Dear Editor,

Semaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 RA) that leads to significant improvements in weight and HbA1c in patients with type 2 diabetes (T2D) [1, 2]. In 2022 and 2023, the worldwide shortage of subcutaneous semaglutide has limited access to this medication. In this regard, recommendations to mitigate the consequences of the supply shortage of GLP-1 RA, including temporary switching to oral semaglutide in patients receiving subcutaneous semaglutide, have been provided by several organizations. However, there are no studies evaluating the implications of the modification of this treatment. Therefore, we aimed to evaluate the impact of switching from once-weekly subcutaneous semaglutide to once-daily oral semaglutide in patients with T2D in the context of drug shortage.

We conducted a prospective study at the Department of Endocrinology, Virgen de la Victoria University Hospital (Malaga, Spain) including patients with T2D treated with subcutaneous semaglutide 1 mg/week (treatment duration >6 months with this dose), and HbA1c <8%. Participants with HbA1c ≥8% were excluded to avoid treatment interferences, as they were candidates for treatment intensification. Patients with additional criteria for T2D treatment intensification/adjustment or undergoing modifications in the last 6 months were also excluded. From November 2022 to February 2023, in the context of subcutaneous semaglutide shortage, participants switched from subcutaneous semaglutide (1 mg/week) to oral semaglutide (14 mg/day). Clinical and biochemical data were obtained at baseline and 3 months following treatment modification. No changes in glucose-lowering medications (including insulin adjustments) were performed during the study. A paired Student's t-test was used for comparisons. The Diabetes Treatment Satisfaction Questionnaire-change version (DTSQc) [3] was used to assess changes in treatment satisfaction. The primary outcome was a change in HbA1c and weight from baseline, together with changes in treatment satisfaction. This study was approved by the Ethics Research Committee of Malaga and was conducted according to the Declaration of Helsinki.

Basal characteristics of the study population are shown in Table 1. In total, 48 patients with T2D were included (7 subjects had been previously excluded due to the need for treatment intensification). Mild adverse gastrointestinal effects were reported in eight participants (six presented nausea and two diarrhea). Of note, four of the aforementioned patients discontinued treatment for this reason (three presenting nausea and one diarrhea) and one patient underwent bariatric surgery before the study's completion and was excluded from the final analyses. The main clinical characteristics of the participants excluded from the analyses were similar to those who were finally included (Table S1). Therefore, 43 patients were analyzed. Changes in weight and HbA1c were assessed from baseline to 3 months. Notably, no differences in weight (98.6 ± 17.9 vs. 98.4 ± 17.5 kg; p = 0.619), body mass index (34.5 ± 5.8 vs. 34.5 ± 5.7 kg/m²; p = 0.645), or HbA1c levels (6.52% ± 0.83% vs. 6.65% ± 1.03%, mean change 0.13%; p = 0.064) were observed. DTSQc's scores are shown in Table S2. Overall, treatment satisfaction decreased as compared to baseline. Participants were particularly less satisfied with oral semaglutide for items 4 (convenience), 5 (flexibility), and 8 (satisfaction to continue with present treatment), compared to subcutaneous semaglutide.

In this study, we show that switching from higher doses of once-weekly semaglutide to the once-daily oral formulation of this molecule in patients with T2D did not result in significant changes in weight or HbA1c in the short term. On the other hand, a decrease in treatment satisfaction was observed following this modification.

Despite the fact that some meta-analyses have compared the efficacy of oral semaglutide versus other GLP-1 RA [4, 5], no head-to-head comparisons between the approved higher doses of oral and subcutaneous semaglutide have been performed. In a phase 2, open-label, dose-finding trial exploring the efficacy of doses of 2.5/5/10/20/40 mg of once-daily oral semaglutide, no statistically significant differences were found between doses of 20/40 mg of oral semaglutide and subcutaneous semaglutide (1 mg) [6]. Nevertheless, there is no previous real-world evidence of the effects of switching between the different formulations of this molecule. Although no significant changes in weight or HbA1c were detected after the switch in our study, it should be noted that the p value for HbA1c was close to statistical significance. Indeed, it cannot be ruled out that a statistically significant p value might have been detected with a larger sample size. However, given the observed differences, these changes in HbA1c may be less clinically relevant.

