Drugs in Perspective: Liraglutide for the treatment of obesity

Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that received FDA approval for the treatment of diabetes mellitus in 2010. The mechanism of action includes slowing gastric emptying, increasing glucose-dependent insulin secretion, decreasing inappropriate glucagon release, and instilling a feeling of satiety. Liraglutide is administered once daily by subcutaneous injection. Common adverse effects of liraglutide include nausea (28%), diarrhea (17%), vomiting (11%), and constipation (10%).¹

Relevance

Liraglutide, a GLP-1 receptor agonist, was studied for its potential role in the treatment of obesity due to the feeling of satiety and slowed gastric emptying mechanisms it displays. To maintain weight loss, the use of long-term pharmacotherapy for the treatment of obesity is recommended.² Liraglutide has the capability to be used long term and was compared head to head with orlistat, the current option on the market for long-term pharmacotherapy for the treatment of obesity.

Studies

In a 20-week, randomized, double-blind study subjects received placebo, orlistat 120 mg orally 3 times daily, or liraglutide 1.2 mg, 1.8 mg, 2.4 mg, or 3 mg subcutaneously daily.³ Liraglutide showed significant weight loss (4.8 kg, P=.003; 5.5 kg, P=.005; 6 kg, P=.005; 7.2 kg, P=.005, respectively) versus placebo. Liraglutide 2.4 and 3 mg showed significant weight loss versus orlistat (2.1 kg, P=.003, and 3 kg, P=.005, respectively). Significantly more subjects taking liraglutide lost over 5% of their bodyweight versus placebo (liraglutide 1.2 and 1.8 mg, P=.002; liraglutide 2.4 mg, P<.001; liraglutide 3 mg, P≤.0001) as well as those taking

liraglutide 3 mg versus orlistat (P≤.0001). At week 20, mean weight loss was 7.2 kg with liraglutide 3 mg and 4.1 kg with orlistat for the intention-to-treat population.  Dropout rates were 19.4%, 15.5%, and 16.8% for placebo, liraglutide, and orlistat, respectively.

The preceding trial was extended to 2 years, crossing all patients to liraglutide 3 mg daily or orlistat 120 mg daily.⁴ Liraglutide showed significantly greater weight loss (5.3 kg) versus orlistat (2.3 kg) after 2 years (P<.05). More subjects achieved a 5% and 10% weight loss with liraglutide (52%, P<.001; 26% P=.04, respectively) versus orlistat (29% and 16%, respectively).

In a 56-week, randomized, double-blind, placebo-controlled study, subjects in the intention-to-treat population taking liraglutide 3 mg daily lost 6.2% of bodyweight versus patients taking placebo losing 0.2% (P<.0001).⁵

Potential advantages and disadvantages

As these studies show, liraglutide at the dose of 3 mg is more efficacious for initiating and maintaining weight loss versus orlistat.^3-5 In terms of tolerability, both orlistat and liraglutide have gastrointestinal side effects; orlistat more commonly results in fecal urgency (3%–22%), flatulence (2%–24%), and abdominal pain (≤26%).¹ More serious but rare side effects observed with liraglutide include pancreatitis (<1%) and malignant neoplasms (<1%).¹ Although the studies did not report a decrease in adherence due to the need for daily subcutaneous injections, this may deter some patients. Finally, when compared to liraglutide, orlistat has more clinically relevant drug interactions that can affect the absorption and kinetics of fat-soluble vitamins, warfarin, and lipophilic drugs such as gabapentin, amiodarone, valproic acid, and lamotrigine.¹

Cost

Liraglutide costs $3,214.10 per month (3 mg daily for 30 days average wholesale price [AWP]).⁶ Orlistat costs $132.32 per month (120 mg 3 times daily for 30 days AWP).⁶

Place in therapy

Liraglutide induces greater weight loss compared to placebo and orlistat. Liraglutide, however, is significantly more expensive than orlistat. For comparison, phentermine/topiramate induced a 10.5% weight reduction after 108 weeks, lorcaserin induced a 5.8% weight reduction after 56 weeks, and phentermine induced a 9.3% weight reduction after 14 weeks.^7-9

A good candidate for liraglutide therapy for the treatment of obesity includes a patient with prescription drug insurance or financial means, a patient who can display proper technique of and is not deterred by self-injections, or a patient who has already tried and did not tolerate other obesity pharmacotherapy options such as orlistat. A patient who has a history of thyroid tumors or pancreatitis should consider other options until further research is conducted.

