Eli Lilly's phase 2 data released this week added a key piece to the post-GLP-1 obesity drug roadmap: its experimental amylin drug eloralintide, when combined with tirzepatide, achieved an average weight loss of 23.3% at 48 weeks in the highest-dose group, far exceeding the 14.8% seen with high-dose tirzepatide alone.

The goal of next-generation obesity drugs is not to replace GLP-1, but to stack on new weight-loss mechanisms.

Eli Lilly and Novo Nordisk are developing a range of injectables, oral pills and combination regimens around amylin 鈥?a hormone released alongside insulin in the pancreas that helps regulate hunger and satiety 鈥?to set a higher ceiling for weight loss while offering alternatives for patients who respond poorly to GLP-1.

Eli Lilly Phase 2 Data: 23.3% Weight Loss, but Tolerability Remains Unresolved

Eli Lilly is advancing eloralintide on two tracks 鈥?both as a standalone therapy and in combination with its blockbuster drug tirzepatide. The phase 2 trial released this week targeted patients with obesity and type 2 diabetes, with the highest-dose combination group achieving an average weight loss of 23.3% at 48 weeks, compared with 14.8% for high-dose tirzepatide alone. These figures are based on an efficacy analysis, which assumes all enrolled patients completed the full course of treatment.

Benjamin Bikman, a metabolic health expert at Brigham Young University, commented that "these results are encouraging. Patients with type 2 diabetes typically lose less weight on these types of therapies than those without diabetes."

Leerink Partners analyst David Risinger predicts that Eli Lilly's eloralintide franchise will reach annual sales of $23.2 billion by the end of 2035, with the standalone therapy expected to launch in 2029 and the combination therapy following in 2030. He believes the standalone eloralintide opportunity could be even larger, because "there may be more than 10 million people who have tried GLP-1 and failed to achieve success due to insufficient efficacy, tolerability issues or genetic factors."

Ken Custer, president of cardiometabolic health at Eli Lilly, said in an interview: "Patients may not be able to get all the efficacy they need from tirzepatide, and they may not be able to get it from eloralintide alone." Bikman also believes that combination therapy offers new possibilities for patients whose weight loss on tirzepatide alone has plateaued.

But Eli Lilly still has much to prove. The data come from a smaller phase 2 trial, with phase 3 trials set to begin later this year. Tolerability is a key challenge: the proportion of patients discontinuing due to side effects ranged from 10.8% to 27% across combination therapy dose groups, compared with only 2.9% in the tirzepatide-alone group. Dr. Caroline Apovian, co-director of the Center for Weight Management and Wellness at Brigham and Women's Hospital, said bluntly, "27% is not a good number." Bikman also emphasized that "a therapy is only effective if patients can stay on it, so tolerability in phase 3 will be just as important as efficacy."

Novo Nordisk's Amylin Strategy: CagriSema to Launch Next Year

Novo Nordisk has been working in the amylin space for years. Its amylin drug cagrilintide has already shown significant weight-loss effects as a standalone therapy in a late-stage clinical trial. CagriSema, which combines cagrilintide with semaglutide, has demonstrated even greater weight loss in clinical research and is expected to launch early next year, with standalone cagrilintide and high-dose CagriSema anticipated in 2028.

New data released by Novo Nordisk this week showed that CagriSema's effects go beyond weight loss. In a one-year brain imaging (fMRI) study, the drug reduced "food noise" 鈥?persistent thoughts about food 鈥?and improved organ and bone health. The research showed that CagriSema changed brain responses to high-calorie foods in regions associated with craving, pleasure and self-control in people with obesity or overweight. "The signaling in the brain changed in a way that was associated with improved quality of life," said Martin Holst Lange, chief scientific officer at Novo Nordisk, in an interview.

Novo Nordisk is also developing amycretin (also known as zenagamtide), a drug that uses a single molecule to mimic the effects of both GLP-1 and amylin hormones, being tested in both once-weekly injection and daily oral tablet forms, with positive phase 2 results announced earlier this year.

The Multi-Target Era: From Dual-Target to Triple-Target

Amylin is not new. The United States approved the first amylin therapy more than two decades ago, but that drug required multiple daily injections, limiting its adoption. The new generation of amylin drugs in development are all long-acting formulations that can be injected once weekly.

Amylin helps produce satiety, suppress appetite and slow gastric emptying 鈥?effects similar to GLP-1 鈥?but the two work through completely different mechanisms in the body. "Same result, different pathway," Bikman told CNBC. The logic of stacking the two mechanisms is intuitive: engaging multiple hormone signals at once may produce greater weight loss while avoiding pushing a single drug's dose to the limit.

This approach has already extended beyond amylin. Tirzepatide itself already targets both GLP-1 and GIP hormones, and Eli Lilly's experimental drug retatrutide goes further, targeting GLP-1, GIP and glucagon simultaneously. It has reported the largest weight-loss data to date in clinical trials, and according to published data, the drug performs notably well in reducing liver fat, triglycerides and fasting insulin. Pfizer, AstraZeneca and Viking Therapeutics are also developing their own amylin products.

It is still too early to judge whether amylin combination drugs are superior to tirzepatide or other next-generation therapies, with more clinical trials and regulatory approvals still ahead. But from dual-target to triple-target, and from injection to oral, the competitive landscape for obesity drugs is rapidly fragmenting.