The GLP-1RA Pipeline is Full - Here's What to Expect

Note: This article originally appeared on partner site Managed Healthcare Executive.

These days, glucagon-like peptide 1 (GLP-1) receptor agonists need no introduction; they are the hot topic in professional meetings and conferences, in Hollywood and on TikTok. Part of a broader class of drugs called incretin mimetics, GLP-1s entered the market as treatments for type 2 diabetes and exploded as the newest drugs for chronic weight management for people living with obesity and for those who are overweight with conditions related to being overweight.

Incretin mimetics imitate the action of incretin hormones, and GLP-1 is one of the incretin hormones. The incretin hormones are produced in the gut to stimulate insulin release in response to meals. GLP-1 agonists stimulate the release of insulin, slow the emptying of the stomach, decrease glucose production in the liver and increase its uptake by the muscles.

Although it seems like the first GLP-1s just burst on the scene, the first one, Byetta (exenatide), was approved by the FDA in 2005 to help manage blood glucose levels in patients with type 2 diabetes. But Byetta, marketed by AstraZeneca, has not been approved for weight loss as its successors have. The more notable agents are those developed and marketed by Novo Nordisk and Eli Lilly and Company. Novo Nordisk, a Danish company, markets the drugs that have liraglutide or semaglutide as their active ingredient, and Eli Lilly markets the tirzepatide products. Liraglutide is sold as Victoza for diabetes and as Saxenda for weight loss. Semaglutide is FDA approved as Ozempic and Rybelsus, an oral formulation, to treat diabetes and Wegovy for obesity. Tirzepatide is sold as Mounjaro for diabetes and as Zepbound for weight management.

Earlier this year, Wegovy received FDA approval for use to reduce the risk of major adverse cardiovascular events, such as heart attack, stroke and cardiovascular death, in adults with cardiovascular disease and obesity or overweight. More drugmakers are developing GLP-1 agonists for other obesity or diabetes complications, including metabolic dysfunction-associated steatohepatitis (MASH; formerly known as nonalcoholic steatohepatitis), chronic kidney disease and osteoarthritis.

With GLP-1 sales skyrocketing, it is little wonder that drug developers have filled the pipeline with versions of GLP-1s with some attributes that would win them a share of a booming market. Several are in phase 3 of development.

Oral GLP-1 agonists

Novo Nordisk completed the phase 3 OASIS 1 trial of an oral, 50-milligram (mg) version of semaglutide that was taken once daily by patients with obesity without type 2 diabetes. After 68 weeks, the study participants taking the semaglutide pill achieved an average of 17.4% weight loss compared with 1.8% for those taking placebo. Almost 90% of participants who took semaglutide reached a weight loss of at least 5% after 68 weeks versus 24.5% of people who received placebo. These results are comparable to the weight loss seen in clinical trials for Wegovy, administered as a 2.4-mg subcutaneous injection.

Semaglutide is available in oral form as Rybelsus 3-mg, 7-mg and 14-mg tablets to treat diabetes. The company is seeking approval of the 50-mg dose for weight management in people with obesity.

Another oral GLP-1 agonist under review is Eli Lilly’s orforglipron. The company has announced positive phase 2 trial results for both weight reduction and diabetes. At 36 weeks, a once-daily dosing of orforglipron resulted in up to 17.7% weight loss in adults with overweight or obesity versus 2.3% for placebo. Adults with type 2 diabetes achieved a mean hemoglobin HbA1c reduction of up to 2.1% at 26 weeks compared with 0.4% with placebo and 1.1% with Trulicity (dulaglutide). The investigational drug is currently in the phase 3 ATTAIN trials for chronic weight management and the phase 3 ACHIEVE trials for type 2 diabetes.

Double duty

Tirzepatide products achieved great success via their dual agonism of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), which are both incretin hormones. Amylin is a pancreatic hormone released along with insulin that decreases appetite and glucagon production and delays gastric emptying. Glucagon is a peptide hormone secreted from the pancreas in response to hypoglycemia; it increases glucose production and energy expenditure and reduces food intake.

CagriSema is an investigational dual GLP-1 and amylase agonist being developed by Novo Nordisk. The once-weekly injection combines 2.4 mg of semaglutide and 2.4 mg of cagrilintide, which is a long-acting amylin analogue. In a phase 2 study, people with type 2 diabetes and overweight or obesity achieved a mean of 15.6% weight loss after 32 weeks compared with 8.1% for cagrilintide alone and 5.1% for semaglutide alone. CagriSema is currently in the REDEFINE phase 3 trials evaluating its safety and efficacy in people with type 2 diabetes, obesity or cardiovascular disease. A review of 76 clinical trials that enrolled people with type 2 diabetes published in BMJ in January 2024 showed that CagriSema resulted in the greatest weight loss among the 15 GLP-1s assessed in the trials.

Survodutide, in codevelopment by German company Boehringer Ingelheim and Copenhagen-based Zealand Pharma, is a dual GLP-1 and glucagon receptor agonist that is currently in phase 3 trials. In a phase 2 trial of survodutide versus placebo in people with overweight or obesity without diabetes, participants receiving the study drug achieved a mean weight loss of up to 18.7% after 46 weeks compared with 2% for those receiving placebo.

For people with type 2 diabetes, twice-weekly dosing with survodutide resulted in 9% weight loss compared with 5.4% with Wegovy 1 mg and 1.2% with placebo at 16 weeks.

Stellar results were also observed in a phase 2 trial of survodutide in adults with liver disease due to MASH versus placebo. Up to 83% of participants receiving survodutide achieved statistically significant improvements in MASH, including improvements in liver fibrosis, after 48 weeks. The FDA granted survodutide fast track designation for adults with MASH.

Triple threat

If dual agonists are promising, then a triple agonist might outshine them. In a phase 2 trial, the investigational triple agonist retatrutide produced a weight loss of up to 24.2% in people with obesity and without diabetes after 48 weeks versus 2.1% with placebo. Enrollees receiving retatrutide also experienced improvements in blood pressure and lipid profile.

Participants with obesity and type 2 diabetes who received retatrutide lost up to 16.9% of their body weight after 36 weeks compared with 2% for those who received Trulicity and 3% with placebo. Retatrutide also achieved a HbA1c reduction of up to 2.2% versus 1.4% with Trulicity and 0.3% with placebo. Retatrutide targets GLP-1, glucose-dependent insulinotropic polypeptide and glucagon receptors. The Eli Lilly product is in the TRIUMPH phase 3 trial program investigating its use in weight management, knee osteoarthritis and obstructive sleep apnea in participants with overweight or obesity with or without diabetes.

Rosanna Sutherby, Pharm.D., is an independent medical writer and community pharmacist in High Point, North Carolina. She is frequent contributor to Managed Healthcare Executive.