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Olmesartan and Intestinal Adverse Effects in the ROADMAP Study

      To the Editor:
      We read the article by Rubio-Tapia and colleagues
      • Rubio-Tapia A.
      • Herman M.L.
      • Ludvigsson J.F.
      • et al.
      Severe spruelike enteropathy associated with olmesartan.
      with great interest. In this article, the authors describe the occurrence of severe spruelike enteropathy in 22 patients, all of whom received olmesartan (predominantly 40 mg/d) besides other drugs. All patients had long-lasting diarrhea (3-53 months) and weight loss (2.5-50 kg). Many patients also experienced nausea and vomiting (68% of patients), abdominal pain (50%), bloating (41%), and fatigue (68%). Interestingly, these symptoms disappeared after use of olmesartan was stopped. The authors draw the conclusion that olmesartan may directly be involved in spruelike enteropathy. However, our observation in a large group of diabetic patients treated with 40 mg of olmesartan daily does not support this conclusion. We detected no association between treatment with 40 mg of olmesartan once daily and the occurrence of intestinal adverse effects in 2232 patients treated for a median of 3.2 years in the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study.
      The largest prospective, randomized, double-blind study with olmesartan is the ROADMAP study.
      • Haller H.
      • Ito S.
      • Izzo Jr, J.L.
      • et al.
      Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes.
      • Haller H.
      • Viberti G.C.
      • Mimran A.
      • et al.
      Preventing microalbuminuria in patients with diabetes: rationale and design of the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study.
      In this study, patients with type 2 diabetes were treated with 40 mg of olmesartan (n=2232) or placebo (n=2215) once daily for a median of 3.2 years, and the occurrence of microalbuminuria (interpreted as an early sign of kidney and vascular damage) was the primary end point. We now analyzed the treatment-emergent adverse events (TEAEs) reported by the study physicians. For this analysis, we selected all intestinal illnesses that typically present with diarrhea and selected all symptoms and conditions that were related to abdominal discomfort, such as pain (Table). A total of 78 patients (3.5%) in the olmesartan arm and 94 (4.2%) in the placebo arm had at least 1 episode of diarrhea or diarrhea-associated diseases. We also observed no difference between the groups in the occurrence of any intestinal TEAE. The incidence of abdominal pain or related symptoms was also comparable (Table). In the olmesartan group, 127 patients (5.7%) experienced at least 1 episode of abdominal discomfort vs 125 (5.6%) in the placebo group. The reported incidences of fatigue and weight decrease were also similar. Furthermore, we determined whether more patients prematurely terminated study participation because of intestinal or abdominal discomfort–related TEAEs. Three patients in the olmesartan group (all 3 having diarrhea) and 3 patients in the placebo group (2 having diarrhea and 1 having gastroenteritis) stopped taking the study medication because of specific gastrointestinal findings. Eight additional patients in each of the 2 study arms stopped taking the study medication because of abdominal discomfort–associated TEAEs not specifically linked to the gastrointestinal tract.
      TABLEGastrointestinal TEAEs Reported in the ROADMAP Database
      EventNo. (%) of patientsP value
      Olmesartan, 40 mg (n=2232)Placebo (n=2215)
      Intestinal-associated TEAE78 (3.5)94 (4.2).20
       Diarrhea51 (2.3)52 (2.3)
       Gastroenteritis17 (0.8)25 (1.1)
       Colitis16 (0.3)
       Enteritis2 (0.1)4 (0.2)
       Gastroduodenitis4 (0.1)2 (0.1)
       Colitis, ulcerative2 (0.1)2 (0.1)
       Duodenitis2 (0.1)2 (0.1)
       Gastrointestinal disorder3 (0.1)1
       Gastrointestinal infection13 (0.1)
       Enteritis, infectious02 (0.1)
      Abdominal discomfort–associated TEAE127 (5.7)125 (5.6).95
       Abdominal pain61 (2.7)52 (2.3)
        Upper26 (1.2)24 (1.1)
        Lower2 (0.1)1
        Location not reported by physician33 (1.4)27 (1.2)
       Dyspepsia34 (1.5)29 (1.3)
       Nausea30 (1.3)34 (1.5)
       Vomiting13 (0.6)13 (0.6)
       Flatulence6 (0.3)9 (0.4)
       Abdominal discomfort4 (0.2)4 (0.2)
       Irritable bowel syndrome2 (0.1)3 (0.1)
       Epigastric discomfort2 (0.1)2 (0.1)
       Gastrointestinal pain10
       Fatigue25 (1.1)20 (0.9)
       Weight decrease17 (0.8)11 (0.5)
      ROADMAP = Randomised Olmesartan and Diabetes Microalbuminuria Prevention; TEAE = treatment-emergent adverse event.
      In summary, in more than 2200 patients taking high-dose olmesartan for more than 3 years, we did not observe an intestinal effect of olmesartan. In the ROADMAP study, we could not find a link between the occurrence of diarrhea-associated complications and the intake of 40 mg/d of olmesartan. This finding might be because spruelike enteropathy is a rare event. Indeed, the 22 reported cases in the report by Rubio-Tapia et al came from 16 different states and were diagnosed at the Mayo Clinic during a time frame of 3 years. We cannot rule out the possibility that in this very rare disease the intestinal renin-angiotensin system plays a role; however, our data from the ROADMAP database did not identify a link between olmesartan use and the occurrence of gastrointestinal disease.

      References

        • Rubio-Tapia A.
        • Herman M.L.
        • Ludvigsson J.F.
        • et al.
        Severe spruelike enteropathy associated with olmesartan.
        Mayo Clin Proc. 2012; 87: 732-738
        • Haller H.
        • Ito S.
        • Izzo Jr, J.L.
        • et al.
        Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes.
        N Engl J Med. 2011; 364: 907-917
        • Haller H.
        • Viberti G.C.
        • Mimran A.
        • et al.
        Preventing microalbuminuria in patients with diabetes: rationale and design of the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study.
        J Hypertens. 2006; 24: 403-408

      Linked Article

      • Severe Spruelike Enteropathy Associated With Olmesartan
        Mayo Clinic ProceedingsVol. 87Issue 8
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          To report the response to discontinuation of olmesartan, an angiotensin II receptor antagonist commonly prescribed for treatment of hypertension, in patients with unexplained severe spruelike enteropathy.
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      • In reply
        Mayo Clinic ProceedingsVol. 87Issue 12
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          We appreciate the communication from Drs Menne and Haller regarding their review of the gastrointestinal adverse events in the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study. The lack of excess adverse effects relating to the gastrointestinal system in individuals enrolled in the ROADMAP study, half of whom were actively treated with olmesartan, puts our report in perspective. Their data suggest that the association we had described is likely quite rare. This finding should be reassuring for both prescribers and patients who are doing well with olmesartan.
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