Pill Pushing©

The Best of Pill Pushing - Proton pump inhibitors – Could your bellyache become a heartache? - (2/16/2020)

By Dr. Ron Gasbarro

The year is 1989. In that year, the first commercial dial-up Internet connection in North America is made. In November, the first Walmart store in the northeastern US, Sam's Club, is opened in Delran, New Jersey. The fall of the Berlin Wall began the evening of November 9, 1989, and continued over the following days and weeks, with people nicknamed Mauerspechte (wall woodpeckers) using various tools to chip off souvenirs, demolishing lengthy parts in the process, and creating several unofficial border crossings. In Beverly Hills, California, Lyle and Erik Menendez shot their wealthy parents to death in the family's den. They received life without parole. Civil unions between partners in a same-sex relationship became legal in Denmark under a law enacted on June 7, the world's first such legislation. Bette Davis, First Lady of American Cinema, died at 81; comedienne and TV pioneer Lucille Ball died at 77. Daniel Radcliffe, British actor, known best as Harry Potter, and Taylor Swift, American pop singer, were born. And in 1989, Prilosec® (omeprazole), the first proton pump inhibitor (PPI), indicated for the treatment of gastroesophageal reflux disease and peptic ulcer disease, was first marketed in the US. 

The drug(s) in question: 
Omeprazole belongs to the class of drugs known as proton pump inhibitors. It prevents hydrogen ions from moving about in the stomach and stops the secretion of acids in the gastrointestinal tract. This, in turn, reduces acidity in the stomach and heals ulcers. In addition, the drug keeps acid reflux in check, minimizing the risk of esophageal cancer. It not only reduces acidity in the stomach but also prevents stomach acid from rising up to the esophagus. This may minimize the risk of esophageal cancer [Miyashita, 2013].

Omeprazole was first marketed in the United States in 1989 by Astra AB, now AstraZeneca, under the brand name Losec. In 1990, at the request of the US Food and Drug Administration, the brand name Losec® was changed to Prilosec® to avoid confusion with the diuretic Lasix® (furosemide). The new name led to confusion between omeprazole (Prilosec®) and fluoxetine (Prozac®), an antidepressant. 

Since the introduction of Prilosec, other PPIs have become available. 
Lansoprazole (Prevacid®)
Dexlansoprazole (Kapidex®, Dexilant®)
Esomeprazole (Nexium®)
Pantoprazole (Protonix®) 
Rabeprazole (AcipHex®)
All are considered therapeutically equivalent [Neumann, 2013].

The good, the bad, and the ugly

What are peptic ulcers?

No solid evidence exists to suggest that the stress of modern life or a steady diet of fast food causes ulcers in the stomach and small intestine. Nevertheless, they are common in our society: About 1 out of every 10 Americans will suffer from the burning, gnawing abdominal pain of a peptic (or gastric) ulcer at some point in life.

Peptic ulcers are holes or breaks in the protective lining of the duodenum (the upper part of the small intestine) or the stomach – areas that come in contact with stomach acids and enzymes. Duodenal ulcers are more common than stomach ulcers. Comparatively rare are esophageal ulcers, which form in the esophagus and are often a result of exposure to medications, like certain antibiotics or non-steroidal anti-inflammatory drugs (NSAIDs), or alcohol abuse.

Until the mid-1980s, the conventional wisdom was that ulcers form as a result of stress, a genetic predisposition to excessive stomach acid secretion, and poor lifestyle habits, including overindulging in rich and fatty foods, alcohol, caffeine, and tobacco. Researchers believed that such influences contributed to a buildup of stomach acids that erode the protective lining of the stomach, duodenum, or esophagus.

While excessive stomach acid secretion certainly plays a role in the development of ulcers, a relatively recent theory holds that bacterial infection is the primary cause of peptic ulcers. Indeed, research conducted since the mid-1980s has shown that the bacterium Helicobacter pylori (H. pylori) is present in more than 90% of duodenal ulcers and about 80% of stomach ulcers. However, more recent figures indicate those percentages are declining.  

Tablets instead of operating tables

The need for ulcer surgery has diminished greatly over the past several decades years due to the discovery of 2 new classes of drugs: H2 blockers such as cimetidine (Tagamet®), famotidine (Pepcid®) and ranitidine (Zantac®) as well as the PPIs. Ulcer surgery meant a hospital stay, a big bill upon discharge and a mandatory bland diet, which did not include pizza or coffee. And your evening highball was replaced with shot glasses of Maalox®.   

