Blockbuster weight-loss medications such as Mounjaro and Wegovy have delivered massive sales figures for the major pharmaceutical companies that developed them.

While these therapies have been widely praised for transforming the often grueling process of weight loss for millions of people, the drugmakers behind them have also encountered a significant hurdle: side effects.

Many patients using incretin-based therapies like Eli Lilly's Mounjaro and Novo Nordisk's Wegovy report gastrointestinal issues, including nausea, constipation, diarrhea, and vomiting.

One London advertising executive who used Mounjaro said she felt slightly nauseous within 20 minutes of her first injection. Side effect reports typically increase with higher doses, but she still experienced symptoms even starting from a micro-dose of just 0.25 milligrams.

The executive documented various symptoms, including stomach pain, bad breath, and belching. She noted that starting on a high dose would have made her feel considerably worse.

Major pharmaceutical companies are now focused on developing new therapies that achieve comparable weight-loss results while addressing the issues that plague current market leaders.

New drugs could also offer additional benefits, such as improved cardiovascular and liver health for patients, while preserving muscle mass.

Martin Holst Lange, chief scientific officer for research and development at Novo Nordisk, said the current class of drugs has completely transformed obesity treatment but still falls short of meeting the diverse, individual needs of many patients.

Most of the leading new drugs in development target the amylin receptor. Amylin is a hormone secreted by the pancreas alongside insulin, and its mechanism is similar to existing GLP-1 drugs like Wegovy and Mounjaro. While GLP-1 medications primarily suppress appetite, amylin-based drugs act on different regions of the brain to enhance satiety, helping the body feel full more quickly.

David Kendall, chief medical officer at Denmark's Zealand Pharma, explained that amylin strengthens the body's signals that you have eaten and are full.

In contrast, he said GLP-1 drugs rely on aversion signals, which are effective but not innate responses of the human brain. Although amylin can produce effects similar to GLP-1, the mechanisms of action in the brain and the resulting side effect profiles are not identical.

Zealand Pharma is developing the amylin candidate drug petrelintide in partnership with Swiss giant Roche, which licensed the drug last year in a deal valued at up to $5.3 billion.

Interim clinical trial results released in March showed that participants lost an average of 10.7% of their body weight after 42 weeks of treatment. The drug's side effects were similar to placebo; the company reported no cases of vomiting even at the maximum dose, and no participants discontinued treatment due to gastrointestinal adverse events.

However, despite the promising side effect profile, the drug's weight-loss efficacy fell short of existing medications, which can achieve weight reductions of up to 25%. Following the trial results, the Danish biotech company's share price fell by one-third.

Nevertheless, Roche and Zealand Pharma are advancing the drug into Phase 3 clinical trials. Kendall noted that participants experienced virtually no serious gastrointestinal adverse reactions, which bodes well for a better long-term treatment experience for patients.

Novo Nordisk is also developing oral and injectable versions of Amycretin, a combination therapy of amylin and semaglutide. Trial data released last year showed that participants using the highest injectable dose achieved an average weight loss of 24.3%.

Other formulations are also in development. Eli Lilly stated that clinical trial data for its new drug retatrutide shows it can reduce food intake, accelerate metabolism, maintain energy expenditure during weight loss, and also reduce inflammation.

Participants treated with the highest dose for 80 weeks achieved an average weight loss of 28%, the largest reduction seen with any drug to date; however, the discontinuation rate due to side effects was also higher, at 11%.

Experts suggest the future trajectory of weight-loss therapies may mirror the diabetes treatment field: over the long term, patients will have a wider range of treatment options and can effectively tailor their own regimens.

Because weight-loss drugs alter normal digestive processes, patients may never be entirely free of gastrointestinal side effects, but new formulations could help reduce their severity.

Catherine Bicknell, professor of pharmacology at the University of Reading, noted that drugs targeting different biological pathways could introduce additional side effects, and clinical trials will identify the most common adverse reactions.

She added, however, that combination drugs targeting multiple pathways could allow patients to use lower doses of weight-loss medications, thereby reducing unpleasant side effects.

This is where combination drugs can offer an advantage, Bicknell said. Combining drugs that target different pathways means each individual medication can be used at a lower dose, achieving the same weight-loss effect while reducing the risk of adverse side effects.