‘Game changing’ data: New obesity drugs tied to major weight loss, may reduce CV risk
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Key takeaways:
- New obesity treatments are associated with significant weight loss not seen in previous clinical trials.
- Emerging data suggest GLP-1 receptor agonists also reduce CV risk for people with obesity.
Editor's Note: This Healio Exclusive report features in-depth interviews with leading experts in the fields of obesity, CVD and cardiometabolic health.
A new generation of obesity drugs is changing the treatment landscape for patients and providers, with options that can lead to weight loss unheard of just a few years ago.
Credit: Regina Schaffer. Printed with permission.
Since the FDA approved once-weekly semaglutide injection in 2021 for chronic weight management for adults with obesity or overweight with at least one weight-related condition, a multibillion-dollar market for anti-obesity medications has followed. Injectable semaglutide 2.4 mg (Wegovy, Novo Nordisk) and its counterpart semaglutide 1 mg (Ozempic), approved to treat type 2 diabetes, are associated with weight loss of as much as 15% to 20% for some patients. The GLP-1 receptor agonists now dominate headlines — and celebrity weight loss speculation — in the mainstream press.
Other anti-obesity agents are likely coming soon. Tirzepatide (Mounjaro, Eli Lilly), an injectable dual agonist approved to treat type 2 diabetes and currently under FDA consideration as a treatment for chronic weight management, was associated with 14.7% weight loss at 72 weeks vs. placebo for people with obesity without diabetes who received the highest 15 mg dose.
New phase 2 data demonstrate even greater weight loss for an investigational triple agonist, retatrutide (Eli Lilly), an injectable once-weekly combination GLP-1 receptor agonist, glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptor agonist. Data presented at the American Diabetes Association Scientific Sessions in June showed that adults with obesity who received the highest dose of retatrutide lost an average of 24.2% of their body weight at 48 weeks compared with placebo.
“We are at an inflection point in our ability to medically treat obesity,” Richard E. Pratley, MD, medical director and the Samuel E. Crockett Chair in Diabetes Research at AdventHealth Diabetes Institute, said during an interview. “In the past, we had a variety of oral medications and all of them had issues — the major one being they were not incredibly efficacious. That was not satisfying for patients. The recent development of the GLP-1 receptor agonists and the combined agonists have changed that landscape considerably. Now, instead of targeting 5% weight loss, which for most people with overweight is a rounding error, we now are able to achieve at least 10%, and we are now pushing that target to 20%, 25% weight loss.”
Emerging data also suggest the newer obesity agents could have CV benefits. In August, researchers reported topline data from the SELECT study demonstrating that injectable semaglutide 2.4 mg reduced risk for major adverse CV events by 20% for people with overweight or obesity and established CVD. The data are the first to demonstrate a reduction in hard CV outcomes for a drug approved for chronic weight management in a large, randomized controlled trial.
“These data are game changing,” Fatima Rodriguez, MD, MPH, FACC, FAHA, FASPC, associate professor in cardiovascular medicine and section chief of preventive cardiology at Stanford University, told Healio. “They lend credence to the fact that controlling obesity as an independent risk factor for heart disease can improve hard outcomes for CV mortality and morbidity, even for those who do not have diabetes.”
In a review published in May in eClinical Medicine, researchers noted that the next few years will be a period during which novel pharmacotherapies will “revolutionize the way we treat obesity,” not just through improvements in body weight, but by also treating the cardiorenal and metabolic complications of obesity.
“Today, we have much more advanced, more potent molecules, with once-weekly dosing, and we are navigating these different, multiple targets now within the same compound,” Jamy D. Ard, MD, professor of epidemiology and prevention and co-director of the Weight Management Center at the Wake Forest School of Medicine, said during an interview. “That is creating much larger treatment effects — much larger than what we ever imagined.”