Now, with the PPIs, you can swallow anything you want: 5-alarm chili, chocolate, onions, tomatoes, sausages, corned beef, sardines, hot sauce, luncheon meats, sloe gin fizzes – the market is your menu! Right? Hold the phone! Even though many PPIs are now available over-the-counter, they are to be used with caution. Larry the Cable Guy can swing around corn dogs and drumsticks all day while pushing Prilosec OTC (now in wildberry flavor – WTH?), but you are still at risk for tummy problems. So you keep taking your favorite PPI and resume eating your Phuket Thai. 

The darker side of the PPIs

Although PPIs are widely used, they are not without risks. According to the American College of Gastroenterology's guidelines for gastroesophageal reflux disease (GERD), potential risks associated with PPIs include [Katz, 2013]:
Osteoporosis due to a reduction in gastric acid and decreased release of ionized calcium from calcium salts and protein-bound calcium [van der Hoorn, 2015].
Clostridium difficile (C. diff) infection due to increased gastric pH levels and growth of gut microflora [Janarthanan, 2012].
Community-acquired pneumonia with short-term usage [Lambert, 2015].
The potential for adverse cardiovascular events, including myocardial infarction (heart attack) among clopidogrel (Plavix®) users taking PPIs [Cardoso, 2015; Shah, 2015].
Increased risk of dementia among PPIs users [Wijarnpreecha, 2016]. However, a newer study did not confirm that the PPIs were associated with either dementia or Alzheimer’s disease [Goldstein, 2017]. Stay tuned. 
Increased risk of kidney damage among PPI users [Moledina, 2016].

The darkest side of PPIs
A 2017 study from Washington University School of Medicine in St. Louis shows that longtime use of PPIs is also associated with an increased risk of death [Xie, 2017]. For the study, the researchers examined medical records of some 275,000 users of PPIs and nearly 75,000 people who took H2 blockers to reduce stomach acid. 

"No matter how we sliced and diced the data from this large data set, we saw the same thing: There's an increased risk of death among PPI users," said senior author Ziyad Al-Aly, MD, an assistant professor of medicine at the Washington University School of Medicine in St. Louis. "For example, when we compared patients taking H2 blockers with those taking PPIs for 1 to 2 years, we found those on PPIs had a 50% increased risk of dying over the next 5 years. People have the idea that PPIs are very safe because they are readily available, but there are real risks to taking these drugs, particularly for long periods of time." PPIs have become one of the most commonly used classes of drugs in the United States with 300 million prescriptions in 2015 for Nexium alone, according to WebMD.

A nephrologist by profession, Al-Aly has previously published studies linking PPIs to kidney disease, and other researchers have shown an association with other health problems. Al-Aly, first author Yan Xie, Ph.D., a data scientist, and colleagues reasoned that since each of these side effects carries a small risk of death, together they may affect the mortality rate of PPI users. To find out, the researchers sifted through millions of de-identified veterans' medical records in a database maintained by the U.S. Department of Veterans Affairs. They identified 275,933 people who had been prescribed a PPI and 73,355 people prescribed an H2 blocker between October 2006 and September 2008 and noted how many died and when over the following 5 years. The database did not include information on the cause of death.

Al-Aly and colleagues found a 25% increased risk of death in the PPI group compared with the H2 blocker group. The researchers calculate that, for every 500 people taking PPIs for a year, there is one extra death that would not have otherwise occurred. Given the millions of people who take PPIs regularly, this could translate into thousands of excess deaths every year, Al-Aly said.

The researchers also calculated the risk of death in people who were prescribed PPIs or H2 blockers despite not having the gastrointestinal conditions for which the drugs are recommended. Here, the researchers found that people who took PPIs had a 24% increased risk of death compared with people taking H2 blockers. Although the recommended treatment regimen for most PPIs is short - 2 to 8 weeks for ulcers, for example - many people end up taking the drugs for months or years.

"A lot of times people get prescribed PPIs for a good medical reason, but then doctors don't stop it and patients just keep getting refill after refill after refill," Al-Aly said. "There needs to be periodic re-assessments as to whether people need to be on these. Most of the time, people aren't going to need to be on PPIs for a year or 2 or 3." As compared with the H2 blocker group, people in the PPI group were older (64 years old, on average, versus 61) and also somewhat sicker, with higher rates of diabetes, hypertension, and cardiovascular disease. But these differences cannot fully account for the increased risk of death since the risk remained even when the researchers statistically controlled for age and illness. Over-the-counter PPIs contain the same chemical compounds as in prescription PPIs, just at lower doses, and there is no way to know how long people stay on them. The FDA recommends taking O-T-C PPIs no longer than 4 weeks before consulting a doctor. Al-Aly emphasizes that deciding whether to take a PPI requires a risk-benefit calculation.

