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Famous weight loss drug trials – and what they taught us

Simon Edward • 4 March 2025

Weight loss drug trials have taught us many interesting things. Explore some of the most famous examples.

Did you know that medications must go through extensive trials before they can be approved? That goes for any drug – including the weight loss injections Wegovy and Mounjaro.

These trials happen in phases. Phase 1 trials are all about finding the best dose and learning about side effects with a small group of participants. Phase 2 trials are similar but involve more participants and also focus on testing how well the treatment works.

Then there are Phase 3 trials. These are large in scale, typically involving hundreds or thousands of participants. They look at how the drug compares to a dummy medicine (known as a 'placebo'), a tried-and-tested treatment or both. A Phase 3 trial is the final stage of research a drug must go through before approval.

Phase 3 weight loss drug trials have taught us many interesting things about these revolutionary medications. In this article, we look at some of the most well-known and important trials of the last 20 years.

The AMIGO trials (exenatide)

Exenatide was a game-changing drug. It was the first of a new class of medications called 'incretin mimetics' to see approval by the US Food and Drug Administration (FDA). This class of drugs also includes modern injectable weight loss medications like Wegovy and Mounjaro.

To test exenatide's safety and effectiveness, its manufacturers conducted three Phase 3 studies known collectively as the 'AMIGO trials'.

The AMIGO trials involved around 1,400 patients with type 2 diabetes. The researchers wanted to learn whether exenatide could help these patients control their blood sugar levels.

To find out, they split the patients into groups. Some would take exenatide in conjunction with other diabetes drugs, while others would take a placebo.

The results were revealed in September 2005 – and were quite impressive for the time. Researchers found that exenatide 'significantly lowered average glucose (blood sugar) levels' among the diabetic patients. Interestingly, the exenatide users also lost weight – between 2.9 and 4.5 kilogrammes over 52 weeks of treatment.

Despite demonstrating potential as an obesity treatment, exenatide was never approved by the FDA for weight loss. It was, however, approved as a treatment for type 2 diabetes in 2005.

The STEP programme (Wegovy/Ozempic)

By 2016, the injectable drug semaglutide was already proven to be effective as a way of managing blood sugar for people with type 2 diabetes. The 'SUSTAIN' trial series showed that 'semaglutide consistently demonstrated superior and sustained [blood sugar] control' compared to placebo and a range of other treatment options.

As a result, semaglutide was approved as a diabetes medication by the FDA and other regulatory authorities under the brand name Ozempic.

However, the SUSTAIN researchers also noticed a positive side effect – semaglutide caused more weight loss among participants than any similar drug available at the time.

To explore this benefit, semaglutide's manufacturer launched another series of trials called the STEP programme. STEP stands for 'Semaglutide Treatment Effect in People with obesity'.

The STEP programme involved more than 5,000 participants, who took part in six separate studies.

STEP 1

STEP 1 was the largest study. It looked at the effects of semaglutide on body weight in people who were living with obesity but didn't have type 2 diabetes.

Participants took either one 2.4mg dose of semaglutide each week or a matching placebo. The participants also changed their diet and started doing more exercise.

The results were extraordinary. After 68 weeks of treatment, the semaglutide users had lost an average of 14.9% of their body

weight.

STEP 2

STEP 2 was similar to STEP 1. This time, however, the researchers looked at people living with type 2 diabetes.

The results were impressive – though not quite as impressive as the STEP 1 trial. After 68 weeks, the semaglutide group had lost 9.6% of their body weight on average.

STEP 3

This trial explored the effects of semaglutide alongside intensive behavioural therapy. As well as taking the drug or a placebo, participants attended 30 counselling sessions.

After 68 weeks, the semaglutide users had lost an average of 16% of their body weight.

STEP 4

The STEP 4 study was a little different to the previous trials. It sought to learn what would happen if participants stopped taking semaglutide after 20 weeks of treatment.

The results showed that continued treatment was necessary for sustained weight loss. Those who continued treatment for the full 68 weeks lost 18.5% of their body weight on average. However, those who stopped taking the drug put some weight back on.

STEP 8

The final trial, STEP 8, compared semaglutide to another type of incretin mimetic called liraglutide. Liraglutide is sold under the brand name Saxenda.

