Can your antacid really cause dementia?

Digesting the buzz over that new study showing a 33% increased risk.

Last week you might have seen headlines like this one from The Washington Post:

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Long-term use of acid reflux medications linked to higher dementia risk

People who take proton pump inhibitors for about 4½ years or more have a 33 percent higher risk of developing dementia, study shows

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Based on the conclusions of a study published the day before in the journal Neurology, this story was picked up and trumpeted by hundreds of news outlets including CNN, People, Huffington Post, Healthline, The Today Show, and even the Hindustan Times… not to mention a bunch of injury lawyer sites. Perhaps you were among the many concerned people who asked their doctors about heartburn/reflux meds over the past week. I don’t blame you!

So let’s translate some knowledge on this matter. We’ll review what’s up with “class III evidence,” and whether people should head for the exits with omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid), pantoprazole (Protonix), and rabeprazole (Aciphex).

And apropos of this topic, I’ll conclude with my pick for the best roast pork sandwich in Philly. It’s far superior to the clichéd cheese steak.

~The problem of mixed messages and scientific uncertainty

One of the problems with scientific inquiry and the public domain is that we often learn conflicting things along the way to consensus.

Here’s a quick example, and then back to heartburn. Consider that one study might find ivermectin helps treat Covid. Another shows it doesn’t help at all. As the evidence accumulates from multiple trials, and we give extra credence to those trials that are well-constructed, we soon learn that ivermectin is worthless for treating Covid. This is despite a few outliers showing benefit.

This evidence-based medicine stuff is complicated, but sticking with the mainstream experts who cite high quality evidence usually works out best. Some uncertainty is inherent, but decreases over time and with further study.

[As a fascinating aside, ivermectin is useless for treating Covid unless you happen to have a case of untreated intestinal worms called strongyloidiasis, then get Covid, then get treated with ivermectin, which helps your worm infection, and thereby helps your immune system focus on fighting Covid! That’s how ivermectin “worked” in a few countries in Latin America, Southeast Asia, and sub-Saharan Africa.]

~Better quality studies of PPIs have shown the opposite results

Getting back to the heartburn meds recently splashed across the news in possible association with dementia. Proton pump inhibitors (PPIs) like omeprazole have been thoroughly studied before this. Much stronger evidence, from much stronger studies, has shown no credible association with dementia.

• A large placebo-controlled randomized trial published in 2019 in Gastroenterology found no correlation between PPI use and the development of dementia.

• A meta-analysis published in Medicine suggested that there was no statistical association between PPI use and increased risk of dementia.

• A systematic review and meta-analysis of prospective studies published in 2020 found PPIs do not increase the risk of dementia.

• A 2022 meta-analysis provided no clear evidence for an association between PPI intake and the risk of dementia.

• A prospective cohort study just published 2 months ago in June 2023 in Gastroenterology found that in adults ≥65 years of age, PPIs were not associated with dementia or decline in cognition over time.

To their credit, the researchers in this new trumpeted study tried to lower expectations:

This study provides Class III evidence that use of prescribed PPIs for > 4.4 years by individuals ages 45 years and older is associated with a higher incidence of newly diagnosed dementia.

If you practice reading these sorts of articles, the Class III evidence pops out. That’s why I italicized and boldfaced it. This sort of evidence is not definitive. In fact, it is the second lowest in quality on a scale that goes like this: Level IA (best), IB, IIA, IIB, III, and IV.

Level III evidence is from at least one non-experimental study. Typically level III evidence would include case series as well as not well-designed case-control or cohort studies.

~People with heartburn are more likely to have other confounding medical conditions that increase the risk of dementia.

Another weakness of the study published last week is that it picks up a lot of static among the signals it’s trying to tune in. An article written by Dr. Keren Landman in Vox explains this with expertise:

Large studies have shown that people taking PPIs are more likely to have other medical conditions than people who aren’t taking them. In a recent study involving 19,000 patients, people who took these medications were more likely to also be taking medications to treat high blood pressure and cholesterol, for example.

These differences are particularly important when dementia is the outcome researchers are looking for because high cholesterol, high blood pressure, and diabetes are themselves thought to increase dementia risk. Indeed, in the study published Wednesday, PPI users were more likely to have high blood pressure and diabetes than nonusers, making them more likely to develop dementia.

