The Endocrine Society recently held a virtual Science Writers Conference dedicated to the current landscape and future horizons of GLP-1 therapies, examining new oral formulations and dual and triple agonists. Endocrine News caught up with the two experts who spoke at the conference — Priya Jaisinghani, MD, DABOM and Mehmet Furkan Burak, MD – to learn what’s next for these medications and what they mean for people with obesity.
On December 10 last year, the Endocrine Society hosted a virtual Science Writers Conference focusing on what’s next for anti-obesity medications (AOMs), including the first pill formations of glucagon-like peptide-1 receptor agonists (GLP-1RAs). Indeed, the FDA approved the pill form of semaglutide (name brand Wegovy) just a couple of weeks later.
The webinar featured Priya Jaisinghani, MD, DABOM, clinical assistant professor at NYU Langone in New York, N.Y. – who discussed new and upcoming oral formulations of AOMs — and Mehmet Furkan Burak, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, Mass. – who highlighted double and triple agonists and spoke to patients who may be intolerant of these medications and what providers can do for them.
Obesity is a medically consequential disease, linked to over 200 diseases and complications, including cardiovascular disease, liver disease, type 2 diabetes, cancer and more. “For decades, we’ve treated metabolic diseases backwards,” Jaisinghani says. “When complications and diseases like diabetes, hypertension, fatty liver disease, sleep apnea develop we then treat each one in isolation, often with multiple medications. If we intervene earlier and more effectively on excess adiposity itself, we can improve, reverse, or even prevent many of these downstream diseases. Treating weight first isn’t simply cosmetic, it’s disease modification. It’s about changing the trajectory of metabolic health before damage occurs.”
Metabolic Therapeutics
Oral semaglutide was just approved for weight loss by the FDA, and now it looks like the small-molecule, nonpeptide oral GLP-1RA orforglipron isn’t far behind it. A paper recently published in the New England Journal of Medicine showed promising results. The authors of the paper (Wharton et al) titled “Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment” write in their conclusion: “In patients with obesity, the use of orforglipron resulted in statistically and clinically significant weight reductions and an adverse-event profile that was consistent with that observed with other GLP-1 receptor agonists.” (The results come from Eli Lilly’s ATTAIN-1 clinical trial. Lilly also sponsored the Science Writers Conference.)
“These medications improve much more than the number on the scale. They have improved insulin resistance, blood pressure, lipids, inflammatory markers, knee osteoarthritis, and have gained indications for glycemic control, fatty liver disease, cardiovascular risk, chronic kidney disease in those living with type 2 diabetes. That’s why calling them ‘weight loss meds’ undersells what they actually do.” — Priya Jaisinghani, MD, DABOM, clinical assistant professor, NYU Langone, New York, N.Y.
Jaisinghani also pointed to Lilly’s ACHIEVE-3 study, which is looking at orforglipron’s efficacy on diabetes, finding that the drug significantly reduced the glycated hemoglobin level over a period of 40 weeks. During her talk, Jaisinghani said that these medications should really be called metabolic therapeutics, rather than “weight loss meds.” “These medications improve much more than the number on the scale,” she tells Endocrine News. “They have improved insulin resistance, blood pressure, lipids, inflammatory markers, knee osteoarthritis, and have gained indications for glycemic control, fatty liver disease, cardiovascular risk, chronic kidney disease in those living with type 2 diabetes. That’s why calling them ‘weight loss meds’ undersells what they actually do.”
As these medications become more and more widely used and indications expand, that means other clinicians beyond endocrinologists (who have long used these therapies in diabetes care) now prescribe them. “Prescribing these medications is far more than simply writing a prescription,” Jaisinghani says. “It requires identifying appropriate candidates, titrating thoughtfully, managing side effects, integrating nutrition and behavior change, and planning for long-term maintenance. Patients also need guidance to set realistic expectations, reduce stigma, and understand that this is treatment for a chronic disease, not a short-term solution.”
