New 'weighs' to treat obesity

Even as the data on weight loss drugs mount, physicians need to help patients navigate potentially prohibitive costs and a continuing need for lifestyle change.

Amid the flurry of headlines about new drugs for obesity, internal medicine physicians must sort through which patients are optimal candidates for the glucagon-like peptide-1 (GLP-1) receptor agonists or for alternative agents, along with lifestyle changes, to pursue their weight loss goals.

Since 2021, research findings about significant weight loss with new drug classes have continued to accrue. Study participants who were prescribed 2.4 mg of semaglutide (Wegovy) weekly lost an average of 14.9% of their weight after 68 weeks, and those taking the highest dose, 15 mg, of tirzepatide (Zepbound) averaged 20.9% in weight loss after 72 weeks, according to two studies published in 2021 and 2022, respectively, in the New England Journal of Medicine (NEJM). More recently, a phase 2 study of retatrutide, which targets GLP-1 and other receptors, found that adults on the highest weekly dose, 12 mg, lost 24.2% of their body weight on average after 48 weeks versus 2.1% in the placebo group, according to results published Aug. 10, 2023, in NEJM.

Not all interested patients meet the body mass index and other criteria to prescribe a GLP-1 receptor agonist yet still fret as they watch the numbers on their scale inch upwards Image by Pvstockmedia
Not all interested patients meet the body mass index and other criteria to prescribe a GLP-1 receptor agonist, yet still fret as they watch the numbers on their scale inch upwards. Image by Pvstockmedia

Meanwhile, more recent data, published in NEJM on Dec. 14, 2023, have indicated that the preventive potential of the GLP-1 receptor agonists extends beyond weight loss alone, said Angela Fitch, MD, FACP, president of the Obesity Medicine Association. The trial, which involved 17,604 nondiabetic patients with preexisting cardiovascular disease, found that semaglutide reduced fatal and nonfatal cardiovascular conditions by 20% compared with placebo after patients took the drug for an average of 33 months.

Given the stigma involved with weight-related discussions, the NEJM findings make it easier for physicians to raise the possibility of a GLP-1 receptor agonist "because it's more of a cardiac risk reduction strategy than an obesity treatment strategy," said Dr. Fitch, who reports consultantships for Eli Lilly, Novo Nordisk, and Vivus, among other companies, and also serves on Eli Lilly's and Novo Nordisk's speakers bureaus. "We have an understanding today that these GLP agonists have a multitude of benefits, potentially a direct drug benefit to their use versus just a weight loss benefit."

Even if patients meet eligibility criteria, physicians report that the hefty cost and lack of insurance coverage can pose an insurmountable barrier for some. According to data cited by the Congressional Budget Office (CBO), the list price for a four-week supply of injectable semaglutide was $1,349 as of September 2023. Physicians also stress that GLP-1 receptor agonists comprise just one component of what should be a highly individualized weight loss approach, which may involve other drugs depending on a patient's contraindications and other medical conditions.

Physicians should remind patients that while the drugs may help them eat less, they will still need to work on their lifestyle habits, said Katie Root, MD, MHA, FACP, an internal medicine physician with an interest in obesity management, who also is an assistant professor of medicine at the University of Texas at Tyler Health Science Center.

"I think one of the biggest misperceptions is that patients can just eat what they want to eat and continue the lifestyle that they had that caused them to gain the weight to begin with," Dr. Root said. "The medication is not going to be something that overrides their diet, overrides their lack of exercise. It's not a miracle."

Gauging the GLP-1s

FDA officials have approved both semaglutide and tirzepatide, in conjunction with a lower-calorie diet and exercise, in adults with a BMI of at least 30 kg/m2, or with a BMI of at least 27 kg/m2 and one or more weight-related conditions, such as high cholesterol or hypertension. More than 40% of U.S. adults meet the 30 kg/m2 criterion for obesity.

The most frequently reported side effects for both semaglutide and tirzepatide are gastrointestinal, including nausea, vomiting, diarrhea, and constipation, according to the FDA. Both drugs contain other warnings, including the risk of pancreatitis, gallbladder problems, and acute kidney injury, among other possible side effects. Physicians shouldn't prescribe the drugs to patients with multiple endocrine neoplasia syndrome or a personal or family history of medullary thyroid cancer, the FDA said.

Since medullary thyroid cancer is inherited, physicians should ask about any family history of the malignancy, said Fatima Cody Stanford, MD, MPH, MPA, MBA, FACP, an obesity medicine physician-scientist at Massachusetts General Hospital and Harvard Medical School in Boston, who served as Chair of ACP's Obesity Management Advisory Committee. Patients who don't know should get a thyroid exam, and any lump that's detected should be checked out to ensure that it's not medullary thyroid cancer before starting a GLP-1, she said.

In a workup with each patient, physicians also should consider the full range of antiobesity medications, Dr. Stanford said. Along with potential cost and access challenges, not all patients will respond to the GLP-1 receptor agonists and others will have contraindications, she noted.

Moreover, different weight loss drugs target varying mechanisms in the brain, she said. When prescribing, Dr. Stanford said, "I'm thinking about the whole patient when I'm thinking about what I need to use for that patient."

For instance, if a patient wants to lose weight and has a history of depression or opioid use disorder, Dr. Stanford might consider the naltrexone and bupropion combination (Contrave), as oral medication targets those conditions. Alternatively, she said patients with a history of migraines might be good candidates for the topiramate portion of the phentermine and topiramate combination (Qsymia).

In patients who have excess weight and metabolic disease, the GLP-1 receptor agonists might be a good option if there's no contraindication like a history of pancreatitis, said Dr. Stanford, who reports consultantships for Eli Lilly and Novo Nordisk, as well as other companies. Since constipation is a common side effect, she often prescribes a laxative or glycerin suppository along with a GLP-1 receptor agonist. She typically avoids the drugs in patients who already struggle with nausea or constipation.

