Weight loss drugs compared: Tirzepatide leads semaglutide and liraglutide

Weight loss drugs have become widespread enough that it can seem as though they all work in much the same way.

Many people identify them by the brand name they know best, or use the option covered by their insurance.

The common belief is that each medication delivers broadly similar outcomes. However, a new study indicates that this is not the case.

After comparing the three leading weight loss drugs, researchers found substantial differences in the amount of weight people lost, with one medicine clearly outperforming the rest.

Same drugs, different results

All of these medicines are part of the GLP-1 family. GLP-1, or glucagon-like peptide-1, is a hormone released by the gut after eating.

The drugs mimic this signal, lowering blood sugar and slowing the stomach so that hunger remains suppressed for longer.

This combination has made the treatments exceptionally popular. A recent survey found that around one in eight American adults now uses one, while almost one in five has tried one.

Previously, the three approved drugs had not been compared directly among people without diabetes who were seeking to lose weight.

The review’s corresponding author was Pooja Gokhale, a pharmacy doctoral student at the University of Georgia (UGA).

Tirzepatide is the standout weight loss drug

The researchers combined findings from 15 large randomised trials involving more than 14,000 people. Most trials compare a single drug with a dummy treatment rather than with a competing medicine.

As there were no direct head-to-head results, the researchers connected the separate studies to produce an indirect ranking of the drugs.

Tirzepatide, marketed as Zepbound for weight loss and Mounjaro for diabetes, ranked first, enabling people to lose more than 20 percent of their starting body weight.

Semaglutide, Wegovy’s active ingredient, followed at approximately 15 percent.

Liraglutide, sold as Saxenda, produced the smallest reduction, at about 8 percent. The largest losses occurred with the highest tirzepatide doses, roughly 10 to 15 milligrams per week.

In this regard, the data indicates that Tirzepatide may be the better choice.

The added hormone effect

Tirzepatide differs because it acts on a second target. Wegovy and Saxenda work solely on the GLP-1 system, whereas tirzepatide also activates another gut hormone that contributes to appetite and digestion control.

In a major obesity trial, participants receiving the highest tirzepatide dose lost nearly a quarter of their body weight across around 16 months.

Rather than one signal, it works through two. The researchers believe this dual action gives the drug its advantage.

Even so, the review assessed outcomes rather than the underlying biology. It can show how much weight each medicine helped people lose, but cannot explain why the two-target method performs better; it only shows that tirzepatide users finished at a lower weight.

Daily injections fall behind

Liraglutide, the oldest of the three treatments, fell well behind the others. It also places greater demands on patients, requiring an injection every day instead of the newer drugs’ once-weekly schedule.

A daily injection can be easier to miss, and missed doses generally lead to less effective results.

Together with the group’s smallest weight reduction, that regimen helps explain why liraglutide has ceded ground to more powerful alternatives.

The researchers also sought a treatment that could work without adding side effects such as nausea and stomach problems, which are common throughout this drug class.

On that measure, the older daily medicine also failed to match the others.

An alternative to injections

Because injections deter many potential users, a tablet form has clear appeal.

The team conducted a separate scenario analysis to assess how an oral version of semaglutide could compare with injectable treatments.

At a 50-milligram dose, the tablet outperformed liraglutide and the lowest tirzepatide dose, although it did not equal tirzepatide’s higher doses.

Gokhale described it as nearly on par with injected semaglutide.

When the review was completed, regulators had not yet approved the oral version for weight loss.

A 25-milligram tablet has since entered the market, highlighting how rapidly the field continues to develop.

Stopping has consequences

Any ranking can obscure an important limitation. These weight loss drugs are effective while people continue taking them, but weight commonly returns after injections are stopped, a pattern seen across the entire class.

“What some people don’t understand is that when they stop taking the medication, they may gain all that weight back,” said the study’s co-author, Lorenzo Villa-Zapata, an assistant professor of pharmacy at UGA.

One study reported that people regained around two-thirds of the weight they had lost within one year of stopping treatment.

The new analysis did not examine what occurs after people stop taking the drugs, meaning its ranking applies only during treatment.

Choosing the right weight loss drug

For the first time, doctors and patients have a clear indirect head-to-head answer for adults without diabetes who take these medicines for weight loss.

Tirzepatide takes off the most, semaglutide comes next, and liraglutide trails. A clear order, at last.

That ranking gives prescribers reason to consider the drug tirzepatide first when the goal is maximum weight loss with the fewest stomach complaints.

It also gives patients a clearer picture before starting a long, costly treatment.

The next challenge is answering the harder questions: how to prevent weight regain after treatment, and whether a less expensive pill can deliver the same results as the shots.