Our contributor takes on the confounding mystery of sprue look-alikes.
Doctors at the Mayo Clinic had a medical mystery on their hands in 2009. A number of their patients were suffering from severe, chronic diarrhea and profound weight loss. Some had lost 20 to 30 pounds in a matter of weeks. When doctors peered inside the patients’ intestines, their villi—the fingerlike projections that line the small intestine, aiding in absorption of nutrients and calories—were flattened or nearly flattened (villous atrophy). But the patients didn’t have key antibodies seen in celiac disease and treatment with the gluten-free diet didn’t help. It wasn’t celiac disease but something closely mimicking it.
By 2012, Mayo doctors had followed 22 similar patients and they’d begun to suspect a popular blood pressure medication played a role in the illness. All 22 were taking the blood pressure-lowering drug, Benicar. When they stopped Benicar, they got better and gained back the weight they’d lost, an average of 27 pounds. The team published a report on their findings, calling the condition sprue-like enteropathy. (Sprue refers to celiac disease, while enteropathy indicates a disease in the intestines.)
“When doctors keep going down the line of celiac disease, treating these patients with the gluten-free diet, these people can get very ill,” says gastroenterologist and celiac expert, Joseph Murray, MD, an author of the Mayo study. “It’s life-threatening.”
Known generically as olmesartan medoxomil or simply, olmesartan, Benicar has been on the market since 2002. According to its manufacturer, Daiichi Sankyo International (DSI), more than 5 million patients worldwide have used olmesartan or a product containing olmesartan. (These include Benicar HCT, Azor and Tribenzor.) In pre-clinical studies, Benicar was shown to be safe, effective and well tolerated, says a representative of DSI. Apart from dizziness, the drug’s most common side effect, the incidence of other side effects, including diarrhea, was similar to those taking a placebo (sugar pill).
But last year, the FDA raised concerns about the drug. Through the agency’s drug safety monitoring system, it identified 23 cases of severe diarrhea and enteropathy. All improved after discontinuing the drug and, in ten of the cases, the diarrhea returned when the medication was resumed.
With evidence mounting—40 more cases were presented at the 2012 meeting of the American College of Gastroenterology—the FDA issued a warning in July 2013 that the drug can cause intestinal problems known as sprue-like enteropathy. It also approved changes to the drug’s label, adding sprue-like enteropathy as a potential side effect.
Peter H.R. Green, MD, director of the Celiac Disease Center at Columbia University, has treated a number of patients who’ve taken Benicar and developed enteropathy.
“These people are very sick,” Green says. “One patient at our center had acute kidney failure (due to dehydration). She was on dialysis and looked like she’d need a transplant. When doctors call and tell us their patients are very, very sick, we ask, are they on Benicar?”
Barbara Dent*, 72, of Gainesville, Florida, began taking Benicar in April 2012. Six months later, she suddenly developed diarrhea.
“I came home from visiting my daughter in New York on October 10,” she says. “On October 11, I was really sick.”
Dent assumed it was just a stomach bug or the flu but when the symptoms hung around, she went to her doctor. She was tested for C. diff but results were negative and her doctor suggested she lay low and stick to a liquid diet for a few days.
Three weeks later, Dent was admitted to the hospital intensive care unit with severe dehydration. With an average of 28 bowel movements a day, she was rapidly losing weight.
“I was scoped and tested for hundreds of things but doctors didn’t know what was wrong,” she says. “They didn’t call it celiac disease but they put me on a gluten-free diet.”
Dent was in the hospital for a month before her condition improved enough for her to go home. She was discharged with Immodium and instructions to stay on the gluten-free diet. But within days, severe diarrhea returned and she was back in the hospital.
This time, Dent’s daughter and son decided to move her to a hospital closer to them in New York. But she was in no shape to fly.
“So we left at 6:00 am and drove 17 hours to Long Island,” says Dent. “Every two hours, my daughter would change my Depends diaper. It was humiliating.”
It was also dangerous. When Dent was discharged from the Florida hospital, doctors wrote that her prognosis was “guarded, death.” They left her IV catheter in place (a picc line) for fluids and nutrition. They also reasoned the picc line would be invaluable should there be a medical emergency while on the road.
