By Cary Blum MD, Marty Fried MD and Shreya P. Trivedi MD || Illustration by Michael Shen MD. Quiz yourself on the 5 Pearls we will be covering:
- What are associated adverse effects for patients are on long-term PPIs? (2:02)
- What are some strategies to get your patient off PPIs? (10:57)
- How do histamine-2 (H2) receptor antagonists blockers work and how can it explain why H2 blockers might not be as effective as PPIs? (13:30)
- How should you educate patients to take PPIs to get the maximize benefit? (16:48)
- How do you manage ongoing symptoms in patients on PPIs? (21:41)
Many thanks to Dr. Peter Stanich from the Division of Gastroenterology, Hepatology and Nutrition at The Ohio State University Medical Center for peer-reviewing this podcast!
To optimize learning, we are providing the podcast transcript to follow along with below:
M: A quick disclaimer –
C: In this episode, we assume more serious pathology has already been considered and ruled out, either by history or more advanced testing. And unless otherwise specified, in this podcast we are primarily referring to management of GERD.
[Sweeper – Pearl 1- Risks of PPIs]
S: Let’s start with a case to take us through our learning points. Cary I think you had someone in mind when you developed the pearls for this podcast.
C: I do – thanks Shreya! My patient was a 74 year old man who had seen several providers in clinic. He had multiple medical problems including, CKD, osteoporosis, some early cognitive impairment, and a problem list with its own table of contents–you know what I mean. Anyway, he had been on omeprazole 20mg for years and years, but from the past bunch of notes, I didn’t even know he had reflux. Turns out he hadn’t had symptoms in a long time.
M: Geez, there’s a lot to unpack there.
S: Yeah I definitely feel you, Cary. More often that not, PPIs are on patients’ medication list and I haven’t started it myself. So where did you start with this patient Cary?
C: So first I had a tums myself because these elderly complicated patients can give even the best of us a bit of heartburn. But seriously, I spent the first visit or two just getting a handle of his medical history, current and ongoing problems, and medications. I realized pretty quickly that the PPI should probably be an early target to discontinue because he hadn’t had GERD symptoms in a long time, and I was concerned the PPI could be contributing to some of his medical problems.
M: Such an incrementalist Cary!
S: Let’s pause there and talk about some of the PPI-induced medical problems that you were worried about in this patient specifically but then also other side effects we should all be familiar with.
C: Right so when I think about adverse effects of PPI I divide them into two big buckets – those related to malabsorption and those related to infection.
M: Nice I do like having a schema to organize these ideas. Cary I’ve recently heard about chronic kidney disease associated with PPIs – that doesn’t seem like either malabsorption or infection. How would you classify that?
C: Well, I should admit, there’s also likey a third “miscellaneous” category, of conditions that are associated with PPI use but the mechanism is very sketchy. CKD is in this category. Its weakly but statistically associated with PPI use in observational studies but the absolute risk comes out to only 1 to 3 additional cases in 1000 patient years.
S: I think dementia probably belongs third miscellaneous category.
C: For sure. Early studies also showed an association between PPIs and dementia, but more recent studies have failed to replicate these findings.
S: Ah nice, that’s really good to know–but how did I know you were gonna go and make things more confusing with a “third category”? Let’s get back to the two buckets of malabsorption and infection. What are the big issues related to the first–malabsorption?
C: Three main complications related to malabsorption – Vitamin B12 deficiency, low magnesium levels and osteoporosis.
S: B12! I’m starting to see the connections with your patient Cary. Vitamin B12 levels are often checked in the initial workup of reversible causes of dementia.
C: That’s definitely true and the combination of initial memory complaints of my patient and long-term PPI use led me to send off levels, which were super low. I started repleting right away.
M: Alright, and did his memory get any better?
C: Well, not exactly… looks like his cognitive issues are bit more complicated and, like many patients, probably multifactorial, but I’m glad we caught that B12 deficiency before it did become a problem.
M: Oh man that would have been perfect if a little B12 fixed him right up. Let’s get into the evidence behind vitamin B12 malabsorption in the setting of PPI use.
C: There is pretty strong evidence that PPIs diminish B12 absorption, but the absolute excess risk of developing vitamin deficiency is not huge–something on the order of 3 to 4 cases per 1000 person years, translating to a relative increase of 60 to 70% over patients not on PPIs.
A well-designed RCT give a pretty convincing case for causation. Healthy volunteers underwent a modified Schilling test both before and after initiating PPI therapy. The authors showed that taking just 20 mg of omeprazole decreases B12 absorption by 3-4 fold.
