Weight loss is one of the most severe and unique risks of Benicar (olmesartan), one of the newest anti-hypertensive drugs on the market. This uncommon sprue-like enteropathy is, in fact, a rare yet much dangerous side effect that threatened the very life of several patients, causing them chronic diarrhea, severe weight loss, and other harmful adverse effects (1).
Benicar (Olmesartan medoximil) is an Angiotensin II Receptor Blocker (ARB) used to reduce high blood pressure in patients suffering from hypertension (2). Often used in association with other drugs such as Amlodipine and Hydrochlorothiazide, olmesartan is the latest “sartan” drug of the ARBs class that received approval from the U.S. Food and Drug Administration (FDA) in 2002. Daiichi Sankyo obtained permission for marketing Benicar (Olmetec in Europe) after just a short 3-months trial, although this drug should be used for a life-long treatment of patients. Due to its similarity to other drugs from its class, this drug qualified, in fact, for the fast track process that granted this medication a vastly accelerated approval (2, 3). However, the lack of proper long-term evaluation of Benicar side effects prevented regulators from adequately understanding all this medication’s risks such as the weight loss caused by a gastrointestinal disorder called sprue-like enteropathy (1, 5).
The dangerous Sprue-like enteropathy
All ARBs medications include diarrhea among their side effects, along with vomit and nausea, but what makes the difference is the peculiar intestinal inflammation caused by this drug’s side effects. The weight loss resulting from this form of chronic diarrhea can be so substantial in fact, that some patients lost up to 60 kilograms. Intestinal inflammation may also prevent the intestine from absorbing adequate amounts of nutrients, leading to harmful forms of malnutrition even in otherwise healthy subjects. Heavy diarrhea and rapid weight loss may also increase the risk of electrolyte imbalance and cardiovascular damage due to dehydration and fluid loss (1, 4, 6). Symptoms of this specific form of gastrointestinal disorder caused by Benicar are quite similar to Celiac Disease, although the specific immune response that characterizes this disorder is not present. Patients who manifest olmesartan sprue-like enteropathy show villous atrophy and mucosal inflammation, but no dietary restriction seems to be able to improve their condition, leading to substantial weight loss (usually about 20 kgs). The only effective way to revert their symptoms and stop severe diarrhea was to stop taking this medication immediately (4, 5).
A first Mayo Clinic report published in June 2012 described 22 patients that developed a severe form of chronic diarrhea while under olmesartan treatment. The team led Dr. Joseph Murray registered a median weight loss of 18 kgs that was identified as a “severe spruelike enteropathy.” Intestinal biopsies showed intestinal inflammation and mucosal atrophy, together with a subepithelial collagen deposition called “sprue.” Patient’s condition improved after they stopped taking this drug, and most of them regained an average of 12.2 kgs after several months of hospitalization (4). A 2013 study published in the American Journal of Gastroenterology showed further evidence of this otherwise unclassified Benicar enteropathy, with some patients losing up to 60 kilograms and requiring several years before they were able to recover fully (5). Both the U.S. FDA and the Italian Agenzia Italiana del Farmaco (AIFA) found substantial proof of a possible risk of chronic diarrhea after two years of use and changed this medication’s label to include a warning about serious intestinal risks (7, 8).
Differences between Benicar Enteropathy and Celiac Disease
Celiac Disease (CD) or Celiac Sprue, is an autoimmune intestinal disorder that damages the small intestine caused by the ingestion of gluten, a protein found in grains. When cells of the intestinal immunity system are exposed to gluten, a reaction occurs causing a local inflammatory reaction that leads to the formation of antibodies. These antibodies attack the intestinal lining, damaging the mucosal and destroying many villi, which are small protrusions that increase the surface area of the intestinal wall. When villi are damaged (villous atrophy), the intestine’s ability to absorb nutrients from food is impaired causing malnutrition as well as other gastrointestinal symptoms such as chronic diarrhea, abdominal bloating and production of bowel gas. More severe forms of CD may lead to severe malnourishment, causing other symptoms such as substantial weight loss, iron deficiency anemia, osteoporosis, muscle cramps and mouth ulcers. The only effective treatment for CD is a strict gluten-free dietary regime (9).
