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Measuring the Promise of Obesity Drugs

By Christiane Truelove

For many people, ringing in 2024 means resolutions to lose weight and be healthier. It’s a pattern that will be repeated as obesity and inactivity rates continue to rise. According to the World Health Organization, worldwide obesity has nearly tripled since 1975. In 2016, more than 1.9 billion adults 18 years and older were overweight, and of these, more than 650 million were obese.

In Trust for America’s Health’s September 2023 report on the antecedents and rates of obesity in the United States, the organization stated that the national adult obesity rate has increased by 37% and the national youth obesity rate increased by 42% since the group published its first obesity report in 2004. Trust for America’s Health says the increases show obesity is a society-wide, population-level issue. “It’s critical to recognize that obesity is a multifactored disease involving much more than individual behavior,” said J. Nadine Gracia, MD, MSCE, President and CEO of Trust for America’s Health. “In order to stem the decades long trend of increasing obesity rates we have to acknowledge that the obesity crisis is rooted in economic, health, and environmental inequities. Ensuring all people and communities have equitable opportunity and access to healthy food and physical activity is fundamental to addressing this crisis.”

Obesity rates are increasing in Europe and Asia as well. The European Commission in August 2023 estimated that 52.7% of the adult (aged 18 and over) population in the European Union (EU) was overweight in 2019. In looking at the EU member countries as well as Norway, Turkey, and Serbia, the commission reported that the proportion of overweight adults varied in 2019 between 37% in Italy and 58% in Croatia for women, and between 53% in France and 73% in Croatia for men. In 2019, for the population aged 18 years and over, the lowest proportion of women considered to be obese was observed in Italy at 10.7%, and for men in Romania at 11.1%. The highest proportion of women considered to be obese were recorded in Malta at 26.7%, while for obese men the highest share was found in Croatia at 23.7%. Data were derived from the European health interview survey.

“In order to stem the decades long trend of increasing obesity rates we have to acknowledge that the obesity crisis is rooted in economic, health, and environmental inequities.” — J. Nadine Gracia, MD, MSCE

The Asian Development Bank Institute reported in June 2017 that more than 40.9% of adults in the region are overweight compared to 34.6% in 1990. “Overall, our estimates suggest the total costs caused by obesity to be 12% of total healthcare expenditures or 0.78% of gross domestic product in the region. Obesity is thus a serious threat to the prosperity of the region and calls for urgent action,” write Matthias Helble and Kris Francisco.

Enter the GLP-1s

While the chatter about glucagon-like peptide receptor-1 (GLP-1) drugs reached a fever pitch in 2023 (in December, Science named GLP-1s its 2023 Breakthrough of the Year), drugs in the class had their debut more than 15 years ago. First came Bayer’s Byetta (exenatide) in 2004 for the treatment of type 2 diabetes. Novo Nordisk launched liraglutide (Victoza) in 2009, which gained approval by the US Food and Drug Administration (FDA) for obesity in 2014. In 2017, Novo Nordisk received its first US approval for semaglutide, which is marketed as Ozempic for the treatment of type 2 diabetes. Novo Nordisk launched a weight-loss version of semaglutide, Wegovy, in 2021.

Semaglutide kicked off intense demand for a few reasons. First, the drug is a once-weekly injection, compared with exenatide and liraglutide. Second, clinical results released in 2021 showed that patients lost 15% of their body weight in 16 months. Then in August 2023, a study in the New England Journal of Medicine revealed that patients with heart failure and obesity who took semaglutide had almost double the heart improvement. Novo Nordisk announced that same month the results of a study of 17,000 people (published in November in the New England Journal of Medicine), which found patients on semaglutide had a 20% lower risk of fatal or nonfatal heart attacks or strokes than those on placebo.

“For those battling obesity, these medications can offer a supportive boost, but the real transformation emerges from a comprehensive lifestyle overhaul.” — Phyllis Pobee, MD

Novo Nordisk has been struggling with supply chain difficulties for Ozempic and Wegovy. Though the company has taken a number of measures to address this, the European Medicines Agency in December 2023 announced a shortage of Ozempic 1 mg, 0.5 mg, and 0.25 mg pre-filled pen. The agency attributed the shortage to increased demand and manufacturing capacity constraints, and predicted that it will continue throughout 2024.

