STEP UP T2D: Evaluating obesity and cardiometabolic target achievement with semaglutide

Achieving clinically meaningful weight-loss and cardiometabolic targets remains a key goal in the management of obesity and type 2 diabetes, particularly in individuals at elevated cardiovascular risk. This analysis of the phase 3 STEP UP T2D trial evaluated the extent to which participants treated with semaglutide 7.2 mg, semaglutide 2.4 mg, or placebo reached predefined BMI, waist-to-height ratio, and cardiometabolic thresholds after 72 weeks of treatment.

In this interview, we spoke with Prof. Carel le Roux (University College Dublin, Ireland) about the rationale for assessing BMI and waist-to-height ratio as obesity treatment targets in the phase 3 STEP UP T2D trial, and the study design used to evaluate these measures alongside key cardiometabolic outcomes. We also discussed the implications of the findings for the use of higher-dose semaglutide in people with obesity and type 2 diabetes, including factors that may influence target attainment in this population.

Abstract: 2829-LB: STEP UP T2D: Participants Achieving BMI, WHtR, and Cardiometabolic Treatment Targets. ADA 2026, June 5–8, 2026, New Orleans, Louisiana, USA.

touchENDOCRINOLOGY coverage of ADA 2026

Questions

1. BMI <27 kg/m² and waist-to-height ratio <0.53 have been proposed as important obesity treatment targets. What was the rationale for evaluating these measures in the STEP UP T2D trial? (0:23)
2. Could you briefly describe the design of this analysis and the key cardiometabolic outcomes that were assessed alongside BMI and waist-to-height ratio targets? (1:10)
3. What were the main findings at Week 72, particularly regarding the proportions of participants achieving BMI, waist-to-height ratio and cardiometabolic treatment targets with semaglutide 7.2 mg? (1.59)
4. Although more participants achieved these targets with semaglutide 7.2 mg, overall target attainment was lower than in the STEP UP trial. What factors may explain this difference in people with type 2 diabetes? (3:35)
5. Based on these findings, how do you see higher-dose semaglutide contributing to the management of obesity and cardiometabolic risk in people with type 2 diabetes? (5:17)

Transcript

My name is Carel le Roux. I’m a clinician-scientist working at University College Dublin.

What was the rationale for evaluating these measures in the STEP UP T2D trial?

So when we think about obesity targets, we need to be honest and say we are only at the beginning of that process, and we are not 100% clear about what these targets would be. However, the BMI of 27 and the waist height ratio of 0.53 were identified in a large general practice database from the UK as the inflection point where patients either had increased metabolic disease or increased functional deficits. Now what we’re able to do is see whether or not we can achieve those targets and when people do achieve them, what health gains materialize?

Could you briefly describe the design of this analysis and the key cardiometabolic outcomes that were assessed alongside BMI and waist-to-height ratio targets?

The analysis simply takes these targets of a BMI of 27 and a waist-to-height ratio of 0.53 and then evaluates if patients are below or above those targets against an outcome. The outcome that we’ve chosen is to represent a low cardiovascular risk state, so that would be normal glycemic, normal blood pressure, normal triglycerides and normal HDL. If you have those four outcomes you can see if people do better – if they achieve these targets versus if they do not achieve these targets.

What were the main findings at Week 72, particularly regarding the proportions of participants achieving BMI, waist-to-height ratio and cardiometabolic treatment targets with semaglutide 7.2 mg?

The most important outcome at this stage was when we looked at percentage weight loss, the old target we always used, and then compared that to meeting these harder targets of a BMI <27 or a waist-to-height ratio of <0.53. What we saw is there was a divergence as far as you came to a weight loss of 15%. There was no difference between targets meeting as well as the percentage weight loss. But the minute you go beyond 15% weight loss, then you see that these targets perform better. What that simply means is if somebody loses a large amount of weight and they get to the target, they do better than somebody that loses a large amount of weight and doesn’t get to the targets equally.

If somebody meets the target and they don’t lose as much weight, then they are better off than somebody that’s lost a large amount of weight and doesn’t meet the target. So percentage weight loss is less powerful than actually meeting these targets. Looking at that allows us to also move obesity into the same space as other chronic diseases, such as hypertension or dyslipidemia, or even type 2 diabetes, where we are treating people to a target and we are not talking about percentage LDL reduction or percentage systolic blood pressure improvement.

Although more participants achieved these targets with semaglutide 7.2 mg, overall target attainment was lower than in the STEP UP trial. What factors may explain this difference in people with type 2 diabetes?

We do not understand fully why it is that people who have the disease of type 2 diabetes lose less weight than people that do not have the disease of type 2 diabetes when we give them exactly the same medication. Of course, what we see is when we compare a medication like the semaglutide 7.2 mg against the treatment, like semaglutide 2.4 mg, more people will achieve these targets. If we have a medication that has more weight loss.

Once you’ve achieved the target, it doesn’t matter if it is with semaglutide 2.4 mg or if it is with semaglutide 7.2 mg, you get the same health benefits. That also allows us to understand that in the future, we are far more likely to be treating against targets that are meaningful to patients. That could be meaningful because we improve metabolic disease, or it could be meaningful because we improve functionality. But rather than thinking about percentage weight loss, we will be thinking about really driving those health gains. That is important to people.

No doubt, if we use more effective treatments like semaglutide 7.2 mg versus semaglutide 2.4 mg, more people will actually achieve these targets. If we treat people without diabetes, we will have more weight loss and more people will achieve the targets. While patients who have the disease of type 2 diabetes do lose less weight and therefore fewer people will actually meet these targets.

Based on these findings, how do you see higher-dose semaglutide contributing to the management of obesity and cardiometabolic risk in people with type 2 diabetes?

If we think about people with type 2 diabetes and we then think about the place of semaglutide 7.2 mg, we see two most important things. Firstly, we get additional weight loss, now instead of getting 10% weight loss with semaglutide 2.4 mg, we get more than 14% weight loss with semaglutide 7.2 mg, but we also see improvements in glycemia. Instead of getting a -1.6% reduction in hemoglobin A1c, we now get -1.9%. Of course, we also see that more people achieve the targets of BMI <27 and waist-to-height of <0.53.

In total, we see that semaglutide 7.2 mg is a very effective treatment, especially for those people that don’t meet our targets and that could be BMI, waist-to-height ratio, high blood pressure, or hemoglobin A1c targets. It could also be other targets that are important to the clinician as well as to the patient.