SURMOUNT-3 and SURMOUNT-4 topline: 26% total weight loss, and fast regain after stopping

Eli Lilly released topline results from two late-stage tirzepatide trials on July 27, 2023, that tackled questions the earlier obesity studies left open: what the drug adds for people who have already lost weight with diet and exercise, and what happens when treatment stops ^[1][2].

In both trials, average total weight loss landed at about 26% — the largest figures reported in the SURMOUNT program to that point ^[2]. Tirzepatide is the molecule in Mounjaro, which at the time was approved in the US only for type 2 diabetes, with a possible obesity approval expected later that year ^[1].

SURMOUNT-3: adding a drug after lifestyle change

SURMOUNT-3 started with a 12-week intensive lifestyle program — a low-calorie diet, exercise and weekly counseling ^[1][2]. Participants who lost at least 5% of their body weight were then randomly assigned to tirzepatide or placebo for 72 weeks ^[2]. BioPharma Dive reported that 579 people were randomized ^[1].

During the lifestyle phase, the group lost an average of 6.9% of body weight ^[2]. Over the following 72 weeks, the tirzepatide group lost an additional 21.1%, while the placebo group gained 3.3%, using what Lilly called the efficacy estimand ^[2]. Among those on tirzepatide, 94.4% lost at least 5% of their body weight during the treatment period ^[2]. From the start of the study to week 84, total weight loss in the tirzepatide group was 26.6% ^[2].

SURMOUNT-4: what happens after stopping

SURMOUNT-4 gave everyone open-label tirzepatide for a 36-week lead-in, then randomly assigned participants to continue the drug or switch to placebo for another 52 weeks ^[2]. BioPharma Dive reported 783 enrollees, with 670 randomized after the lead-in ^[1].

By the end of the lead-in, average weight loss was 21.1% ^[2]. Over the next 52 weeks, people who stayed on tirzepatide lost an additional 6.7%, while the placebo group regained 14.8% ^[2]. Those who stayed on the drug for all 88 weeks lost a mean of 26% of their body weight ^[2]. BioPharma Dive described the same results with rounded numbers — about 15% regained and roughly 7% more lost — so the two accounts agree on direction and differ only in rounding ^[1].

Lilly said the safety profile in both trials was similar to earlier SURMOUNT and SURPASS trials and to other incretin-based drugs approved for overweight and obesity, with gastrointestinal side effects the most common and mostly mild to moderate ^[2].

"The findings from SURMOUNT-3 challenge the notion that patients living with obesity or overweight can achieve their weight loss goals with diet and exercise alone," said Jeff Emmick, Lilly's senior vice president of product development. "Additionally, the findings from SURMOUNT-4 reinforce that obesity should be regarded like other chronic diseases where chronic therapy may be needed to maintain treatment benefits" ^[1][2].

Why it matters for patients

The stopping data are the practical headline. In SURMOUNT-4, roughly two-thirds of the weight lost during the 36-week lead-in came back over the next year on placebo — 14.8% regained against 21.1% lost ^[2]. That pattern points to these medicines working while they are being taken, not as a one-time course, which has direct consequences for insurance coverage, drug supply and long-term cost.

SURMOUNT-3 speaks to a different group: people who succeeded with diet and exercise and then plateaued. Even after already losing 6.9%, the tirzepatide group lost another 21.1% while the placebo group regained weight ^[2]. In other words, prior success with lifestyle change did not appear to use up the benefit the drug could add.

Some caveats matter. These were company-issued topline numbers from a press release, not peer-reviewed publications ^[2]. The reported figures use the "efficacy estimand," a way of analyzing results that reflects what happens if people stay on treatment as directed ^[2]. Neither trial compared tirzepatide to semaglutide, so nothing here says which drug is better. And the sources do not report dropout rates, side effect percentages or results by subgroup.

What happens next

Lilly said full SURMOUNT-3 results would be presented at ObesityWeek and full SURMOUNT-4 results at the European Association for the Study of Diabetes annual meeting, both in October 2023 ^[2]. BioPharma Dive noted these two trials may not be needed for FDA approval of tirzepatide in obesity, but could help guide how doctors use it once cleared ^[1]. If approved for weight loss, tirzepatide would compete with Novo Nordisk's Wegovy and with Ozempic, both semaglutide ^[1].