Meanwhile, a new GLP-1 drug has entered the market. In November 2023, Eli Lilly received FDA approval for tirzepatide, the active drug in its type 2 diabetes medication Mounjaro, to be marketed as Zepbound for obesity. Back in July, Lilly had released results from its SURMOUNT-3 trial for tirzepatide showing additional 21.1% weight loss after 12 weeks of intensive lifestyle intervention, for a total mean weight loss of 26.6% from study entry over 84 weeks. While Lilly is still in the process of producing cardiovascular data for tirzepatide, several physicians speaking with Reuters in December stated that they believe that the drug will show a similar heart benefit to Wegovy.

Always and Forever?

Physicians recognize the potential of new medications as part of a broader treatment strategy for obesity,” explains Phyllis Pobee, MD, a family practice physician and weight-loss coach with a focus on comprehensive health solutions encompassing cosmetic and weight loss medicine. “While these drugs can play a role in reducing appetite and supporting initial weight loss efforts, it’s imperative to integrate them within a holistic framework that includes dietary changes, physical activity, and psychological support. For those battling obesity, particularly with concurrent health conditions, these medications can offer a supportive boost, but the real transformation emerges from a comprehensive lifestyle overhaul. The clinical success of these medications underscores their value as one component of a multifaceted approach to sustainable health and wellness,” says Pobee.

In her practice, Pobee has guided patients through comprehensive weight loss journeys, where some have experienced significant weight reductions of 30, 40, or even 50 pounds, using medications as one element of a broader, personalized health and lifestyle strategy.

“The focus on pharmaceutical solutions may overshadow the importance of lifestyle changes. A holistic approach to obesity, including diet, exercise, and behavioral therapy, is often more sustainable.” — Phyllis Pobee, MD

According to William Samuel Yancy Jr, MD, MHS, a specialist located at Duke Lifestyle and Weight Management Center, his practice is using “considerably more” medications than it did just 2 or 3 years ago, due to patient and physician interest. “I see 20 new patients a week. And that’s just me, we have 5 other medical providers doing this. We’re seeing 40 to 50 new patients a week and prescribing these medicines to many of them.”

However, both physicians state that the reliance on medication raises concerns. The long-term side effects of this class of drugs are not fully understood, and this uncertainty poses a risk to users, Pobee says. “Moreover, the focus on pharmaceutical solutions may overshadow the importance of lifestyle changes. A holistic approach to obesity, including diet, exercise, and behavioral therapy, is often more sustainable. Such methods not only address weight loss but also encourage overall health improvements.”

Yancy says patients need to understand that drugs such as Wegovy and Zepbound are not a “magic bullet.” “They work through the eating plan, just like bariatric surgery. These medications are a tool that helps people to adhere to their eating plan more closely. They reduce hunger, they can make you feel full faster, they can even reduce cravings.”

He adds that these drugs must be paired with a sustainable, healthy eating plan as well as exercise. That’s because some patients might continue eating the same unhealthy foods yet lose weight—but instead of losing mostly fat, they might lose muscle and can suffer nutritional deficiencies. Providers also need to be able to explain the side effects of the drugs, such as nausea, to patients and address them appropriately.

Yancy points out that the way many insurance companies who cover the medications want physicians to administer the drugs could also cause unintended effects. Insurers sometimes require physicians to increase the dose every month, rather than letting the patient stay on a lower dose for a longer period of time when needed. But if patients lose weight too fast, complications could occur. Rapid weight loss can lead to gallbladder disease or gallstones, bone loss, dehydration, hair loss, and even electrolyte abnormalities that lead to cardiovascular issues such as arrhythmias. “Also, if you have to ramp the dose too quickly, the patient may be less likely to learn a healthy eating plan.”

