The next generation of obesity medicines is not seeking to replace GLP-1 drugs. Instead, developers are pursuing treatments that could complement existing medicines, increase weight loss, or offer alternatives for people who do not receive enough benefit from GLP-1s.

Amylin has emerged as a central target in that effort. The hormone is released by the pancreas alongside insulin and helps regulate hunger and fullness, giving drugmakers another biological pathway for treating obesity and Type 2 diabetes.

Eli Lilly provided a promising look at the strategy with eloralintide, its experimental treatment targeting amylin. In a Phase 2 trial, combining eloralintide with tirzepatide produced substantially more weight loss among patients with obesity and Type 2 diabetes than tirzepatide alone.

Tirzepatide is the active ingredient in Lilly’s Zepbound and Mounjaro injections. After 48 weeks, participants receiving the highest dose combination lost an average of 23.3% of their body weight, compared with 14.8% among those taking a high dose of tirzepatide.

Those figures came from an efficacy analysis assuming that participants remained on treatment during the trial. Benjamin Bikman, a Brigham Young University professor and expert on metabolic health and insulin resistance, called the findings encouraging.

“Adults with type 2 diabetes typically lose less weight on these therapies than those without diabetes,” Bikman said. That distinction makes the results particularly notable within the population studied.

Lilly is developing eloralintide as both an independent treatment and part of a combination regimen. Some analysts view those two approaches as the foundation of a significant future franchise for the company.

Leerink Partners analyst David Risinger forecasts that Lilly’s eloralintide products will generate $23.2 billion in annual sales by the end of 2035. He expects the independent drug to launch in 2029, followed by the combination in 2030.

Risinger said potentially more than 10 million people have tried GLP-1 medicines without success because of efficacy, tolerability, or genetic issues. He sees particular potential for eloralintide alone because of the large population that has not benefited from existing GLP-1 options.

Lilly also sees a role for combining the medicines. Ken Custer, president of Lilly Cardiometabolic Health, said some patients may not receive what they need from tirzepatide or eloralintide when either drug is used independently.

Bikman said the combination may offer another option for patients whose weight loss plateaued after starting tirzepatide alone. However, Lilly must confirm the results in Phase 3 trials scheduled to begin later this year.

Tolerability remains a major challenge. Depending on the dose, 10.8% to 27% of patients receiving both drugs discontinued treatment because of side effects, compared with 2.9% of those taking only tirzepatide.

“A therapy is only effective if patients can remain on it, so tolerability in Phase 3 will be as important as efficacy,” Bikman said. Dr. Caroline Apovian, co director of the Center for Weight Management and Wellness at Brigham and Women’s Hospital, added that “27% is not a good number.”

Novo is pursuing a similar amylin strategy. Its experimental amylin based drug cagrilintide produced meaningful weight loss as an independent treatment in a late stage trial, while its combination with semaglutide produced greater weight loss in clinical studies.

That combination, called CagriSema, is expected to launch early next year. Independent cagrilintide and a higher dose version of CagriSema are expected in 2028.

Novo is also developing amycretin, or zenagamtide, as a single molecule targeting both GLP-1 and amylin. The company is testing it as a once weekly injection and a daily tablet after promising Phase 2 results earlier this year.

The first and only approved amylin therapy entered the United States market more than two decades ago as an additional mealtime injection for insulin users with diabetes. Adoption was limited partly because patients needed multiple daily injections, while the newer treatments are designed for once weekly use.

Amylin signals fullness, suppresses appetite, and slows food movement through the stomach, producing an outcome similar to GLP-1 through a different pathway. Novo also reported that CagriSema reduced persistent thoughts about food and improved measures involving organ and bone health in a yearlong brain imaging study.

The broader obesity drug race is increasingly focused on targeting several hormonal pathways. Tirzepatide combines GLP-1 and GIP, while Lilly’s experimental retatrutide adds glucagon and has produced some of the largest weight loss results reported in obesity drug trials.

It remains too early to determine whether amylin combinations will outperform tirzepatide or other emerging treatments. Further clinical trials and regulatory reviews must come first, but the development programs are expanding the range of potential options for patients with obesity and diabetes.