Olmesartan medoxomil, the angiotensin II receptor blocker (ARB), has been widely used to manage cardiovascular diseases including hypertension since its approval in 2002 [1] with estimated worldwide sales of US $2 billion in 2009. Rubio-Tapia et al. [2] first described a case series of severe sprue-like enteropathy at the Mayo Clinic in the United States in 2012, which was linked to the use of olmesartan. Similar cases have been reported at other locations in the United States, Europe [3], and India [4]. A class effect of ARBs was suspected after several case reports of other ARB-associated enteropathy [5,6].

In July 2013, the United States Federal Drug Administration changed the olmesartan medoxomil combination label to include warnings of sprue-like enteropathy [7]. Recently, a French nationwide cohort study found an association between olmesartan and the risk of enteropathy, using claim data [8]. In April 2016, Agence Nationale de Sécurité du Médicament et des Produits de Santé (The national agency for the safety of medicines and health products) delisted specialties containing olmesartan in France because of the risk of sprue-like enteropathy and its unproven effectiveness in terms of improving morbidity and mortality related to hypertension.

The prevalence of celiac disease is very low or unknown in Northeast Asian countries such as Korea, Japan, and China [9]. To date, no cases of olmesartan- or other ARB-associated sprue-like enteropathy have been reported in Northeast Asia. We investigated the associations of olmesartan and other ARBs with enteropathy in Korea. We investigated the associations of olmesartan and other ARBs with enteropathy in Korea using a large nationwide cohort. We also compared changes in weight, hemoglobin, and serum cholesterol levels in patients taking angiotensin converting enzyme inhibitors (ACEis) and olmesartan.

Our nationwide cohort study found that olmesartan use was not associated with a higher incidence of intestinal malabsorption than ACEis or other ARBs in Koreans. The subgroup comparisons of clinical and biochemical parameters before initiation and during drug use revealed that decrease of BMI or weight loss is more apparent in ACEis group than in olmesartan group. The risk of decrease in cholesterol levels, which is a feature of celiac disease, was not evident in patients using olmesartan, either.

Following the study of Rubio-Tapia et al. [2], which suggested an association between olmesartan and spruelike enteropathy of unknown causes, several similar cases have been reported. Ianiro et al. [14] identified several shared symptoms and disease courses in patients suspected to have olmesartan-associated enteropathy. Most cases were old Caucasians who had been exposed to olmesartan for more than 6 months. A gluten-free diet did not improve the symptoms in the most patients; however, the symptoms resolved following the cessation of olmesartan. Moreover, several cases of profound sprue-like enteropathy associated with other ARBs have been reported [5,6].

A national survey conducted in France studied 36 patients suspected to have olmesartan-associated enteropathy [15]. Although the study did not include a deliberate rechallenge test, interruption of the drug was followed by remission, and reintroduction of the drug resulted in relapse. In the study using the French National Health Insurance Claim database, Basson et al. [8] found that olmesartan was associated with an increased risk of hospitalization for intestinal malabsorption and celiac disease. The risk of enteropathy was higher in patients with a longer duration of treatment. However, according to the Naranjo probability scale, a cause-effect relationship is only probable because none of patients with suspected olmesartan-associated enteropathy was exposed to a rechallenge test [16]. Following a search of the Mayo Clinic endoscopy database, Greywoode et al. [17] concluded that olmesartan-associated enteropathy is a rare adverse drug effect, and that milder presentations causing diarrhea in a substantial number of outpatients are unlikely. The large randomized clinical trial found no significant differences in the rate of gastroenterological adverse events and diarrhea between olmesartan and placebo groups with DM [18]. The cohort study using a United States integrated insurance and laboratory claim database found no difference in olmesartan- and other ARB-associated hospital admissions in patients with DM, either [19]. The mechanisms underlying the putative association between olmesartan and spruelike enteropathy are not known. Previous case reports have shown that symptoms appear months to years after olmesartan initiation. Intestinal biopsies have revealed that villous atrophy and mucosal inflammation improve after drug discontinuation, but are not affected by a gluten-free diet. Moreover, IgA transglutaminase antibodies are notably absent. A cell-mediated or delayed hypersensitivity reaction, potentially associated with the human leukocyte antigen-DQ cell surface receptor type 2, has been proposed [2]. The HLA-DQ2 or HLA-DQ8 haplotype is present in 70% of reported patients [3]. The fact that the prevalence of DQ2/DQ8 is estimated to be 30% to 40% in normal Western populations [20] and that reported cases have a higher prevalence of a susceptible genetic background for celiac disease, suggests a possible role for genetics in olmesartan-induced enteropathy.

The actual prevalence of celiac disease in Northeast Asia, including Korea and Japan, is not known. To date, celiac disease has only been described in two case reports in Korea [21,22]. One reason for the low prevalence of celiac disease is the low prevalence of HLA DQ2/DQ8 haplotypes in these countries. In contrast to the relatively high prevalence of the haplotypes in Western countries and India (more than 20%), the prevalence of the haplotypes is less than 5% in Japan and Korea [9]. Variance in the HLA DQ2 and DQ8 haplotypes among countries may explain geographic differences in olmesartan-associated enteropathy. However, possible adverse effects induced by olmesartan should not be overlooked. Although our findings suggest that there is no association between olmesartan and the incidence of enteropathy in the Korean population, awareness of olmesartan-associated enteropathy may help physicians to avoid misclassification of the disorder, and once identified, the intervention (switching antihypertensive medication) is simple and effective.

The reason why enteropathy was more prevalent in patients using ACEi than patients using ARBs is not clear. This result should be interpreted with caution due to a relatively small number of patients developing intestinal malabsorption. Patients using ACEi had more DM, heart failure, autoimmune disease, history of organ transplantation and ongoing cancer compared with those using olmesartan. Although we adjusted all these comorbidities and income levels, our findings may result from differences in baseline characteristics which were not adjusted. In order to more accurately correct baseline characteristics, we performed additional analysis with propensity score matching of various results from health examination. In this analysis, we also found that body weight was more decreased in ACEi group. However, there was no difference in significant body weight loss, which might affect the prognosis in elderlies [12]. Further researcher is needed on antihypertensive medication and subclinical weight changes in Asians.

The strength of this study is the first to identify the relationship between olmesartan and intestinal malabsorption in Asians by analyzing nationally representative cohort with relatively large sample size and long follow- up duration. The limitations of our study include the observational nature of the study design and our inability to access complete medical records. Because we used NHIS claim data, it is likely that missing diagnoses or misclassification of intestinal malabsorption or other comorbidities occurred as a result of diagnostic or coding errors, which could cause misinterpretation of the adverse drug effects. Celiac disease is rare in Korea; thus, it may have been underdiagnosed in our sample. Furthermore, milder presentations of drug-associated enteropathy may have been overlooked by physicians and patients. We tried to correct these errors by comparing body weight, hemoglobin, and cholesterol in the drug groups, which can be affected by hidden intestinal malabsorption [23]. The NHIS-NSC 2002 to 2013 is a random sample of 2% of the general Korean population. Although this national cohort is a relatively small proportion of the population, it represents a stratified random sample of the Korean population with a long-term follow up. Further prospective larger-scale studies are required to investigate olmesartan-associated enteropathy and other adverse effects in Asians.

In conclusions, we found no evidence to suggest that olmesartan is associated with intestinal malabsorption or significant body weight loss in the general Korean population.