That makes it challenging to isolate any risks PPIs might have from the risks associated with the diseases they’re being used to treat.

~Why was this study even published by the journal Neurology?

With much higher quality studies preceding it, I’m not really sure. Back in 2016 a decent study out of Germany showed an increased risk of dementia with PPI use - so once again there are some conflicting results out there. Yet this German study was a cohort study, probably of Level IIb authority, and is outranked by subsequent analyses listed above. It’s good to keep a conversation going, but…

~What are some other known risks of PPI’s?

Like all medications, there are possible side effects and adverse events. More consistent evidence from higher quality studies has shown an association between long term PPI use and higher risks of stroke, bone fractures, C. difficile colitis, and chronic kidney disease. Relatively small increased risks… but increased nonetheless.

~Why would anyone take PPI’s?

These medicines help reduce acid secretion in the stomach, thereby reducing heartburn symptoms which can be pretty awful. They promote the healing of ulcers, gastritis, and esophagitis which can progress to bleeding, hemorrhage, and other complications such as esophageal cancer. A florid poet might state that PPI’s mercifully deliver us from the caustic hellfire of hydrochloric acid mayhem.

~What does the American Gastroenterology Society say about PPI’s?

So if you’re on a PPI, and you're worried about dementia and cognitive decline, the mainstream consensus is that the proton pump inhibitor will not significantly impact your risk. At the risk of this post becoming too technical, I’m going to quote the most recent American Gastroenterology Association guidance for clinicians in terms of best practice. You can read fluff elsewhere; I’m going to share the better examined details here, because I know you can handle it:

• All patients taking a PPI should have a regular review of the ongoing indications for use and documentation of that indication. This review should be the responsibility of the patient’s primary care provider.

• All patients without a definitive indication for chronic PPI should be considered for a trial of de-prescribing.

• Most patients with an indication for chronic PPI use who take twice-daily dosing should be considered for step down to once-daily PPI.

• Patients with complicated gastroesophageal reflux disease, such as those with a history of severe erosive esophagitis, esophageal ulcer, or peptic stricture, should generally not be considered for PPI discontinuation.

• Patients with known Barrett’s esophagus, eosinophilic esophagitis, or idiopathic pulmonary fibrosis should generally not be considered for a trial of de-prescribing.

• PPI users should be assessed for upper gastrointestinal bleeding risk using an evidence-based strategy before de-prescribing.

• Patients at high risk for upper gastrointestinal bleeding should not be considered for PPI de-prescribing.

• Patients who discontinue long-term PPI therapy should be advised that they may develop transient upper gastrointestinal symptoms due to rebound acid hypersecretion.

• When de-prescribing PPIs, either dose tapering or abrupt discontinuation can be considered.

• The decision to discontinue PPIs should be based solely on the lack of an indication for PPI use, and not because of concern for PPI-associated adverse events [PAAEs]. The presence of a PAAE or a history of a PAAE in a current PPI user is not an independent indication for PPI withdrawal. Similarly, the presence of underlying risk factors for the development of an adverse event associated with PPI use should also not be an independent indication for PPI withdrawal.

* Cheese steak, or roast pork sandwich?

If this post has not given you heartburn, congratulations. Perhaps you have a strong enough stomach to partake in one of the unsung glories of the Philadelphia foodie scene. I’m not talking about the played out cheesesteak made from beef. I’m talking about the James Beard Award winning, world famous, Italian Roast Pork Cheesesteak from John’s Roast Pork.

John’s delivers world wide, too, although I can’t vouch for how well these hold up to shipping. Order with sharp provolone and wilted spinach.

~Takeaway

Although the headlines last week read Long-term use of acid reflux medications linked to higher dementia risk, the truth is that they probably are not linked. Higher quality studies have been published for several years now showing better evidence to the contrary. PPIs are like any other medication with risks, benefits, and alternatives that should be carefully discussed with your doctor. And depending on the situation, perhaps the utility of taking these medications long term should be discussed more frequently, as they can have other adverse effects in the body. But increasing one’s risk of dementia? The consensus favors a headline reading more like this:

New Study of Lesser Authority than Previous Studies Suggests Increase in Dementia Rates for Patients Taking PPI’s Long Term, But Provides a Valuable Reminder That All Medicines, PPI’s Included, Have Risks and Benefits, and Should Be Periodically Reassessed With Your Doctor.

Would we click on that?