S: Alright, what’s the take home here, Cary?
C: My practice now is to monitor patients’ B12 levels about annually if they are on PPIs.
M: Listeners – We are in a guideline free zone here! We’d love to hear what your practice regarding B12 monitoring and long-term PPI use. Anyway, what’s the next stop on the malabsorption express?
C: That would be hypomagnesemia comin’ up next.
M: I personally like to shorten that to “hypo-mag” because it sounds cooler on rounds
S: Hah alright. So what’s the evidence for “hypo-mag” in PPI users?
C: The absolute risk of low magnesium individual patients is likely small, but the association is convincing and PPI’s even carry an FDA warning regarding hypomagnesemia. A meta-analysis of 9 studies confirmed that people on long term PPI therapy have an almost 50% greater relative risk for low magnesium levels than a control group. We’ll link that paper in the show notes.
S: The other big thing is–low magnesium predisposes to other electrolyte problems like hypocalcemia.
M: Ahh. “Hypocal” So hypomag may predispose to hypocal.
C: Right, which is actually a nice transition into the third major malabsorptive issue – osteoporosis and fracture.
S: Smooth Dr. Blum.
C: Thank you, thank you. But yeah, I will say the mechanism is a bit hand-wavy involving impaired calcium absorption and also possibly direct osteoclast inhibition. But a convincing association does exist.
M: Yeah? Lay it on us
C: The best data comes from the Nurses Health Study – you guys know that long term prospective cohort study of women. The authors observed a 35% relative increase in risk of hip fracture after 2+ years of PPI use. The thing is–this association was driven almost entirely by smokers, and when only never-smokers were considered, no statistically significant association was detected.
M: If this were Mythbusters I’d definitely label the risk of osteoporosis plausible though not sure we have enough data to confirm it.
S: I’d have to agree. Maybe i’ll be on the lookout more for osteoporosis in my patients who have combined hit of smokers and on PPIs.
C: Yeah I think that sounds about right.
M: Perfect, so the three adverse effects of PPIs in the malabsorption bucket are Vitamin B12 and magnesium deficiencies as well as osteoporosis due at least in part to calcium malabsorption. Let’s move on to our next bucket of adverse effects of PPIs – infections.
C: This is much smaller and really limited to C. diff and other forms of colitis.
S: Yes yes, I’ve definitely heard about risk for C. diff infection. So let’s talk about the data first and then the mechanism.
C: Again the data is all observational, but pretty strong associations here. A 2012 meta-analysis of FORTY TWO studies showed the pooled odds ratio of C. diff infection in PPI users was 1.74 with the confidence interval going from 1.47 to 2.85.
S: Ok so that’s real. Any data on recurrent C. diff?
C: You betcha. I don’t have the numbers offhand but there is also an association with higher rates of recurrent C. Diff.
M: You know C. diff is something we see all the time on the inpatient side and I never think about addressing the PPI use on the discharge medication reconciliation. It is definitely something to think about in the future…
S: For sure. Is there any thought into the causal mechanism behind PPis and c.diff?
C: The authors of the meta analysis propose it could be due to loss of the protective effect of gastric acid and/or changes in the gut microbiota.
M: Well, I, for one, never argue when someone suggests “microbiota” as an answer to any medical question. It’s like the “cytokine” wild card… Sure, fine, can’t argue it, so I guess I’ll buy it.
S: Cytokines is always the right answer. Alright, so let’s review this section. Major adverse effects of PPIs can be thought about in two major buckets – malabsorptive side effects and infection. Within malabsorption we should be on the lookout for Vitamin B12 and magnesium deficiency as well as osteoporosis. Within the infectious bucket, C. diff is the major culprit.
C: And there’s the “miscellaneous” bucket that includes weaker associations like CKD and dementia.
[Sweeper – Pearl 2 – De-prescribing]
M: So now that we’ve laid out our argument against PPIs, what are some strategies for getting patients off PPIs?
C: That’s a great question! Unfortunately DC’ing PPI therapy can be difficult because of rebound symptoms. There is no one-size-fits all strategy, and there is little-to-no evidence guiding us on this question.
S: We do have some guiding strategies that may help you to de-escalate therapy. First, when you do prescribe, write for a short duration of PPI therapy and do not give a ton of refills. Often 2-4 weeks of PPI may be enough. Set up close follow-up appointment.
C: And prepare your patient for what to expect when stopping PPI therapy – for example patients often do experience a worsening of reflux symptoms. But emphasize the positive – you’re saving them from all the unwanted side effects we just reviewed!
