How to deal with the occurrence of rare drug-induced adverse events: the example of sprue-like enteropathy induced by olmesartan medoxomil and other angiotensin-receptor blockers

Angiotensin receptor blockers (ARBs) are effective antihypertensive drugs that have been available for the treatment of hypertension, heart failure and nephropathies since the early 1990s. Today, ARBs are the best-tolerated class of antihypertensive agents with no dose-dependent side effects and a tolerability profile better than placebo or angiotensin-converting enzyme inhibitors (ACEi) in clinical studies. Their efficacy in lowering blood pressure is well demonstrated and comparable to other antihypertensive drug classes.

In 2012, physicians at the Mayo Clinic reported on 22 cases of sprue-like enteropathy in patients receiving the ARB olmesartan medoxomil [1]. The clinical presentation included abdominal pain, chronic diarrhoea and weight loss, sometimes leading to malnutrition and mimicking coeliac disease, which was excluded in these patients. Symptoms resolved after discontinuation of olmesartan. Villous atrophy and lymphocytic infiltration of the mucous membrane of the small intestine were detected, suggesting a localized delayed hypersensitivity or a cell-mediated immune response. Several subsequent reports have indicated that this drug-induced enteropathy can occur with other ARBs [2,3], indicating that this complication may be a class-effect of ARBs. Several recent large observation cohort studies that have been conducted in Europe did not confirm the increased risk of intestinal malabsorption with ARBs, including olmesartan, when compared with ACEi [4]. Moreover, in a case-control study, no significant association was found between olmesartan medoxomil and diarrhoea in patients undergoing upper endoscopy or colonoscopy [5]. Sprue-like enteropathy is recognized as a rare complication. According to the review of studies by the Food and Drug Administration (FDA), gastrointestinal events in olmesartan medoxomil users affect only 3–147 per 100,000 patient-years [4,6,7]. Approximately, nine cases/100,000 patients with ACEi and between 9.8 and 14 cases/100,000 patients with ARBs were reported in more recent analyses [2]. Importantly, one cannot exclude the possibility that the true incidence may be higher because physicians do not always recognize the entity.

Publication of cases of ARB-induced sprue-like enteropathy has generated diverse and sometimes surprising reactions from national authorities. French Health authorities stopped reimbursement for olmesartan medoxomil because of a negative benefit/risk ratio. In addition to the rarity of sprue-like enteropathy, their argument also cited a lack of evidence that olmesartan lowers mortality in hypertension. This evidence is actually lacking for several other ARBs, except in the setting of heart failure. In the US, a petition was sent to the FDA to withdraw olmesartan from the market using the same arguments. The FDA refused the petition on the grounds that: (1) the incidence of the adverse effect is very low, (2) the adverse effect is easy to diagnose and reversible upon withdrawal, (3) cases of the adverse effect have been documented with other ARBs, (4) the warnings implemented in 2013 were sufficient and finally (5) the benefit/risk of olmesartan-based therapies remains highly favourable [6]. Today, several European countries are evaluating the issue of delisting olmesartan.

When stopping reimbursement or withdrawing a drug, authorities should consider the global impact that such a decision will have on patient management. For example, in France, the switch to another ARB in patients well controlled on olmesartan led to uncontrolled hypertension in 20% of patients [8]. Of note, the FDA has put forward this risk in their refusal of the petition. Thus, one can question whether it is reasonable and ethically acceptable to destabilize 9999 patients for one possible case of reversible easily diagnosed sprue-like enteropathy. Moreover, together with valsartan, olmesartan medoxomil is the only ARB that fulfils ESC/ESH guidelines recommending starting treatment of hypertension with a dual single pill combination as the first step and following with a triple single pill combination as second step in most hypertensive patients [9]. Coupled with the recent recall of valsartan [10], the unavailability of olmesartan would severely limit the ability of physicians to follow the ESC/ESH guidelines.

Whenever a new adverse event of a medication is identified, informing physicians and patients should be the first and major preventive step, particularly when the incidence of the adverse event is very low. The benefit/risk ratio and the potential clinical consequence of withdrawing the medication should be evaluated carefully, avoiding biased arguments, before deciding to delist a drug. ARB-related enteropathy is now a distinct clinical entity that physicians should include in their differential diagnosis when evaluating abdominal discomfort, diarrhoea and weight loss in ARB-treated patients.

Disclosure statement

No potential conflict of interest was reported by the author(s).