Issue: August 2021
Disclosures: Novo Nordisk funded the STEP studies. Ard reports he serves on the corporate advisory boards of Amgen and Novo Nordisk and receives consultant fees from Boehringer Ingelheim and Nestle Healthcare Nutrition. Fujioka reports he has received consultant and speaker fees from Amgen, Boehringer Ingelheim, Gelesis, Janssen, Novo Nordisk, Phenomix, Sunovion and Takeda. Heymsfield reports he received personal fees from Medifast and Tanita. Rubino reports she has served as a clinical investigator for AstraZeneca and Boehringer Ingelheim, has received speaker fees, consultant fees and honoraria from Novo Nordisk, and is a shareholder in Novo Nordisk. Stanford reports she is a consultant for Calibrate, Doximity, GoodRX and Novo Nordisk.
August 23, 2021
10 min read
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‘A new era’: How semaglutide could change the obesity treatment landscape

Issue: August 2021
Disclosures: Novo Nordisk funded the STEP studies. Ard reports he serves on the corporate advisory boards of Amgen and Novo Nordisk and receives consultant fees from Boehringer Ingelheim and Nestle Healthcare Nutrition. Fujioka reports he has received consultant and speaker fees from Amgen, Boehringer Ingelheim, Gelesis, Janssen, Novo Nordisk, Phenomix, Sunovion and Takeda. Heymsfield reports he received personal fees from Medifast and Tanita. Rubino reports she has served as a clinical investigator for AstraZeneca and Boehringer Ingelheim, has received speaker fees, consultant fees and honoraria from Novo Nordisk, and is a shareholder in Novo Nordisk. Stanford reports she is a consultant for Calibrate, Doximity, GoodRX and Novo Nordisk.
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The prevalence of overweight and obesity continues to rise in the United States and globally at an alarming rate. By 2025, data from the NCD Risk Factor Collaboration suggest 18% of men and 21% of women globally will have obesity.

Approved treatments for obesity — particularly pharmacotherapy — remain underutilized, according to experts. The reasons underlying low uptake of medical therapy for obesity are complex, ranging from practical issues of insurance coverage and cost to concerns about safety and efficacy, as well as continued disease-related stigma, even among providers.

Semaglutide is the first of better medical therapies for obesity, allowing for individualized treatment, according to Domenica M. Rubino, MD.

Photo by Paul Driggers. Printed with permission.

“Many of my colleagues do not appreciate the neuroendocrine regulation around weight,” Domenica M. Rubino, MD, director of the Washington Center for Weight Management and Research in Arlington, Virginia, told Endocrine Today. “Obesity, still, has so much stigma. We accept chronic treatment for diabetes or hypertension. With obesity, no one wants to accept medication as a chronic treatment. People want to believe you prescribe a medication, obesity is ‘cured,’ and then you come off of the medicine. Treating obesity is not like treating an infection.”

A new agent is changing that conversation. In June, the FDA approved once-weekly injectable semaglutide 2.4 mg (Wegovy, Novo Nordisk) for chronic weight management in adults with obesity or with overweight and at least one weight-related condition. The drug, a higher-dose version of injectable semaglutide 1 mg (Ozempic) for adults with type 2 diabetes, is the first-approved agent for chronic weight management in adults with general obesity or overweight since 2014.

Data from the Semaglutide Treatment Effect in People with Obesity (STEP) clinical trial program, published in late 2020 and early 2021, have been hailed as game changing for obesity management. Approximately 33% of participants assigned semaglutide 2.4 mg in the studies lost more than 20% of body weight over 68 weeks — weight loss that rivals what is typically seen with bariatric surgery.

“The thing that is most exciting about the semaglutide data is this is the beginning of a potentially new era in how we think about what pharmacotherapy can do — and can do safely — with achieving larger volume weight loss,” Jamy D. Ard, MD, professor of epidemiology and prevention and co-director of the Weight Management Center at the Wake Forest School of Medicine, told Endocrine Today. “We know there are other drugs in the pipeline with similar mechanisms of action or molecular targets. When we start to talk about options on where treatment can escalate to, those will now be significantly different. That will open possibilities that more people can have a successful treatment response.”

The data also show clinicians have a new opportunity to control obesity and its medical complications, including type 2 diabetes, according to Ken Fujioka, MD, former director of the Center for Weight Management and director of the Nutrition and Metabolic Research Center at Scripps Clinic San Diego.

Jamy D. Ard

“With this drug, you have the potential not just to keep someone from developing type 2 diabetes, but reducing risk for prediabetes,” Fujioka told Endocrine Today. “When someone has prediabetes, that is when the cardiovascular issues start. You are at higher risk for strokes and heart attacks. With this drug, you are taking some prediabetic patients to normoglycemia. You take away that CV risk. That is a huge step forward in health care.”

