Heartburn/Acid Reflux

What if there were tests that could tell you whether the following drugs were a good match for your patients: Antidepressants, statins, painkillers, anticlotting medicines, chemotherapy agents, HIV treatments, organ transplant antirejection drugs, proton pump inhibitors for heartburn, and more?

That’s quite a list. And that’s pharmacogenetics, testing patients for genetic differences that affect how well a given drug will work for them and what kind of side effects to expect.

“About 9 out of 10 people will have a genetic difference in their DNA that can impact how they respond to common medications,” said Emily J. Cicali, PharmD, a clinical associate at the University of Florida College of Pharmacy, Gainesville.

Dr. Cicali is the clinical director of UF Health’s MyRx, a virtual program that gives Florida and New Jersey residents access to pharmacogenetic (PGx) tests plus expert interpretation by the health system’s pharmacists. Genetic factors are thought to contribute to about 25% or more of inappropriate drug responses or adverse events, said Kristin Wiisanen, PharmD, dean of the College of Pharmacy at Rosalind Franklin University of Medicine and Science in North Chicago.

“Pharmacogenetics helps consumers avoid drugs that may not work well for them or could cause serious adverse events. It’s personalized medicine,” Dr. Cicali said.

Through a cheek swab or blood sample, the MyRx program — and a growing number of health system programs, doctors’ offices, and home tests available across the United States — gives consumers a window on inherited gene variants that can affect how their body activates, metabolizes, and clears away medications from a long list of widely used drugs.

Why PGx Tests Can Have a Big Impact

These tests work by looking for genes that control drug metabolism.

“You have several different drug-metabolizing enzymes in your liver,” Dr. Cicali explained. “Pharmacogenetic tests look for gene variants that encode for these enzymes. If you’re an ultrarapid metabolizer, you have more of the enzymes that metabolize certain drugs, and there could be a risk the drug won’t work well because it doesn’t stay in the body long enough. On the other end of the spectrum, poor metabolizers have low levels of enzymes that affect certain drugs, so the drugs hang around longer and cause side effects.”

While pharmacogenetics is still considered an emerging science, it’s becoming more mainstream as test prices drop, insurance coverage expands, and an explosion of new research boosts understanding of gene-drug interactions, Dr. Wiisanen said.

Politicians are trying to extend its reach, too. The Right Drug Dose Now Act of 2024, introduced in Congress in late March, aims to accelerate the use of PGx by boosting public awareness and by inserting PGx test results into consumers’ electronic health records. (Though a similar bill died in a US House subcommittee in 2023.)

“The use of pharmacogenetic data to guide prescribing is growing rapidly,” Dr. Wiisanen said. “It’s becoming a routine part of drug therapy for many medications.”

What the Research Shows

When researchers sequenced the DNA of more than 10,000 Mayo Clinic patients, they made a discovery that might surprise many Americans: Gene variants that affect the effectiveness and safety of widely used drugs are not rare glitches. More than 99% of study participants had at least one. And 79% had three or more.

The Mayo-Baylor RIGHT 10K Study — one of the largest PGx studies ever conducted in the United States — looked at 77 gene variants, most involved with drug metabolism in the liver. Researchers focused closely on 13 with extensively studied, gene-based prescribing recommendations for 21 drugs including antidepressants, statins, pain killers, anticlotting medications for heart conditions, HIV treatments, chemotherapy agents, and antirejection drugs for organ transplants.

When researchers added participants’ genetic data to their electronic health records, they also sent semi-urgent alerts, which are alerts with the potential for severe harm, to the clinicians of 61 study volunteers. Over half changed patients’ drugs or doses.

The changes made a difference. One participant taking the pain drug tramadol turned out to be a poor metabolizer and was having dizzy spells because blood levels of the drug stayed high for long periods. Stopping tramadol stopped the dizziness. A participant taking escitalopram plus bupropion for major depression found out that the combo was likely ineffective because they metabolized escitalopram rapidly. A switch to a higher dose of bupropion alone put their depression into full remission.