Dent made it to New York—but just barely. She developed an infection in the picc line and her potassium levels bottomed out. Her illness confounded her new team of doctors. When she was discharged a week later—to stay with her daughter, who could administer her daily IV treatments and cook gluten-free for her—one of her doctors suggested she see celiac expert Peter Green.
“Dr. Green immediately put two and two together with Benicar,” Dent recalls. “’Why don’t more doctors know about this?”
Making the Connection
It was two patients who first suggested that Benicar might be linked to their severe diarrhea. They were being treated at the Mayo Clinic for what doctors thought was refractory celiac disease (celiac that doesn’t get better with the gluten-free diet). While in the hospital, the patients’ blood pressure dropped and Benicar was temporarily withheld. Their diarrhea eased. When they were discharged and resumed Benicar, the diarrhea returned.
At the same time, Mayo doctors were studying a group of patients with collagenous sprue, an intestinal disorder that can cause flattening of the villi and collagen deposits in the GI tract. Doctors discovered that a third of these patients also happened to be taking olmesartan. They began to investigate a possible link, the results of which became the first published report of 22 cases of olmesartan-associated enteropathy.
Not only did all 22 patients get better off the drug, they improved relatively quickly. Diarrhea resolved and, after an average of eight months, intestinal damage healed. With celiac disease, this recovery can take years, especially in older adults. (The average age of patients in the Benicar study was 69.) Furthermore, patients who’d been told to follow a gluten-free diet were able to resume eating gluten again without any trouble.
All this implicated Benicar but doctors couldn’t prove the drug actually caused sprue-like enteropathy because it was too risky to deliberately “challenge” or give Benicar to these patients again. However, two patients reportedly resumed Benicar before a link was clearly recognized and their symptoms worsened.
How It Happens
It’s unclear how Benicar can trigger sprue-like enteropathy. Many of the Mayo patients took the drug for months or even years before developing symptoms, suggesting it could be a type of delayed hypersensitivity (allergic) reaction or a cell-mediated immune response (i.e., a reaction that doesn’t involve the production of antibodies).
However, another leading theory suggests an inactive ingredient in the drug could be the culprit. There are seven other drugs in the same class, known as angiotensin II receptor blockers or ARBs. So far, only Benicar appears to be associated with this problem, says Daniel A. Leffler, MD, MS, director of Clinical Research at the Celiac Center at Beth Israel Deaconess Medical Center. The preference for one ARB over another tends to vary around the country, in part because of insurance, he says. In New England and, specifically, Boston, where Beth Israel is located, use of Benicar is low compared to other places, says Leffler.
Leffler and other celiac experts struggle to make projections about how common olmesartan-associated enteropathy may be.
“The guess is that since the drug has been around for a while, it can’t be that common,” says Leffler. “But we really have no idea of the prevalence of this disorder because we don’t do routine endoscopies on people taking this drug. Those with mild symptoms may fly under the radar.”
Last year, Bernie Guy*, a registered dietitian from Chicago, read about a possible link between Benicar and sprue-like symptoms. Guy was interested because she takes Benicar. She also has celiac disease, diagnosed more than 20 years ago.
“Getting on a good blood pressure medication was difficult for me,” Guy says. “Benicar was the fourth drug I tried. The others caused terrible side effects but I haven’t had any since being on Benicar.”
Guy has taken the medication for five years now. Her blood pressure is well-controlled and she has no plans to switch.
However, Guy is also in the unique position of having been told the drug isn’t having any detrimental effects on her intestinal villi. Earlier this year, before she underwent an endoscopy for an unrelated issue, she showed the Benicar study to her physician. After the procedure, she was told all looked good. She was “clear.”
There’s no official warning that celiacs should exercise caution with Benicar but celiac experts say those with celiac disease may want to consider taking an alternative medication.
“It’s probably safe—but why not switch?,” says Leffler. “If one already has significant gastrointestinal disease, why not lower the risk as much as possible by using an alternative that’s not associated with this problem?”
