The Major GLP-1 Trials, Summarized: STEP, SURMOUNT, SUSTAIN, SURPASS

If you want to understand what GLP-1 medications can actually do, the trial program acronyms are the place to start. Five major sets of studies underpin nearly everything we know.

STEP — Semaglutide for obesity

The Semaglutide Treatment Effect in People with obesity program. Multiple trials (STEP-1 through STEP-8 and beyond), all focused on semaglutide 2.4 mg/week (later marketed as Wegovy).

Key findings:

• STEP-1: Average 14.9% body weight loss over 68 weeks vs 2.4% on placebo
• STEP-3: Combined with intensive behavioral therapy, average 16% loss
• STEP-4: Patients who stopped after 20 weeks regained two-thirds of lost weight; patients who continued kept losing
• STEP-5: Two-year sustained loss: 15% on continued semaglutide
• STEP-8: Direct head-to-head with liraglutide; semaglutide produced ~10% more weight loss

What it established: Semaglutide 2.4 mg produces sustained, clinically meaningful weight loss. Stopping causes rebound. Combining with behavioral support helps. Wegovy was approved in 2021 based on STEP data.

SURMOUNT — Tirzepatide for obesity

The dual GIP/GLP-1 agonist tirzepatide tested specifically for obesity.

Key findings:

• SURMOUNT-1: Average 21% body weight loss over 72 weeks at 15 mg dose. Roughly one-third of patients lost more than 25% of body weight
• SURMOUNT-2: Same drug in patients with type 2 diabetes; ~16% weight loss (slightly less than non-diabetics, as is typical)
• SURMOUNT-3: Tirzepatide added after intensive lifestyle intervention; produced additional 18% loss on top
• SURMOUNT-4: Stopping after 36 weeks produced ~14% rebound within a year; continuing produced additional loss

What it established: Tirzepatide produces meaningfully more weight loss than semaglutide on average. Confirmed the rebound pattern. Zepbound was approved in late 2023 based on SURMOUNT data.

SUSTAIN — Semaglutide for diabetes

The original program that led to Ozempic approval.

Key findings:

• HbA1c reductions of 1.5–1.8% on semaglutide 1.0 mg
• Significant weight loss as a side benefit
• Very low hypoglycemia risk on monotherapy
• Compared favorably to other diabetes medications

What it established: Semaglutide is highly effective for type 2 diabetes. Ozempic was approved in 2017 based on SUSTAIN.

SURPASS — Tirzepatide for diabetes

The diabetes-focused program for tirzepatide.

Key findings:

• HbA1c reductions of 1.9–2.1% at 15 mg
• Significantly more weight loss than insulin or GLP-1 monotherapy
• Strong cardiovascular markers
• Direct head-to-head with semaglutide showed tirzepatide ~5% more weight loss

What it established: Tirzepatide is the most effective diabetes drug currently approved. Mounjaro was approved in 2022 based on SURPASS.

SELECT — Cardiovascular outcomes

A separate, very important trial: did semaglutide reduce major cardiovascular events in non-diabetic patients with obesity and prior cardiovascular disease?

Key finding: 20% reduction in major adverse cardiovascular events (heart attack, stroke, cardiovascular death) vs placebo over ~3 years.

What it established: GLP-1 medications produce real cardiovascular benefit beyond weight loss. This data shifted prescribing — many cardiologists now recommend GLP-1 for high-risk obese patients regardless of diabetes status.

Other notable studies

FLOW — Semaglutide in chronic kidney disease patients with type 2 diabetes; reduced kidney disease progression.

STEP-HFpEF — Semaglutide in heart failure with preserved ejection fraction; meaningful symptom and biomarker improvements.

OASIS — Oral semaglutide for obesity (oral version of Wegovy); modest weight loss but less than injection.

Phase 2/3 retatrutide trials — Triple agonist showed ~24% weight loss at 48 weeks (still in development).

Phase 3 CagriSema trials — Combination of cagrilintide (amylin analog) and semaglutide; showed numerically more weight loss than semaglutide alone in Phase 2.

What the trials don't fully tell us

Important things the trial program is still incomplete on:

Long-term (5+ year) outcomes. Most trials are 1–2 years. We don't yet have great long-term data on:

• Cancer outcomes
• Bone density at 5+ years
• Cognitive outcomes
• Pancreatic cancer (signal still controversial)

Real-world adherence. Trial patients have tighter monitoring. Real-world dropout rates are higher.

Body composition. Most trials measure weight, not lean mass specifically. Sub-studies that did DEXA show meaningful lean mass loss; this could be more or less than the average suggests.

Mental health outcomes. Trial data is largely reassuring on suicidality, but long-term mood data is limited.

Pediatric outcomes. Small but growing trials in adolescents (ages 12–17 for both semaglutide and liraglutide).

How to use this

When you read a popular news article about a GLP-1, knowing the underlying trial helps you sanity-check the claim:

• "Average 15% weight loss" → consistent with STEP/SURMOUNT
• "Most patients regain after stopping" → STEP-4 / SURMOUNT-4
• "Reduces heart attacks by 20%" → SELECT
• "Better than Ozempic" → likely a SURMOUNT vs SUSTAIN comparison
• "Diabetes remission" → mostly observational + SURPASS sub-analyses

Bottom line

The trial program is large, consistent, and generally positive. STEP and SURMOUNT establish the weight loss claims. SELECT establishes cardiovascular benefit. SUSTAIN and SURPASS establish diabetes utility. The honest gaps: long-term (5+ year) outcomes are still being collected, and body composition data (lean mass vs fat mass) is less detailed than the headline weight loss numbers suggest.