To the Editor:

Horowitz et al. have, in a Letter to the Editor,¹ raised a series of concerns related to the use of paracetamol for evaluation of gastric emptying as applied in our published work ‘Oral semaglutide improves postprandial glucose and lipid metabolism, and delays gastric emptying, in subjects with type 2 diabetes’.² While the authors of the manuscript acknowledge that Horowitz et al. have a genuine intent in promoting scintigraphy as a preferred method for assessment of gastric emptying, the authors assert that the data generated on the effects of semaglutide on gastric emptying are valid, relevant and consistent, and have been accepted by reviewers in peer-reviewed publications as well as by health authorities.^{3, 4} Below, we comment on the specific concerns raised by Horowitz et al. in relation to the data published in our manuscript.

Horowitz et al. comment that area under the curve (AUC) for paracetamol in the period of 0-2 hours was not evaluated.¹ The prespecified endpoints for paracetamol were based on previous data from subcutaneous semaglutide showing that slowing of gastric emptying was only detectable in the 0-1 hour period postdose.⁵ We have investigated the paracetamol data from the current study again and no significant difference arising from oral semaglutide treatment between the AUCs for paracetamol in the 0-2–hour period was observed (Table 1). Absence of a significant difference is not interpreted as an absence of a biological effect, but it indicates that a potential slowing of gastric emptying in the period 1-2 hours after a meal was at least not of a size that could be detected within the current dataset, that is, a minimal-to-moderate effect.

It is pointed out by Horowitz et al. that it would be illogical that oral semaglutide, after repeated dosing and at steady state exposure level, would only influence the first hour of postprandial gastric emptying.¹ They seem to imply that an effect on the period 0-1 hours after a meal would be an acute effect comparable with that observed from administration of other shorter-acting glucagon-like peptide-1 (GLP-1) receptor analogues. However, we do not conclude that the duration of treatment or the steady state level of exposure is related to the timing of an effect on gastric emptying. Rather, from our data, we conclude that following dosing of oral semaglutide to steady state (a total of 12 weeks including dose escalation), gastric emptying is decreased by 30% in the first hour after a meal and that we were not able to detect any effects on gastric emptying beyond that first hour. As for other GLP-1 receptor agonists, the effect on gastric emptying is expected to add to the lowering of postprandial glucose.

Horowitz et al. mention that the optimal conditions for testing gastric emptying are in the morning after an overnight fast.¹ In this trial, the dosing of paracetamol with a standardized lunch meal instead of a breakfast was carried out because of the oral semaglutide formulation and dosing requirements. Like most other oral semaglutide trials, oral semaglutide tablets were dosed in the fasting state, and breakfast was served 30 minutes after dosing. This allowed for absorption of oral semaglutide, which can only take place correctly in the fasting state. Paracetamol was ingested together with the subsequent lunch to avoid any interference of paracetamol absorption caused by the absorption enhancer with which oral semaglutide is co-formulated. To facilitate absorption of oral semaglutide, the peptide has been co-formulated with an absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC).⁶ SNAC is present to facilitate absorption of the semaglutide molecule from the gastrointestinal (GI) tract (specifically the stomach) by stabilizing and protecting the peptide during GI transit and facilitating its absorption across the gastric mucosa. To avoid any interference in the absorption of paracetamol by SNAC, the paracetamol dosing time was shifted from the breakfast to the lunch meal, thereby ensuring that no SNAC was left in the GI tract at the time of paracetamol dosing. Of note, at the time when we were designing our trial, it was not established whether the presence of SNAC in the GI tract could facilitate absorption of other drugs present at the same time. Later evaluations have shown that, for SNAC to facilitate absorption, SNAC and the payload have to be very close to each other and thus presumably co-formulated.^{6, 7}

It is acknowledged that the breakfast may not have been entirely emptied from the stomach at the time of the lunch meal, which may be a limitation of the trial design. However, in case some food remained in the stomach at the start of lunch, a more pronounced delay of paracetamol appearance in the blood would be anticipated. The findings of our study are very much in line with what has been reported for subcutaneous semaglutide, suggesting that even though the gastric emptying assessment was performed at the lunch meal, this did not disrupt the results.

