ADA: Liraglutide Shows Potential as Treatment for Weight Loss

Liraglutide, recently approved in the United States for the treatment of type 2 diabetes, has demonstrated its potential as a weight-loss drug for nondiabetic, obese patients….

At the American Diabetes Association 71st Scientific Sessions, investigators reported the results from the SCALE (Satiety and Clinical Adiposity – Liraglutide Evidence in Non-Diabetic and Diabetic Subjects) study. Not only was the weight loss that was required for initial randomization to therapy maintained, but further weight loss out to 56 weeks was achieved by patients receiving the drug. 

"This trial had 2 phases," explained SCALE’s lead investigator, Thomas A. Wadden, PhD, professor of psychology in psychiatry at the University of Pennsylvania School of Medicine, and director of the Center for Weight and Eating Disorders, in Philadelphia. "Patients had to participate in a run-in period, where they consumed only 1200 to 1600 calories a day, with a target weight loss of 5% from baseline." After a run-in period of 4 to 12 weeks, patients were randomized to active treatment, titrated in increments of 0.6 mg liraglutide per/week, to a total of 3 mg, or to placebo (n = 422). 

"The reason that the 3 mg dose was chosen, rather than the usual 1.8 mg used in diabetes, is that this dose was found by Rössner and colleagues to have greater efficacy for weight loss." (Lancet. 2009;374:1606-1616). 

The study looked at 3 coprimary end points: the proportion of patients who maintained full run-in weight loss; the proportion of patients who achieved further weight loss after randomization; and the proportion of patients who lost 5% of their weight or more after randomization.

At baseline, the average age of the SCALE patients was 46 years, average weight was 106 kg, and average body mass index (BMI) was 38 kg/m2. "It was striking that this study had about one third of patients with a BMI greater than 40 kg/m2," said Dr. Wadden. "This reminds us of the growing need to find options for heavier patients who are often now thought not to be able to respond to treatment." He went on to point out that the vast majority of patients enrolled in SCALE were female (82%), and that this is typical of weight-loss studies. Roughly one third of patients had hypertension, but otherwise the patients were relatively healthy. 

After an average run-in weight loss of 6%, more patients in the liraglutide group than in the placebo group maintained the run-in weight loss 56 weeks after randomization (81% vs 49%). 

Furthermore, liraglutide induced an additional average reduction in weight of 6.1% after randomization, with the majority of these patients losing at least 5%; there was no additional effect in the placebo group. "This is the biggest surprise to me as an obesity researcher. I did not think we would see additional weight loss," said Dr. Wadden. "I just thought we would see maintenance." 

Reported rates of adverse events were comparable between groups, with a higher than expected rate of subject retention; 25% in the liraglutide group and 31% in the placebo group withdrew from the study. "Dropout rates of 40% at 1 year are not uncommon in weight-loss trials, he explained. 

The most common adverse event for liraglutide was nausea (48% of patients). "The important thing about nausea is that patients experience this when you are introducing the drug during the first 4 to 5 weeks of titration, but thereafter it resolves."

Importantly, given the recent history of weight-loss agents, there were no psychological events reported, no suicidal ideation, and no major depression. 

Liraglutide Works, But How?

Liraglutide appears to be acting on a couple of different mechanisms," explained Dr. Wadden. "There seems to be decreasing gastric emptying, which is associated with improved satiety and decreased intake . . . and it may be operating in the caudal brain stem." This would make sense for a GLP-1 agent, and would thereby increase satiation, he said. 

Eva Tomas-Falco, PhD, instructor in medicine in the division of endocrinology at the Massachusetts General Hospital, Boston, has her own ideas. "I’m very interested in this because we have found in our own studies that when we infuse with GLP-1-like peptides, we also see an effect on body weight. However, you can relate that change to an increase in energy expenditure. Unfortunately, the SCALE study didn’t look at that."

She is further intrigued because of the great need. "This is pretty much the only [agent] right now that is not only safe for affecting glucose homeostasis, but has this additional property of lowering body weight in obese individuals."

She did raise one note of caution regarding the drug’s general use. "What we’re looking at here is patients with visceral fat (who often progress to diabetes). For those who are so-called ‘fit obese,’ this probably won’t work." The mechanisms at work in SCALE’s weight loss, Dr. Tomas-Falco reasoned, would not apply.

American Diabetes Association (ADA) 71st Scientific Sessions: Abstract 1859-P. Presented June 25, 2011.