Published On November 11, 2022
Sarah’s story is familiar in a country where more than 40% of adults and a fifth of children have obesity. At school, she was bullied for her weight and, starting in her teens, dreaded getting weighed by doctors because they were always critical. At age 26, she had bariatric surgery—yet after dropping 80 pounds, her weight returned. Year after year passed with cycles of strict dieting and trials of various anti-obesity medications. “The weight always came back,” says Sarah, who asks that her real name not be used.
Last fall, Sarah’s care team, including obesity specialist Fatima Cody Stanford, a physician at Massachusetts General Hospital’s Weight Center, recommended that Sarah try a new drug, semaglutide. “I knew within the first week that it was going to work,” says Sarah, now 46. “Without trying, I was eating less than what I normally did, but I didn’t feel hungry or deprived.” Within a year, she had lost 63 pounds. And although only time will tell whether the weight stays off, for now she feels as if “the battle is over” and she can get on with her life.
Treating people with anti-obesity drugs isn’t new. Historically, however, most indicated medications have proved ineffective, dangerous or both—between 1964 and 2009, 25 of these compounds were withdrawn from the U.S. market because of serious side effects, including psychiatric problems, cardiotoxicity, and drug misuse and dependence. Bariatric surgery works better, but the screening requirements can be prohibitive, most people don’t want it and weight loss after the procedure isn’t always permanent.
New treatment semaglutide—approved in 2017 by the U.S. Food and Drug Administration to treat type 2 diabetes and in 2021 for weight loss—and a second drug, tirzepatide, which received the Fast Track designation from the FDA for obesity treatment this past October, could improve on that record dramatically. Like most anti-obesity drugs, they target parts of the brain that control appetite. These medications get there in a novel way, mimicking naturally occurring hormones to help prevent overeating. In recent studies, patients taking semaglutide lost an average of about 15% of their total weight, and those taking tirzepatide for diabetes reported losing 15% to 21%.
“After years and years of trying, we can finally replicate the efficacy of bariatric surgery with medication,” says Louis Aronne, director of the Comprehensive Weight Control Center at Weill Cornell Medicine in New York City and an investigator on the tirzepatide trial. Yet optimism for a safe, attractive treatment for obesity—a condition that is estimated to cost the United States nearly $200 billion annually and underlies rising rates of heart disease, diabetes, cancer and many other conditions—is tempered by the barriers these new drugs face.
Although better tolerated than their predecessors, semaglutide and tirzepatide can have significant side effects. Both need to be taken forever. Most pressingly, they are covered by only a handful of health insurance plans, and semaglutide’s $1,557-per-month cost is well beyond most household budgets. For these and other reasons, most physicians have been reluctant to prescribe anti-obesity drugs of the current or past generations. According to Stanford, only 1% of patients with obesity received a prescription for obesity management drugs from 2011 to 2016, in part because of the drugs’ price.
Moreover, obesity specialists note a persistent knowledge gap about how best to treat the condition. “Many physicians still believe that people with obesity need to eat less and exercise more, which is completely wrong,” says Stanford, who notes that it wasn’t until 2013 that the American Medical Association finally recognized obesity as a chronic disease.
“We can finally replicate the efficacy of bariatric surgery with medication.”
“Obesity is where diabetes was 30 years ago, when clinicians would tell patients to stop eating sugar,” says W. Timothy Garvey, director of the Diabetes Research Center and senior scientist at the Nutrition Obesity Research Center at the University of Alabama at Birmingham. “Many physicians don’t believe that obesity should be treated medically, so they blame the patient for overeating and not exercising. In turn, patients blame themselves.”
Losing weight through diet and exercise—and keeping the weight off—can be next to impossible for some people with obesity. According to a theory accepted in many quarters, the body has a defended fat mass set point—a fat mass that the brain, hormones and metabolism “want” that person to have. The basic equation for losing weight—to expend more calories than you take in—can indeed lead to significant weight reduction. Yet because the body’s fat mass set point doesn’t recalibrate to the lower weight, body and brain connive to regain the lost pounds.
Environmental as well as genetic factors affect fat mass set point. Today most Americans have a fat mass set point that’s higher than ever before, thanks to a combination of pressures. These include readily available, highly processed foods; chronic sleep deprivation; an increase in stress levels; less need for physical activity; and social lives that revolve around food. Nearly three-quarters of the U.S. population is now considered to be overweight or to have obesity.
People with obesity can also have the additional problem of a siren’s chorus of hormones being released from the gastrointestinal tract when they eat, nudging the pounds back on. “When people with obesity lose weight, there’s an increase in hormones that make you eat more, while the hormones that make you eat less go down,” says Stanford. “The combined effect is that the brain is driving you back to a certain equilibrium of body fat mass—and that equilibrium is set much higher in people with obesity.”