‘This raises the bar’
Historically, large randomized controlled trials for anti-obesity medications and intensive lifestyle regimens have been considered clinically meaningful if they demonstrated at least 5% weight loss. Newer drugs continue to show weight loss well beyond that threshold, leading some experts to question if the 5% goalpost should move.
“We should be thinking beyond that 5% weight loss in terms of not the degree of weight loss, but the quality of the weight reduction, looking at health measures and percent of fat mass lost,” Ania M. Jastreboff, MD, PhD, associate professor of medicine and pediatrics (endocrinology) at Yale University School of Medicine, director of weight management and obesity prevention at the Yale Stress Center and co-director of the Yale Center for Weight Management, told Healio.
With the highest 12 mg dose of retatrutide, nearly two-thirds of participants lost 20% or more of their body weight, half of participants lost 25% of their body weight and one-quarter of participants lost more than 30% of their body weight. The results were a first for a trial of less than 1-year duration with an anti-obesity medication, Jastreboff said during the ADA press conference.
“In about 11 months, participants lost nearly a quarter of their body weight, an average of 58 lb,” Jastreboff said during an interview. “And we don’t know what the actual efficacy is, because people were still losing weight at the end of the trial.”
In results stratified by sex, the mean percentage change in body weight was greater for women vs. men, Jastreboff said, with mean weight loss of 28.5% vs. 21.9% for women and men, respectively.
“There have been post hoc analyses on this, and it looks like women have been losing more weight than men,” Jastreboff said. “Now we have to look at the mechanisms, what may be contributing to these findings.”
The results for retatrutide, if confirmed in a larger phase 3 study, could be revolutionary for people with obesity, Carel Le Roux, MD, PhD, professor of experimental pathology at University College Dublin, said during a panel discussion at a press conference.
“This raises the bar. This is way beyond my wildest dreams,” Le Roux said. “To see something like this in my lifetime is impressive.”
More obesity treatments coming
Several other drugs in the pipeline are currently being investigated as potential anti-obesity treatments, including more combination agents and oral therapies.
“There are many other agents in development for obesity treatment within this class,” Jastreboff said. “Those are combinations of GLP-1 and glucagon, triple-hormone receptor agonist, like retatrutide, and there are also oral medications in development for treatment of obesity, either peptides or small molecules. This is a truly exciting and transformational time for the treatment landscape for obesity.”
Survodutide (Boehringer Ingelheim and Zealand Pharma), an injectable glucagon/GLP-1 receptor agonist, was associated with up to 18.7% weight loss vs. placebo at 46 weeks in a phase 2 study, with most participants losing more than 15% of their body weight. As for other GLP-1 receptor agonists and combination agents, the most common adverse events were gastrointestinal-related, including nausea, vomiting and diarrhea.
During an ADA press conference about the findings, Le Roux said studies have not yet been conducted comparing survodutide with semaglutide or other medications, but he said the new agent could play a role alongside other dual agonists.
“What we see with all of this class of drugs, we are actually able to get to this 15% to 20% weight loss,” Le Roux said. “That’s very encouraging that we have so many assets now.”
Oral formulations also show promise. In the phase 3 OASIS 1 study, adults with obesity but without diabetes lost more than 15% of their body weight at 68 weeks with a 50 mg dose of semaglutide — a significantly higher dose than the 14 mg version (Rybelsus, Novo Nordisk) approved for adults with type 2 diabetes in 2019. The higher formulation semaglutide had two excipients removed with slightly smaller tablet size, resulting in higher bioavailability, according to researchers.
“If you give someone a peptide like semaglutide orally, our digestive enzymes degrade it,” Jastreboff said. “The bioavailability of a peptide is lower, so you have to give more of it or protect it somehow. Here, they tested a 25 mg and 50 mg dose of oral, daily semaglutide. What they found was that the average weight efficacy was 15.1% at 68 weeks.”