Green agrees. “One doesn’t know if Benicar poses a risk to those with celiac disease. It’s early in the Benicar story but I encourage celiac disease patients to not take it.”
In fact, Green has identified some of his celiac patients who take Benicar and has contacted them, suggesting they consider switching. But, he says, it’s difficult to know what drugs patients are taking, since it is common to change medications when managing hypertension.
Recently, Green came across two particularly troubling cases involving Benicar.
“Usually when we identify Benicar as the problem, patients stop taking the drug and they get better,” he says. “Their biopsy results improve and if they were on the gluten-free diet, they reintroduce gluten and most do just fine. But two of my patients look like they’re actually developing celiac disease. When they were taking Benicar and were very sick, their tests for celiac antibodies were negative. Now that they’ve recovered and are back on a regular, gluten-containing diet, their antibodies appear to be going up.”
It’s too early to say whether this is coincidental or if the drug could possibly have triggered celiac disease in these two patients. Green is carefully following them to see if antibody levels stay elevated and if celiac disease does, indeed, develop. For now, the patients reportedly feel fine and have agreed to stay on a gluten-containing diet.
Benicar isn’t the first drug to mimic celiac disease. Chemotherapy agent, methotrexate, as well as immune suppressants, mycophenolate mofetil and azathioprine, can cause intestinal damage—villous atrophy—that looks like celiac, too.
Recently, a study homed in on mimics of celiac disease. In the study, researchers looked at 72 people who didn’t have celiac antibodies but had unexplained flattening of their villi. The biggest group—20 in total—was determined to have seronegative celiac disease, or celiac that developed without detectable antibodies. The next biggest group had olmesartan (Benicar)-associated enteropathy. All 15 of these patients got better when they discontinued Benicar. In three additional patients, villous atrophy was attributed to the drugs, mycophenolate mofetil and methotrexate. The rest had disorders, including giardia infection, Crohn’s disease and T-cell lymphoma. (In ten cases, no cause could be identified.)
“When people have celiac-like damage in the intestine that doesn’t respond to the gluten-free diet, medications have always been things to be concerned about,” says Leffler. “Benicar can really look like celiac disease but there are many other potential causes.”
One of the more common ones is known as autoimmune enteropathy (AIE), a condition halfway between celiac disease and Crohn’s disease. Others include collagenous sprue and common variable immune deficiency (CVID), a problem with the immune system leaving too few antibodies to fight infection. A condition called post-viral syndrome, when ongoing fatigue and malaise continues after a viral illness, can also be associated with villous atrophy.
“The lesson here is that not everyone with damage to the intestine has celiac disease,” says Leffler. “The best clue that you don’t have celiac disease is the absence of antibodies. In these cases, we become suspicious that we’re dealing with something else.”
A Good Outcome
On a recent trip to her pharmacy, Dent was picking up her new blood pressure medication when, to her surprise, she found an insert warning about a “serious intestinal problem” linked with Benicar. Her pharmacist explained they were giving out this information with all prescriptions.
“I hope other drug stores are doing that,” she says. “Maybe others will avoid the nightmare I went through.”
Dent’s case was reported to the FDA, as all serious drug reactions should be. The agency maintains a system of drug surveillance to identify problems. Some adverse events may not appear until large numbers of people have taken a drug for long periods of time.
Benicar’s manufacturer, DSI, monitors data from various sources to identify potential safety risks.
“Patient safety is our utmost concern,” says a DSI representative. “We’ll continue our safety surveillance and continue to work with the FDA.” DSI has no plans to study drug-related gastrointestinal problems at this time.
The FDA suggests talking with your doctor about concerns with olmesartan. The drug shouldn’t be stopped without first discussing it with your physician since stroke, heart attack, kidney failure and other serious harm can result when blood pressure isn’t appropriately treated.
Several months after Dent quit taking Benicar, Dr. Green told her that she could also stop the gluten-free diet. She’s been healthy since then, aside from needing physical therapy to help her regain the strength to walk independently.
“I’m incredibly grateful that life is getting back to normal,” she says.
Senior medical correspondent Christine Boyd lives in Baltimore, Maryland.