Brain inflammation may also help explain why people with obesity have abnormally high fat mass set points. “Adults don’t grow additional fat cells,” says W. Scott Butsch, director of obesity medicine in the Bariatric and Metabolic Institute at the Cleveland Clinic. “Rather, their existing fat cells expand when they gain weight and contract when they lose it.” When a fat cell expands, that increases inflammation in the body and, in some studies, in the hypothalamus, which centrally controls body weight. The chronic low-grade inflammation may disrupt the brain architecture that regulates the body fat mass set point.
Genetics also plays a major role. “If your parents have obesity, there is a 50% to 85% likelihood that you will too, regardless of your diet quality, activity level and stress management,” says Stanford.
What obesity is not, however, is a behavioral disorder. “Just as people with diabetes cannot will their blood sugars to be normal, people with obesity cannot will their bodies to carry less fat,” says Ania Jastreboff, director of weight management and obesity prevention at Yale Stress Center and lead investigator of the tirzepatide trial. Yet this attitude of weight loss as a matter of will has pervaded culture and the thinking of many physicians.
Earlier anti-obesity drugs did little to inspire confidence that obesity could be successfully treated—or that medical treatment was appropriate. Over many decades, more and more such medications were withdrawn from the market for safety reasons, which only reinforced clinicians’ bias that overeating and personal behavior were the real problem, says Butsch.
One of the first weight-loss drugs was phentermine, approved in 1959 by the FDA, which continues to be the most widely prescribed drug to treat obesity. Phentermine is thought to suppress appetite by increasing the levels of the neurotransmitter norepinephrine in the hypothalamus. But it’s indicated only for short-term use—no more than three months—because if taken for longer periods and at higher doses, it can cause anxiety, rapid heart rate and high blood pressure.
In 1973, fenfluramine was introduced as an anti-obesity drug, and for years it was paired with phentermine to create the wildly popular fen-phen, a cocktail that produced substantial weight loss. But fenfluramine, too, was approved only for short-term use, and it was withdrawn in 1997 after it was found to stimulate the growth of muscle cells in the heart, leading to heart-valve damage and pulmonary hypertension. Another appetite-suppressing drug, sibutramine, was also associated with major cardiovascular problems, including stroke and heart attack, and was taken off the market in 2010. The most recent anti-obesity drug to be withdrawn was lorcaserin, pulled in 2020 because of cancer risks.
It wasn’t until 2012 that reasonably safe, effective anti-obesity drugs came on the market. People who took Qsymia, a combination of phentermine and the migraine medication topiramate, lost an average of 8% to 10% of their body weight. Contrave, which combines naltrexone, used to treat alcohol and opioid dependency, and bupropion, an antidepressant and smoking-cessation drug, results in an average loss of 5% to 7% of body weight.
The new drugs, semaglutide and tirzepatide, contain a glucagon-like peptide-1 (GLP-1) receptor agonist, which mimics a hormone secreted in the intestines during eating that signals when a person is full and should stop eating. The GLP-1 receptor agonists reinforce that signal and help suppress appetite in people with obesity. “We think these medications help the brain reset the defended fat mass set point, resulting in people eating less,” says Jastreboff. “Often, they feel full earlier and don’t go back for seconds.”
Tirzepatide also targets a second receptor with another human gut hormone—glucose-dependent insulinotropic polypeptide (GIP). That additional target may explain why it tends to result in greater weight reduction than semaglutide.
Changes in GLP-1 are also responsible for weight loss after bariatric surgery. “The surgery alters the speed at which food passes through the stomach, and that changes the hormonal milieu and causes people to have much higher levels of GLP-1 after they eat compared with people who haven’t had surgery,” says Judith Korner, director of the Metabolic and Weight Control Center at NewYork Presbyterian/Columbia University Medical Center in New York.
A precursor to the new drugs, exenatide, was approved by the FDA in 2005 to treat type 2 diabetes. Also a GLP-1 receptor agonist, exenatide improved insulin secretion from the pancreas and regulated blood sugar. But it also had an unexpected benefit—significant weight loss—and that discovery led drugmakers to explore the potential of GLP-1 drugs to help people lose weight, says Samuel Klein, director of the Center for Human Nutrition at Washington University School of Medicine. In 2014, liraglutide, a daily injection, became the first GLP-1 receptor agonist approved for treating obesity.
Both semaglutide and tirzepatide are marketed for type 2 diabetes treatment—semaglutide at a lower dose than when prescribed for weight loss. But for reasons that aren’t yet known, people who have diabetes and take the drugs tend to lose fewer pounds than those who don’t have the disease. “That just underscores the importance of treating obesity early—before people develop type 2 diabetes or other weight-related diseases,” says Jastreboff. “If we can help someone lose a significant amount of weight, we can treat the root cause of or main contributor to diabetes.”
Louis Aronne at Weill Cornell Medicine points out that well over 2 million people have taken GLP-1 receptor agonists since they were first approved for treating type 2 diabetes. That’s a substantial number to observe for side effects, and those patients have suffered few serious issues. Yet the phase 3 trial of semaglutide for obesity, which ran for 68 weeks and included nearly 2,000 adults, raised a few short-term side effects. Three out of four people taking the drug had gastrointestinal problems—nausea, diarrhea, vomiting, constipation—compared with half of those in the placebo group. More serious problems, including cardiovascular or liver disorders, were reported by 10% of the semaglutide group and just over 6% of the placebo group.