Patient-reported outcomes are increasing in importance in clinical studies. In this regard, oral semaglutide improved treatment satisfaction assessed by the DTSQ in patients with T2D compared to placebo, whereas treatment satisfaction has been reported to be similar to other GLP-1 RA, such as liraglutide [7]. In the REVISE study, a cross-sectional survey of patients with T2D (92.8% taking oral glucose-lowering agents and 26.3% using injectable formulations), participants initially preferred a once-daily oral formulation (76.5%) over a once-weekly injectable (23.5%), although no differences in preferences were detected when detailed information about product-specific administration was provided [8]. However, in light of our results, patients with long-term treatment with subcutaneous semaglutide may prefer this route, due to better convenience and flexibility.

This study has some limitations. First, these findings should be cautiously interpreted due to the limited sample size. Moreover, the effects of switching from subcutaneous to oral semaglutide were assessed in the short term, and results might differ in longer follow-ups, or in patients with different characteristics. On the other hand, this study's main strength lies in its prospective design. Furthermore, to our knowledge, this is the first study that evaluates the impact of subcutaneous-to-oral semaglutide switch in patients with T2D.

In conclusion, in the context of GLP-1 RA shortage, once-daily oral semaglutide (14 mg) might be a useful alternative to once-weekly subcutaneous semaglutide (1 mg) for patients with T2D in the short term. However, patients with previous use of subcutaneous semaglutide may prefer this treatment to the oral formulation.

亲爱的编辑，

索马鲁肽是一种胰高血糖素样肽 1 受体激动剂 (GLP-1 RA)，可显着改善 2 型糖尿病 (T2D) 患者的体重和 HbA1c [ 1, 2 ]。2022 年和 2023 年，全球皮下注射索马鲁肽的短缺限制了这种药物的获取。在这方面，多个组织已提出减轻 GLP-1 RA 供应短缺后果的建议，包括对接受皮下注射索马鲁肽的患者暂时改用口服索马鲁肽。然而，没有研究评估这种治疗方法修改的影响。因此，我们的目的是评估在药物短缺的情况下，从每周一次皮下注射索马鲁肽改为每日一次口服索马鲁肽对 T2D 患者的影响。

我们在 Virgen de la Victoria 大学医院（西班牙马拉加）内分泌科进行了一项前瞻性研究，研究对象包括接受皮下注射索马鲁肽 1 毫克/周（该剂量治疗持续时间 >6 个月）且 HbA1c <8% 的 T2D 患者。HbA1c ≥8% 的参与者被排除以避免治疗干扰，因为他们是强化治疗的候选者。具有 T2D 治疗强化/调整或在过去 6 个月内接受修改的附加标准的患者也被排除。2022年11月至2023年2月，在皮下注射索马鲁肽短缺的背景下，参与者从皮下注射索马鲁肽（1毫克/周）改为口服索马鲁肽（14毫克/天）。在基线和治疗修改后 3 个月获得临床和生化数据。研究期间没有改变降糖药物（包括胰岛素调整）。使用配对学生t检验进行比较。糖尿病治疗满意度调查问卷变更版本（DTSQc）[ 3 ]用于评估治疗满意度的变化。主要结果是 HbA1c 和体重相对于基线的变化，以及治疗满意度的变化。这项研究得到了马拉加伦理研究委员会的批准，并根据赫尔辛基宣言进行。