Semaglutide was proven to be more effective than liraglutide. Those taking semaglutide lost 15.8% of their body weight over 68 weeks. Those taking liraglutide, meanwhile, lost 6.4%.

The SURMOUNT programme (Mounjaro)

The SURMOUNT trial programme is similar to the STEP programme. However, this time researchers are looking at the effects of a newer injectable weight loss drug called 'tirzepatide'. This is the active ingredient in Mounjaro.

Five SURMOUNT trials have been conducted so far. Like the STEP trials, they involve large groups of participants randomly assigned to take a drug or a placebo. The participants also undertook lifestyle changes, such as exercise and a calorie-controlled diet.

SURMOUNT-1

This trial looked at the effects of tirzepatide versus placebo on 2,539 participants. As with the STEP 1 trial, these participants were living with obesity but did not have diabetes. However, they did have at least one weight-related health condition.

The results were among the best researchers had yet seen for a drug of this type. The participants who took the highest dose (15mg) of tirzepatide lost 20.9% of their body weight on average. Even those who stuck to the lowest dose (5mg) lost an impressive 15%.

SURMOUNT-2

The SURMOUNT-2 trial was similar to SURMOUNT-1, except it involved participants who were living with obesity alongside type 2 diabetes.

Participants who took the highest dose of tirzepatide saw an average weight loss of 14.7%. This is similar to the STEP 2 trial results, where participants with diabetes lost less weight using semaglutide than those with obesity alone.

SURMOUNT-3

Researchers conducted this trial in two stages. First, participants underwent 12 weeks of intensive lifestyle changes, including a low-calorie diet, exercise and weekly counselling sessions. Next, they were randomised into groups that would take either a placebo or a weekly dose of tirzepatide for 72 weeks.

After the initial 12 weeks, participants lost an average of 6.9% of their body weight. Then, after the second stage of treatment, the tirzepatide group lost a further 21.1%.

SURMOUNT-4

Like the STEP 4 semaglutide trial, the SURMOUNT-4 trial sought to learn what happens when participants stop taking tirzepatide after a period of treatment.

In the first stage, all participants took tirzepatide for 36 weeks. Then, for a further 52 weeks, some participants continued treatment while others switched to a placebo.

Those who took tirzepatide over the entire 88-week trial period lost an average of 26% of their body weight. However, those who switched to placebo ended up putting some of their weight back on.

SURMOUNT-5

SURMOUNT-5 is the most recent trial to be published. It was the first study that directly compared the effects of semaglutide and tirzepatide.

The results proved that Mounjaro is better than Wegovy for weight loss. After 12 months of treatment, those taking semaglutide lost 8.3% of their body weight on average. However, those taking tirzepatide lost an average of 15.3%.

Are you interested in exploring Wegovy or Mounjaro injections for weight loss? You might want to try SemaPen's simple online consultation. Your answers go directly to our experts, who'll recommend the best treatment plan for your unique needs and circumstances.

Sources

1. https://investor.lilly.com/news-releases/news-release-details/scientific-presentations-exenatide-data-show-significant

2. Aroda, V.R. et al. (2019) "Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: Insights from the SUSTAIN 1-7 trials" Diabetes & Metabolism, 45(5)

https://doi.org/10.1016/j.diabet.2018.12.001

3. Bergmann, N.C. et al. (2022) "Semaglutide for the treatment of overweight and obesity: A review" Diabetes Obesity & Metabolism, 25(1) https://doi.org/10.1111/dom.14863

4. Wadden, T.A. et al. (2021) "Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial" JAMA, 325(14)

https://doi.org/10.1001/jama.2021.1831

5. Jastreboff, A.M. et al. (2022) "Tirzepatide Once Weekly for the Treatment of Obesity" New England Journal of Medicine, 387(3) https://doi.org/10.1056/NEJMoa2206038

6. Garvey, W.T. et al. (2023) "Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial" The Lancet, 402(10402) https://doi.org/10.1016/S0140-6736(23)01200-X

7. https://investor.lilly.com/news-releases/news-release-details/tirzepatide-demonstrated-significant-and-superior-weight-loss

This article was reviewed by and approved by Alice Fletcher, Bariatric Dietitian, on 28 February 2025.

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