Diabetes Drug Mounjaro Shown to Have Extraordinary Weight Loss for People Without Diabetes
Lilly announced headline results from two clinical trials of tirzepatide (known as Mounjaro for type 2 diabetes) in patients with obesity. In addition to offering some of the highest weight reduction ever seen, these trial results show the marked impact of medication on obesity, as well as the need for ongoing treatment in order to maintain weight loss.
Lilly has released positive initial results of two new studies of tirzepatide (sold under the name Mounjaro for type 2 diabetes) in patients with obesity, SURMOUNT-3 and SURMOUNT-4. SURMOUNT-3 underscored the argument that diet and exercise alone are not sufficient in treating obesity. SURMOUNT-4 showed that continued use of tirzepatide is crucial in maintaining any weight loss achieved by taking the medication.
Positive outcomes from both trials – including a total average weight loss of 26% or more among those taking tirzepatide – would appear to make tirzepatide the most effective drug for weight loss that currently exists on the market, although right now it is approved for use only in type 2 diabetes. (Another investigational obesity drug from Lilly, retatrutide, has demonstrated even greater weight loss, but it is not yet available and remains in mid-stage clinical trials.) The results are consistent with an expected upcoming FDA approval of tirzepatide as an obesity drug. Tirzepatide won’t be easy to obtain anytime soon, however: The FDA has added a new dose of Mounjaro to its drug shortage list and expects supply issues of other doses will persist longer than anticipated.
What are the latest SURMOUNT trial results, and what do they mean?
SURMOUNT-3 trial results
The SURMOUNT-3 trial highlighted the difference between weight loss using intensive lifestyle modifications and weight loss while taking tirzepatide.
For SURMOUNT-3, 806 participants with a BMI greater than 30 underwent a 12-week program of intensive calorie restriction, exercise, and weekly counseling; those who lost at least 5% of body weight after 12 weeks were then randomly assigned to take either tirzepatide or a placebo.
Over the course of 72 weeks, participants lost about an additional 21% of their body weight for a total 88-week weight loss of more than 24%. Participants receiving tirzepatide had an average weight reduction of close to 27% from study entry after 12 weeks of intensive lifestyle intervention followed by 72 weeks of tirzepatide treatment – the highest weight reduction ever observed in a phase 3 clinical trial.
In contrast, participants taking a placebo actually regained more than 3% of the weight they’d lost during the 12-week intensive lifestyle program. More than 87% of those taking tirzepatide achieved weight loss 5% or more, compared with only 16% in the placebo group achieving weight loss of at least 5%.
SURMOUNT-4 trial results
Lilly’s SURMOUNT-4 trial demonstrated the necessity of taking tirzepatide on an ongoing basis to maintain any weight loss achieved from the medication.
In SURMOUNT-4, 783 participants with a BMI greater than 30 agreed to take a dose of either 10 mg or 15 mg tirzepatide over 36 weeks. At the end of 36 weeks, participants lost more than 21% of their body weight on average.
After 36 weeks, SURMOUNT-4 participants either continued on their dosage of tirzepatide Mounjaro or received a placebo treatment for the following year, without knowledge of which treatment they were receiving. Those who were still taking tirzepatide by the completion of the study at 88 weeks lost close to an additional 7% of their body weight (for a total weight loss of 26% on average over the entire study), whereas at 88 weeks those on the placebo had actually regained close to 15% of their body weight (for a total weight gain of 14% over the entire study).
Treating obesity with incretin drugs like tirzepatide long-term
The SURMOUNT-3 trial underscored the dramatic effectiveness of incretin-based drugs such as tirzepatide compared to traditional nonsurgical interventions such as diet and exercise. The results of Lilly’s SURMOUNT-4 trial, however, suggest that taking tirzepatide on an ongoing basis will be necessary to maintain any weight loss achieved from the medication.
“Obesity is often a chronic lifetime disease, and for such diseases patients often need to take therapy for the life of the disease,” he said. “People clearly can observe the benefits the drug is having on their health, and unfortunately, when you stop taking the drug, it’s likely that it can no longer work.”
Researchers are continuing to evaluate second-generation weight loss drugs over the long term. Novo Nordisk, which manufactures the competing obesity medication semaglutide (sold as Wegovy for obesity), has just updated Wegovy’s labeling with an additional option for maintenance dosing.
Public health leaders have expressed concern over the safety of using such medications long-term. The World Health Organization (WHO) recently issued a statement on why it excluded incretin-based medications like GLP-1s from its biannual essential medications list. This list plays a role in guiding countries on which medications to purchase. “Data are lacking on long term effectiveness, optimal duration of treatment, [and] maintenance of weight reduction once therapy is stopped,” WHO said.