A broader strategy

Since the underpinnings of obesity can be multifaceted, including psychological components, patients may achieve more success with a combination of drugs, said Matthew Swan, MD, FACP, an internal medicine and obesity medicine physician at AdventHealth Primary Care, who practices in Overland Park, Kan.

Dr. Swan, who has written about his own weight loss journey that started about four years ago, said that his initial plan, developed under the care of an obesity medicine physician, included the medication diethylpropion to help suppress his appetite. But he also ramped up his exercise, consumed a controlled diet of packaged meals, stopped skipping breakfast, and committed to getting eight hours of sleep a night instead of staying up until 2 a.m.

More recently, Dr. Swan tried a GLP-1 receptor agonist for several months. "But it didn't really provide me with significant benefit," he said, adding that the drug class doesn't always work for his patients.

Not all interested patients meet the BMI and other criteria to prescribe a GLP-1 yet still fret as they watch the numbers on their scale inch upwards, said Sharon Herring, MD, MPH, FACP. She empathizes with those patients and discusses various strategies, including exercising more, joining Weight Watchers, and making other lifestyle modifications.

"Also loving themselves for who they are, because I do think that the societal pressure [to be thin] is a lot," said Dr. Herring, an associate professor of medicine and director of the Program for Maternal Health Equity at the Center for Urban Bioethics at the Lewis Katz School of Medicine at Temple University in Philadelphia.

But for the most part, patients who ask about the drugs meet the FDA criteria, Dr. Fitch said. "They are not just trying to lose five or 10 pounds to fit into a bathing suit," she said. "They are really worried about their metabolic health."

Access and rebound challenges

As of January, Dr. Stanford said she struggled to locate any starter doses of semaglutide (Wegovy) within a 250-mile radius of her practice. FDA officials recommend that the dose be increased gradually over 16 to 20 weeks, starting at 0.25 mg once weekly for four weeks, then adjusted upwards in four-week intervals until the 2.4-mg dose is reached. Dr. Stanford stressed those starter doses can't be skipped over: "They are there for a reason—it's not safe."

In January 2024, officials at Eli Lilly, tirzepatide's manufacturer, announced a direct-to-consumer pharmacy option, including access to prescribing clinicians, for patients having difficulty locating various medications, including for diabetes, migraines, and obesity.

But ACP has raised concerns about the direct-to-consumer telemedicine approach, with President Omar T. Atiq, MD, MACP, releasing a written statement in January saying that this practice is primarily intended to promote telehealth services as a way to prescribe a drugmaker's products. "For telemedicine services to take place responsibly, there should be an established and valid patient-physician relationship, or the care should happen in consultation with a physician who does have an established relationship with the patient," Dr. Atiq wrote.

Meanwhile, Medicare doesn't cover antiobesity drugs, including GLP-1 receptor agonists. Congress has regularly introduced related legislation, most recently the Treat and Reduce Obesity Act of 2023, which would enable coverage. But even with manufacturer discounts, coverage of the drugs would have a "significant" effect on Medicare's budget over the next decade, according to a Congressional Budget Office writeup about the legislation published on Oct. 5, 2023.

On the brighter side, some commercial insurers have started to cover weight loss drugs, Dr. Stanford said. "Throughout the country, we're seeing a slow shift towards coverage of antiobesity medications," she said, adding: "Let's call it a glacial-paced shift."

Research indicates that the GLP-1 receptor agonists may not be easy to stop without risking the rebound effect. One 2022 study published in Diabetes, Obesity and Metabolism found that participants had regained two-thirds of the weight they'd lost within a year after stopping semaglutide. But taking the drugs year after year may not be feasible for some amid changes to insurance coverage, physicians point out.

A patient covered today could lose coverage for the GLP-1 receptor agonists if they change jobs or their employer alters the drug formulary, Dr. Herring said. But she described herself as likely to start a patient on a GLP-1 receptor agonist if she thought the drug would be covered for at least a year.

"I do talk to my patients that I don't recommend them going off any time soon," she said. But even a few years on one of the GLP-1 receptor agonists might help, she added.

Perhaps by then, more insurers will cover the drugs in the wake of recent cardiovascular findings, Dr. Herring said. In addition, researchers are still in the early phases of learning about this new class of weight loss drugs. If a patient stops taking the drug after a year or two, she said, "Does your body physiologically behave differently? I don't know. I don't think we understand that yet."

Dr. Swan is similarly not convinced that all patients will need to continue the drugs indefinitely. Instead, physicians could frame them as more of a temporary tool, enabling patients to work on behavior changes, mental health issues, and other challenges that have impeded losing weight—similar to using a kickboard while learning how to swim.

But Dr. Swan, no stranger to weight loss struggles and related stigma, maintains that patients shouldn't be criticized if they require the drugs on an ongoing basis to improve their overall health. Adults who take antihypertensive medications chronically, he pointed out, aren't chided for relying on them too much as a crutch.

"Yet for obesity, we do," Dr. Swan said. "And why do you think that is? There is an underlying belief that obesity is secondary to a lack of self-control and gluttony. That it's not really a disease, it's not really an addiction. That if a person wanted to be skinny, they could."

For patients who have long struggled to shed significant weight, the GLP-1 receptor agonists may offer their brightest hope to date to rewrite their own weight loss story, Dr. Herring said.

"I am more optimistic than I've ever been in medicine around these newer drugs," she said. "I would have never imagined that we would have drugs leading to 20% body weight loss. That to me is pretty amazing. So I do think the next five years are going to look really bright for weight loss."