SAN DIEGO ― The introduction of new, highly potent incretin-based drugs for treating obesity and type 2 diabetes is being greeted with great excitement, although there have been a few notes of caution.
Agents that target two or three incretin receptors have been shown to produce far greater weight loss than previous medications. They significantly reduce glucose levels and improve other metabolic parameters. At the same time, the single-agent glucagon-like peptide-1 (GLP-1) receptor agonists are proving beneficial for cardiovascular health, while other combinations and oral formulations are also emerging.
Tirzepatide (Mounjaro), Eli Lilly’s once-weekly injectable agonist of both the GLP-1 and the glucose-dependent insulinotropic polypeptide (GIP) receptors, was the first “twincretin” drug approved in the United States for treating type 2 diabetes and now awaits approval for obesity, given the “unprecedented” 22.5% weight loss.
Even greater weight loss was seen in phase 2 data for Lilly’s investigational weekly injectable agent retatrutide, a single molecule that acts as a triple agonist of the GLP-1 receptor and the GIP receptor and is a glucagon receptor activator; the latter adds a liver fat-clearing benefit. That “triagonist” produced weight loss of up to 24% in people with obesity without type 2 diabetes and weight loss of nearly 17% in those with both conditions.
“You need synergistic dual and triple receptor combinations…. There is no part of metabolic disease where mono-agonists are better than dual or triple,” says Matthias H. Tschöp, MD, the Alexander von Humboldt Professor at the Technical University of Munich, Germany.
While working at Eli Lilly, Tschöp ― along with biochemist Richard DiMarchi, PhD, of Indiana University ― pioneered the strategy of combining multiple natural human gut hormone receptor agonists in the brain into a single molecule to promote weight loss.
“Our claim to fame is that you need synergistic dual and triple receptor combinations and that GIP as well as glucagon agonism can be helpful. This is what we contributed ― and that it’s glucagon agonism, not antagonism,” Tschӧp told Medscape Medical News.
Indeed, Daniel J. Drucker, MD, an endocrinologist and professor of medicine at the University of Toronto, Canada, told Medscape, “The GLP1 story is 18 years old now. What we hadn’t been able to do is bring meaningful medicines to help people lose weight…. I think we’ve entered an exciting new chapter in metabolic medicine where we’re able to help people not just with their type 2 diabetes but [also] living with obesity, and we’ll learn soon how that translates to benefits.”
Exciting, but No Long-Term Data Yet
But Drucker says there is reason to pause for thought: “Five years ago, it didn’t seem possible to lose 20% of body weight with a medication. This raises new and important questions. We need to study [these agents] for safety and make sure we’re not prescribing inappropriately. We need to learn about rare adverse events, how to deliver to the right people and make them more affordable.”
Nisa Marisa Maruthur, MD, agrees. “I think the exciting thing is we’ve never had a medication class that lowers cardiovascular disease risk and also causes this much weight loss. But we still don’t know the long-term effects…. Certainly, when I’m starting people on tirzepatide, I tell them it looks really effective for weight loss and it will lower your glucose, but I also tell them we don’t have all the long-term data yet,” she told Medscape.
In her experience, tirzepatide has been so effective for some patients that they drastically reduce the amount they’re eating, to the point where she worries about nutritional deficiency.
“They were eating three meals a day and now they’re down to one, and it could be a bowl of cereal. That’s certainly not everybody, but patients are definitely eating less, and it means they may also be consuming less nutrients. For some people, especially older patients, I’m not comfortable with that long term,” says Maruthur, associate professor of medicine at Johns Hopkins University School of Medicine, Baltimore, Maryland.
She also pointed out, “Physical activity may also be a problem because when people lose weight quickly, they often have less energy. That can certainly happen if you decrease your caloric intake substantially. I think there is an added benefit to lifestyle, and I still counsel people on that. The fact is, physical activity independently is associated with lower CVD risk.”
Regarding all GLP-1 receptor agonists, Maruthur says, “These drugs are well tolerated but not 100% tolerated. The gastrointestinal side effects are real, and these drugs aren’t going to be for everyone or work for everyone. I’ve had people who can’t take them because of those side effects…but for those who can, they’re very effective.”
According to Tschӧp, “As with the mono-agonists, the side effects like nausea and vomiting are in the beginning. That seems to go away with time.”
Mono-Agonist Heart Benefits, New Combinations on the Horizon
While the multireceptor incretins have been capturing attention for their dramatic weight loss effects, data suggest other benefits for the single-agonist GLP-1 agonists, alone or in combination with other agents.
The weight-loss dose of Novo-Nordisk’s once-weekly injectable semaglutide recently showed significant reductions in major cardiovascular outcomes and improvements in symptoms of heart failure with preserved ejection fraction. Both trials were conducted in patients with obesity but who did not have type 2 diabetes.
And in the wings, Novo Nordisk’s investigational coadministered long-acting amylin analogue cagrilintide plus the GLP-1 agonist semaglutide, dubbed CagriSema, produced significant reductions in A1c and in weight for patients with type 2 diabetes and a body mass index ≥27 kg/m2.
Potentially more impactful in terms of ease of manufacture and affordability is Eli Lilly’s investigational oral daily nonpeptide GLP-1 agonist orforglipron, which produced both glucose-lowering and weight loss comparable to other injectable and oral GLP-1 agonists for treating both obesity and type 2 diabetes.
In addition, phase 2 data for Boehringer Ingelheim and Zealand Pharma’s dual GLP-1 and glucagon receptor agonist survodutide suggest that tirzepatide may face some competition.
Tschӧp says that the mono-agonists may play a role in weight maintenance once the desired weight loss and A1c goals have been achieved with the dual or triple agonists.
“It may be enough to have a mono-agonist or maybe give some leptin at that point. I think there’s a future version of this where you have interventional drugs and you have maintenance drugs. But we’re not there yet. I think there’s a lot we need to learn about tailor-made drug therapies for patients.”
Drucker said, “To me, this is a really exciting time because we are going to be able to differentiate amongst some of these medicines not just by weight loss per se but also the other challenges that people living with metabolic disorders face ― [fatty liver disease], heart failure, sarcopenic obesity, or type 2 diabetes.
“Some will be better than others for some of these comorbidities. I think that’s where we’re going, toward really personalizing medicine in people with metabolic disease, beyond weight loss and A1c. It’s a fantastic thing to look forward to.”
Tschöp and Maruthur have disclosed no relevant financial relationships. Drucker has served as a consultant or speaker within the past 12 months to Altimmune, Amgen, Boehringer Ingelheim, Kallyope, Merck Research Laboratories, Novo Nordisk Inc, and Pfizer Inc. He holds nonexercised options in Kallyope.
Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter @MiriamETucker.
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