‘A new era’: How semaglutide could change the obesity treatment landscape
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. 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.
“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 Cardiology 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), a GLP-1 receptor agonist, 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 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.
“Cardiologists should realize that this class of medication, along with the SGLT2 inhibitors, has the best clinical event data for diabetes,” Carl J. Lavie Jr., MD, FACC, FACP, FCCP, professor of medicine, medical director of cardiac rehabilitation and preventive cardiology, director of the Exercise Testing Laboratory and staff cardiologist in the Echocardiographic Laboratory at the John Ochsner Heart and Vascular Institute, Ochsner Clinical School-The University of Queensland School of Medicine, told Cardiology Today. “This agent at higher dose has the most effective data and safety profile for weight loss, coming close to the benefits of bariatric surgery. Most realize that over 40% of the U.S. adult population are obese, most having comorbidities, and now close to 10% meet criteria for class 3 or morbid obesity, which is a very serious problem. Many cardiologists have recommended bariatric surgery but not usually the prescription medications due to concerns of cardiac and other toxicities, which should not be an issue with this medication.”
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.
“With this drug, you have the potential not just to keep someone from developing type 2 diabetes, but reducing risk for prediabetes,” Fujioka told Cardiology 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.”
These implications may spur cardiologists to become more involved in managing their patients’ weight and prescribing weight-loss drugs, Ian J. Neeland, MD, FAHA, FACC, director of cardiovascular prevention and co-director of the Center for Integrated and Novel Approaches in Vascular-Metabolic Disease for University Hospitals Harrington Heart & Vascular Institute and associate professor of medicine at Case Western Reserve University School of Medicine, told Cardiology Today.
“Just as diabetes therapies have now become squarely under the purview of cardiologists, weight loss medications could follow suit — a new tool for cardiovascular prevention in the future,” Neeland said.
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 an individual’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.”
Of note for cardiologists, Neeland said in an interview, semaglutide “hits on multiple different metabolic aspects — GLP-1s for example, can reduce weight and lower BP, and there are data suggesting kidney protection and cardioprotection. This makes it an attractive drug to treat many of the cardiometabolic parameters that we are interested in.”
Assessing the STEPs
For the four phase 3 STEP trials (Table), 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. The clinical development program is one of the largest trial programs for the management of obesity.
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).
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).
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).
“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%,” 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 Cardiology Today. “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.”
CV effects to be determined
The data from the STEP program indicate use of semaglutide 2.4 mg “should lead to long-term reductions in clinical cardiovascular events and reductions in long-term medical costs, but future studies will need to better define and quantify these effects,” Lavie said in an interview.
While the weight-loss data for semaglutide are encouraging, “to really get the cardiologists excited about prevention and weight loss, especially addressing weight loss in the context of a cardiovascular visit, what is needed are CV outcomes trials that show meaningful outcomes differences,” Neeland said in an interview. “That is where this next step in weight-loss therapies, we hope, is going.”
He noted that in the SELECT trial program, scheduled to be completed in 2023, semaglutide 2.4 mg is being compared against placebo for CV death, MI and stroke in patients with obesity receiving the standard of care.
“The STEP program showed weight loss approaching what you see with bariatric surgery. So the question is, does larger-scale weight loss — 10% to 15% of your body weight — improve CV outcomes? There is a strong appetite among cardiologists for CVOTs for these novel weight medications,” Neeland said.
He also said a CV outcomes trial for tirzepatide (Eli Lilly), a novel glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, is expected to be completed in 2024.
“Whether there are CV benefits that are independent of glucose control will be tested in these trials, where they are enrolling people without diabetes,” Neeland said. “It will also be interesting to see how the different trial designs can help us examine if the amount of weight loss can account for the extent or pattern of CV benefits, beyond their direct effects on atherosclerosis outcomes.”
‘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 Cardiology 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.”
Learning from nonresponders
Weight loss achieved with any weight-management intervention can vary widely among individuals, experts 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.
“Identifying high and low responders would be helpful to determine better cost-effectiveness,” Lavie said in an interview. “Also, although there is clinical event reduction data at lower doses in diabetics, getting these data at higher doses in obesity will be very important, especially to support insurers paying a substantial part of the cost of this medication.”
Also important to learn, Neeland said, is that “what is not known, and is not able to be known from the STEP program, are whether there are select benefits in patients with excess visceral adiposity as opposed to excess subcutaneous fat — where the fat is in the body, is that related to the weight-loss response, and is it, potentially, then related to the CV benefit?”
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.
- Davies M, et al. Lancet. 2021;doi:10.1016/S0140-6736(21)00213-0.
- Kabiri M, et al. Obesity. 2020;doi:10.1002/oby.22696.
- Kaplan LM, et al. 3-CT-SY27. Presented at: American Diabetes Association Scientific Sessions; June 25-29, 2021 (virtual meeting).
- Rubino D, et al. JAMA. 2021;doi:10.1001/jama.2021.3224.
- Wadden TA, et at. JAMA. 2021;doi:10.1002/jama.2021.1831.
- Wilding JPH, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2032183.
- For more information:
- Jamy D. Ard, MD, can be reached at email@example.com; Twitter: @drard.
- Ken Fujioka, MD, can be reached at firstname.lastname@example.org.
- Carl J. Lavie Jr., MD, FACC, FACP, FCCP, can be reached at email@example.com.
- Ian J. Neeland, MD, FAHA, FACC, can be reached at firstname.lastname@example.org.
- Domenica M. Rubino, MD, can be reached at email@example.com.
- Fatima Cody Stanford, MD, MPH, MPA, MBA, FAAP, FACP, FAHA, FAMWA, FTOS, can be reached at firstname.lastname@example.org; Twitter: @askdrfatima.