A ‘sophisticated impact’

Semaglutide, an incretin mimetic that imitates the functions of natural incretin hormones in the body, works in four different ways, according to Fatima Cody Stanford, MD, MPH, MPA, MBA, FAAP, FACP, FAHA, FAMWA, FTOS, an obesity medicine physician scientist at Massachusetts General Hospital and Harvard Medical School. The drug slows gastric emptying, improving satiety, so a person feels full longer. It also functions as a neurotransmitter, inhibiting the neuropeptide Y pathway, one the most potent orexigenic peptides found in the brain, while stimulating the anorexigenic pro-opiomelanocortin (POMC) pathway. At the same time, semaglutide increases insulin secretion and decreases glucagon secretion, improving glucose response.

Semaglutide has a different structure from another GLP-1 receptor agonist, liraglutide 3 mg (Saxenda, Novo Nordisk), a once-daily injection FDA approved for weight management in 2014. As a weekly agent, semaglutide prolongs the half-life compared with a daily drug.

All GLP-1 receptor agonists work similarly, though new evidence points to GLP-1 receptor agonists targeting different areas of the brain, which may impact effectiveness of the individual agents as well as a person’s sensitivity to a given agonist, Rubino said.

“We are learning that there are endogenous GLP-1s that are produced in the brain communicating, neuron to neuron, in regions that not only govern hunger, but also the hedonic and reward pathways,” Rubino said. “Additionally, they may affect executive functioning. You are seeing a sophisticated impact on multiple pathways. This is why there is development of multiple medications affecting these pathways; hence, the dual and tri-agonists that are now in the pipeline.”

Assessing the STEPs

Steven B. Heymsfield

For the four phase 3 STEP trials, researchers assessed semaglutide 2.4 mg in more than 4,300 adults with obesity or overweight with a weight-related comorbid condition. Each study had the same coprimary endpoints of percentage change in body weight and weight reduction of at least 5% from baseline to 68 weeks compared with placebo. Researchers used the primary estimand to assess effects regardless of treatment discontinuation or rescue interventions. The clinical development program is one of the largest trial programs for the management of obesity.

“Having worked in that business for a few years, I am impressed that they could mount that number of different studies, all over the world, ending within a tight timeline,” Steven B. Heymsfield, MD, FTOS, professor in the department of metabolism and body composition at Pennington Biomedical Research Center, Louisiana State University, who formerly worked in drug development at Merck, told Endocrine Today. “That is so nontrivial. All of us in that industry are impressed with how they pulled this off.”

The pivotal STEP 1 trial, published in The New England Journal of Medicine in February, included 1,961 adults without diabetes who had obesity or overweight with a weight-related comorbid condition. Researchers randomly assigned participants semaglutide 2.4 mg or placebo; both groups received lifestyle intervention. Researchers found that mean change in body weight from baseline to week 68 was –14.9% for the semaglutide group and –2.4% for the placebo group, for an estimated treatment difference of –12.4 percentage points (95% CI, –13.4 to –11.5). Participants assigned semaglutide lost a mean –15.3 kg vs. –2.6 kg in the placebo group, for an estimated treatment difference of –12.7 kg (95% CI, –13.7 to –11.7).

STEP 2, published in March in The Lancet, included 1,210 adults diagnosed with type 2 diabetes with overweight or obesity. At 68 weeks, estimated change in mean body weight from baseline was 9.6% with semaglutide 2.4 mg vs. 3.4% with placebo, for an estimated treatment difference of 6.2 percentage points (95% CI, 7.3 to 5.2). At week 68, more patients on semaglutide 2.4 mg achieved weight reductions of at least 5% vs. placebo (68.8% vs. 28.5%), for an OR of 4.88 (95% CI, 3.58-6.64).

“With these gastrointestinal hormones and their neuroendocrine impact when we target these pathways, we can get significant weight loss for a majority of people, improve their comorbidities and help people start to make improvements in their lives,” Rubino said. “We are starting down a path that has a future now of better and better medical therapies, so we can offer obesity treatments to more people. We are not replacing bariatric surgery, but a lot more people can be treated. Semaglutide is another tool, and we need a lot of tools, because everyone’s brain is a little bit different.”

STEP 3, published in JAMA in February, assessed the effect of semaglutide 2.4 mg on body weight in 611 adults with obesity but without diabetes when added to intensive behavioral therapy that consisted of 30 counseling visits with an initial low-calorie diet for 8 weeks. At 68 weeks, semaglutide plus intensive behavioral therapy and a low-calorie diet resulted in reductions in body weight of 16% vs. 5.7% for placebo ( P < .001).

“This shows that this [intervention] can be done in primary care, because the intensive behavioral therapy was not critical to achieve the weight loss,” Rubino said. “Any prescribing health professional can prescribe the medicine and help people. You do not need to go to a specialized center. Those centers can take care of the people who are more complex.”

