Oral Semaglutide and Change in Cardiovascular Risk Factors in High-Risk Type 2 Diabetes: A Post Hoc Secondary Analysis of the SOUL Randomized Clinical Trial.

In the SOUL randomized clinical trial, once-daily oral semaglutide reduced risk of major adverse cardiovascular (CV) events by 14% vs placebo in people with T2D and ASCVD and/or chronic kidney disease (CKD) receiving standard of care (SoC); however, whether oral semaglutide modifies recognized CV risk factors in the long term is unclear.

在SOUL随机临床试验中，每日一次口服司美格鲁肽在标准治疗（SoC）下，与安慰剂相比，使T2D合并ASCVD和/或慢性肾脏病（CKD）患者的主要不良心血管（CV）事件风险降低了14%；然而，口服司美格鲁肽是否长期改变了已知的心血管风险因素尚不清楚。

Background

To investigate whether treatment with oral semaglutide was associated with changes in ASCVD risk factors vs placebo.

研究口服司美格鲁肽治疗是否与安慰剂相比，会带来动脉粥样硬化性心血管疾病（ASCVD）风险因素的变化。

DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis comprises post hoc intention-to-treatanalyses of the SOUL (A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes) double-blindmulticenter randomized clinical trial (randomization 1:1 to oral semaglutide or placebo) among adults with T2D and ASCVD and/or CKD receiving SoC.

设计、环境和参与者：这项次要分析包括了SOUL（一项针对2型糖尿病患者的司美格鲁肽心脏疾病研究）的双盲多中心随机临床试验的事后意向治疗分析（随机分配比例为1:1，口服司美格鲁肽或安慰剂），研究对象为接受标准治疗的患有2型糖尿病、ASCVD和/或CKD的成年人。

Participants underwent randomization from June 2019 to March 2021, with a mean (SD) of 47.5 (10.9) months of follow-up, and data were analyzed from February to December 2025.

参与者从2019年6月到2021年3月进行了随机分组，平均随访时间为47.5（标准差10.9）个月，数据从2025年2月到12月进行了分析。

INTERVENTION(S): Participants were treated with either once-daily oral semaglutide (maximum dose, 14 mg) or placebo, in addition to standard care.

干预措施：参与者除了接受标准治疗外，还接受了每日一次口服司美格鲁肽（最大剂量14毫克）或安慰剂治疗。

main_outcomes_and_measures

The primary outcome was the association of oral semaglutide vs placebo with glycated hemoglobin (HbA1c), body weight, and blood pressure (BP) using estimated treatment differences (ETDs) and with high-sensitivity C-reactive protein (hsCRP) and lipid plasma levels using estimated treatment ratios (ETRs).

主要结果是口服司美格鲁肽与安慰剂相比对糖化血红蛋白（HbA1c）、体重和血压（BP）的影响，使用估计治疗差异（ETDs），以及对高敏C反应蛋白（hsCRP）和脂质血浆水平的影响，使用估计治疗比率（ETRs）。

Results

Of 9650 randomized participants (mean [SD] age, 66.1 (7.6) years; 2790 female participants [28.9%]), 9495 participants (98.4%) completed the trial. Early (13 weeks) improvements in HbA1c (-0.87 percentage points), body weight (-2.54%), systolic BP (SBP, -3.84 mm Hg), pulse pressure (-3.81 mm Hg), hsCRP (-18.08%), total cholesterol (TC, -7.00%), non-high-density lipoprotein cholesterol (non-HDL-C, -8.02%), HDL-C (-4.49%), and triglycerides (-8.15%) were observed with oral semaglutide vs placebo and sustained over the trial duration.

在9650名随机参与者中（平均年龄[标准差]为66.1（7.6）岁；2790名女性参与者[28.9%]），有9495名参与者（98.4%）完成了试验。与安慰剂相比，口服司美格鲁肽在早期（13周）观察到HbA1c（-0.87个百分点）、体重（-2.54%）、收缩压（SBP，-3.84毫米汞柱）、脉压（-3.81毫米汞柱）、hsCRP（-18.08%）、总胆固醇（TC，-7.00%）、非高密度脂蛋白胆固醇（non-HDL-C，-8.02%）、高密度脂蛋白胆固醇（HDL-C，-4.49%）和甘油三酯（-8.15%）的改善，并在试验期间持续。

Body weight reductions were gradual across both groups.

两组的体重减轻都是逐渐发生的。

At week 156, in favor of oral semaglutide were ETDs for HbA1c (-0.47 percentage points; 95% CI, -0.52 to -0.42), body weight (-3.26 percentage points; 95% CI, -3.55 to -2.98), SBP (-1.83 mm Hg; 95% CI, -2.47 to -1.18), and pulse pressure (-2.17 mm Hg; 95% CI, -2.72 to -1.61) and ETRs for hsCRP (0.77; 95% CI, 0.74-0.81), TC (0.99; 95% CI, 0.98-1.00), non-HDL-C (0.98; 95% CI, 0.97-0.99), HDL-C (1.01; 95% CI, 1.01-1.02), and triglycerides (0.94; 95% CI, 0.93-0.96).

在第156周，口服司美格鲁肽在HbA1c（降低0.47个百分点；95%置信区间，-0.52至-0.42）、体重（降低3.26个百分点；95%置信区间，-3.55至-2.98）、收缩压（降低1.83毫米汞柱；95%置信区间，-2.47至-1.18）和脉压（降低2.17毫米汞柱；95%置信区间，-2.72至-1.61）方面显示出效果差异（ETDs），以及在高敏C反应蛋白（hsCRP）（0.77；95%置信区间，0.74-0.81）、总胆固醇（TC）（0.99；95%置信区间，0.98-1.00）、非高密度脂蛋白胆固醇（non-HDL-C）（0.98；95%置信区间，0.97-0.99）、高密度脂蛋白胆固醇（HDL-C）（1.01；95%置信区间，1.01-1.02）和甘油三酯（0.94；95%置信区间，0.93-0.96）方面显示出效果比率（ETRs）。

No significant treatment differences were observed for low-density lipoprotein cholesterol or diastolic BP.

在低密度脂蛋白胆固醇或舒张压方面，未观察到显著的治疗差异。

conclusions_and_relevance

In this post hoc secondary analysis of the SOUL randomized clinical trial, oral semaglutide was associated with early and sustained improvements vs placebo in multiple ASCVD risk factors in high-risk participants with T2D and ASCVD and/or CKD, incremental to SoC.

在这项SOUL随机临床试验的事后次要分析中，与安慰剂相比，口服司美格鲁肽在高风险的2型糖尿病和ASCVD及/或CKD参与者中，与标准治疗相结合，早期且持续改善了多个ASCVD风险因素。

trial_registration

ClinicalTrials.gov Identifier: NCT03914326.

临床试验注册号：NCT03914326。