{"id":138704,"date":"2025-03-29T17:10:12","date_gmt":"2025-03-29T21:10:12","guid":{"rendered":"https:\/\/cardiologynownews.org\/?p=138704"},"modified":"2026-01-28T18:00:28","modified_gmt":"2026-01-28T23:00:28","slug":"soul-oral-semaglutide-reduced-cv-events-in-high-risk-patients-with-t2dm-with-ascvd-or-ckd","status":"publish","type":"post","link":"https:\/\/cardiologynownews.org\/?p=138704","title":{"rendered":"SOUL: Oral Semaglutide Reduced CV Events In High-Risk Patients With T2DM with ASCVD or CKD"},"content":{"rendered":"<p><span style=\"font-weight: 400;\">Key Points<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Injectable semaglutide, a GLP-1 receptor agonist, reduces CV events in patients with T2DM, however whether the oral form of semaglutide confers the same CV risk reduction is uncertain.<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">The SOUL trial randomized 9650 participants age \u226550 with T2DM and established CAD, cerebrovascular disease, symptomatic PAD, or CKD to oral semaglutide or placebo. The primary outcome was 3-point MACE (CV death, nonfatal MI, and nonfatal stroke).<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Oral semaglutide was associated with a significant 14% relative reduction in MACE compared to placebo (HR 0.86 [95% CI: 0.77 \u2013 0.96]), primarily driven by reduction in non-fatal MI. At 3 years, the absolute risk reduction with semaglutide was 2.0 percentage points, for number needed to treat of 50 persons. Serous adverse events were higher in the placebo group, but GI events were more common with semaglutide.<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Oral semaglutide is the first and only oral GLP-1 receptor agonist with proven CV benefits, demonstrating a risk reduction comparable to injectable GLP-1 agents, with no new safety signals identified.<\/span><span style=\"font-weight: 400;\"><br \/>\n<\/span><span style=\"font-weight: 400;\">\u00a0<\/span><\/li>\n<\/ul>\n<p><!--more--><\/p>\n<p><span style=\"font-weight: 400;\">Cardiovascular (CV) disease is a leading cause of death and disability in patients with type 2 diabetes mellitus (T2DM). Injectable formulations of semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been shown to reduce CV risk in patients with T2DM, but whether oral formulations confer a similar benefit is unknown. This is important because many patients are hesitant or unable to perform weekly injections. If effective, an oral formulation could improve access to this class of medications for purposes of CV risk reduction.<\/span><span style=\"font-weight: 400;\"><br \/>\n<\/span><\/p>\n<p><span style=\"font-weight: 400;\">On March 29<\/span><span style=\"font-weight: 400;\">th<\/span><span style=\"font-weight: 400;\">\u00a0 2025, findings from \u201cOral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes\u201d trial were presented at ACC Scientific Sessions 2025 on behalf of the\u00a0 Semaglutide Cardiova<\/span><span style=\"font-weight: 400;\">scular Outcomes Trial (SOUL) study group, with simultaneous publication in the <\/span><a href=\"about:blank\"><i><span style=\"font-weight: 400;\">New England Joal of\u00a0<\/span><\/i><\/a><a style=\"font-family: Merriweather, serif; font-size: 16px; font-weight: 300; font-style: normal; font-variant-ligatures: normal; font-variant-caps: normal; color: #000000;\" href=\"about:blank\"><span style=\"font-weight: 400;\">urn<\/span><\/a><a href=\"about:blank\"><i><span style=\"font-weight: 400;\">Medicine<\/span><\/i><\/a><i><span style=\"font-weight: 400;\">.<\/span><\/i><span style=\"font-weight: 400;\"> The purpose of this investigation was to evaluate whether oral semaglutide reduces CV events among high-risk patients with T2DM.\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400;\">This was a <\/span><a href=\"https:\/\/clinicaltrials.gov\/study\/NCT03914326\"><span style=\"font-weight: 400;\">double-blind, placebo-controlled, event-driven, superiority trial<\/span><\/a><span style=\"font-weight: 400;\"> which randomized 9650 participants age \u2265 50 years with T2DM, a hemoglobin A1c of 6.5-10%, and either coronary artery disease (CAD), cerebrovascular disease, symptomatic peripheral artery disease (PAD), or chronic kidney disease (CKD; defined as an eGFR &lt;60 mL\/min\/1.73 m2) to oral semaglutide or placebo in a 1:1 fashion on top of standard of care. The dose was escalated from 3mg to 14mg, with dose reductions and treatment pauses allowed. The primary outcome was 3-point MACE, including CV death, non-fatal myocardial infarction (MI) and non-fatal stroke, over an estimated 5 year study period. Secondary outcomes included 5-point composite kidney outcome, CV death, and major adverse limb events.