Horowitz et al. conclude in their Letter to the Editor that ‘We believe that the study by Dahl et al. strongly suggests that oral semaglutide has the capacity to delay gastric emptying markedly in at least some individuals with type 2 diabetes’.¹ In our article, we conclude that a 30% decrease of gastric emptying was evident in the first postprandial hour, and we were not able to detect any slowing of gastric emptying resulting from oral semaglutide in the period after the first hour. We, therefore, find it puzzling that Horowitz et al. felt able to make such strong conclusions based on the reported data. We argue that the effect of semaglutide on gastric emptying is modest, irrespective of the route of administration. When the first GLP-1 agonist, exenatide (Byetta®, dosed twice-daily), was evaluated, paracetamol was used to assess its effects on gastric emptying.⁸ By use of this methodology, a pronounced effect on gastric emptying was shown. The effect was so pronounced that, depending on the timing of the exenatide dose in relation to meal intake, the postprandial blood glucose level actually dropped from baseline, implying that hypoglycaemia could be a potential risk. A subsequent study of exenatide (twice-daily) using scintigraphy supported the notion that the compound has a marked effect on gastric emptying of both liquids and solids.⁹ The effects of semaglutide on gastric emptying were less by comparison when tested at the time of maximum semaglutide exposure. This lesser effect of semaglutide was also reflected in postprandial glucose profiles, which were lowered compared with the placebo response, but not to zero incremental response or below baseline values. Therefore, the wording of modest or minor when describing the effect of semaglutide on gastric emptying has been employed and accepted by peer reviewers as well as health authorities.

In summary, we agree that semaglutide has a clinically relevant impact on gastric emptying. The effect is clear (but modest compared with some short-acting GLP-1 agonists) and significantly different to the placebo response during the first hour after a meal. However, when evaluating the total postprandial period of 5 hours (or even the period up to 2 hours), a statistically significant difference in gastric emptying between semaglutide and placebo could not be detected under the treated conditions. This knowledge is communicated and accepted by reviewers in peer-reviewed publications as well as in approved regulatory texts. The effect is regarded as a class effect and is communicated as such by all regulatory agencies across GLP-1 receptor agonists in their prescribing texts.

On behalf of the author group

Kirsten Dahl and Tine Bækdal

致编辑：

霍洛维茨等人。在给编辑的一封信中，¹提出了一系列与使用扑热息痛评估胃排空相关的担忧，如我们已发表的著作“口服司美鲁肽改善餐后葡萄糖和脂质代谢，并延迟胃排空，在患有以下疾病的受试者中” 2型糖尿病'。²虽然手稿作者承认 Horowitz 等人。有真正的意图促进闪烁扫描作为评估胃排空的首选方法，作者断言关于司美鲁肽对胃排空影响的数据是有效的、相关的和一致的，并且已被同行评审出版物的审稿人接受以及卫生当局。^3、4下面，我们对 Horowitz 等人提出的具体问题发表评论。关于我们手稿中发表的数据。

霍洛维茨等人。评论未评估对乙酰氨基酚在 0-2 小时内的曲线下面积 (AUC)。¹对乙酰氨基酚的预设终点基于先前皮下注射司美鲁肽的数据，该数据显示仅在给药后 0-1 小时内可检测到胃排空减慢。⁵我们再次调查了当前研究的扑热息痛数据，并没有观察到口服司美鲁肽治疗在 0-2 小时内扑热息痛的 AUC 之间存在显着差异（表 1）。不存在显着差异并不解释为不存在生物学效应，但它表明饭后 1-2 小时内胃排空的潜在减慢至少不是当前可检测到的大小。数据集，即最小到中等的效果。

Horowitz 等人指出了这一点。口服司美鲁肽，在重复给药并处于稳态暴露水平后，只会影响餐后胃排空的第一小时，这是不合逻辑的。¹他们似乎暗示，对餐后 0-1 小时的影响将是一种急性影响，可与其他短效胰高血糖素样肽 1 (GLP-1) 受体类似物的给药观察到的影响相媲美。然而，我们并未得出结论，治疗持续时间或稳态暴露水平与影响胃排空的时间有关。相反，根据我们的数据，我们得出结论，口服司美鲁肽达到稳态后（总共 12 周，包括剂量递增），饭后第一小时胃排空减少了 30%，我们无法检测到超过第一个小时对胃排空的任何影响。至于其他 GLP-1 受体激动剂，对胃排空的影响预计会增加餐后血糖的降低。

