Incretin drugs arrived as diabetes drugs and were later tested for weight. Each molecule therefore has at least two families of trials, and the numbers from one family get quoted as if they came from the other. Here is how to keep them apart.
Three kinds of trial
Weight-management trials in people without diabetes. STEP 1, 3, 4, 5, 8; SURMOUNT-1, 3, 4, 5; ATTAIN-1; REDEFINE 1; the retatrutide phase 2. Entry is by BMI (30 or more, or 27 or more with a complication). Diabetes is an exclusion. Primary endpoint is percent weight change, usually with a 5 percent responder coprimary. Duration 48 to 104 weeks.
Weight-management trials in people with type 2 diabetes. STEP 2, SURMOUNT-2, ATTAIN-2, REDEFINE 2. Same BMI logic (27 or higher), plus an HbA1c window, typically 7 to 10 percent. Weight is still the primary endpoint. These are the trials to use when someone with diabetes asks what to expect.
Diabetes trials. SURPASS-2, TRANSCEND-T2D-1, SUSTAIN-6, PIONEER 6, FLOW. Entry is by diabetes, not BMI (TRANSCEND-T2D-1 required only BMI 23 or higher). Primary endpoint is HbA1c or an event rate. Weight is secondary, sometimes reported only as a difference between arms (SURPASS-2 gives -1.9, -3.6 and -5.5 kg versus semaglutide 1 mg, and no absolute per-arm change in its abstract). Doses may be the diabetes doses, not the weight-management doses: SURPASS-2 used semaglutide 1 mg; FLOW used 1.0 mg; SUSTAIN-6 used 0.5 or 1.0 mg.
The gap, trial by trial
Same drug, same dose, same duration: weight change without and with type 2 diabetes. All figures from the primary publications' abstracts.
| Drug and dose | Without diabetes | With type 2 diabetes | Ratio |
|---|---|---|---|
| Semaglutide 2.4 mg, 68 wk | STEP 1: -14.9% (placebo -2.4%) | STEP 2: -9.6% (placebo -3.4%) | 0.64 |
| Tirzepatide 10 mg, 72 wk | SURMOUNT-1: -19.5% (placebo -3.1%) | SURMOUNT-2: -12.8% (placebo -3.2%) | 0.66 |
| Tirzepatide 15 mg, 72 wk | SURMOUNT-1: -20.9% | SURMOUNT-2: -14.7% | 0.70 |
| Orforglipron 36 mg daily, 72 wk | ATTAIN-1: -11.2% (placebo -2.1%) | ATTAIN-2: -9.6% (placebo -2.5%) | 0.86 |
| CagriSema 2.4/2.4 mg, 68 wk | REDEFINE 1: -20.4% (placebo -3.0%) | REDEFINE 2: -13.7% (placebo -3.4%) | 0.67 |
The ratio column is simple division of the two arm means and is ours, not the papers'. It is there to show the pattern: for the injectables the diabetes population lost roughly two-thirds as much. Orforglipron's gap was smaller in its pair of trials. Placebo arms were similar across each pair, so the gap is in the drug arms, not the background programme.
Why the designs differ
Entry criteria. A diabetes weight trial requires HbA1c 7 to 10 percent, which selects people whose diabetes is not well controlled and who are usually on background glucose-lowering drugs. SURMOUNT-2 stratified by nothing in its abstract; STEP 2 stratified by background medication and HbA1c. Those background drugs are absent from the non-diabetes trials by definition.
Population. People in the diabetes trials were older (SURMOUNT-2 mean age 54.2; STEP 3 and STEP 4 non-diabetes cohorts were 46) and started slightly lighter (SURMOUNT-2 100.7 kg; SURMOUNT-1 104.8 kg). Neither difference is large, and neither is shown by the trials to explain the gap.
Rescue therapy. Diabetes trials must allow rescue glucose-lowering treatment when HbA1c stays high. The treatment-regimen or treatment-policy estimand counts people who received rescue at their final weight. Some rescue drugs (insulin, sulfonylureas) add weight. The abstracts do not quantify this.
Comparator dose. When a diabetes trial uses an active comparator, it is the diabetes dose. SURPASS-2's semaglutide arm was 1 mg. The SURMOUNT-5 semaglutide arm, in obesity, was 1.7 or 2.4 mg. A tirzepatide-versus-semaglutide weight difference from SURPASS-2 is not the same comparison as one from SURMOUNT-5, and quoting the former as if it were the latter overstates the gap.
Reading each kind
For a person without diabetes asking about weight: use the non-diabetes weight-management trial for the drug and dose in question. Report the placebo-subtracted difference and the estimand. Say "average".
For a person with type 2 diabetes: use the diabetes weight-management trial. The number is smaller, and it is the right number.
For anyone asking about heart, kidney or glucose outcomes: use the diabetes trials and the event trials, and do not import a weight figure into the conversation unless the abstract reports one. FLOW's and SELECT's abstracts do not.
For a comparison between drugs: only SURMOUNT-5, STEP 8 and SURPASS-2 are head-to-head. Everything else is a cross-trial comparison with different populations and estimands, which the how to read a GLP-1 trial guide covers.
What this guide does not say
It does not explain the gap. The candidate explanations (background medication, rescue therapy, metabolic differences, population age and weight) come from discussion sections and reviews, not from the primary endpoints of these trials, and this site keeps to what the primary publications state. If you need a mechanism, the sibling site The Science covers incretin physiology; FormBlends' own semaglutide guide and tirzepatide guide cover what the labels say about use in people with and without diabetes. Compounded versions of these drugs were not studied in any of the trials above and are not FDA approved.
Questions people ask
Why do people with type 2 diabetes lose less weight on GLP-1 drugs in trials?
The trials document the gap but do not test its cause. Possible contributors discussed in the literature include background glucose-lowering medication, differences in baseline metabolism, and population differences in age and weight. None of the primary papers digested here settles the question, so this site does not claim an explanation.
Is a diabetes trial's weight result relevant to me if I do not have diabetes?
It is a lower bound in a different population, not a prediction for you. Use the weight-management trial for your population, and remember both are averages.
Sources
- Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). PubMed 33567185 Accessed September 4, 2026.
- Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2). PubMed 33667417 Accessed September 4, 2026.
- Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). PubMed 35658024 Accessed September 4, 2026.
- Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2). PubMed 37385275 Accessed September 4, 2026.
- Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment (ATTAIN-1). PubMed 40960239 Accessed September 4, 2026.
- Orforglipron for the treatment of obesity in people with type 2 diabetes (ATTAIN-2). PubMed 41275875 Accessed September 4, 2026.
- Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity (REDEFINE 1). PubMed 40544433 Accessed September 4, 2026.
- Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes (REDEFINE 2). PubMed 40544432 Accessed September 4, 2026.
- Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2). PubMed 34170647 Accessed September 4, 2026.
Canonical URL: https://formblendsresearch.com/methods/weight-management-vs-diabetes-trials. Written by the FormBlends editorial team. This page is educational and is not medical advice; see the medical disclaimer.