Tirzepatide produced up to 22.5% weight loss in Lilly's phase 3 SURMOUNT-1 trial

Eli Lilly reported on April 28, 2022 that tirzepatide, an experimental once-weekly injection, produced average weight reductions of 16.0% to 22.5% over 72 weeks in adults with obesity or overweight, depending on dose, in the phase 3 SURMOUNT-1 study. The company called it the first investigational medicine to average more than 20% weight loss in a phase 3 trial ^[1]. Lilly shares rose about 3% that day ^[2]. At the time, tirzepatide was not approved for any use; it was under regulatory review for type 2 diabetes ^[1].

SURMOUNT-1 assigned 2,539 participants in equal numbers to tirzepatide 5 mg, 10 mg or 15 mg, or to placebo, all alongside a reduced-calorie diet and increased physical activity. Enrollment spanned the United States, Argentina, Brazil, China, India, Japan, Mexico, Russia and Taiwan. Participants had obesity, or were overweight with at least one of high blood pressure, abnormal cholesterol, obstructive sleep apnea or cardiovascular disease, and none had type 2 diabetes. Dosing began at 2.5 mg weekly and rose in steps every four weeks to the assigned maintenance dose. The average starting weight was 231 lb (105 kg) ^[1].

Among people still on treatment — the efficacy estimand — average loss was 16.0% (35 lb, or 16 kg) at 5 mg, 21.4% (49 lb, or 22 kg) at 10 mg and 22.5% (52 lb, or 24 kg) at 15 mg, against 2.4% (5 lb, or 2 kg) for placebo. At least 5% loss occurred in 89% of the 5 mg arm and 96% of the 10 mg and 15 mg arms, versus 28% on placebo. At least 20% loss occurred in 55% of the 10 mg arm and 63% of the 15 mg arm, versus 1.3% on placebo; 32% of the 5 mg arm hit that mark in a secondary endpoint Lilly noted was not controlled for type 1 error ^[1].

A second accounting, the treatment-regimen estimand, counts everyone regardless of whether they stopped the drug. That version put average loss at 15.0%, 19.5% and 20.9% for 5, 10 and 15 mg, versus 3.1% on placebo. Losses of at least 20% were reached by 30% (5 mg, not controlled for type 1 error), 50% and 57%, versus 3.1% on placebo ^[1].

Gastrointestinal complaints were the most frequent side effects and, according to Lilly, generally mild to moderate and concentrated in the period when doses were being raised. Nausea affected 24.6%, 33.3% and 31.0% of the three dose groups versus 9.5% on placebo; diarrhea 18.7%, 21.2% and 23.0% versus 7.3%; vomiting 8.3%, 10.7% and 12.2% versus 1.7%; constipation 16.8%, 17.1% and 11.7% versus 5.8%. Side effects drove 4.3%, 7.1% and 6.2% of participants to quit, versus 2.6% on placebo. Total dropouts, for any reason, were 14.3%, 16.4% and 15.1%, versus 26.4% on placebo ^[1].

Louis J. Aronne of Weill Cornell Medicine, an investigator on the trial, said tirzepatide "delivered impressive body weight reductions" that "could represent an important step forward for helping the patient and physician partnership treat this complex disease" ^[1]. Lilly's Jeff Emmick said obesity "requires effective treatment options" and said the results reinforced confidence in the drug's potential ^[1]. On Wall Street, Wells Fargo's Mohit Bansal wrote that the data "likely validates Street thinking" about tirzepatide's future role and estimated about $4 billion in peak sales, while Mizuho's Vamil Divan called it a possible multibillion-dollar product for diabetes and weight loss ^[2].

Why it matters for patients

The size of the average reductions set a new reference point for what a late-stage obesity trial had shown ^[1]. That matters for people weighing treatment options because it changed the scale against which later obesity drugs would be judged.

The trade-off is tolerability. Nausea, diarrhea, vomiting and constipation were more common on every dose than on placebo, and roughly 4% to 7% of participants stopped the injections because of side effects ^[1].

The results came from a specific group: adults with obesity or overweight and at least one related condition, but no diabetes. Weight loss in people with type 2 diabetes was not measured in this trial ^[1]. The data were topline, with full results not yet presented or peer-reviewed, so the figures could be refined ^[1]. Whether weight stays off after stopping, and whether the drug changes heart or other health outcomes, has not been reported ^[1]. No price or coverage information was disclosed ^[1].

What happens next

Participants who had pre-diabetes when the study began will stay in SURMOUNT-1 for 104 additional weeks of treatment after the first 72 weeks, to measure body weight and differences in progression to type 2 diabetes at three years ^[1].

Results from the SURMOUNT-2, -3 and -4 trials were anticipated in 2023 ^[1]. Lilly said the SURMOUNT-1 data would be presented at an upcoming medical meeting and submitted to a peer-reviewed journal, without giving dates ^[1]. The company also said tirzepatide was being studied for non-alcoholic steatohepatitis and heart failure with preserved ejection fraction, with trials in obstructive sleep apnea and in obesity-related illness and death planned ^[1]. No date for an obesity approval decision has been disclosed ^[1].