M: And make sure to emphasize lifestyle modifications that sometimes seem obvious but can sometimes work just as well as the meds themselves! I know I have my schtick when I counsel patients on heartburn. What do you guys tell patients who report symptoms of dyspepsia – once of course you’ve convinced yourself there’s nothing more serious going on.
S: I definitely have a little GERD song-and-dance that I go through with my patients about not eating two hours before bedtime, staying upright after you eat, weight loss
C: In addition to lifestyle changes I use other classes of medications as “rescue” options if symptoms flare. What other rescue meds do you guys use?
S: So simple stuff like tums and maalox.
C: For sure! These include aluminum hydroxide, magnesium hydroxide and calcium carbonate.
M: I kind of just think of these as chalk that coats the stomach.
C: Yeah they’re all bases that neutralize the acid after symptom onset, which is actually a huge disadvantage in that they don’t prevent symptoms.
S: But since they work fast they are in fact fantastic rescue meds.
C: Exactly. What other medication classes do you guys use?
M: I try to offer histamine receptor blockers like ranitidine – which goes by the trade name zantac – or famotidine – trade name pepcid
S: So, let’s review. Some strategies to take patients off PPIs include short, finite prescriptions to begin with, managing expectations and using rescue meds. Other, non PPI options include antacids that simply neutralize stomach acid and histamine receptor blocker.
[Sweeper Pearl 3 – H2 Blocker mechanism and less effective for dyspepsia]
S: You know I have to say, some of my patients never find H2 blockers as effective in controlling dyspepsia as PPIs
C: And there’s a good reason why! So let’s take a step back to remember the biology behind acid secretion… sorry to get all basic-science on you guys, but understanding physiology can really make the pharmacology less mystifying.
S: Alright Cary we’ll allow it.
M: We have a great graphic of the physiology that might be helpful to follow along with on any of our social media
C: Great. So remember that gastric acid is secreted by what cells?
M: Umm… Stomach cells?
C: Ummm, yes… but more specifically [pause for beat] parietal cells [M: ahhhhh]. They have the hydrogen-potassium ATPase – otherwise known as…
S: the proton pump!
C: That’s right! The infamous proton pump – purveyor of agida, head honcho of heartburn, the regal ruler of the reflux regime, the- you guys get my point.
M: I was fully ready to let you keep going.
S: Yess! Tell us more about the proton pump!
C: I for sure will, Shreya– but you’ll have to wait until pearl 4 for the specifics. For now, let’s remind ourselves: what stimulates secretion of acid from parietal cells?
S: There’s the direct stimulation by gastrin.
C: Yep! Two more. [one beat pause]
M: All I know is that I’m hungry as heck right now, and I just saw a hilarious cheeseburger meme on reddit and now my stomach is pretty much screaming at me.
C: Exactly Marty!
M: Wait, what?
C: So when your mouth waters and stomach churns in response to a visual stimulus, a lot of that is mediated by the vagus nerve! That’s the second major mechanism of parietal cell activation – the old vagoose!
M: Nice! I totally knew that…
C: And the last activating signal is paracrine signalling mediated by histamine from the enterochromaffin-like cells in the stomach. Remember those dudes from histology?
S: Ugh, it’s all coming back now
M: Like a bad case of C. diff… so I’m guessing that histamine receptor blockers target this last pathway.
C: Yep. Understanding those three activating pathways for acid, what is the major drawback to the h2 blocker medication class?
S: Oh wow, now it’s all coming together. Ranitidine and famotidine are only blocking one of three activating signals that result in the parietal cell activation. There are two other pathways that are still intact!
C: Right, and even worse over time the histamine receptors become upregulated which causes tachyphylaxis – a big word that just means diminishing returns after a while. This can occur after just a few weeks.
M: And for the record, H2 blockers are not without their own side effects – in fact they share many with PPIs, though to a lesser degree.
S: Right, thanks for pointing that out Marty. To some up, histamine antagonists only block paracrine parietal cell activation. There are still two more ways that parietal cells become activated –
M: The VAGOOSE!
C: haha, and gastrin…
[Sweeper – Pearl 4 – PPI patient education]
S: So guys, after all this reflux talk I have a problem…
M: You’re telling me, I’m on my fourth tums of this episode… these things are delicious!
S: No no no… I mean, yes, they are quite good, but no seriously. I’m all on board with the adverse effects and how to deprescribe. But as long as my patients are these PPIs, I want to help them get the maximum benefit from the drug.
