Severe intestinal malabsorption associated with ACE inhibitor or angiotensin receptor blocker treatment. An observational cohort study in Germany and Italy.

Peter Malfertheiner,Claudio Ripellino,Nazarena Cataldo

doi:10.1002/pds.4402

Abstract

PurposeThe angiotensin II receptor blocker (ARB) olmesartan has been recently associated with sprue‐like enteropathy (SLE), a gastrointestinal condition characterized by intestinal malabsorption (IM) and severe diarrhea. Whether the increased risk of SLE is substance‐specific or a class effect involving all ARBs is uncertain. The aim of this study is to assess the risk of enteropathy associated with ARBs and angiotensin converting enzyme inhibitors (ACE‐i) by using data from large administrative and claim databases.MethodsWe obtained data from Italian local health‐care units and a large German claim database and included patients treated with olmesartan, other ARBs, and ACE‐i. In the absence of a specific diagnosis code for SLE, International Classification of Diseases codes for IM were used. Analysis implemented a Poisson regression with robust error variance procedure, which allowed accounting for different clusters (local health‐care units and countries) and correctly estimating the standard error for the relative risk of rare event occurrence.ResultsPatients were divided into 3 groups: olmesartan (25.591, 5.5%), other ARBs (104.901, 22.5%), and ACE‐i patients (334.951, 72.0%). Baseline characteristics were similar overall. The incidence of unspecified IM in ACE‐i patients was not different compared with that of olmesartan, whereas a higher rate ratio was observed when comparing ARB patients with the olmesartan group (RR: 2.50, 95% CI 1.21 to 5.19, P .01). When International Classification of Diseases codes for coeliac disease were included, no differences were observed.ConclusionsWe could not confirm previous findings of a higher risk of malabsorption in olmesartan‐only patients, and drug‐induced enteropathy should be considered the result of exposure to the class of ARBs rather than a specific drug‐related effect.

Highlights

Clinical picture of sprue‐like enteropathy (SLE) resembles celiac disease and presents with symptoms varying from mild oligosymptomatic to severe malabsorption and chronic diarrhea with substantial weight loss.[1]
The incidence of unspecified intestinal malabsorption (IM) in angiotensin converting enzyme inhibitors (ACE‐i) patients was not different compared with that of olmesartan, whereas a higher rate ratio was observed when comparing angiotensin II receptor blocker (ARB) patients with the olmesartan group (RR: 2.50, 95% CI 1.21 to 5.19, P .01)
We could not confirm previous findings of a higher risk of malabsorption in olmesartan‐only patients, and drug‐induced enteropathy should be considered the result of exposure to the class of ARBs rather than a specific drug‐related effect

Summary

Introduction

Clinical picture of sprue‐like enteropathy (SLE) resembles celiac disease and presents with symptoms varying from mild oligosymptomatic (anemia and irritable bowel syndrome‐like symptoms) to severe malabsorption and chronic diarrhea with substantial weight loss.[1]. Antibiotics, nonsteroidal antiinflammatory agents, chemotherapeutics, immunosuppressants, and, recently, olmesartan (an angiotensin‐II receptor blocker, ARB) have been associated with SLE occurrence.[5] The association between severe SLE and the treatment with olmesartan medoxomil (OM) has initially been reported in a case series of 22 patients diagnosed with refractory celiac disease[6] followed by a small series of individual case reports.[4,7,8,9,10] A large observational cohort study, based on the French health insurance claim database and using International Classification of Diseases, Tenth Revision (ICD‐10) codes for intestinal malabsorption (IM) and coeliac disease diagnosis, highlighted an increased risk of hospitalization in patients treated with OM when compared with other ARBs and angiotensin converting enzyme inhibitors (ACE‐i).[11] Otherwise, it is not appropriate to rule out the class‐effect hypothesis[12] because recent case reports suggested an association between severe enteropathy and other ARBs, including valsartan, irbesartan, telmisartan, eprosartan, losartan, and candesartan.[10,13,14,15,16,17,18,19,20] A large population‐based study of ARB‐treated patients managed by the general practitioners in Italy and Germany showed similar low proportions of unspecified IM diagnosis among the different drugs belonging to the same class. These previous findings even more emphasize the need to clarify the role of hypertensive medications in the onset of severe forms of enteropathy

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