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September 17, 2026Diabetes TherapyOpen Access

Comparing Cardiovascular Outcomes in New Users of Oral Semaglutide Versus Other Noninsulin Glucose-Lowering Therapies Among Adults with Type 2 Diabetes and Atherosclerotic Cardiovascular Disease

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Key result

Oral semaglutide is linked to ~17% lower 3-point MACE risk in T2D with ASCVD.

HR 0.83
95% CI 0.72-0.96
P=0.001
n=39,517

Why the study?

Does initiating oral semaglutide reduce the risk of major adverse cardiovascular events compared with other noninsulin glucose-lowering therapies (including DPP4 inhibitors and SGLT2 inhibitors) in US adults with type 2 diabetes and atherosclerotic cardiovascular disease?

Study Design

Type

Cohort (n=39,517)

Multicenter

Yes

Structured PICO

Does initiating oral semaglutide reduce the risk of major adverse cardiovascular events compared with other noninsulin glucose-lowering therapies (including DPP4 inhibitors and SGLT2 inhibitors) in US adults with type 2 diabetes and atherosclerotic cardiovascular disease?

P

Population

39,517 propensity score-matched US adults with type 2 diabetes and established atherosclerotic cardiovascular disease (mean age ~70.2 years, ~47% female) initiating oral semaglutide or other noninsulin glucose-lowering therapies, followed for a mean of 9.6 to 10.6 months.

E

Exposure

Oral semaglutide initiation (new users with ≥2 prescriptions; 51.7% and 30.2% reached maximum doses of 7 mg and 14 mg during follow-up, and 18–19% remained on 3 mg)

C

Comparator

Propensity score-matched new users (up to 3:1 matching) of other noninsulin glucose-lowering therapies (ONIGLTs, n=28,639), with separate matched subgroup comparisons against new users of dipeptidyl peptidase 4 inhibitors (DPP4is, 1:1 matched, n=7,218 each) and sodium-glucose cotransporter 2 inhibitors (SGLT2is, up to 3:1 matched, n=7,491 oral semaglutide vs n=21,572 SGLT2i)

O

Outcome

Incidence rate (per 1000 person-years) and time to first 3-point MACE (composite of ischemic stroke, myocardial infarction, and cardiovascular-related death) and modified 3-point MACE (ischemic stroke, myocardial infarction, and all-cause death) over a mean follow-up of 9.6 to 10.6 monthscomposite

Main Result

Hazard Ratio: 0.83 (95% CI 0.72–0.96)

Absolute Event Rate: 27.48% vs 32.57%

p-value: p=0.001

Limitations

Observational retrospective design cannot establish causal relationships and is subject to residual confounding and healthy user bias
Administrative claims data lack clinical granularity (e.g., detailed kidney function, albuminuria, smoking, blood pressure, lipids) and may contain coding/measurement errors, especially for CV-related death
Relatively short follow-up duration (mean ~9.6 to 10.6 months) limits evaluation of long-term cardiovascular outcomes
Informative censoring related to treatment discontinuation or switching in the primary as-treated analysis cannot be excluded
Findings from US commercial and Medicare Advantage beneficiaries may not generalize outside the US
Observational study design cannot establish causal relationships between medication use and clinical outcomes
Administrative claims data lack clinical granularity (e.g., detailed kidney function, albuminuria, smoking, blood pressure, lipids, social determinants of health, lifestyle factors)
Potential measurement errors and outcome misclassification inherent to claims data, particularly for claims-derived CV-related death
Potential residual confounding (e.g., healthy user bias) and informative censoring in the primary as-treated analysis
Relatively short follow-up period (~9–11 months) and limited generalizability outside the US commercial and Medicare Advantage population

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Answers are grounded in this paper and cite their sources.

Implication

In real-world US clinical practice, initiating oral semaglutide was associated with significantly lower risks of 3-point, modified 3-point, and 5-point MACE as well as lower inpatient health care utilization and medical costs compared with DPP4 inhibitors, SGLT2 inhibitors, and pooled noninsulin glucose-lowering therapies among adults with T2D and ASCVD.

Abstract

INTRODUCTION: Clinical trials have found semaglutide reduces the risk of major adverse cardiovascular events (MACE) among people with type 2 diabetes (T2D) at high risk of MACE. Less is known about oral semaglutide's impact on real-world cardiovascular risk. METHODS: This observational cohort study used administrative claims data from Optum's deidentified Clinformatics® Data Mart Database to compare 3-, modified 3-, 5-, modified 5-, and 2-point MACE, ischemic stroke (IS), myocardial infarction (MI), and all-cause and cardiovascular-related death rates among people with T2D and atherosclerotic cardiovascular disease (ASCVD) who initiated oral semaglutide vs other noninsulin glucose-lowering therapies (ONIGLTs). Cardiovascular outcomes were compared between new users of oral semaglutide and propensity score-matched new users of dipeptidyl peptidase 4 inhibitors (DPP4is) or sodium-glucose cotransporter 2 inhibitors (SGLT2is). RESULTS: Oral semaglutide users (n = 10,878) had risk reductions of 17% and 21% in 3- and modified 3-point MACE, respectively, and significant risk reductions in 5-, modified 5-, and 2-point MACE, IS, and all-cause death vs ONIGLT users (n = 28,639). People who initiated oral semaglutide (n = 7218) had 22% and 24% lower risks of 3- and modified 3-point MACE, respectively, and significantly lower risks of 5- and modified 5-point MACE, IS, and all-cause death vs people who initiated DPP4is (n = 7218). Compared with SGLT2i users (n = 21,572), oral semaglutide users (n = 7491) had 21% and 22% lower risks of 3- and modified 3-point MACE, respectively, and significantly lower risks of 5-, modified 5-, and 2-point MACE. CONCLUSION: Consistent with clinical trial evidence, oral semaglutide was associated with a lower risk of cardiovascular outcomes among people with T2D and ASCVD in real-world settings.

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Cite This Study

Tan et al. (2026) conducted a cohort in Type 2 diabetes and atherosclerotic cardiovascular disease (n=39,517). Oral semaglutide vs. Other noninsulin glucose-lowering therapies (ONIGLTs), including DPP4 inhibitors and SGLT2 inhibitors was evaluated on 3-point MACE (composite of ischemic stroke, myocardial infarction, and cardiovascular-related death) (HR 0.83, 95% CI 0.72-0.96, p=0.001). Oral semaglutide was associated with a 17% lower risk of 3-point MACE (HR 0.83, 95% CI 0.72-0.96, P=0.001) compared to other noninsulin glucose-lowering therapies in adults with T2D and ASCVD.

synapsesocial.com/papers/6ac468d8341f77e8cd75b879 https://doi.org/10.1007/s13300-026-01919-8

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