Real-world data: Semaglutide reduces MACE and all-cause mortality vs dulaglutide in T2D and ASCVD

In patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD), subcutaneous (SC) semaglutide Q1W was associated with lower risks of 3-point and 5-point major adverse cardiovascular events (3P- and 5P-MACE) and all-cause mortality vs dulaglutide, according to the real-world REACH study presented at the European Association for the Study of Diabetes (EASD) 2025 Annual Meeting.

From ESC to EASD: Another CV win for semaglutide
The real-world STEER study, re­cently presented at the European So­ciety of Cardiology (ESC) Congress 2025, demonstrated that SC sema­glutide was associated with a lower risk of cardiovascular (CV) events vs tirzepatide in patients with overweight or obesity and ASCVD. [Wilson L, et al, ESC 2025]

The EASD 2025 Annual Meeting, held in mid-September 2025, featured another positive real-world CV out­come study – REACH – that compared effectiveness of semaglutide Q1W vs dulaglutide (both are glucagon-like peptide-1 receptor agonists [GLP- 1 RAs]) in patients with T2D and ASC­VD. [Tan X, et al, EASD 2025]

REACH: Semaglutide vs dulaglutide in T2D and ASCVD
“Direct comparisons of CV out­comes within the class of GLP-1 RAs in real-world settings are lacking — a critical gap for the US Medicare popu­lation,” said Xi Tan from Novo Nordisk, Inc., Plainsboro, New Jersey, US, at EASD 2025. “This gap is even more concerning, given the growing pop­ulation of US Medicare beneficiaries, who are older, often multimorbid, and underrepresented in clinical trials.”

By analyzing US Medicare free-for-service claims data from 1 January 2006 to 31 December 2022, patients with T2D and established ASCVD treat­ed with semaglutide Q1W or dulaglutide were included in the REACH study.

“REACH was conducted under a target-trial emulation framework, which is a rigorous causal inference approach that used real-world data to simulate a hypothetical randomized controlled trial to estimate the treat­ment effect,” pointed out Tan.

Following propensity score match­ing, there were no significant differenc­es in baseline characteristics between the semaglutide (n=29,168; mean age, 73.20 years; male, 60.5 percent; mean follow-up time, 12 months) and dulaglutide (n=29,168; mean age, 73.25 years; male, 60.9 percent; mean follow-up time, 13 months) groups. The mean durations of T2D and AS­CVD history were approximately 6 and 7 years, respectively, in both groups.

23 percent risk reduction in 3P-MACE with semaglutide
The primary outcome was 3P-MACE, which included MI, stroke (ischaemic and haemorrhagic), and all-cause mortality.

Notably, semaglutide significantly reduced the risk of 3P-MACE by 23 percent (hazard ratio [HR], 0.77; 95 per­cent confidence interval [CI], 0.71–0.84; p<0.001) vs dulaglutide. (Figure 1A) “The cumulative incidence curves separated early,” reported Tan.

“When replacing overall stroke with ischaemic stroke, the results remained the same,” noted Tan. “Semaglutide consis­tently reduced the risk of 3P-MACE by 23 percent [HR, 0.77; 95 percent CI, 0.71– 0.85; p<0.001] vs dulaglutide.” (Figure 1B)

“Similar results were observed in a replicate analysis using US commercial and Medicare Advantage data,” Tan add­ed.

As for the individual MACE compo­nents, semaglutide was associated with lower risks of:

• Stroke (HR, 0.67; 95 percent CI, 0.56–0.80; p<0.001);
• Ischaemic stroke (HR, 0.65; 95 per­cent CI, 0.53–0.80; p<0.001);
• All-cause mortality (HR, 0.74; 95 per­cent CI, 0.66–0.83; p<0.001).

However, no significant difference in the risk of MI (HR, 0.90; 95 percent CI, 0.76–1.06; p=0.21) was observed be­tween the two groups.

25 percent risk reduction in 5P-MACE with semaglutide
5P-MACE was defined as MI, stroke, hospitalizations for unstable angina and heart failure, and all-cause mortality. Semaglutide significantly reduced the risk of 5P-MACE by 25 percent (HR, 0.75; 95 percent, 0.70–0.82; p<0.001) vs dulaglu­tide. (Figure 2A) When replacing overall stroke with ischaemic stroke, the results remained entirely unchanged. (Figure 2B)

Clinical implications
“This is the first real-world compari­son of CV outcomes between semaglu­tide Q1W and dulaglutide in US Medi­care beneficiaries with T2D and ASCVD, strengthening existing evidence in the context of lacking head-to-head trials,” said Tan.

In summary, semaglutide was associ­ated with reduced risks of CV outcomes, including a 23 percent risk reduction in 3P-MACE, a 25 percent risk reduction in 5P-MACE, and a 26 percent risk reduc­tion in all-cause death compared with an­other GLP-1 RA, dulaglutide.

“Our findings reinforce that the CV benefits of semaglutide are multifaceted, molecule-specific, and can­not be generalized to the entire GLP-1 RA class,” pointed out Tan.

The REACH study addresses a critical evidence gap that is crucial for informing treatment decisions for clinicians and pol­icymakers, particularly amid increasing use of GLP-1 RAs and ongoing Medicare price negotiations.

Strengths and limitations
The strengths of the real-world REACH study include its large Medicare population, use of the target trial emula­tion framework, advanced methodology, various definitions of outcomes and sen­sitivity analyses. Limitations included observational study design, data avail­ability, and other constraints.

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