JAMA: High-Dose Liraglutide With Diet and Exercise Causes Significant Weight Loss in Overweight Persons With T2DM

The study may lead to more widespread use of the therapy, the lead author said. Coverage has been a challenge despite a declaration of obesity as a disease 2 years ago.

Liraglutide, at a dose of 3 mg per day, can be combined with diet and exercise to produce an average weight loss of 6% for patients with type 2 diabetes mellitus (T2DM), according to a study reported today in JAMA.1

Weight loss for more than one-quarter of the patients in the randomized controlled trial exceeded 10%, after the group started with an average body mass index (BMI) of 37, according to the researchers.

The study, led by Melanie J. Davies, MD, of Leicester Diabetes Centre in the United Kingdom, also suggests that patients with T2DM taking 3 mg of liraglutide may be able to scale back their use of other anti-diabetic oral medications, while maintaining good glycemic control.1

Davies and her team focused on the T2DM population as part of the SCALE study; these results follow the 3731-patient study reported in the New England Journal of Medicine in July, which evaluated the overall effectiveness of liraglutide in treating obesity.2

“To our knowledge, this is the first study specifically designed to investigate the efficacy of liraglutide for weight management in patients with type 2 diabetes and also the first study to investigate liraglutide at the higher 3 mg dose in a population with type 2 diabetes,” the authors wrote in JAMA. “In the present trial, liraglutide (3 mg) as an adjunct to a reduced-calorie diet and increased physical activity, was effective and generally well-tolerated and was significantly better than placebo on all 3 co-primary weight-related end points.”

The overall study reported in July found that 63.2% of the patients in the liraglutide group lost at least 5% of their body weight, compared with 27% of placebo; 33.1% lost 10.6%, compared with 10% on placebo.2 Results of the SCALE study were provided to the FDA to gain approval in the United States for the 3 mg dose of liraglutide; it is approved to treat obesity in adults with a BMI of at least 30 and for those with a BMI of 27 and at least one weight-related condition, such as T2DM, hypertension, or high cholesterol. FDA approved the 3 mg dose of liraglutide, to be marketed as Saxenda by Novo Nordisk, on December 23, 2014. FDA had previously approved liraglutide at doses of 1.8 mg or 1.2 mg, marketed as Victoza, to treat T2DM.3

More Widespread Use? Publication of the findings may lead to more widespread use of liraglutide, both in the United States and in the United Kingdom. Just this week, a leading British nonprofit, Diabetes UK, called for more attention to the rise of the disease, better care and greater focus on prevention, lest the resources of Britain’s National Health Service be overwhelmed by the cost of serious complications such as amputations and strokes. In an email to The American Journal of Managed Care, Davies said she anticipated the results would lead to increased use of the therapy, both for treatment of obesity and for diabetes, “because at the current time it really hasn’t been an option, and this new data provides an evidence base.”

In the United States, patient advocates have been frustrated at the slow pace of coverage for obesity therapy more than 2 years after the American Medical Association declared obesity a disease, a move that many hoped would lead to increased treatment options.3 As the authors noted in today’s study, even moderate weight loss of 5% to 10% can improve glycemic control and other cardiometabolic risk factors and disorders, but weight loss is especially difficult for those with T2DM.1

The findings reported today involved 846 patients who were randomized from a larger group 1361 patients assessed for eligibility; 423 began the study taking 3 mg of liraglutide, while 211 were give 1.8 mg of the study drug and 212 were given placebo. The study drug was administered daily by injection with a modified insulin pen for 56 weeks. Participants were also instructed to take a diet that reduced their intake by 500 kcal/d and increased their exercise by at least 150 minutes per week.

More patients reported gastrointestinal disorders on the 3 mg dose than on the 1.8 mg dose or placebo, and more hypoglycemia episodes were reported on liraglutide than placebo. However, no pancreatitis was reported; this has been of concern to the FDA for all diabetes and cardiovascular therapies.

Diabetes Measures. The results reported in JAMA today highlight the needs of persons with T2DM, who are frequently taking at least 1 if not multiple anti-diabetic therapies to maintain glycemic control. Besides weight loss, which was the primary endpoint, the study also measured levels of glycated hemoglobin (A1C) and fasting plasma glucose, both compared to placebo and compared with liraglutide at a dose of 1.8 mg. Among the 411 patients who completed the study at the 3 mg dose, 278 (69.2%) achieved an A1C target of < 7%, and 227 (56.5%) achieved 6.5% or less. The average change in A1C was 1.3%. The results surpassed those of patients taking the 1.8 mg dose or placebo; 66.7% of patients taking the 1.8 mg dose achieved < 7% A1C and only 27.7% of those on placebo did. The 3 mg dose produced similarly positive effects for improving overall levels of cholesterol and triglycerides, but less pronounced effects for reducing high-blood pressure relative to the 1.8 mg dose.

“These findings suggest that, in addition to clinically relevant weight loss liraglutide (at 3 mg) may offer better glycemic control over (the 1.8 mg dose) while reducing use of oral hypoglycemic agents and maintaining a low risk of hypoglycemia,” the researchers wrote. The only difference in adverse events between the 2 doses was a higher incidence of nausea for the 3 mg dose.

Weight Loss. The primary results involve how much weight patients lost over the 56-week period (the study featured a 12-week follow-up to see if patients regained weight once they stopped taking the study drug). At week 56, the average weight loss was 6% or 14 lbs. for those on the 3 mg dose of liraglutide, 4.7% of 11 lbs. for those on the 1.8 mg dose, and 2% or 4.8 lbs. for those on placebo.

The percentage of patients who achieved weight loss of at least 5% was 54.3% for those on 3 mg dose, compared with 40.4% at the 1.8 mg dose and 21.4% on placebo. The percentage who lost more than 10% of their body weight was 25.2% on the 3 mg dose, compared with 15.9% on the 1.8 mg dose and 6.7% on placebo.

Quality of Life. This study presented data on quality-of-life measures—everything from improvement in physical function to self-esteem to changes in patients’ sex life. Researchers found significant improvements for those who took the 3 mg dose but not those at the 1.8 mg dose, “primarily driven by a significant improvement in the participants’ physical function.”

In her email, Davies said, “The relationship between quality of life, weight loss, and adherence is complex; from our study it’s difficult to pick out this interrelationship, but clearly there was improved quality of life—particularly functional quality of life—related to increased weight loss.

In the article, the researchers said more work would be needed to pin down the relationship to better adherence. “It is possible that such improvement in quality of life and treatment satisfaction would lead to better adherence to treatment and lifestyle interventions and reinforce desired behavior, although further studies would be needed to confirm this,” they wrote.”

The study reported today, as well the findings reported in July in NEJM, were funded by Novo Nordisk.

References

1. Davis MJ, Bergenstal R, Bode B, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes. JAMA. 2015;314(7):687-699.

2. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J of Med. 2015;373:11-22.

3. Smith A. Higher-dose liraglutide creates new options to treat obesity, by payment remains a challenge. Am J Manag Care. 2015; 21(SP5)SP146-SP147.