Intermittent therapy may be a ‘practical strategy’ for maintaining weight loss
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Key takeaways:
- The body’s physiology may require people with obesity to use medications long-term.
- Intermittent use of medications may provide benefits while combatting issues regarding costs and access.
DALLAS — People with obesity who are prescribed anti-obesity medications may need to use the agents for life, but intermittent therapy can still confer health benefits, according to a speaker.
During a keynote lecture at ObesityWeek, Lee Kaplan, MD, PhD, section chief of obesity medicine at the Geisel School of Medicine at Dartmouth and director of The Obesity and Metabolism Institute in Boston, said continued use of anti-obesity medications may be necessary for people with obesity to avoid weight regain because medications change, but do not permanently fix the body’s fat mass set point.
“Intermittent therapy may be an effective strategy and a very practical strategy to address the challenges of high costs, limited drug availability and inadequate access to care,” Kaplan said during a presentation. “Intermittent may be necessary to address specific life events like pregnancy.”
The physiology of body fat mass
Kaplan said body fat mass is physiologically regulated, and body fat changes occur throughout a person’s life span. Some key stages of development where body fat mass may change include during infancy, puberty, menopause, throughout the aging process, and during and after pregnancy.
“These regulatory events in life occur without conscious or purposeful input,” Kaplan said. “Boys who lose weight during puberty don’t go on a diet. Parents who have babies that are going to lose baby fat don’t put them on a diet. Weight loss after pregnancy, even if it’s not as much as what the woman wants, happens without going on a diet.”
Kaplan said the physiological basis of obesity is when the body is unable to properly regulate fat mass. Food intake and energy expenditure are used by the body to reach and defend its set fat mass. Kaplan said people with obesity have a fat mass set point that is higher than that for someone with normal weight, and any durable anti-obesity therapy must lower that set point to be effective.
“If you decrease the intended fat mass by a small amount, as has been done in the past by certain medications ... or certain lifestyle modifications, such as improvement in sleep, circadian rhythms, decreased stress, healthier diet, more exercise ... you might get a small effect,” Kaplan said. “If you have bariatric surgery or one of the newer medications, you might get a much larger effect. The size of the effect doesn’t change the physiology.”
Weight regain after drug cessation
In the STEP 5 trial, adults with obesity and without diabetes who received semaglutide 2.4 mg (Wegovy, Novo Nordisk) achieved their maximum weight loss at 68 weeks and maintained that weight loss up to 104 weeks with continued therapy. However, in the STEP 1 trial, adults with obesity who stopped treatment with semaglutide at 68 weeks had an increase in body weight through 120 weeks, although body weight did not return to baseline.
“The anecdotal reports were, because the patients [in STEP 1] had lost so much weight on average with this medication, when they stopped the medication ... their hunger was so high and their craving was so high that they came to the principal investigators and said you have to do something to help me,” Kaplan said. “The more the initial weight loss, the greater that effect. Many of the patients found themselves on liraglutide [Saxenda, Novo Nordisk] and other medications just to try to blunt the powerful physiological effect of trying to regain the lost weight.”
For adults who undergo bariatric surgery, Kaplan said, appetite, meal size and energy intake go down in the months following surgery and then rebound 1 year post-surgery. Bariatric surgery does not permanently lower defended fat mass, according to Kaplan. He said a few adults who had gastric bypass reversed decades after the procedure had a rapid increase in appetite and regain of body weight, similar to what happens when anti-obesity medications are stopped.
“What these medications do is they change the dynamic regulation of fat mass to something that’s more normal rather than fixing it at an arbitrarily lower point,” Kaplan said.
Intermittent therapy as a strategy
Kaplan said while a noninvasive therapy that permanently lowers the body fat mass set point could allow for weight loss maintenance after the therapy ends, it could also have disadvantages. Some of the disadvantages include an inability to reverse the effects, possible problems with responding to acute injury or illness, and potential issues for women supporting pregnancy and lactation if they are unable to gain body fat. He said adults with obesity will likely have to continue therapy indefinitely until researchers can find a way to repair the cellular and molecular mechanisms that the body uses to regulate fat mass.
However, using anti-obesity medications for life does not mean using them continuously. Kaplan said there are numerous reasons a person may need to discontinue a medication and that after therapy stops, weight regain happens over a long period as changes in fat regulation may take months to occur. This gives providers the opportunity to support interruptions to anti-obesity therapy with a different approach.
“Modest short-term regulation by voluntary energy intake management can be effective,” Kaplan said. “Until we have strategies for decreasing the cost of effective treatment and ensuring more equitable access to obesity care, optimizing algorithms for the use of intermittent therapy may be an effective stopgap measure.”
Perspective
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Katherine H. Saunders, MD, DABOM
Preparing patients to take anti-obesity medications long-term is one of the hardest, and most important, responsibilities obesity medicine providers have. Although people generally understand that chronic diseases require lifelong management, there is a huge disconnect when it comes to obesity. Most patients initially assume they can discontinue medication at their goal weight, and many are understandably extremely frustrated when we tell them otherwise. This is a conversation that requires reinforcement over the years.
Despite our best efforts, many patients stop medical management for a variety of reasons and then experience the inevitable post-discontinuation regain. Individuals who start to regain immediately tend to get back on track sooner than those who keep their weight off for months and then gradually gain it back.
Lee Kaplan’s talk on this subject at ObesityWeek was brilliant and thought-provoking because he offered new perspectives on this complex challenge. Of course, patients aren’t happy about requiring medication long-term so it’s critical for providers to take the time to review risks, benefits and alternatives. We need to teach and reinforce the biology of weight loss, the inevitability of metabolic adaptation and proven strategies for weight maintenance. We shouldn’t prescribe anti-obesity medications to patients who are not committed to managing their weight long-term with some form of medical obesity treatment. We know most patients will regain at least part of their weight if they stop anti-obesity medications. What’s worse, sometimes the same medications are considerably less effective the next time.
Kaplan’s proposed solution of intermittent therapy for weight management may work well for the newer powerful anti-obesity medications. Greater efficacy and, in the case of the weekly injectables, longer half-lives may lead to slower regain — enabling decreased frequency of administration. We need to meet patients where they are in order to manage their chronic disease effectively. And with the current high costs, limited access and supply challenges, intermittent therapy may be particularly appealing until the situation improves. Hopefully one day we’ll have a cure for obesity, and our conversations with patients will be very different.
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Kaplan L. Always and forever? Chronic use of anti-obesity medications. Presented at: ObesityWeek; Oct. 14-17, 2023; Dallas.
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