研究人群的基本特征如表 1 所示。总共包括 48 名 T2D 患者（之前因需要强化治疗而排除了 7 名受试者）。据报道，八名参与者出现了轻微的胃肠道不良反应（其中六名出现恶心，两名出现腹泻）。值得注意的是，上述患者中的四名患者因此停止治疗（三名患者出现恶心和一名腹泻），一名患者在研究完成之前接受了减肥手术，并被排除在最终分析之外。排除在分析之外的参与者的主要临床特征与最终纳入的参与者相似（表S1）。因此，对 43 名患者进行了分析。评估从基线到 3 个月的体重和 HbA1c 变化。值得注意的是，体重（98.6 ± 17.9 vs. 98.4 ± 17.5 kg； p  = 0.619）、体重指数（34.5 ± 5.8 vs. 34.5 ± 5.7 kg/m ²；p  = 0.645）或 HbA1c 水平（6.52%）没有差异 观察到± 0.83% 与 6.65% ± 1.03%，平均变化 0.13%；p = 0.064。DTSQc 的得分如表 S2 所示。总体而言，与基线相比，治疗满意度有所下降。与皮下注射索马鲁肽相比，参与者对口服索马鲁肽的第 4 项（便利性）、第 5 项（灵活性）和第 8 项（对继续当前治疗的满意度）的满意度特别低。

在这项研究中，我们表明，对于 T2D 患者，从每周一次较高剂量的索马鲁肽转为每天一次口服该分子制剂，短期内不会导致体重或糖化血红蛋白 (HbA1c) 发生显着变化。另一方面，这种修改后观察到治疗满意度下降。

尽管一些荟萃分析比较了口服索马鲁肽与其他 GLP-1 RA 的疗效 [ 4, 5 ]，但尚未对已批准的较高剂量口服索马鲁肽和皮下注射索马鲁肽进行直接比较。在一项探索 2.5/5/10/20/40 mg 每日一次口服索马鲁肽剂量功效的 2 期、开放标签剂量探索试验中，20/40 mg 剂量之间没有发现统计学显着差异。口服索马鲁肽和皮下注射索马鲁肽（1 mg）[ 6 ]。然而，之前没有任何现实世界证据表明该分子的不同配方之间切换的效果。尽管在我们的研究中切换后没有检测到体重或 HbA1c 的显着变化，但应该注意的是， HbA1c 的p值接近统计显着性。事实上，不能排除较大样本量可能检测到统计显着性p值的可能性。然而，考虑到观察到的差异，HbA1c 的这些变化在临床上的相关性可能较低。

患者报告的结果在临床研究中越来越重要。在这方面，与安慰剂相比，口服索马鲁肽提高了根据 DTSQ 评估的 T2D 患者的治疗满意度，而据报道治疗满意度与其他 GLP-1 RA 相似，例如利拉鲁肽 [ 7 ]。REVISE 研究是一项针对 T2D 患者的横断面调查（92.8% 服用口服降糖药，26.3% 使用注射制剂），参与者最初更喜欢每日一次口服制剂 (76.5%)，而不是每周一次注射剂(23.5%)，尽管在提供有关产品特定管理的详细信息时没有发现偏好差异[ 8 ]。然而，根据我们的结果，长期皮下注射索马鲁肽治疗的患者可能更喜欢这种途径，因为它具有更好的便利性和灵活性。

这项研究有一些局限性。首先，由于样本量有限，应谨慎解释这些发现。此外，从皮下注射转为口服索马鲁肽的效果是在短期内评估的，在较长时间的随访中或在具有不同特征的患者中，结果可能会有所不同。另一方面，本研究的主要优势在于其前瞻性设计。此外，据我们所知，这是第一项评估皮下注射转口服索马鲁肽对 T2D 患者影响的研究。

总之，在 GLP-1 RA 短缺的情况下，短期内每日一次口服索马鲁肽（14 mg）可能是 T2D 患者每周一次皮下注射索马鲁肽（1 mg）的有效替代品。然而，先前使用过皮下注射索马鲁肽的患者可能更喜欢这种治疗而不是口服制剂。