"PPIs save lives," Al-Aly said. "If I needed a PPI, I absolutely would take it. But I wouldn't take it willy-nilly if I didn't need it. And I would want my doctor to be monitoring me carefully and take me off it the moment it was no longer needed."

Special concerns for Asians and the medication-sensitive 
One-size-fits-all Prilosec OTC may pose particular risks for Asians, many of whom develop 400% higher blood levels of Prilosec than Caucasians. Low-dose Prilosec would be a better place to start, yet the dosage guidelines for Prilosec and its OTC counterpart are the same for Asians and Caucasians.

Actually, 3% Caucasians also metabolize Prilosec very slowly, generating Prilosec plasma levels that are 500% higher than in other people [Andersson, 1996]. How can you tell if you are one of these people? You can't. That's why it is important to market the lowest effective doses of all drugs. But quizzically, Prilosec 10 mg is only available with a prescription. Why? Ask the manufacturer, because there is no logical reason, only financial. Prilosec 10 mg should be made available OTC for these slow metabolizers and other medication-sensitive individuals, as well as for elderly, smaller persons, and other at-risk groups.

Drug interactions: Another reason to use the lowest dose 
Prilosec inhibits one of the key liver enzymes (cytochrome P450 2C19) involved in eliminating drugs from our systems. This may lead to increased blood concentrations of drugs such as Coumadin® (warfarin), Dilantin® (phenytoin), Valium® (diazepam), and others. Indeed, the box of OTC Prilosec mentions these drug interactions and others (including digoxin). If you are taking prescription drugs, be sure to check with your pharmacist about potential drug interactions with Prilosec OTC and other PPIs. Again, a lower dose would lessen these risks.

Where the drug(s) are today

Despite all the new data that show the potential problems associated with the PPIs, the drug class is alive and making big bucks for Big Pharma. With the PPIs entering the O-T-C market, the public is often unaware of the long-term side effects – from flatulence to death – that these widely advertised and seemingly innocuous drugs have been shown to produce. 

Depending on your diagnosis, use these drugs sparingly. Going out for Mexican tonight? Take a pill before you leave. Have an ulcer? Check in with your doctor to make sure it is healed. Often, it is easier to take a pill rather than make a lifestyle change. But with the mounting evidence that these drugs are not your “get out of jail free” ticket to a pro-glutton life, caveat emptor – let the buyer beware! 

Ron Gasbarro, PharmD, is a registered pharmacist, medical writer, and principal at Rx-Press.com. Read more at www.rx-press.com


Cardoso RN, Benjo AM, DiNicolantonio JJ, et al. Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: an updated meta-analysis. Open Heart. 2015;2:e000248. 

Goldstein FC, Steenland K, Zhao L, Wharton W, Levey AI, Hajjar I. Proton pump inhibitors and risk of mild cognitive impairment and dementia. J Am Geriatr Soc. 2017 Jun 7. doi: 10.1111/jgs.14956. [Epub ahead of print]

Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol. 2012;107:1001-10.

Katz P, Gerson L, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108:308-28.

Lambert AA, Lam JO, Paik JJ, Ugarte-Gil C, Drummond MB, Crowell TA. Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis. PLoS One. 2015;10:e0128004.

Miyashita T, Shah FA, Harmon JW, et al. Do proton pump inhibitors protect against cancer progression in GERD? Surg Today. 2013;43:831-7.

Moledina DG, Perazella MA. PPIs and kidney disease: from AIN to CKD. J Nephrol. 2016;29:611-6.

Neumann I, Letelier LM, Rada G, et al. Comparison of different regimens of proton pump inhibitors for acute peptic ulcer bleeding. Cochrane Database Syst Rev. 2013:CD007999. 

Shah NH, LePendu P, Bauer-Mehren A, et al. Proton pump inhibitor usage and the risk of myocardial infarction in the general population. PLOS One. 2015;10:e0124653.

van der Hoorn MM, Tett SE, de Vries OJ, Dobson AJ, Peeters GM. The effect of dose and type of proton pump inhibitor use on risk of fractures and osteoporosis treatment in older Australian women: A prospective cohort study. Bone. 2015;81:675-82.

Wijarnpreecha K, Thongprayoon C, Panjawatanan P, Ungprasert P. Proton pump inhibitors and risk of dementia. Ann Transl Med. 2016;4:240.

Xie Y, Bowe B, Li T, Xian H, Yan Y, Al-Aly Z. Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans. BMJ Open. 2017;7:e015735.


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