At a press briefing at the 2023 ADA Scientific Sessions, Dr. Timothy Garvey, a professor of medicine at the University of Alabama at Birmingham and lead researcher for the SURMOUNT-2 trial, touched on the long-term use of tirzepatide and other incretin-based therapies that make up the category of second-generation weight loss drugs.
“These drugs have only been out for a couple of years. We don’t have long-term experience – this is data we need – and this is going to be developed by clinical experience over time,” he said, noting that possible additional benefits such as cardiovascular improvements will hopefully be answered by additional trials.
“Can we use lower doses in a maintenance format, or intermittent therapy? We just don’t know,” he admitted. “We need data on how to manage this disease using these powerful drugs over the long term.”
FDA approval of tirzepatide for weight loss
Last fall, the FDA granted the medication a “fast-track” designation for review to treat obesity and overweight. When asked at an ADA 2023 briefing about the timeline for the agency green-lighting tirzepatide as a weight loss agent, Dr. Garvey stated that he and his team “anticipate it will be approved later this year.”
FDA approval of tirzepatide for weight loss would position it as a direct competitor to Novo Nordisk’s wildly popular weight loss drug Wegovy (semaglutide), which is also available for diabetes management at lower doses under the name brand Ozempic. These incretin-based medications have emerged as extremely effective weight loss and diabetes treatments, quickly gaining star status as so-called miracle drugs for weight loss in celebrity and social media circles, leading to a surge in demand coupled with a global shortage.
Unlike semaglutide (prescribed as Ozempic and Wegovy), tirzepatide is a dual GIP and GLP-1 agonist. From results of a series of trials, tirzepatide appears to be more effective than semaglutide. The most common side effects of this drug class are mild to moderate gastrointestinal issues like nausea, diarrhea, and constipation.
About the SURMOUNT clinical trial program
Lilly's SURMOUNT clinical trial program has demonstrated promising results that tirzepatide is effective in helping people both with and without diabetes lose weight. In addition to SURMOUNT-3 and SURMOUNT-4, the rest of the SURMOUNT trial series results are as follows.
A Lilly clinical trial last year in people with obesity but not diabetes, SURMOUNT-1, tested tirzepatide 5 mg, 10 mg, or 15 mg. The results, published in the New England Journal of Medicine, showed participants lost an average of 52 pounds (more than 20% of their weight) on the highest dose of tirzepatide.
Additionally, the SURMOUNT-1 trial found that 95% of people with obesity who also had prediabetes and took tirzepatide reverted to normal glucose levels. People also experienced improvements in their fasting glucose, A1C, blood pressure, waist circumference, and normal levels of insulin while taking tirzepatide.
At the 2023 ADA Scientific Sessions in San Diego last month, researchers unveiled full results of the SURMOUNT-2 clinical trial evaluating tirzepatide for weight loss in adults with obesity or overweight and type 2 diabetes.
In addition to an average weight reduction of 15.7% at the highest dose, the majority of participants saw other health benefits including normalized A1C levels; reductions in fasting blood sugars, waist circumference, and body mass index; and improvements in cardiometabolic disease risk factors such as lipid levels, cholesterol, and blood pressure.
In Lilly’s SURMOUNT-2 global phase 3 clinical trial, 938 adult participants with obesity or overweight and type 2 diabetes took weekly treatments of 15 mg tirzepatide, 10 mg tirzepatide, or placebo for 72 weeks. Study participants were generally representative of the US population, with 58% being female, 18% Black, and 41% Hispanic or Latinx.
Participants taking 15 mg of the medication achieved average weight reductions of 15.7% losing up to roughly 34 pounds. Those taking 10 mg lost up to 13.4% or almost 30 pounds. In comparison, participants in the placebo group only lost an average of 3.3% or 7 pounds over the 72 weeks.
SURMOUNT-5, which will evaluate Lilly’s tirzepatide against Novo Nordisk’s semaglutide (Wegovy) in obese patients or those who are overweight with weight-related health conditions (except diabetes), is expected to complete in 2025.
A cardiovascular trial examining morbidity and mortality outcomes in participants taking tirzepatide, SURMOUNT-MMO, is expected to wrap in 2027. The trial, which will last up to 5 years, will evaluate mortality as well as nonfatal myocardial infarction or stroke, coronary revascularization, and heart failure events.
Photo credits: University of Alabama (Garvey); iStock (all other photos).