Background

On December 20, 2013, Novo Nordisk filed for regulatory approval of liraglutide (Victoza) 3 mg for weight management in obese or overweight patients with one or more comorbidities (for example, hypertension, diabetes, heart disease). If approved, a chronic weight loss management indication will significantly increase sales of Victoza, which currently top 2 billion dollars. 

Since 2010, liraglutide has been approved by the FDA (Food and Drug Administration) under the brand name Victoza. It is an injectable medication used by adults with Type 2 diabetes mellitus at doses of 0.6 mg, 1.2 mg and 1.8 mg. It is used along with diet and exercise to improve blood glucose control. In addition to maintaining normal blood glucose levels, liraglutide also appears to have therapeutic potential as a weight loss drug.  

How does liraglutide work?

Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that is 97% similar to GLP-1 hormone produced by our bodies. Liraglutide binds to and activates GLP-1 receptors, which are found on pancreatic beta cells and in the brain. After food is ingested, liraglutide increases production of insulin from pancreatic beta cells and also reduces output of glucose from the liver. Liraglutide also controls appetite by reducing the feeling of hunger. It also delays the emptying of food from the stomach and increases the feeling of fullness. This may result in weight loss.

Victoza Weight Loss Studies

Liraglutide 3 mg has been studied under the SCALE (Satiety and Clinical Adiposity – Liraglutide Evidence in Non-diabetic and Diabetic people) clinical trial program, which involved more than 5,000 people with obesity defined as Body Mass Index (BMI) of 30 or more, or those who are overweight (BMI of 27 or more) with one or more comorbidities. 

The SCALE  program consists of the following trials:

SCALE Obesity and Pre-diabetes

A randomized trial designed to show clinically meaningful and safe weight loss in people with obesity or overweight people with comorbidities. 3,731 participants were randomized to receive treatment. This study evaluated liraglutide 3 mg injected daily against a placebo for a treatment period of 56 weeks and 160 weeks. Both treatment arms also used diet and exercise.

Results after 56 weeks:

• The average weight loss for people treated with liraglutide 3 mg was higher (8%) compared to placebo (2.6%)
• More participants lost 5% or more weight with liraglutide 3 mg (64%), compared to placebo (27%)
• More participants lost 10% or more weight with liraglutide 3 mg (33%), compared to placebo (10%)
• Of the participants with pre-diabetes at the beginning of the study, 69% on liraglutide 3 mg no longer had signs of pre-diabetes by week 56 compared to placebo (33%)
• Of the participants without pre-diabetes at the beginning of the study, 7% on liraglutide 3 mg developed pre-diabetes by week 56 compared to placebo (21%)
• Participants on liraglutide 3 mg had statistically significant improvements in obesity-related risk factors such as lipids, blood pressure and cardiovascular risk biomarkers compared to participants on placebo

The longer term 160-week trial is still ongoing.

SCALE Maintenance

A randomized trial designed to show maintenance of weight loss in people with obesity or overweight people with comorbidities. 422 participants were randomized to receive treatment. Prior to treatment, the participants had successfully achieved 5% or greater weight loss during a three-month run-in period. The run-in period consisted of a lifestyle intervention program with a low-calorie diet and exercise. This study evaluated liraglutide 3 mg injected daily against a placebo for a treatment period of 56 weeks.

Results

• Participants had lost an average of 6% of starting body weight during the run-in period
• After 56 weeks, an additional weight loss of 6.2% occurred with liraglutide 3 mg, compared to 0.2% with placebo
• More participants receiving liraglutide 3 mg maintained the run-in period weight loss (81.4%), compared to placebo (48.9%)
• More participants lost 5% or more of randomization weight with liraglutide 3 mg (50.5%), compared to placebo (21.8%)
• Liraglutide produced more gastrointestinal disorders than placebo. Common side effects reported were: nausea, constipation, diarrhea, vomiting, dyspepsia and abdominal pain

This study has been completed.

SCALE Diabetes

A randomized trial designed to show clinically meaningful and safe weight loss with liraglutide 3 mg in people with obesity, or overweight people with type 2 diabetes. 846 participants were randomized to receive treatment. This study evaluated liraglutide 3 mg and liraglutide 1.8 mg injected daily against a placebo, for a treatment period of 56 weeks.

Results

• After 56 weeks, participants’ weight loss from baseline was 6% and 5% for liraglutide 3 mg and 1.8 mg respectively, compared to 2% with placebo
• More participants achieved a weight loss of 5% or more with liraglutide 3 mg and 1.8 mg (50% and 35% respectively), compared to 13% with placebo
• More participants achieved a weight loss of 10% or more with liraglutide 3 mg and 1.8 mg (22% and 13% respectively), compared to 4% with placebo
• More participants achieved a target HbA_1c target of 7% or less with liraglutide 3 mg and 1.8 mg (69% and 67% respectively), compared to 27% with placebo. Baseline HbA_1c was 8.0%.
• Participants in the liraglutide treatment group experienced moderate weight regain during the 12-week follow-up period.

This study has been completed.

A previous 20-week trial of 564 obese participants compared liraglutide with Orlistat and placebo. Study results showed that participants on liraglutide lost more weight compared to Orlistat and placebo, and more achieved the target 5 to 10% weight reduction. A two-year follow-up study was conducted on these participants to determine the safety, tolerability and long-term weight loss efficacy of liraglutide.

After 1 year, participants on liraglutide 3 mg had lost 3.8 kg more weight than those on Orlistat, and 5.8 kg more weight than those on placebo. After 2 years, participants on liraglutide 3 mg had lost 3.0 kg more weight than those on Orlistat.

Conclusion

From the current SCALE trial results, it appears that liraglutide holds promise as a weight loss medication for obese patients. However, its effects on pre-diabetes, cardiovascular risk factors and likelihood for weight regain may need further investigation.

Liraglutide 3 mg is still under investigation as a weight loss drug and is not yet approved by the FDA for the management of obesity.

References and Resources

Astrup A, et al. Effects of liraglutide in the treatment of obesity: a randomized, double blind, placebo-controlled study.  Lancet. 2009; 374:1606-1616.

Astrup A, 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.

Effect of liraglutide on body weight in overweight or obese subjects with type 2 diabetes: SCALE - Diabetes. Novo Nordisk Trial Registry. 

Novo Nordisk files for regulatory approval of liraglutide 3 mg for the treatment of obesity. Novo Nordisk Company Announcement. Dec 30, 2013. 

Novo Nordisk reports 8% weight loss in phase 3a obesity trial with liraglutide 3 mg. Novo Nordisk Company Announcement. May 23, 2013. 

People with type 2 diabetes achieve 6% weight loss with liraglutide 3 mg in phase 3a obesity trial. Nordisk Company Announcement. Mar 18, 2013. 

Victoza Prescribing Information (Package insert)

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 Obes. 2013; 37:1443-1451.