The sprue-like enteropathy shows several symptoms of the CD such as the abnormal subepithelial deposition of collagen called “sprue,” as well as the villous atrophy, chronic diarrhea, weight loss and mucosal inflammation. However, the main difference between intestinal disorder and Celiac Disorder is the absence of remission even if the patient is not exposed to gluten. The typical immunological and histological findings of CD, such as the presence of tissue transglutaminase antibodies, is also absent in olmesartan enteropathy. The simultaneous presence of other gastrointestinal disorders such as a collagenous and a microscopic colitis also further endanger the patients’ health by causing a much more substantial weight loss than regular CD. However, recovery of intestinal mucosa in Benicar sprue-like enteropathy happens in a much shorter time (8 months) than in CD (usually several years) (1, 5).
Many previously unclassified cases of sprue gastrointestinal disorders have been demonstrated to be otherwise unaccounted instances of this unique enteropathy. A large retrospective review published in 2014 in the Journal of Pharmacy Practice indicated that almost one-quarter of unidentified sprue cases were linked to the use of this medication. In 2012 in fact, nearly 2 million U.S. patients received approximately 10.6 million olmesartan prescriptions (6, 10).
The real mechanism of this chronic diarrhea is still being investigated. Although many other drugs may cause diarrhea, in fact, their mechanisms are very diverse, including gastric acid suppression, drug-induced hypomotility or hypermotility, and increased stool fluidity (10). Even the specific ARBs-induced TGF-β inhibition does not cause a diarrhea of this magnitude, and the only answer may be an immuno-mediated hyper reaction of the intestinal epithelial cells (11).
Can Benicar weight loss increase the risk of cardiovascular diseases?
Olmesartan is prescribed to reduce the cardiovascular risk by lowering blood pressure. Hypertension is, in fact, associated with an increased risk of fatal and nonfatal cardiovascular events such as myocardial infarctions and strokes (1, 12). As a consequence, if a patient has received an olmesartan prescription, it’s safe to assume he’s at risk for cardiovascular events. Studies performed on hemodialysis patients, however, showed how malnutrition and inflammation may increase the mortality rate and lead to less favorable outcomes (13, 14). Atherosclerosis can be, in fact, properly defined as a chronic inflammatory disorder, and represents a major risk factor for cardiovascular diseases and accidents. It’s then safe to assume than any other inflammatory disease may have detrimental effects on atherosclerosis by further increasing the body inflammatory state (15). Malnutrition, on the other hand, aggravates existing inflammation and heart failure, and decreases the natural body defenses against infection. Inflammation itself is also associated with congestive heart failure, leading to a syndrome aptly called malnutrition, inflammation, and atherosclerosis (MIA) that affects patients with renal disease (13, 14).
Previous studies already pointed how Celiac Disease can be associated with an increased risk of ischaemic heart disease and higher cardiovascular mortality. Weight loss, chronic diarrhea, and consequent malnutrition, as well as the inflammatory state, may thus worsen the general cardiovascular profile of the patient. In other words, it may be allegedly be considered as a complication for potential cardiovascular patients, or, at least, in those who manifest symptoms of the dreaded enteropathy (16, 17).
Although FDA recently approved a label change to warn patients and doctors about the risks of severe intestinal problems (7), many people had to face a significant weight loss that negatively affected their lives for several years. People who suffered the injuries caused by this medication’s gastrointestinal damage filed a Benicar lawsuit to ask for compensation, and the number of litigations brought to court by personal injury lawyers kept growing through the whole 2015. Today over 30 litigations have been consolidated in a Multidistrict Litigation in the U.S. District Court for the District of New Jersey.
Article written by: Dr. Claudio Butticè, Pharm.D.
Published: 2016/04/01
Last Updated: 2016/06/13
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