes and metabolic syndrome decreased by 52% and 59% for pooled doses of 2.4 and 3.0 mg.3
CLINICAL IMPLICATIONS
Liraglutide is the most recent drug or drug combination approved for weight management. Lorcaserin and topiramate/phentermine were approved in 2012 and bupropion/naltrexone and liraglutide in 2014. The FDA benchmarks for weight loss efficacy are made up of two criteria: mean weight loss between drug and placebo is at least 5% (and statistically significant), and the proportion of subjects who lose ≥ 5% of baseline weight in the drug group is at least 35% and approximately double the proportion in the placebo-treated group (and the difference is statistically significant). Liraglutide fell a little short with the first criteria, -3.7% and -4.5%. For the second criteria, the proportion achieving 35% was met in the two studies (62% and 49%) but was double the placebo only in the study with type 2 diabetics. The wholesale cost for Saxenda is $231.66 for a 3 ml pen (18 mg).
REFERENCES
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Saxenda Prescribing Information. Novo Nordisk. December 2014.
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Wadden TA, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: The SCALE Maintenance randomized study Int J of Obes 2013;37:1443-1451.
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Astrup A, et al. Safety, tolerability, and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide Int J of Obes 2012;36:843-854.