C: Good points Shreya. And that brings me back to my favorite topic… physiology!
M: I mean this guy doesn’t miss a beat…
C: But I did promise Shreya more on the proton pump, so if you’ll allow me…
M: Oh I insist.
C: So where did I leave off. Ahh, that’s right. The pump itself! So as we said before, PPIs work by blocking the final common pathway of all acid secretion. But I ask you, how do they do that?!?
M: So I used to have this idea of the PPI molecules just kind of moseying on down to the stomach after being swallowed and, like, plugging up the proton pump.
C: This is super interesting. PPIs take back door to shut down the proton pump! They actually first enter the circulation and THEN enter the parietal cell. From there they are secreted through the pump itself, where in acidic conditions only, they will irreversibly bind to the outside of pump, rendering it inactive forever. That’s why PPIs have such a long duration of action.
S: Whoa I see the PPIs has quite a journey to get to that pump! I, like Marty, thought it just goes down the stomach and plugs up the pump
C: It is quite a journey, and disappointingly it sometimes gets stopped abruptly at the last step, right before the PPI has a chance to work. . .
S: That makes sense bc in order for the PPI be secreted into the gastric lumen and bind to the proton pump, the parietal cell must be activated first.
C: Right. So the the proton pump is a protein that hangs out in vesicles when the parietal cell is resting, and when the activation signal comes the vesicle migrates to the luminal membrane. Once here it shells protons into the gastric lumen which creates a more acidic environment.
S: Yep, and this physiology explains why PPIs should be taken before a meal – they need a little time to float around in the circulation looking for the parietal cell. If things work perfectly, then right at meal time, when the pump is active and the GI lumen is acidic, the drug will be in the right place and the cell is ready for that spicy tandoori chicken.
M: Okkk now I’m picking up what you’re putting down So how long before a meal should PPIs be taken?
C: Ideally about 15-30 minutes. Despite having a long duration of action due to suicide inhibition of the pump, PPI’s have a short half life in circulation, so taking the PPI at the right time is pretty important. You want the drug to be in circulation when the parietal cell is activated!
S: OK so timing is important–but how important really? It’s easy for us to say “take this pill 15 minutes before a meal” but you know, for some patients, it can be kinda hard.
C: The importance of timing was shown quite elegantly in a study of healthy volunteers. And you know what I mean when I say healthy volunteers, right?
M/S: Med students…
C: Probably… not sure for this study, but in general, unfortunately yes… Anyway, these healthy subjects underwent continuous esophageal pH monitoring for two separate periods of 7 days each. During period 1, a PPI was taken 15 minutes before breakfast. During period 2, the PPI was taken at the same time in the morning, the pt’s fasted until at least noon. The authors found that when PPIs were taken shortly before a meal, there was about a 60% reduction in the duration of acidic conditions.
S: A 60% difference is a major deal. Alright, one more question, Cary, does it matter which meal the PPI should be taken before? Does 15 minutes before lunch or dinner work just as well as 15 minutes before breakfast?
C: Glad you asked Marty. Ideally, the PPI should be taken before the first meal of the day. This is because the longer one fasts prior to eating, the more proton pumps are activated in response to a meal.
M: Think of it like overnight while you are fasting your proton pumps are just building up in the cells for a morning time proton ambush!
S: Well Marty . . .if you forget to take your PPI before your bacon and eggs, at least you’ll have good old antacids to rescue you.
M: I’m on tums number 9 now, I can’t stop. Ok, let’s review this section on patient counseling. The main takeaway here is that patients who must be on PPIs really should take it 15 to 30 minutes before breakfast. This ensures that the medication is in the serum and ready to work once the parietal cell is activated and the proton pumps migrate to the luminal surface where the PPI will be secreted and block acid secretion.
[Sweeper – pearl 5 – monitoring and follow-up]
S: Let’s finish out our PPI discussion with some more management issues – what to do when patients are still reporting symptoms while on the PPI?
M: [in a loudspeaker voice] Sir, step away from the Siracha. Put the Franks down, and take three steps back from the chili pepper flakes…
C: Well yes, obviously reviewing diet and medication timing is important here. But like any other situation in medicine when the plan isn’t working as, well, planned, we should reconsider the diagnosis.
S: Super important! PPIs are super effective at reducing acid secretion in nearly all patients when taken correctly–I know we did our fair share of PPI-bashing in the beginning of the episode, but patients and doctors alike continue to use them because they work and are by-and-large safe.