STEP 4, published in JAMA in March, assessed continued weight loss or weight maintenance among 535 adults with obesity who continued semaglutide therapy beyond 20 weeks vs. 268 participants who were switched to placebo at 20 weeks. After randomization, the estimated mean weight change from week 20 to week 68 was –7.9% with continued semaglutide vs. a mean increase of 6.9% among participants switched to placebo, for a difference of –14.8 percentage points (95% CI, –16 to –13.5).

Fatima Cody Stanford

“A few things are important to note in these studies — one is the overwhelming majority of people are experiencing what we call clinically meaningful treatment response, or weight loss of at least 5%,” Ard said. “We know that leads to improvements in risk factors for complications of obesity, and quality of life. But most exciting about this drug is the magnitude of the response is larger. That means one can begin to chip away at the notion of needing intense intervention, support and expertise to get that treatment response. Maybe we do not need all of those things for people to be successful. The pharmacotherapy changes the biology and when you do that, people can move into a lifestyle change that is sustainable and feels easy to do.”

‘Can I get it for my patients?’

In a study published in Obesity in February 2020, researchers used the Health Economics Medical Innovation Simulation, a well-established simulation model, to quantify the societal value of anti-obesity medications for American adults in 2019. Four scenarios with differential uptake among the eligible population (15% and 30%) were modeled, with efficacy from current and nextgeneration medications. Societal value was measured as monetized quality of life, productivity gains, and savings in medical spending, subtracting the costs of drugs.

For the 217 million U.S. residents aged at least 25 years, anti-obesity medications generated $1.2 trillion in lifetime societal value under a conservative scenario of 15% annual uptake using currently available treatments. The introduction of nextgeneration treatments increased societal value to $1.9 trillion to $2.5 trillion, depending on uptake. Societal value was higher for younger individuals and for Black and Hispanic adults compared with white adults.

“Policies promoting broader clinical access to and use of anti-obesity medications warrant consideration to reach national goals to reduce obesity,” the researchers wrote.

However, the approval of semaglutide 2.4 mg comes with two possible hurdles to reaching those eligible adults, according to experts — access and affordability.

“People with obesity can potentially glean a lot of benefit from an agent like semaglutide,” Stanford told Endocrine Today. “My only concern is, can I get it for my patients? Sometimes a new drug is like a shiny ornament on a shelf, and that can be even more frustrating. I hope insurers step up to the plate.”

“The big elephant in the room is cost,” Fujioka said. “If semaglutide is not covered by insurance, I do not see patients using this. You need insurance companies to buy in and pay for this. Unfortunately, [coverage] varies from state to state and from employer to employer.”

Many patients are also likely already to be prescribed multiple agents for other conditions, Rubino said, increasing polypharmacy burden.

Ken Fujioka

“It is important to remember most people with obesity generally have two to three comorbid conditions, if not more,” Rubino said. “Many of those comorbid conditions also require medicine. The whole point of treating obesity is to improve those conditions, but while you are in the process, they are spending money on other medicines. There are economic, practical and logistical barriers that need to be dealt with.”

Learning from nonresponders

Weight loss achieved with any weight-management intervention can vary widely among individuals, Fujioka said. In the overall STEP program, nearly 10% of participants without diabetes and more than 30% of participants with type 2 diabetes experienced less than 5% weight loss, despite use of a potent GLP-1 receptor agonist plus lifestyle intervention.

“The pathophysiology of obesity for everyone is roughly the same, but the reasons why someone will gain weight are all over the place,” Fujioka said. “Someone might struggle with night eating or has trouble sleeping. Another might have binge eating disorder. About two-thirds experience classic increased hunger and do not feel full when eating. Those patients will do great on this drug. With semaglutide, between 75% and 85% do respond. There will be 15% to 20% of people that just do not respond, because they are gaining weight for other reasons.”

For those people, individualized interventions coupled with the right pharmacotherapy are key, though that often involves trial and error, Stanford said.

“I tell patients that unlike cancer therapies, where a clinician gives you a target, we don’t have that level of precision,” Stanford said. “Much like diabetes or hypertension, there is guesswork involved. There will be above-average responders and there will be nonresponders. It is about finding the right drug for you, and we have to find what that drug is.”

Stanford said there are likely different obesity phenotypes and genotypes that researchers are just beginning to learn more about, which one day could help determine response to a therapy.

“For those who did not respond, or experienced a less-than-average response, what do we know about them?” Ard said. “We have to continue to look at this in more challenging patient populations, such as those with mental health conditions, who were not included in these studies, as well as racial and ethnic differences in treatment response. There is more we need to learn. That said, this is the beginning of a new era in what we are going to expect as a part of our arsenal of obesity treatment.”

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