Key takeaways
- Real-world evidence from REACH highlights semaglutide’s differentiated cardiovascular benefit compared with dulaglutide, reinforcing the value of RWD in older, comorbidity-heavy populations often underrepresented in RCTs.
- Large-scale trial emulation using Medicare claims data demonstrates how timely data can inform trial design, regulatory strategy, and access discussions, particularly in CV outcomes research.
- REDEFINE 1 results confirm the scalability of semaglutide-based therapies for obesity, underscoring the need for robust site support to manage large patient cohorts, complex endpoints, and long follow-up periods.
Novo Nordisk has released new data from the REACH real-world study evaluating cardiovascular disease-related outcomes of once-weekly glucagon-like peptide 1 receptor agonists (GLP-1 RAs), including Ozempic (semaglutide).1
Positive results from REACH
When compared to dulaglutide, Ozempic was associated with a reduced risk of major adverse cardiovascular events such as a heart attack or stroke by 23%. The results of the REACH study were recently presented at the European Association for the Study of Diabetes (EASD) 2025 Annual Meeting in Vienna, Austria.
In a press release, Filip Krag Knop, senior vice president and incoming chief medical officer at Novo Nordisk, said: “As we age, the risk of experiencing a heart attack, stroke or dying from a cardiovascular event increases. At the same time, there are limited clinical data for people living with diabetes and cardiovascular disease aged 66 years or older. These data, showing a 23% risk reduction of a heart attack, stroke and death, fill an important gap and reinforce the well-established clinical evidence of semaglutide. This is great news for older patients as well as healthcare professionals, as these results build on the importance of our randomized clinical trial data assessing the effectiveness of treatments in a real-life setting. This also supports what we already know from our clinical development programs that not all GLP-1 RAs are the same.”
Additional REACH outcomes
Additional results from REACH demonstrate that once-weekly semaglutide was associated with a 25% risk reduction of heart attack, stroke, hospitalization for unstable angina or heart failure, and death from any cause (five-point MACE).
Real-world design of the study
REACH is a research program evaluating cardiovascular outcomes of once-weekly GLP-1 receptor agonists compared with other glucose-lowering therapies, as well as within-class comparisons using real-world data sources.
- At the 2025 EASD Annual Meeting, results were presented from a real-world analysis of semaglutide and dulaglutide in people with type 2 diabetes and atherosclerotic cardiovascular disease.
- The study used Medicare fee-for-service claims data and a target-trial emulation design, including 58,336 matched patients aged 66 years and older (29,168 in each treatment group).
- Findings provide direct cardiovascular outcome comparisons between semaglutide and dulaglutide, addressing evidence gaps in an older, comorbidity-heavy population often underrepresented in randomized trials.
REDEFINE 1 provides further evidence
Earlier in June, The New England Journal of Medicine (NEJM) published detailed findings from the Phase IIIa REDEFINE 1 study (NCT05567796) which showed that a once-weekly combination of cagrilintide and semaglutide (CagriSema) demonstrated unprecedented weight loss in adults with overweight or obesity.2
Results from REDEFINE 1 showed:
- At week 68, patients receiving CagriSema achieved a mean body weight reduction of 20.4% compared to 3.0% with placebo, for an estimated treatment difference of –17.3 percentage points (95% CI: –18.1 to –16.6; P<0.001).
- Patients in the CagriSema arm were significantly more likely than those on placebo to achieve weight-loss thresholds of ≥5%, ≥20%, ≥25%, and ≥30%.
“The mean weight reduction observed with cagrilintide–semaglutide is in the highest range of that observed with existing weight-loss interventions,” the study authors wrote in NEJM. “We posit that these effects on body weight probably result from the complementary effect of the two molecules on appetite regulation through direct actions in brain regions known to be involved in hedonic and homeostatic appetite regulation, such as the hypothalamus, hindbrain, and septum.”
Trial design of REDEFINE 1
REDEFINE 1 is a multicenter, double-blind, placebo- and active-controlled trial.
- The trial enrolled 3,417 adults without diabetes who had a BMI ≥30, or ≥27 with at least one obesity-related condition.
- Participants were randomized in a 21:3:3:7 ratio to receive CagriSema (semaglutide 2.4 mg plus cagrilintide 2.4 mg, n=2,108), semaglutide alone (n=302), cagrilintide alone (n=302), or placebo (n=705), alongside lifestyle interventions.
- The coprimary endpoints were percent change in body weight and achievement of at least 5% weight loss at week 68 for CagriSema versus placebo.
- Confirmatory secondary endpoints included achievement of at least 20%, 25%, and 30% weight loss.
References
1. Novo Nordisk A/S: Ozempic® reduces the risk of heart attack, stroke and death by 23% compared to dulaglutide in the first head-to-head real-world study. News release. Novo Nordisk. September 18, 2025. Accessed September 19, 2025. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916430
2. REDEFINE 1 Trial Finds Cagrilintide–Semaglutide Combo Delivers Over 20% Weight Loss in Majority of Patients. Applied Clinical Trials. July 1, 2025. Accessed September 19, 2025. https://www.appliedclinicaltrialsonline.com/view/cagrilintide-semaglutide-weight-loss
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