Both Pobee and Yancy expressed concerns that patients may have to be on these medications long-term because once they are off the drugs the weight comes back.

Yancy has seen this occur. “I have a patient who was taking the medicine and then the supply ran out and he couldn’t get it. He’s been off of it for 3 or 4 months now and he’s gained back 40 pounds.”

“These medications are a tool that helps people to adhere to their eating plan more closely. They reduce hunger, they can make you feel full faster, they can even reduce cravings.” — William Samuel Yancy Jr, MD, MHS

The patient had initially lost weight through a low carbohydrate eating plan and then had hit a plateau, Yancy says. He requested and was prescribed Wegovy. “We added the medicine and he made more progress and was in a really good spot, but then he couldn’t get the drug at his pharmacy. He ended up regaining the weight that he lost with the medicine, in addition to some of the weight that he lost with the eating plan. That’s because the medicine can distract you from the eating plan.”

Despite these concerns, Yancy and Pobee see the potential benefits of these drugs from a societal perspective in improving quality of life and possibly saving costs for hospitalizations related to diabetes and heart disease—although how payers and health plans see the value of these medications still remains to be seen.

Yancy says one area that is understudied, when it comes to the value of weight-loss interventions, is measuring the use of other medicines in treating comorbidities of obesity such as type 2 diabetes and hypertension. “When we have patients losing weight in the clinic, we frequently have to cut back on our medicines—and to me, that’s one of the best barometers of how their disease control is going.” And while Ozempic specifically reduces blood glucose, patients may be able to reduce other medicines they take for their diabetes, “I still think that’s a meaningful outcome.”

According to Jonathan Levin, PhD, policy researcher at the RAND Corporation, improved coverage of these drugs could save downstream costs resulting from the complications of untreated obesity or untreated type 2 diabetes. “There’s potentially a financial incentive there, depending on the lag time from the increased cost of taking the medication versus reduced costs later,” he says. “At this point, it’s hard to say when those financial savings would be realized.”

Levin says payers also need to account for the commonly known side effects of the GLP-1s—particularly nausea and constipation—in looking at why patients may not be sticking with these drugs as well as they should. “As a researcher, what we may observe is that patients—whether or not it’s in their best interest or their health—may stop taking the medication for those reasons. That could attenuate the positive impacts of these drugs.”

“Cost analysis on these medications indicates they are currently the costliest prescription drugs paid for by the plan on an annual basis.” — University of Texas health system executives

This patient recalcitrance was observed by executives at the University of Texas employee health system. In September 2023, the University of Texas health system decided that as of September 2023, it would stop covering Wegovy and Saxenda (liraglutide) for its health plan members. Executives stated that the cost rose from about $1.5 million per month to more than $5 million as of May 2023. “Cost analysis on these medications indicates they are currently the costliest prescription drugs paid for by the plan on an annual basis, even more costly than medications for complex conditions like cancer,” executives said.

In monitoring compliance with these medications under the plans, the university saw that less than 46% of users remain on the medication. “This equates to a significant cost to the plan with less than desirable compliance with medication and treatment protocols,” executives said. While some patients were benefiting from using these medications for weight loss, “the plan is not seeing the expected reduction in cost for other conditions a member may be attempting to control as a result of using Wegovy or Saxenda,” executives said. “These savings are not being realized due to the excessive cost the drug manufacturer charges for the weight-loss medication.”

The University of Texas is not the only payer who has decided to stop covering GLP-1s for obesity. On January 25, the state of North Carolina’s governing board for its health plan voted that it would stop paying for weight-loss medications as of April 1, 2023. Health plan executives say that the cost for GLP-1s prescribed for weight loss has increased from about $3 million per month 3 years ago, to more than $14 million per month in 2023, before manufacturer rebates. In total for 2023, trustees estimated the cost of Wegovy, Zepbound, and Saxenda to be $170 million before rebates, and $102.2 million with rebates applied. Costs were projected to exceed $600 million annually before rebates within the next 5 years.