Sarah recalls feeling nauseous when she started taking semaglutide, but this side effect has since abated. Others reported needing to learn to eat more slowly and pay attention to feelings of fullness—and they sometimes vomit because their stomachs don’t empty as quickly as before. People who take the new drugs, which they inject at home, start on a low dose that is increased gradually over 17 weeks. “The GI side effects of semaglutide and tirzepatide usually occur as we’re escalating the dose,” says Jastreboff. “When people get their maintenance, those problems lessen and, most often, resolve.”
People who have regained weight after bariatric surgery may also be candidates for semaglutide and tirzepatide. “Our research shows that the use of anti-obesity medications can get people who’ve had surgery back to their lowest weight or even below that,” Aronne says.
Other drugs now being developed show promise for helping people lose even more weight. A recent article in Nature listed 26 compounds being evaluated in human trials. One combines semaglutide with an analog of amylin, a hormone secreted by the islet cells of the pancreas that delays gastric emptying after eating and suppresses glucagon, a hormone that stimulates glucose production. In a phase 1 trial, the amylin analog and semaglutide resulted in greater weight loss—up to 17% of body weight—than semaglutide alone. Other early trials are evaluating the effectiveness of GLP-1 agonists in concert with two additional compounds. “Combining a GLP-1 receptor agonist at a lower dose with one or two other compounds can reduce the gastrointestinal side effects associated with high-dose GLP-1 therapy,” says Klein. “Many other chronic diseases, such as hypertension and diabetes, are treated with combinations of medications. So this is the future of effective obesity management.”
Yet even as these drugs work their way through the pipeline, several structural issues may restrict the widespread use of even existing drugs. For one, semaglutide and tirzepatide aren’t yet approved to treat children and younger adolescents, although obesity specialists stress the importance of helping young people overcome obesity, in particular as a way to head off type 2 diabetes. Trials on young people are underway, and in the meantime, some physicians say they’re comfortable prescribing the drugs off-label to kids.
Another problem is that extreme weight loss, whether from bariatric surgery or medications, also results in loss of muscle mass and bone density. Exercise can help counteract that loss, but researchers are also investigating pharmaceutical fixes. In a trial of bimagrumab, a monoclonal antibody, people with type 2 diabetes lost about 21% of total body fat but had a nearly 4% increase in lean muscle mass.
Still, the lack of insurance coverage remains one of the biggest obstacles—and one of the most frustrating to obesity specialists. “It’s a travesty that insurers will pay for 10 medications people take for weight-related conditions but they won’t cover the treatment that could help prevent those diseases,” says Korner.
“Bias is the culprit that prevents optimal care of this disease.”
The Treat and Reduce Obesity Act, which has ongoing bipartisan support in Congress, was first introduced in 2013 and would require Medicare to cover FDA-approved anti-obesity medications. Yet each year it has fallen short of the votes needed to pass, in part because of bias and misunderstanding about obesity, says Joe Nadglowski, president and CEO of the Obesity Action Coalition. “Too many people still think obesity is a condition of personal fault, not a complex chronic disease requiring treatments like counseling, medications and surgery,” he says. One sign that attitudes may be changing, however, is an announcement from the federal Office of Personnel Management that, beginning in 2023, anti-obesity medications will be covered for federal employees.
For widespread use of the drugs, though, primary care physicians will need to become more willing to prescribe them. Anti-obesity medications won’t be used effectively and sufficiently unless primary care physicians are engaged in obesity treatment, say obesity experts. And a 15-minute appointment isn’t enough to manage the complex disease of obesity.
Moreover, no medication, however effective, can banish the unfair notion—from society, physicians and patients themselves—that obesity is a lifestyle choice. “Weight bias prevents patients from being informed, engaged and empowered. And it keeps clinicians from acquiring the training to provide anti-obesity interventions,” says Garvey. “Bias is the culprit that prevents optimal care of this disease.”
“Treatment of Obesity: Pharmacotherapy Trends of Office-Based Visits in the United States from 2011 to 2016,” by Mechelle D. Claridy et al., Mayo Clinic Proceedings, December 2021. The authors document that only 1% of people with obesity who visited physicians received anti-obesity medication.
“Once-Weekly Semaglutide in Adults With Overweight or Obesity,” by John P. H. Wilding et al., New England Journal of Medicine, March 2021. This pivotal trial showed that weight loss from medical treatment can rival bariatric surgery and led to FDA approval of semaglutide for obesity.
“Describing the Weight-Reduced State: Physiology, Behavior, and Interventions,” by Louis J. Aronne et al., Obesity, April 2021. The authors describe the effects of behavioral factors, exercise and drug therapy in maintaining weight loss long term.
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