M: Right, ho many times can you name when an entire class of drugs went from prescription to over-the-counter?
S: So if the symptoms truly continue through PPI therapy, and the drug is being taken correctly ie 30 mins before meals, preferably before breakfast, we should have a low threshold to refer for endoscopy.
M: Yeah i mean that kind of goes back to the disclaimers to start the podcast, and PPI failure might be an indication that we’re not dealing with straightforward GERD.
S: And endoscopy can look for things that PPIs won’t treat, like hiatal hernias or malignancy.
M: So true. So let’s say the upper scope comes back benign with the presumptive diagnosis remaining GERD. What medication options are available at this point?
S: I’ve seen GI double up the PPI.
C: Yep, and you can double in two ways – you can make the dosing twice-daily or you can make it a double-dose in the morning to maintain once-daily dosing. And if patients STILL have symptoms you can pump it all the way up to double dose BID, which is considered “max” dosing.
M: So would that be like 80mg pantoprazole twice daily?
S: What about using H2 blockers plus PPIs?
C: The addition of H2RA can be considered once maxed on PPI. I would only do this if there’s actual evidence of continued acid reflux on esophageal pH testing, because realistically the potential benefit slim.
M: And for the reasons mentioned above, I would still take PPI first in the morning 30 mins before meals to ensure the parietal cells are maximally activated. Then you can add the ranitidine later because it’s faster acting and not reliant on parietal cell activation… matter of fact it prevents it!
S: Ahh great point Marty. So let’s review this pearl. A diagnostic “time out” is warranted for patients who continue to experience symptoms despite being on PPI therapy AND taking it correctly. Have a low threshold for further testing – be it upper endoscopy or pH testing – to rule out other etiologies. In the case of true, refractory reflux PPI dosing can be increased both by adding an evening administration and/or doubling the dose. This 4x dosage is considered max therapy, and additional H2 blocker therapy can be considered but the additional benefit is likely minimal.
- Komazawa Y, Adachi K, Mihara T, Ono M, Kawamura A, Fujishiro H, Kinoshita Y. Tolerance to famotidine and ranitidine treatment after 14 days of administration in healthy subjects without Helicobacter pylori infection. J Gastroenterol Hepatol. 2003 Jun;18(6):678-82.
- Sigterman KE, van Pinxteren B, Bonis PA, Lau J, Numans ME. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev. 2013
- Wang WH, Huang JQ, Zheng GF, Xia HH, Wong WM, Lam SK, Wong BC. Head-to-head comparison of H2-receptor antagonists and proton pump inhibitors in the treatment of erosive esophagitis: a meta-analysis. World J Gastroenterol. 2005 Jul;11(26):4067-77.
- McDonagh MS, Carson S. Drug Class Review: Proton Pump Inhibitors: Final Report. Portland (OR): Oregon Health & Science University; 2006 Jul. Results. Available from:
- Wolfe MM, Sachs G. Acid suppression: optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome. Gastroenterology. 2000;118(2 Suppl 1):S9
- Hatlebakk, J. G., Katz, P. O., Camacho‐Lobato, L. and Castell, D. O. (2000), Proton pump inhibitors: better acid suppression when taken before a meal than without a meal. Alimentary Pharmacology & Therapeutics, 14: 1267-1272.
- Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med. 1994;120(3):211.
- Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310(22):2435.
- Mizunashi K, Furukawa Y, Katano K, Abe K. Effect of omeprazole, an inhibitor of H+,K(+)-ATPase, on bone resorption in humans. Calcif Tissue Int. 1993;53(1):21.
- Khalili H, Huang ES, Jacobson BC, Camargo CA Jr, Feskanich D, Chan AT. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ. 2012;344:e372. Epub 2012 Jan 30
- Cheungpasitporn W, et al. Proton pump inhibitors linked to hypomagnesemia: a systematic review and meta-analysis of observational studies. Ren Fail. 2015;37(7):1237.
- Kwok CS, Arthur AK, Anibueze CI, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol. 2012;107(7):1011. Epub 2012 Apr 24.
- Tariq R, Singh S, Gupta A, Pardi DS, Khanna S. Association of Gastric Acid Suppression With Recurrent Clostridium difficile Infection: A Systematic Review and Meta-analysis. JAMA Intern Med. 2017
- Jena AB, Sun E, Goldman DP. Confounding in the association of proton pump inhibitor use with risk of community-acquired pneumonia. J Gen Intern Med. 2013 Feb;28(2):223-30. Epub 2012 Sep 7.