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">A total of 4825 patients were randomized from 450 medical centers in 44 countries to each arm, with &lt;2% drop out. Overall, ~29%\u00a0 were female, with an average age of 66.1, average A1c of 8%, and average BMI of 31.0 kg\/m<\/span><span style=\"font-weight: 400;\">2<\/span><span style=\"font-weight: 400;\">; more than half of participants had established ASCVD. At 54 months, 579 patients in the semaglutide group and 688 patients in the placebo group experienced the primary outcome for an event rate of 3.1 and 3.7 per 100 person-years, respectively. Oral semaglutide was associated with a significant 14% relative risk reduction in 3-point MACE compared to placebo (HR 0.86 [95% CI: 0.77, 0.96];\u00a0 <\/span><i><span style=\"font-weight: 400;\">p<\/span><\/i><span style=\"font-weight: 400;\">=0.0028 for superiority). The absolute risk reduction was 2% over three years, representing a number needed to treat of 50 patients (95% CI: 31 to 125). There was a consistent trend towards benefit for oral semaglutide vs. placebo in each of the individual components: CV death (6.2% vs. 6.6%, HR 0.93 [95% CI: 0.80, 1.09]), non-fatal MI (4.0% vs. 5.2%, HR 0.74 [95% CI: 0.61, 0.89]), and nonfatal stroke (3.0% vs. 3.3%, HR 0.88 [95% CI: 0.70, 1.11]). Major adverse limb events were also lower in the semaglutide group (HR 0.71 [95% CI: 0.52, 0.96]). There was no differences between the groups for major kidney disease events. No heterogenous treatment effects for the primary outcome were observed across the subgroup analyses, with similar efficacy by age, sex, BMI, eGFR, and concomitant SGLT2i use, suggesting a complimentary role for these medications in the management of high-risk patients with T2DM.\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400;\">Serious adverse events were significantly higher in the placebo group (50.3% vs. 47.9%; <\/span><i><span style=\"font-weight: 400;\">p=<\/span><\/i><span style=\"font-weight: 400;\">0.02), the majority of which were defined cardiac disorders and infections. Gastrointestinal disorders were more common with semaglutide than placebo (5.0% vs. 4.4%, respectively), and discontinuation of the study drug was more common on the oral semaglutide group (15.5%) than in the placebo group (11.6%), driven by gastrointestinal side effects (6.4% vs. 2.0%, respectively). However, rates of acute pancreatitis (0.4%) and eye disorders (2.0%) were similar for both groups.<\/span><span style=\"font-weight: 400;\"><br \/>\n<\/span><span style=\"font-weight: 400;\">\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400;\">This trial was funded by Novo Nordisk; Black patients were under-represented due to low enrollment at non-North American sites.<\/span><\/p>\n<p><span style=\"font-weight: 400;\"><br \/>\n<\/span><span style=\"font-weight: 400;\">The risk reduction observed in this study aligns with pooled results of eight previous trials of injectable GLP-1 receptor agonists, according to the researchers. Darren K. McGuire, M.D., MHSc, from the University of Texas Southwestern Medical Center, and Parkland Health System, Dallas, Texas, concluded: \u201cWe found that the oral formulation looks just like the rest of the class of GLP-1 inhibitors. The same cardiovascular benefits can be derived from the tablet that we\u2019ve seen from the injectables before\u2026Oral semaglutide is the first and only oral GLP-1 RA with proven CV benefits.\u201d<\/span><\/p>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Key Points Injectable semaglutide, a GLP-1 receptor agonist, reduces CV events in patients with T2DM, however whether the oral form of semaglutide confers the same CV risk reduction is uncertain. The SOUL trial randomized 9650 participants age \u226550 with T2DM and established CAD, cerebrovascular disease, symptomatic PAD, or CKD to oral semaglutide or placebo. The [&hellip;]<\/p>\n","protected":false},"author":40618,"featured_media":138705,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[898,8],"tags":[899,45,47,185],"ppma_author":[1072],"class_list":{"0":"post-138704","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-acc-2025","8":"category-news","9":"tag-acc-2025","10":"tag-conference","11":"tag-featured","12":"tag-news","13":"author-lucas-marinacci-md"},"authors":[{"term_id":1072,"user_id":40618,"is_guest":0,"slug":"lucas-marinacci-md","display_name":"Lucas Marinacci MD","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/cd81d2064c6f6263719c24aeb738faf718e9bd869c5a840718bc535238ae72f6?s=96&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/138704","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/users\/40618"}],"replies":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=138704"}],"version-history":[{"count":1,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/138704\/revisions"}],"predecessor-version":[{"id":138706,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/138704\/revisions\/138706"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/media\/138705"}],"wp:attachment":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=138704"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=138704"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=138704"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=138704"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}