Adults with obesity who received the oral GLP-1 receptor agonist orforglipron (Eli Lilly) lost 8.6% to 12.6% of their body weight at 26 weeks, according to phase 2 data presented at ADA. In that study, most adults receiving 24 mg or more per day orforglipron, a nonpeptide molecule, lost 10% or more of their body weight at 36 weeks, and weight loss approached 15% at 36 weeks in the highest-dose group. Unlike some other oral agents, orforglipron can be taken without restrictions on food, water or other medicines and has a half-life that enables once-daily dosing, according to the researchers.
“Orforglipron, which is moving into phase 3, is a small molecule, so it does not have the same degradation and the bioavailability is different,” Jastreboff said.
Pratley, who called orforglipron “promising,” said the drug is competitive with injectable GLP-1 receptor agonists and has the advantage of being oral.
“One of the problems we had with the oral medications is they had unacceptable side effects, like sibutramine and fen-phen (fenfluramine/phentermine),” Pratley said. “Even lorcaserin washed up due to side effects. The peptides are different because they have very specific targeting. They are metabolized as proteins are, so there is not a lot of off-target activity. That has allowed this field to progress, and makes people feel more comfortable with the notion of using these drugs.”
Cardiometabolic improvements
Until very recently, currently available data for the latest obesity treatments did not support a reduction in hard CV outcomes for people without diabetes. That changed with topline results from the SELECT study.
For SELECT, researchers analyzed data from 17,604 adults aged 45 years or older with overweight or obesity and established CVD but without diabetes, randomly assigned once-weekly semaglutide 2.4 mg or placebo, with follow-up for 5 years, according to a press release from Novo Nordisk. The primary endpoint was a composite outcome of the first occurrence of major adverse CV events, defined as CV death, nonfatal MI or nonfatal stroke.
During follow-up, 1,270 major adverse CV events occurred.
The trial achieved its primary objective by demonstrating a significant and superior reduction in major adverse CV events of 20% for participants assigned semaglutide 2.4 mg compared with placebo, and all three components of the primary endpoint contributed to the superior major adverse CV event reduction.
“This is the first randomized controlled trial data we have that shows treating obesity in people without diabetes can reduce CV risk, something we tried to see in the LOOK AHEAD trial using intensive lifestyle intervention,” 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 Healio. “Semaglutide 2.4 mg, beyond robust weight reduction and improvements in surrogate markers of CVD, such as lipids and glucose, is now associated with benefits for hard CV outcomes — CV death, nonfatal MI and nonfatal stroke.”
Additionally, while presenting cardiometabolic outcomes for retatrutide, Jastreboff said participants who received the 12 mg dose also experienced a mean 40% reduction in triglyceride levels and a mean 22% reduction in LDL cholesterol at 48 weeks, in addition to reductions in HbA1c and blood pressure.
The ongoing SURPASS-CVOT study, which is evaluating the impact of tirzepatide on CV events in an active comparator trial with dulaglutide (Trulicity, Eli Lilly), may help to define the role of that agent in CV prevention for people with type 2 diabetes.
“From a medical standpoint, we know that more weight loss is associated with more medical benefits,” Pratley said. “With 10% weight loss, we see improvements in glycemia, blood pressure and lipids. As we push the weight loss, we see improvements in sleep apnea, functional mobility and a host of things associated with obesity. That is the exciting part, for me. We have patients and providers excited about what we can do now with these new drugs.”
Ard said when it comes to cardiometabolic risk factors, the magnitude of weight loss drives the magnitude of response.
“Once you cross that double-digit percentage weight-loss threshold, you are starting to see the ability to improve things like fatty liver, remission of type 2 diabetes, certainly even improvements in things like sleep apnea,” Ard said. “Those are the reasons we treat obesity: to help mitigate, improve, resolve many of these complications that come from excess body fat.”
No ‘magic pill’ for weight loss
While presenting the results for retatrutide, Jastreboff said the findings, although impressive, should not supplant those of similar drugs like semaglutide or tirzepatide.
Data have shown that not every person with obesity responds to a therapy; a small group of nonresponders may lose little to no weight when prescribed certain drugs.
