Effect of oral semaglutide on CV outcomes across the vascular disease spectrum, from no vascular disease to polyvascular disease, in high-risk type 2 diabetes

Abstract Introduction In the SOUL trial, oral semaglutide, a glucagon-like peptide-1 receptor agonist, reduced major adverse cardiovascular events (MACE) when compared with placebo in people with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD). Purpose In these pre-specified analyses of the SOUL trial, we sought to determine whether the effect of oral semaglutide on cardiovascular (CV) outcomes varies based on the extent of vascular disease at baseline. Methods In SOUL, 9,650 participants aged ≥50 years with T2D (HbA1c 6.5–10%) and ASCVD and/or CKD were randomised to oral semaglutide or placebo. Cox regression models were used to evaluate the treatment effect of oral semaglutide on time to first MACE (CV death, non-fatal myocardial infarction [MI], non-fatal stroke) by number of vascular beds (coronary, cerebral or peripheral) affected at baseline (0, 1 or ≥2 [polyvascular]). Results Of 8,291 participants in whom data about the exact number of vascular beds were known, 1,244 (15.0%) had CKD but no known ASCVD, 5,122 (61.8%) had a single vascular bed affected and 1,925 (23.2%) had polyvascular disease at baseline. Coronary heart disease (CHD) was the most common type of vascular disease reported (69.8%), followed by cerebrovascular disease (24.3%) and peripheral arterial disease (17.5%) with significant overlap among the 3 affected vascular beds (Figure 1). Participants with vascular disease were more likely to be male, White and current smokers, compared with those without known atherosclerosis. Body weight and body mass index (BMI) were balanced across subgroups. Of those with single-bed vascular disease, 45.4% had a prior MI and 12.6% had a prior stroke while in those with polyvascular disease, 48.5% had a prior MI and 42.6% had a prior stroke. Compared with participants who had CKD but no known ASCVD (98/1244 [7.9%]; incidence rate [IR] 2), the risk of MACE was progressively higher in those with single-bed vascular disease (617/5122 [12.0%]; IR 3.1 [HR 1.56; 95% CI 1.27–1.94]) and polyvascular disease (369/1925 [19.2%]; IR 5.3 [HR 2.62; 95% CI 2.11–3.29]) (Figure 2). Despite being at lower overall risk of CV events, those with CKD but no known ASCVD who were randomised to semaglutide had fewer MACE (38/633 [6.0%]; IR 1.5) when compared with placebo (60/611 [9.8%]; IR 2.5) (HR 0.59, 95% CI 0.39–0.88; Figure 2). However, there was no evidence that the effect of oral semaglutide varied based on number of vascular beds affected by atherosclerosis (p-value [interaction]=0.15). Numbers needed to treat were low (38–58) across subgroups (Figure 2). Conclusion In the SOUL trial, more extensive vascular disease was associated with higher risk of MACE. Oral semaglutide reduced the risk of MACE, irrespective of number of affected vascular beds, which supports the initiation of semaglutide in T2D with CKD, even in the absence of known ASCVD.

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