Population-level modeling study applying SOUL trial eligibility criteria to NHANES data of US adults with type 2 diabetes. An estimated 6.1 million Americans met eligibility for oral semaglutide. Without treatment, 847,598 major adverse cardiovascular events (MACE) were projected over 4.5 years; with treatment, 728,934 — a potential prevention of 118,664 events (14% relative reduction; NNT 55). At 50% uptake and 15.5% discontinuation (as in SOUL), this translates to roughly 59,000 MACE prevented, including 14,000 CV deaths, 41,000 non-fatal MIs, and 12,000 non-fatal strokes. The findings support oral semaglutide as a scalable cardiometabolic intervention and argue for system-level strategies to enhance access and uptake.
Oral semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), has been shown to reduce major adverse cardiovascular events (MACE) in high-risk individuals with type 2 diabetes in the SOUL trial. Its potential population-level impact in the United States, however, remains unclear.
We applied SOUL trial eligibility criteria to U.S. adults in the National Health and Nutrition Examination Survey (NHANES, 1988–2018) to estimate the number eligible for oral semaglutide and the projected reduction in cardiovascular events over 4.5 years. MACE—defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke—was the primary outcome. Event rates and hazard ratios were derived from the SOUL trial and applied to weighted NHANES data.
An estimated 6.1 million U.S. adults met eligibility criteria for oral semaglutide. Without treatment, 847,598 MACE events were projected, compared to 728,934 with treatment—corresponding to 118,664 events potentially prevented (14% relative reduction; number needed to treat [NNT] = 55). This included 28,430 cardiovascular deaths (NNT = 254), 83,489 nonfatal myocardial infarctions (NNT = 78), and 24,521 nonfatal strokes (NNT = 284). Cardiovascular benefits were consistent across sex, race/ethnicity, and clinical subgroups. At 50% uptake, and assuming a 15.5% discontinuation rate as observed in the SOUL trial, an estimated 59,332 MACE, 14,215 cardiovascular deaths, 41,744 nonfatal myocardial infarctions, and 12,260 nonfatal strokes could be prevented.
Widespread use of oral semaglutide among eligible U.S. adults with type 2 diabetes could substantially reduce cardiovascular events. These findings support its potential as a scalable, population-level cardiometabolic intervention and highlight the need for system-level strategies to enhance access and uptake. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40842-026-00299-z.
