Upcoming wave of hormone-based therapies set to change field of diabetes, obesity care
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Key takeaways:
- GLP-1 therapy can provide benefits beyond glycemic control for adults with type 2 diabetes.
- Dual and triple agonist therapies currently in development may expand the number of future pharmacotherapy options.
A slew of new medications currently in development may allow health care providers to go beyond glycemic management in the treatment of type 2 diabetes, according to a speaker.
During the opening lecture at the International Conference on Advanced Technologies & Treatments for Diabetes, Melanie Davies, CBE, MB, ChB, MD, FRCP, FRCGP, professor of diabetes medicine at the University of Leicester and an honorary consultant diabetologist at the University Hospitals of Leicester NHS Trust, reviewed how GLP-1 receptor agonists such as semaglutide (Ozempic/Wegovy, Novo Nordisk) have changed the way providers approach the treatment of type 2 diabetes and obesity and discussed some of the medications that combine GLP-1 with other molecules.
“The possibilities now are almost unlimited,” Davies said during the presentation. “Medicinal peptide chemistry is now applied in an increasingly modular fashion, and therefore, the intelligent assembly of these modules could lead to multifunctional molecular medicines, which may have better efficacy, may improve pharmacokinetic properties and allow us to do more targeted delivery and almost precision medicine.”
Semaglutide leads the way
Obesity can cause a wide range of health complications and losing weight can help resolve those conditions. Davies said weight loss of up to 5% can improve hyperglycemia and hypertension, 5% to 10% weight loss can prevent type 2 diabetes and improve polycystic ovary syndrome and dyslipidemia, 10% to 15% weight loss can lead to improvements in cardiovascular disease and 15% or greater weight loss may induce type 2 diabetes remission and lower risks for CV mortality and heart failure with preserved ejection fraction. She cited GLP-1 receptor agonists as a key therapy that can promote weight loss and benefit multiple conditions.
“We now know after more than 15 years of GLP-1 therapy that we can see cardioprotection, reduction in blood pressure, and we know we can see a reduction in body weight,” Davies said.
Semaglutide has vaulted treatment of obesity and type 2 diabetes into a new era. In three separate SUSTAIN trials, semaglutide 1 mg conferred a greater weight loss among adults with type 2 diabetes than exenatide 2 mg (Bydureon, AstraZeneca), dulaglutide 1.5 mg (Trulicity, Eli Lilly) and liraglutide 1.8 mg (Saxenda, Novo Nordisk). In the STEP 2 trial, adults with obesity or overweight plus type 2 diabetes lost a mean 9.6% of their body weight at 68 weeks with semaglutide 2.4 mg vs. a 3.4% weight reduction with placebo. Additionally, in the SELECT trial, adults with obesity and without diabetes receiving semaglutide had a 20% lower risk for major adverse CV events compared with placebo (HR = 0.8; 95% CI, 0.72-0.9; P < .001).
“This has changed the way that we view pharmacotherapy in terms of the management of obesity,” Davies said of the SELECT trial.
Many agents in the pipeline
Davies said the next step forward with obesity and diabetes pharmacotherapy is development of dual and triple agonists. Gut hormones used in newer medications have different mechanisms of action, Davies said, and combination therapy can be used to potentially enhance the efficacy of pharmacotherapy. One of those dual agonists, tirzepatide (Mounjaro/Zepbound, Eli Lilly), was associated with a mean 14.7% weight loss for adults with overweight or obesity and type 2 diabetes in the SURMOUNT-2 trial compared with a 3.2% weight loss with placebo.
The FDA approved semaglutide and tirzepatide for treatment of type 2 diabetes and obesity. However, Davies said, more medications may join those two agents in the years ahead.
A few GLP-1 agonists currently in phase 3 trials are higher-dose injectable semaglutide 7.2 mg (Novo Nordisk), oral semaglutide 50 mg (Novo Nordisk) and orforglipron (Eli Lilly). Danuglipron (Pfizer) is another oral GLP-1 currently in phase 2 trials, and CT-996 (Carmot Therapeutics) is in phase 1 trials.
Davies said several companies have amylin agonists in phase 1 and phase 2 studies. CagriSema (Novo Nordisk), a combination drug that includes semaglutide and cagrilintide, is a GLP-1/amylin dual agonist currently in phase 3 trials. An oral GLP-1/amylin agonist named oral amycretin (Novo Nordisk) is also in phase 1 development.
Several companies have GLP-1/glucose-dependent insulinotropic polypeptide (GIP) dual agonists in phase 1 studies, including SCO-094 (Scohia Pharma), VK2735 (Viking Therapeutics) and CT-388 (Carmot Therapeutics). A GIP agonist, ZP6590 (Zealand Pharma) is currently in a phase 1 trial, and a GLP-1/GIP antagonist, maridebart cafraglutide (formerly AMG 133, Amgen) is currently in phase 2 trials.
Davies said several GLP-1/glucagon dual agonists have moved on to phase 2 or phase 3 trials, including survodutide (Boehringer Ingelheim), efinopegdutide (Hanmi Pharmaceutical), mazdutide (Eli Lilly and Innovent) and pemvidutide (Altimmune). Retatrutide (Eli Lilly) is a GLP-1/GIP/glucagon triple agonist currently in phase 3 trials, and Hanmi Pharmaceutical is also investigating a GLP-1/GIP/glucagon triple agonist in a phase 1 study. A pure glucagon agonist, HM15136 (Hanmi Pharmaceutical) is in phase 1 trials. There are also three peptide YY (PYY) agonists and two GLP-1/PYY dual agonists currently in phase 1 or phase 2 studies.
Davies said several agents in phase 2 and phase 3 trials have induced large reductions in both HbA1c and body weight for people with type 2 diabetes. With findings from numerous trials on glycemic, body weight and CV outcomes scheduled to be presented over the next 4 years, many more treatment options could be become available for providers in the near future, Davies said.
“We’re going to have lots of new opportunities for pharmacotherapies in our hands in the next couple of years,” Davies said. “It is going to be a stellar time for people practicing in this field.”
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Davies M. A new era in the management of T2DM and obesity – scanning what’s on the horizon. Presented at: International Conference on Advanced Technologies & Treatments for Diabetes; March 6-9, 2024; Florence, Italy (hybrid meeting).
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