Incretin-based medications transforming treatment of type 2 diabetes and obesity
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Key takeaways:
- Incretin-based therapies are continuing to evolve with the development of longer-acting and oral agents.
- Combination therapies, dual and triple agonists may boost the number of available therapies in the future.
The development of incretin-based molecules has led to therapies that can induce greater reductions in HbA1c and body weight for people with type 2 diabetes and obesity than other classes of medication, according to a speaker
At the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease, Richard E. Pratley, MD, a Healio | Endocrine Today Co-editor and the Samuel E. Crockett chair in diabetes research and medical director at AdventHealth Diabetes Institute, discussed the history of incretin-based therapies and continuing advances today.
“This is a really important pathway,” Pratley said of incretin-based medications. “There are a lot of very important developments that are changing the lives of patients with diabetes and obesity, but there is yet more to come.”
Pratley discussed why incretin-based therapies were developed for the treatment of diabetes and obesity. Incretin, which plays a key role in maintaining glucose homeostasis, has diminished effects for people with type 2 diabetes. Incretin-based therapies are able to target defects that are not addressed by other medications. Additionally, incretin-based drugs do not cause hypoglycemia and can also induce weight loss.
GLP-1 receptor agonists differ from each other in several aspects despite all being incretin-based, according to Pratley. Differences between molecules lead to varying effects on half-life and satiety.
“In general, the longer-acting GLP-1 receptor agonists are more efficacious at lowering HbA1c,” Pratley said. “That’s because they not only decrease prandial glucose responses, but they also have more sustained effects on fasting glucose levels. We also know that even among the long-acting molecules like dulaglutide (Trulicity, Elil Lilly) and semaglutide (Ozempic/Wegovy, Novo Nordisk), there are differences in potency. It’s not just the pharmacology of the molecules that affects the efficacy.”
Those differences between medications extend to weight change, according to Pratley. Head-to-head comparisons of GLP-1 trials showed agents such as semaglutide induced a greater weight reduction than exenatide (Bydureon, AstraZeneca) and dulaglutide.
“This suggests we can manipulate the GLP-1 agonist in order to get a more potent profile that has better weight loss,” Pratley said.
Development of incretin-based medications has extended to oral formulations. Data from global trials demonstrate oral semaglutide (Rybelsus, Novo Nordisk) can reduce HbA1c by as much as 1.7% at 52 weeks. Similarly, oral semaglutide reduced body weight by 3.5% to 4.5% in most trials.
“It looks like oral semaglutide is a very effective oral medication,” Pratley said. “It beats SGLT2 inhibitors, certainly DPP-4 inhibitors, but perhaps not quite to the extent that long-acting semaglutide does.”
In recent years, the development of dual agonists has advanced incretin-based therapies even more. The advantage of dual agonists is their ability to increase the number of pleiotropic effects on the heart, liver, kidney and more, according to Pratley. Tirzepatide (Mounjaro/Zepbound, Eli Lilly), a GLP-1/GIP dual agonist, reduced HbA1c as much as 2.5% and body weight by as much as 12% in a pooled analysis of the SURPASS trials. Weight loss with tirzepatide was even greater for adults with obesity, peaking at 20.9% for those who received the highest dose at 72 weeks in the SURMOUNT-1 trial.
“The treatment of obesity is evolving,” Pratley said. “Our usual obesity medications were on the order of 3% to 17% [weight loss] and we’re now in the 20% to 25% range.”
More incretin-based medications are currently in development, including single agents, combination drugs, dual agonists and triple agonists. Some of the medications currently in the pipeline include higher-dose oral semaglutide 50 mg (Novo Nordisk), the nonpeptidic GLP-1 receptor agonist orforglipron (Eli Lilly), the GIP/GLP-1/glucagon triple agonist retatrutide (Eli Lilly), and CagriSema (Novo Nordisk), which is a combination drug that includes semaglutide and cagrilintide.
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Pratley R. Incretins in diabetes: The new, the newest and the future. Presented at: World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease; Dec. 7-9, 2023; Los Angeles.
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