“It is not [about] one medicine, one injection or one magic pill,” Jastreboff said. “It is all the different therapies. It is pairing it with bariatric surgery. It is combining therapies.”
Le Roux agreed, noting that drugs like retatrutide must be taken for life to maintain any weight loss. That will present a challenge for clinicians and patients alike, he said.
“These are treatments for the disease of obesity. They are not cures for the disease of obesity,” Le Roux said. “The minute we discontinue the treatments, the disease relapses. That will be a challenge for us, because patients want to start these treatments, but the next question is, how do we keep these patients on these treatments for the rest of their lives?”
Although the latest anti-obesity agents are largely in the same class, head-to-head studies will demonstrate if people respond more to one drug vs. another, according to Steven B. Heymsfield, MD, FTOS, professor in the department of metabolism and body composition at Pennington Biomedical Research Center at Louisiana State University.
“In the obesity medicine space, we have semaglutide, tirzepatide and now retatrutide, all coming out within the space of about a year or so,” Heymsfield told Healio. “This is a remarkable paradigm change — and I do not use that phrase often. These agents will make obesity management a major issue in clinical medicine. Having worked in drug development for many years, there is no question that there are responders, nonresponders and partial responders to these various therapies.
“There are also other drugs in the pipeline, including the human monoclonal antibody bimagrumab (Versanis Bio) and cagrilintide (Novo Nordisk),” Heymsfield said. “This will be an interesting time going forward.”
Rodriguez said cardiologists must become comfortable with prescribing obesity pharmacotherapies for patients, considering obesity as a potent CV risk factor.
“It would be ideal if everyone could be an obesity specialist, but that simply is not feasible. The magnitude of the problem is too large,” Rodriguez said. “As cardiologists, obesity is a problem we need to focus on — the same way that we focus on BP and lipids and blood glucose — and feel comfortable using pharmacological agents as needed. We have more tools in our armamentarium to treat this metabolic disease that affects heart health.”
Ard said the changing obesity treatment landscape will hopefully bring with it changes in the way people view obesity and adiposity-related diseases.
“I’ve heard some say these drugs will put bariatric surgery out of business,” Ard said. “What we will ultimately see, I hope, is less bias and stigma about the treatment of obesity, and a greater acceptance from the general public and health professionals that treating obesity as a disease is the norm. I hope we will have tailored treatments that allow us to identify the type of obesity a person has, identify a treatment path that makes the most sense for them, and be able to adeptly prescribe treatment that minimizes risk for side effects and increases potential for benefit.”
We want to hear from you:
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References:
- Chakhtoura M, et al. eClinicalMedicine. 2023;doi:10.1016/j.eclinm.2023.101882.
- Jastreboff A, et al. N Engl J Med. 2023;doi:10.1056/nejmoa2301972.
- Knop FK, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)01185-6.
- Rosenstock J, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)01053-x.
- Wharton S, et al. N Engl J Med. 2023;doi:10.1056/NEJM0a2302392.
For more information:
Jamy D. Ard, MD, can be reached at jard@wakehealth.edu; X (Twitter): @drard.
Steven B. Heymsfield, MD, FTOS, can be reached at steven.heymsfield@pbrc.edu.
Ania Jastreboff, MD, PhD, can be reached at ania.jastreboff@yale.edu; X (Twitter): @aniajastreboff.
Carel Le Roux, MD, PhD, can be reached at carel.leroux@ucd.ie; X (Twitter): @carel_leroux.
Ian J. Neeland, MD, FAHA, FACC, can be reached at ian.neeland@uhhospitals.org.
Richard E. Pratley, MD, can be reached at Richard.pratley.md@adventhealth.com; X (Twitter): @rpratleymd.
Fatima Rodriguez, MD, MPH, FACC, FAHA, FASPC, can be reached at frodrigu@stanford.edu; X (Twitter): @farodriguezmd.
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