“So many factors play into how you respond to medications,” said Mayo Clinic pharmacogenomics pharmacist Jessica Wright, PharmD, BCACP, one of the study authors. “Genetics is one of those pieces. Pharmacogenetic testing can reveal things that clinicians may not have been aware of or could help explain a patient’s exaggerated side effect.”

Pharmacogenetics is also called pharmacogenomics. The terms are often used interchangeably, even among PGx pharmacists, though the first refers to how individual genes influence drug response and the second to the effects of multiple genes, said Kelly E. Caudle, PharmD, PhD, an associate member of the Department of Pharmacy and Pharmaceutical Sciences at St. Jude Children’s Research Hospital in Memphis, Tennessee. Dr. Caudle is also co-principal investigator and director of the National Institutes of Health (NIH)-funded Clinical Pharmacogenetics Implementation Consortium (CPIC). The group creates, publishes, and posts evidence-based clinical practice guidelines for drugs with well-researched PGx influences.

By any name, PGx may help explain, predict, and sidestep unpredictable responses to a variety of drugs:

• In a 2023 multicenter study of 6944 people from seven European countries in The Lancet, those given customized drug treatments based on a 12-gene PGx panel had 30% fewer side effects than those who didn’t get this personalized prescribing. People in the study were being treated for cancer, heart disease, and mental health issues, among other conditions.
• In a 2023  from China’s Tongji University, Shanghai, of 650 survivors of strokes and transient ischemic attacks, those whose antiplatelet drugs (such as clopidogrel) were customized based on PGx testing had a lower risk for stroke and other vascular events in the next 90 days. The study was published in Frontiers in Pharmacology.
• In a University of Pennsylvania  of 1944 adults with major depression, published in the Journal of the American Medical Association, those whose antidepressants were guided by PGx test results were 28% more likely to go into remission during the first 24 weeks of treatment than those in a control group. But by 24 weeks, equal numbers were in remission. A 2023 Chinese  of 11 depression studies, published in BMC Psychiatry, came to a similar conclusion: PGx-guided antidepressant prescriptions may help people feel better quicker, perhaps by avoiding some of the usual trial-and-error of different depression drugs.

PGx checks are already strongly recommended or considered routine before some medications are prescribed. These include abacavir (Ziagen), an antiviral treatment for HIV that can have severe side effects in people with one gene variant.

The US Food and Drug Administration (FDA) recommends genetic testing for people with colon cancer before starting the drug irinotecan (Camptosar), which can cause severe diarrhea and raise infection risk in people with a gene variant that slows the drug’s elimination from the body.

Genetic testing is also recommended by the FDA for people with acute lymphoblastic leukemia before receiving the chemotherapy drug mercaptopurine (Purinethol) because a gene variant that affects drug processing can trigger serious side effects and raise the risk for infection at standard dosages.

“One of the key benefits of pharmacogenomic testing is in preventing adverse drug reactions,” Dr. Wiisanen said. “Testing of the thiopurine methyltransferase enzyme to guide dosing with 6-mercaptopurine or azathioprine can help prevent myelosuppression, a serious adverse drug reaction caused by lower production of blood cells in bone marrow.”

When, Why, and How to Test

“A family doctor should consider a PGx test if a patient is planning on taking a medication for which there is a CPIC guideline with a dosing recommendation,” said Teri Klein, PhD, professor of biomedical data science at Stanford University in California, and principal investigator at PharmGKB, an online resource funded by the NIH that provides information for healthcare practitioners, researchers, and consumers about PGx. Affiliated with CPIC, it’s based at Stanford University.

You might also consider it for patients already on a drug who are “not responding or experiencing side effects,” Dr. Caudle said.

Here’s how four PGx experts suggest consumers and physicians approach this option.