Context: Impact on patient outcomes

Currently, 69% of the United States population is estimated to be overweight (25–29.9 kg/m²) or obese (≥30 kg/m²).¹⁰ The greater the patient’s body mass index (BMI), the greater the risk for cardiovascular disease, diabetes, and all-cause mortality.¹⁰ Subjects who received liraglutide for the treatment of obesity lost, on average, more weight than those taking placebo or orlistat. Additionally, more subjects receiving liraglutide were able to achieve higher benchmarks of weight loss including 5% and 10% of bodyweight lost. Health benefits can be seen with as little as a 3% to 5% reduction in bodyweight and include decreased blood glucose, hemoglobin A1C, and a decrease in the likelihood of the development of diabetes.¹⁰ Further weight loss can induce positive changes in blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and the likelihood for the need of pharmacotherapy to control blood pressure, blood glucose, and lipids.¹⁰ The benefits of weight loss are seen if patients maintain this loss for an extended period of time; liraglutide has shown a greater maintenance of weight loss versus orlistat over 2 years. Moreover, positive trends have been seen in which liraglutide reduced waist circumference, blood pressure, percent of subjects with metabolic syndrome, and percent of subjects with prediabetes status. Importantly, if future complications and diseases such as diabetes can be avoided, overall healthcare dollars can be saved. Finally, subjects reported significantly improved physical function and self-esteem with liraglutide versus placebo and orlistat in the studies discussed previously.

Context: Impact on the class

Liraglutide, a GLP-1 receptor agonist, was studied for its potential use in the treatment of obesity. Given that the feeling of satiety and slowing of gastric emptying is seen throughout this class of medications, it would not be out of the question to further investigate the outcomes of additional GLP-1 receptor agonists, including exenatide, in the treatment of obesity and to study the patient outcomes in terms of significant and sustained weight loss. Furthermore, there may even be increased adherence to the drug therapy regimen if administration of the drug was once weekly such as with the extended-release formulation of exenatide. The updated American Heart Association/American College of Cardiology/The Obesity Society guidelines on the treatment of obesity specify that patients with a BMI exceeding 30 kg/m² or 27 kg/m² with a minimum of one obesity-associated comorbidity may consider FDA-approved pharmacotherapy as an adjunct to lifestyle interventions to help achieve weight loss and health goals.¹⁰ There is an increased push for the diagnosis and treatment of obesity through these guidelines, and even a small amount of weight loss may yield health benefits. Therefore, additional pharmacotherapy options may be beneficial to the 69% of patients who are currently estimated to be overweight or obese and the additional percentage of patients who will be diagnosed as such and given the recommendation of weight loss.

References

1. Lexi-Comp Online, Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc. Accessed January 2, 2014.

2. NHLBI Obesity Education Initiative. The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. (NIH Publication No. 00-4084). National Institutes of Health; National Heart, Lung, and Blood Institute; 2000. http://www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf. Accessed February 12, 2014.

3. Astrup A, Rössner S, Van Gaal L, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009:374;1606–1616.

4. Astrup A, Carraro R, Finer N, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes. 2012:36;843–854.

5. Wadden TA, Hollander P, Klein S, et al; NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: The Scale Maintenance randomized study. Int J Obes. 2013;37:1443–1451.

6. Red Book Online, Micromedex 2.0. Ann Arbor, MI: Truven Health Analytics. Accessed January 2, 2014.

7. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012:95;297–308.

8. Fidler MC, Sanchez M, Raether B, et al; BLOSSOM Clinical Trial Group. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011:96;3067–3077.

9. Kim KK, Cho HJ, Kang HC, et al. Effects on weight reduction and safety of short-term phentermine administration in Korean obese people. Yonsei Med J. 2006:27;614–625.

10. Jenson MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2013 Nov 12. [Epub ahead of print] 

Dr Murphy is clinical associate professor; Ms Doughty is a candidate for doctor of pharmacy; and Dr Mangan is clinical assistant professor, The University of Toledo College of Pharmacy and Pharmaceutical Sciences, Ohio.

Disclosure information: The authors report no financial disclosures as related to producted discussed in this article.