While the state decided in October 2023 to grandfather in obesity patients already taking GLP-1s, CVS Caremark, who administers the health plan, told executives that the state would lose all rebates for these drugs if it did not restart the weight-loss therapy program. Before losing the rebates, the plan was paying $880 per member per month. Without the rebates, the price went up to $1349 per member. In total, if the rebate had remained at the 2023 level, the plan would have paid $85 million for its grandfathered members. With the rebate, the cost would rise to $139 million.

Because of these well-publicized high costs, Levin believes that manufacturers will need to go beyond the standard contracting approach and think differently about how they approach federal, state, and city governments and structure rebates in a creative manner to make sure patients get access to GLP-1s.

“Manufacturers will need to go beyond the standard contracting approach and think differently about how they approach federal, state, and city governments and structure rebates in a creative manner to make sure patients get access to GLP-1s.” — Jonathan Levin, PhD

Eli Lilly’s experiment

On January 4, 2024, Lilly announced the launch of LillyDirect, a website that the company calls an “end-to-end digital healthcare experience” for US patients living with obesity, migraine, and type 2 diabetes. The company says LillyDirect offers disease management resources, including access to independent healthcare providers, tailored support, and direct home delivery of select Lilly medicines—including Zepbound, which Lilly CEO David Ricks says hit 25,000 new prescriptions per week at the end of December—through third-party pharmacy dispensing services.

“We know that people have come to depend on the efficiency and convenience of digital solutions to meet a variety of their everyday needs—healthcare being one of them,” stated Frank Cunningham, group vice president, global value and access at Lilly. “We launched LillyDirect with the hope that it will offer patients an innovative end-to-end experience to manage their health and access their medicines, so they can get back to living their lives.”

The website offers lists of area physicians who provide telehealth services as well as in-person visits. However, Yancy doubts that these services will be able to improve patient access to Zepbound. “The reason that patients are having trouble accessing the medicine is because their insurance doesn’t cover it,” he says. “They either can’t get it because their insurance is not covering it or the supply is not there. So, having more providers is not really going to help the issue.”

Another potential problem is that in looking at the list that LillyDirect provides of physicians in his area, Yancy found some physicians he knows are practicing weight-loss medicine—such as himself and all the physicians at his practice—have been left out, and others who are included do not know they are listed.
“I spoke with the chief of endocrinology at Duke [David D’Alessio] and he said, ‘Oh, I didn’t know I was listed.’ He then looked at the list and said, ‘Oh, that person’s not even seeing patients anymore. And that person works at the VA, so they can’t see patients in the public. And that person retired.’ So some of the providers on Lilly’s website may not know that they’re listed, and some of them may not even able to prescribe these medications.”

The role of ISPOR and HEOR

Research done by ISPOR members will play a particularly important role in helping payers—whether private insurance or government entities—figure out if they should cover these new obesity drugs, how they should be prescribed, and how to pay for them.

Research presented at ISPOR Europe 2023 addressed the growing use of GLP-1s for obesity. A poster, “Real-World Prescribing of GLP-1 RAs Among Patients with Overweight or Obesity in the United States,” presented by authors from Truveta, looked a large and diverse real-world dataset and found that new prescribing of GLP-1 receptor agonists among patients with obesity has increased since 2021, including new prescriptions for type 2 diabetes-labeled medications to patients with no evidence of type 2 diabetes. A second poster by authors from Envision Pharma Group, “Overview of Recent Systematic Literature Reviews on Glucagon-like Peptide-1 Receptor Agonists for Weight Loss in Adults with Obesity,” sought to identify key trends in the literature on the use of GLP-1 RAs in adults with obesity. While recent systematic literature reviews reflect the growing use of GLP-1s for obesity, their long-term benefits are not yet known. Researchers from both poster presentations indicate that additional work is needed in this area to synthesize the existing evidence on anti-obesity medications to better understand the initiation, adherence, and outcomes among patients newly prescribed GLP-1 RAs.

Christiane Truelove is a healthcare and medical freelance writer.

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VOL. 10, NO. 1

January/February 2024

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