奥美沙坦可引起乳糜泻样疾病

芝加哥——一项法国队列研究显示，降压药奥美沙坦与重度口炎性腹泻样肠病风险增加有关。

法国全民健康保险基金的Myriam Mezzarobba博士在美国消化疾病周（DDW）上报告称，这种奥美沙坦相关性疾病以绒毛萎缩、重度慢性腹泻和体重减轻为特点，而乳糜泻血清学检查结果为阴性。

研究者指出，因该病住院的发生率具有时间依赖性。在治疗的第1年内，这一风险并未显著增加，但此后急剧升高。重要的是，在这项法国研究中，除了奥美沙坦之外的血管紧张素受体阻断剂（ARB）与重度肠道吸收障碍无关。血管紧张素转换酶抑制剂（ACEI）也与此类肠道疾病无关。

关于奥美沙坦与重度肠道吸收障碍的可能相关性，既往有若干项患者数量相对较少和/或随访时间较短的研究得出了相互矛盾的结果。在此背景下，Mezzarobba博士及其合作者利用SNIIRAM数据库（覆盖5千万居民的法国全民健康保险计划）及与之关联的住院数据库开展了这项队列研究。

研究者主要关注了在2007~2012年期间开始服用ARB或ACEI的450万例患者。在超过900万人年的随访过程中，218例患者住院并被诊断为肠道吸收障碍。其中，服用奥美沙坦者在服药第1年内的发生率为2.6例/10万人年，而在第2年骤升至6.7例/10万人年，服药2年后进一步增至8.9例/10万人年。

与之相比，服用其他ARB的患者在这3个治疗时间段的肠道吸收障碍住院发生率分别为2.1、2.0和1.5例/10万人年，服用ACEI的患者分别为3.7、2.0和0.9例/10万人年。校正年龄、性别的回顾分析显示，与服用ACEI的患者相比，服用奥美沙坦不足1年的患者的肠道吸收障碍住院发生率比率为0.7，服用1~2年者为3.3，服用2年以上者为10.3。这种疾病的典型特征是停用奥美沙坦后获得临床和组织学缓解。

会议评论员、哥伦比亚大学的胃肠病学家Benjamin Lebwohl博士强调，这项法国研究给所有消化科医生都上了重要一课。“我们必须记住，绒毛萎缩并不总是乳糜泻引起的。而且很重要的一点是，奥美沙坦引起的重度肠道吸收障碍并不是一种急性药物反应，而是可以在服用奥美沙坦期间的任何时间点发生。”

Mezzarobba博士和Lebwohl博士报告称无相关利益冲突。

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By: BRUCE JANCIN, Cardiology News Digital Network

CHICAGO – The antihypertensive agent olmesartan is associated with increased risk of a severe sprue-like enteropathy, as highlighted in a nationwide French cohort study.

This olmesartan-related illness is characterized by villous atrophy, severe chronic diarrhea, and weight loss, with negative serology for celiac disease.

The hospitalization rate for this disorder is time dependent. The risk doesn’t increase significantly until after the first year on therapy but climbs steeply thereafter, Dr. Myriam Mezzarobba reported at the annual Digestive Disease Week.

Importantly, angiotensin receptor blockers other than olmesartan (Benicar) were not associated with an increased risk of severe intestinal malabsorption in the French study. Neither were ACE inhibitors, added Dr. Mezzarobba of the French National Health Insurance Fund, Paris.

A few prior reports based on relatively limited patient numbers and/or short follow-up have indicated conflicting results regarding a possible association between olmesartan and severe intestinal malabsorption. This controversy provided the impetus for Dr. Mezzarobba and coinvestigators to conduct a cohort study harnessing the database of SNIIRAM, the French national health insurance plan covering 50 million residents, with linkage to the country’s centralized hospitalization database.

The investigators zeroed in on 4.5 million patients who started on an angiotensin receptor blocker or ACE inhibitor during 2007-2012. During more than 9 million person-years of follow-up, 218 of these individuals were hospitalized with a discharge diagnosis of intestinal malabsorption.

The incidence rate for this outcome among patients on olmesartan was 2.6 cases per 100,000 person-years during their first year on the medication, rising to 6.7 per 100,000 person-years during the second year and 8.9 per 100,000 person-years after 2 years on the drug.

In contrast, the rates among patients on other angiotensin receptor blockers were 2.1, 2.0, and 1.5 per 100,000 person-years, respectively, during the same treatment duration periods. And in patients on an ACE inhibitor, the rates were 3.7, 2.0, and 0.9 cases per 100,000 person-years during the first, second, and beyond the second year on therapy.

In a regression analysis controlled for age and sex, the adjusted rate ratio for hospitalization for intestinal malabsorption in patients on olmesartan compared with those on an ACE inhibitor was 0.7 for those on medication for less than a year, 3.3 during years 1-2, and 10.3 for those on olmesartan for longer than 2 years.

The typical pattern of this disorder is clinical and histologic remission following olmesartan discontinuation, Dr. Mezzarobba noted.

Session discussant Dr. Benjamin Lebwohl stressed that the French study holds a key lesson for gastroenterologists everywhere.

"Lest we become very aggressive in our case finding for celiac disease – and many of us are now looking more closely for this disease – we need to remember that villous atrophy is not always due to celiac disease," said Dr. Lebwohl, a gastroenterologist at Columbia University, New York.

He characterized the association between olmesartan and severe intestinal malabsorption found in the French national study as "robust," adding: "Importantly, this risk was not an acute risk. It increased over time. This is not an acute drug reaction, this is something that can develop at any point, even years after starting olmesartan."

Dr. Mezzarobba and Dr. Lebwohl reported having no financial conflicts.