霍洛维茨等人。提到测试胃排空的最佳条件是在禁食过夜后的早晨。¹在该试验中，由于口服司美鲁肽制剂和剂量要求，对乙酰氨基酚与标准化午餐一起给药，而不是早餐。与大多数其他口服索马鲁肽试验一样，口服索马鲁肽片在禁食状态下给药，给药后 30 分钟供应早餐。这允许口服司美鲁肽的吸收，这只能在禁食状态下正确发生。扑热息痛与随后的午餐一起摄入，以避免与口服司美鲁肽共同配制的吸收促进剂对扑热息痛吸收造成任何干扰。为了促进口服司美鲁肽的吸收，该肽与吸收促进剂 N-(8-[2-羟基苯甲酰基]氨基)辛酸钠 (SNAC) 共同配制。⁶SNAC 的存在是为了通过在 GI 转运过程中稳定和保护肽并促进其跨胃粘膜吸收来促进 semaglutide 分子从胃肠 (GI) 道（特别是胃）的吸收。为避免SNAC对扑热息痛的吸收产生任何干扰，扑热息痛的给药时间从早餐转移到午餐，从而确保扑热息痛给药时没有SNAC留在胃肠道中。值得注意的是，在我们设计试验时，尚未确定胃肠道中 SNAC 的存在是否可以促进同时存在的其他药物的吸收。后来的评估表明，为了使 SNAC 能够促进吸收，SNAC 和有效载荷必须非常接近，因此可能是共同配制的。^6、7

众所周知，在午餐时早餐可能没有完全从胃中排空，这可能是试验设计的局限性。然而，如果午餐开始时一些食物留在胃中，预计血液中扑热息痛的出现会更明显延迟。我们的研究结果与皮下注射司美鲁肽的结果非常一致，这表明即使在午餐时进行胃排空评估，也不会破坏结果。

霍洛维茨等人。在给编辑的信中得出结论，“我们相信 Dahl 等人的研究。强烈表明，至少在某些 2 型糖尿病患者中，口服司美鲁肽具有显着延迟胃排空的能力。¹在我们的文章中，我们得出的结论是，在餐后第一个小时胃排空明显减少了 30%，并且在第一个小时后的一段时间内，我们无法检测到任何由口服司美鲁肽导致的胃排空减慢。因此，我们发现 Horowitz 等人令人费解。感觉能够根据报告的数据做出如此有力的结论。我们认为，无论给药途径如何，司美鲁肽对胃排空的影响都是适度的。在评估第一种 GLP-1 激动剂艾塞那肽（Byetta®，每天给药两次）时，使用扑热息痛来评估其对胃排空的影响。⁸通过使用这种方法，显示了对胃排空的显着影响。效果如此显着，根据与进餐相关的艾塞那肽剂量时间，餐后血糖水平实际上从基线下降，这意味着低血糖可能是一个潜在的风险。随后使用闪烁扫描法对艾塞那肽（每天两次）进行的研究支持了该化合物对液体和固体的胃排空有显着影响的观点。⁹当在最大semaglutide暴露时测试时，semaglutide对胃排空的影响相比之下较小。semaglutide 的这种较小影响也反映在餐后血糖谱中，与安慰剂反应相比降低了，但不是零增量反应或低于基线值。因此，在描述司美鲁肽对胃排空的影响时，适度或轻微的措辞已被同行评审员和卫生当局采用并接受。

总之，我们同意司美鲁肽对胃排空具有临床相关影响。效果很明显（但与一些短效 GLP-1 激动剂相比是适度的），并且与餐后第一小时内的安慰剂反应显着不同。然而，当评估 5 小时的总餐后时间（或什至长达 2 小时的时间）时，在治疗条件下无法检测到司美鲁肽和安慰剂之间胃排空的统计学显着差异。这些知识在同行评审的出版物以及批准的监管文本中被评审员传达和接受。该效应被视为一类效应，并由所有监管机构跨 GLP-1 受体激动剂在其处方文本中传达。

代表作者组

Kirsten Dahl 和 Tine Bækdal