Jaisinghani goes on to say that we are in the middle of a fundamental shift in how we treat metabolic disease. Obesity is no longer something we manage on the margins while we treat its complications, it is something we can now treat directly, effectively, and earlier. “These therapeutics give us a chance to change lives and long-term health outcomes if we use them thoughtfully, equitably, and as part of comprehensive metabolic care,” Jaisinghani says. “We are just at the tipping point of a new era in obesity and metabolic therapeutics, with oral agents and next-generation injectables targeting multiple hormone receptors poised to further transform how we treat these diseases.”
Obesity: A Disease Modifier
During his talk, Burak pointed out that GLP-1RAs aren’t just treating obesity, but all the diseases caused by obesity, echoing Jaisinghani’s sentiment above. As Burak puts it, obesity itself is already a standalone disease but it most often comes packaged metabolic diseases: heart failure, fatty liver disease, even asthma.
“[Obesity] is a disease modifier,” Burak says, who goes on to explain that the complication of obesity in heart failure means you’re not able to treat with classic heart failure medications like diuretics. “But when you use GLP analogs or [gastric inhibitory polypeptide (GIP)] GLP analogs, it decreases hospitalizations by 70%.”
“Even with low dose GLP-1, there’s a cardiovascular benefit of people having fewer heart attacks and strokes, even with just a 2.5-kilogram weight loss. GLP-1s are really addressing increasing the access by any means, from simple manufacturing, for easier access to the world. These drugs might be utilized as a primary prevention drug like aspirin to really reduce the cardiovascular rate in a big portion of the population.” — Mehmet Furkan Burak, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.
Metabolic dysfunction-associated fatty liver disease (MAFLD) – the most common cause of liver transplantation used to be untreatable. But Burak says medications like Zepbound and Ozempic have been shown to reverse hepatitis and even fibrosis. “It treats the untreatable disease,” he says.
And while that’s all great news, there’s still work to be done. According to Burak, the main problem in treating obesity – even with bariatric surgery – is regaining the weight while losing muscle mass. “We call it weight cycling — even your immune system, autonomous nervous system — can cause arrhythmias. The biggest reason [for that] is losing the muscle, which decreases your metabolic rate.”
Burak says a big agenda for him and his colleagues is preventing muscle loss in those they treat for obesity, but it’s an extremely hard task. There are ways to minimize muscle loss – resistance training, a high protein diet – but it’s still a tall order, so they’re looking into mechanisms of muscle loss.
Burak explains that the body enters a catabolic state the body releases myostatin which breaks down the muscle to make up for the energy deficit. “When you inhibit the myostatin signaling, people preserve muscle and they increase the lipolysis,” he says. “It’s basically directing this energy deficit or energy demand to the fat source, which is really favorable. So we are just testing what is the safest way to inhibit this myostatin pathway.”
Another problem with some GLP-1 alone therapies is that sometimes patients taking them express anhedonia, claiming they can’t even enjoy family dinners anymore. Burak says that sometimes GLP-1 medications can cause nausea or a depressed appetite, even some losing the ability to taste. “Some people really live around the meal clocks and social interactions through the meals or with some of the drinks and stuff,” he says says. “When they lose this and then they stop socializing, they stop going out to dinners, they stop having family dinners and just take little things, which can cause some anhedonia — not feeling the same pleasures when they eat.”
But Burak says that GIPs have shown promise in this area, because the nausea effect is much less, which also lessened the feeling of anhedonia. “We didn’t see as much anhedonia with a GIP/GLP analog as much as we observed in GLP-alone analogs,” he says.
Access to these medications still remains a barrier for a lot of patients who need them. For many GLP-1 therapies are unaffordable, especially if they’re not covered by insurance. Burak says that it’s quite expensive to produce injectables, and in some parts of the world, injectables are taboo. But pills are much less expensive to produce, and as more medications are introduced to the market, prices of these therapies will continue to decrease.
“That brings us to a point that I think since we are seeing, even with low dose GLP-1, there’s a cardiovascular benefit of people having less heart attack and stroke, even with just a 2.5-kilogram weight loss,” Burak says. “GLP-1s are really addressing increasing the access by any means, from simple manufacturing, for easier access to world. These drugs might be utilized as a primary prevention drug like aspirin to really reduce the cardiovascular rate in a big portion of the population.”
Bagley is the senior editor of Endocrine News. In the January issue he wrote about the connection between the thyroid and cardiac health.
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