The SURMOUNT Program: Tirzepatide in Obesity and Related Conditions

What the SURMOUNT program set out to answer

By the time SURPASS trials were generating large weight-loss signals in people with type 2 diabetes, Eli Lilly recognized that tirzepatide's weight effects deserved dedicated study in populations defined by obesity itself rather than primarily by glycemia. The SURMOUNT program was designed to ask: How much weight can tirzepatide produce in adults with obesity but without diabetes? Does the benefit extend to people who already have T2DM plus obesity? What happens after treatment stops? And can the metabolic effects of tirzepatide reach beyond weight to correct the intermittent hypoxia of obstructive sleep apnea?

The five trials that form SURMOUNT collectively enrolled thousands of participants and generated a dataset that the FDA used to approve Zepbound for chronic weight management in November 2023, followed by a separate OSA indication in 2024.

Constituent trials

Approximate results from primary publications. AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure; OSA = obstructive sleep apnea.

SURMOUNT-1: The headline weight-loss trial

SURMOUNT-1 (NCT04184622) enrolled 2,539 adults with a BMI of 30 or greater, or 27 or greater with at least one weight-related comorbidity, and without type 2 diabetes. Participants were randomized to tirzepatide 5, 10, or 15 mg once weekly or placebo for 72 weeks, all with lifestyle counseling.^[1]

The 15 mg arm produced a mean body-weight reduction of approximately 22.5% from baseline, translating to roughly 23.6 kg in absolute terms. Placebo participants lost about 2.4%. All tirzepatide doses met the co-primary endpoints of percentage body-weight change and the proportion of participants achieving at least 5% weight loss. The proportion reaching 20% or more weight reduction was 57% with 15 mg versus 3% with placebo.

SURMOUNT-1 produced weight reductions substantially larger than those observed with semaglutide 2.4 mg in the STEP-1 trial (approximately 14.9%), though cross-trial comparisons are limited by differences in baseline characteristics, protocols, and populations. The trial established tirzepatide as the most efficacious approved pharmacotherapy for obesity at the time of its publication.

SURMOUNT-2: Weight loss with coexisting T2DM

SURMOUNT-2 (NCT04657003) enrolled approximately 938 adults with both obesity (BMI 27 or greater) and type 2 diabetes who were managed with diet and exercise alone or with one to three oral antidiabetic agents. The 72-week randomized phase assigned participants to tirzepatide 10 mg, 15 mg, or placebo.^[2]

Weight reduction with tirzepatide 15 mg was approximately 15.7%, and with 10 mg approximately 13.4%, both significantly greater than the 3.3% reduction with placebo. The attenuated weight effect compared with SURMOUNT-1 is consistent with observations from other anti-obesity trials in populations with T2DM, where the metabolic environment limits the magnitude of weight loss from any pharmacotherapy. HbA1c also fell substantially; approximately 2.0 percentage points at 15 mg, which is consistent with the SURPASS program findings.

SURMOUNT-3: Augmenting lifestyle intervention

SURMOUNT-3 (NCT04865978) tested whether tirzepatide could build on weight already lost through intensive lifestyle intervention. After a 12-week open-label lead-in combining a very low calorie diet (800 kcal/day) with intensive counseling, participants who had lost at least 5% of body weight were randomized to tirzepatide 15 mg or placebo for an additional 72 weeks.^[3]

Participants who had already lost approximately 6.9% of body weight during the lead-in then lost an additional 18.4% with tirzepatide versus a 2.5% regain with placebo, for a total mean weight reduction of approximately 26% from the original pre-lead-in baseline. The design mimics a real-world scenario where pharmacotherapy is introduced after a structured weight-loss program, and the results confirmed that the two interventions are additive rather than redundant.

SURMOUNT-4: What happens when treatment stops

SURMOUNT-4 (NCT04660643) addressed a practical and commercially important question: what is the durability of tirzepatide's weight effect after treatment stops? After a 36-week open-label phase in which participants received 15 mg tirzepatide and lost approximately 20.9% of body weight, they were randomized to continue tirzepatide or switch to placebo for an additional 52 weeks.^[4]

Participants who continued tirzepatide maintained most of the weight loss, adding a further 5.5% reduction on average. Those switched to placebo regained approximately 14% of body weight, recovering roughly two-thirds of the weight they had lost during the open-label phase. The total difference between the groups at the end of the randomized period was about 20 percentage points of body weight.

These findings parallel those from the STEP-4 trial with semaglutide 2.4 mg and from earlier studies with liraglutide 3.0 mg. They confirm that obesity pharmacotherapy, like antihypertensive or lipid-lowering therapy, requires continued use to maintain benefit. This has informed payer discussions around long-term coverage and clinical guidance on treatment expectations.

SURMOUNT-OSA: A new indication

SURMOUNT-OSA (NCT05412004) was a pair of parallel randomized trials (one in adults not using CPAP and one in those using CPAP) that enrolled approximately 469 total participants with moderate-to-severe obstructive sleep apnea and obesity. The primary endpoint was the change in apnea-hypopnea index (AHI) at 52 weeks, with tirzepatide 10 or 15 mg versus placebo.^[5]

Both trials met their primary endpoints. In the non-CPAP cohort, tirzepatide produced a mean AHI reduction of approximately 27.4 events per hour from a baseline of around 51.5 events per hour, versus a 4.8 events per hour reduction with placebo. The CPAP cohort showed a similar treatment effect. Weight loss in the tirzepatide arms was approximately 20%, consistent with SURMOUNT-1 results.

The FDA granted a separate indication for Zepbound in treating moderate-to-severe obstructive sleep apnea in adults with obesity in 2024, based principally on the SURMOUNT-OSA data. This represented the first new pharmacological treatment option for OSA in decades and the first indication for any GLP-1 class agent in a respiratory disorder.

Regulatory and clinical context

The FDA approved Zepbound (tirzepatide injection) for chronic weight management in November 2023, making it the second injectable GLP-1-class agent approved specifically for obesity after Wegovy (semaglutide 2.4 mg, 2021). The EMA granted approval for weight management under the Mounjaro brand in the same year, and the MHRA approved the obesity indication in the UK.

Reimbursement has been a consistent challenge. In the United States, Medicaid and Medicare Part D coverage has been limited and varies by state, with expanded coverage for the OSA indication creating a pathway for some previously ineligible patients to access the drug. In the UK, the NHS has begun rolling out tirzepatide for obesity through specialist weight management services following NICE appraisal TA1026, though access is constrained by capacity.

A dedicated cardiovascular outcomes trial for tirzepatide in the obesity indication (SURMOUNT-MMO, NCT05556512) is ongoing and will determine whether the MACE benefit signal seen in SELECT for semaglutide 2.4 mg extends to tirzepatide in a comparable high-CV-risk population.