In a phase 3 trial where all participants received intensive behavior therapy, investigational 2.4-mg once-weekly subcutaneous semaglutide (Novo Nordisk) resulted in a 10.3% greater average weight loss than placebo over a period of 68 weeks.
If approved, this medication could be a “potential major breakthrough” in obesity management, the investigators suggested. But other experts urged caution, as cost and uptake are important considerations.
‘Potential weight loss that patients would be happy with’
Thomas A. Wadden, PhD, presented results from the study of 611 adults with overweight or obesity but no diabetes at the virtual ObesityWeek® Interactive 2020 meeting.
“Perhaps even more impressive was the finding that 75% of patients lost 10% or more of baseline body weight,” said Dr. Wadden, of the department of psychiatry at the University of Pennsylvania, Philadelphia.
Moreover, in this trial of semaglutide, a glucagonlike peptide–1 (GLP-1) receptor agonist that is approved for treating type 2 diabetes at a weekly subcutaneous dose of 1 mg, but is being investigated at the higher dose for weight loss – 55% of patients lost ≥15% of their initial weight, and 36% lost ≥20% of their initial weight.
“These large categorical weight losses – particularly of 15% and 20% of initial weight – are potentially a major breakthrough in the management of obesity,” Dr. Wadden said in an interview.
Weight losses of this size, he added, “should confer greater improvements in cardiometabolic risk factors (such as hypertension, sleep apnea, and type 2 diabetes) as compared with losses of 5%-10% achieved with current behavioral or pharmacological approaches.” And patients are generally not satisfied with losses of less than 10% of initial weight when participating in intensive behavior programs or taking weight-loss medications.
Now, “the larger categorical weight losses will mean that a greater number of patients with obesity will be able to achieve a weight loss with which they are ... happy,” Dr. Wadden said in an interview.
According to Louis J. Aronne, MD, Weill Professor of Metabolic Research, Weill Cornell Medicine, New York, who is an investigator for another trial of semaglutide: “Even though it has the same mechanism of action [as liraglutide], the weight loss is two or more times greater [with semaglutide]. In my opinion, it’s really going to be a major advance in the treatment of obesity.”
In the discussion that followed the virtual presentation, one attendee asked about potential weight regain if a patient stopped taking the drug. Based on experience with another subcutaneous injectable GLP-1 receptor agonist, liraglutide (Saxenda), already approved for obesity, it may be that taking medicine for chronic overweight may become like taking a statin for elevated cholesterol, said Dr. Wadden.
Novo Nordisk has now completed the four trials in the STEP (Semaglutide Treatment Effect in People With Obesity) global phase 3 clinical development program, and plans to file applications with the Food and Drug Administration later this year and with the European Medicines Agency in early 2021 for review of semaglutide 2.4 mg for weight management.
“Fundamental issues need to be figured out”
Invited to comment, Scott Kahan, MD, said: “This is impressive data, confirming that semaglutide, particularly when used in concert with evidence-based counseling, is a highly effective agent for obesity management.”
However, “the real question, though, is what comes next,” stressed Dr. Kahan, director of the National Center for Weight and Wellness, Washington, DC.
“Will it be approved by the U.S. FDA? I believe so,” he said in an interview. “Yet we already have several effective obesity medications approved over the past decade – all of which are rarely used and therefore make little impact for patients in the real world.”
“Will there be insurance coverage, and therefore practical access for those who could most benefit?” he continued. “Will prescribers counsel their patients about obesity management, including the use of effective medications? Will patients utilize available options?”
“These and other fundamental issues must be figured out before we anoint any treatment option as a meaningful step forward, let alone a transformative development,” according to Dr. Kahan.
Similarly, Irl B. Hirsch, MD, stressed that, should this medication be approved for weight loss, cost would be a major factor in its uptake.
“I’m old enough to recall when we started using lovastatin in the late 1980s,” Dr. Hirsch, professor of medicine, University of Washington Medicine Diabetes Institute, Seattle, said in an interview.
“We used it without the type of evidence of statin use we have today. A pill, but in those days the statins were expensive. But over time, the evidence for statins grew and over the next 15 years it was quite clear that for both primary prevention (for those with diabetes) and secondary intervention these drugs needed to be used by millions of people. These recommendations became easier once the drugs became generic.
“Will the same thing happen for GLP-1 agonists? The problem is we need both ‘hard-outcome data’ [such as 3-point major adverse cardiovascular events] and more reasonable cost before we see this expanding to an entire population.
“In the future perhaps we could have a biosimilar GLP-1 agonist that would be more affordable than what we pay now, but even before that we need agreement from our reimbursement thought leaders that our society should reimburse these agents.
“My thinking now is the cost-benefit could be favorable, but this is all dependent on what happens to the cost of the drugs over time,” he said.
Additive effect of intensive behavior therapy plus medication
Dr. Wadden explained that intensive behavioral therapy “provides 14 or more counseling sessions in 6 months to modify diet and physical activity, through the patients’ use of behavioral strategies (such as keeping daily food and activity diaries).”
Such programs typically produce mean weight loss of 5%-8% of initial weight; less frequent (e.g., monthly) programs typically produce weight loss of only 1%-3%.
Prior studies suggest that intensive behavioral therapy and medication have additive effects. To investigate this, Dr. Wadden and colleagues randomized 611 adults (81% women) who were a mean age of 46 years and had a mean body mass index of 38 kg/m2.
All participants received 30 intensive behavior therapy sessions provided by a registered dietitian (or other qualified provider), which typically lasted 20-30 minutes and were given weekly for 12 weeks, every other week for the next 12 weeks, and then monthly.
The dietitian gave participants behavioral strategies to help them adhere to diet and physical activity goals.
During the first 8 weeks, participants were provided with a 1,000-1,200 kcal/day meal replacement diet that included liquid shakes, meal bars, and prepared entrees designed to facilitate a large initial weight loss.
They then transitioned to a diet of conventional foods (of their choosing), with a goal of 1,200-1,800 kcal/day based on body weight.
The physical activity goal was 100 minutes/week of walking or other aerobic activity in the first month, building up to 200 minutes/week by month 6.