Find a Test

More than a dozen PGx tests are on the market — some only a provider can order, others a consumer can order after a review by their provider or by a provider from the testing company. Some of the tests (using saliva) may be administered at home, while blood tests are done in a doctor’s office or laboratory. Companies that offer the tests include ARUP Laboratories, Genomind, Labcorp, Mayo Clinic Laboratories, Myriad Neuroscience, Precision Sciences Inc., Tempus, and OneOme, but there are many others online. (Keep in mind that many laboratories offer “lab-developed tests” — created for use in a single laboratory — but these can be harder to verify. “The FDA regulates pharmacogenomic testing in laboratories,” Dr. Wiisanen said, “but many of the regulatory parameters are still being defined.”)

Because PGx is so new, there is no official list of recommended tests. So you’ll have to do a little homework. You can check that the laboratory is accredited by searching for it in the NIH Genetic Testing Laboratory Registry database. Beyond that, you’ll have to consult other evidence-based resources to confirm that the drug you’re interested in has research-backed data about specific gene variants (alleles) that affect metabolism as well as research-based clinical guidelines for using PGx results to make prescribing decisions.

The CPIC’s guidelines include dosing and alternate drug recommendations for more than 100 antidepressants, chemotherapy drugs, the antiplatelet and anticlotting drugs clopidogrel and warfarin, local anesthetics, antivirals and antibacterials, pain killers and anti-inflammatory drugs, and some cholesterol-lowering statins such as lovastatin and fluvastatin.

For help figuring out if a test looks for the right gene variants, Dr. Caudle and Dr. Wright recommended checking with the Association for Molecular Pathology’s website. The group published a brief list of best practices for pharmacogenomic testing in 2019. And it keeps a list of gene variants (alleles) that should be included in tests. Clinical guidelines from the CPIC and other groups, available on PharmGKB’s website, also list gene variants that affect the metabolism of the drug.

Consider Cost

The price tag for a test is typically several hundred dollars — but it can run as high as $1000-$2500. And health insurance doesn’t always pick up the tab.

In a 2023 University of Florida study of more than 1000 insurance claims for PGx testing, the number reimbursed varied from 72% for a pain diagnosis to 52% for cardiology to 46% for psychiatry.

Medicare covers some PGx testing when a consumer and their providers meet certain criteria, including whether a drug being considered has a significant gene-drug interaction. California’s Medi-Cal health insurance program covers PGx as do Medicaid programs in some states, including Arkansas and Rhode Island. You can find state-by-state coverage information on the Genetics Policy Hub’s website.

Understand the Results

As more insurers cover PGx, Dr. Klein and Dr. Wiisanen say the field will grow and more providers will use it to inform prescribing. But some health systems aren’t waiting.

In addition to UF Health’s MyRx, PGx is part of personalized medicine programs at the University of Pennsylvania in Philadelphia, Endeavor Health in Chicago, the Mayo Clinic, the University of California, San Francisco, Sanford Health in Sioux Falls, South Dakota, and St. Jude Children’s Research Hospital in Memphis, Tennessee.

Beyond testing, they offer a very useful service: A consult with a pharmacogenetics pharmacist to review the results and explain what they mean for a consumer’s current and future medications.

Physicians and curious consumers can also consult CPIC’s guidelines, which give recommendations about how to interpret the results of a PGx test, said Dr. Klein, a co-principal investigator at CPIC. CPIC has a grading system for both the evidence that supports the recommendation (high, moderate, or weak) and the recommendation itself (strong, moderate, or optional).

Currently, labeling for 456 prescription drugs sold in the United States includes some type of PGx information, according to the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling and an annotated guide from PharmGKB.

Just 108 drug labels currently tell doctors and patients what to do with the information — such as requiring or suggesting testing or offering prescribing recommendations, according to PharmGKB. In contrast, PharmGKB’s online resources include evidence-based clinical guidelines for 201 drugs from CPIC and from professional PGx societies in the Netherlands, Canada, France, and elsewhere.

Consumers and physicians can also look for a pharmacist with pharmacogenetics training in their area or through a nearby medical center to learn more, Dr. Wright suggested. And while consumers can test without working with their own physician, the experts advise against it. Don’t stop or change the dose of medications you already take on your own, they say . And do work with your primary care practitioner or specialist to get tested and understand how the results fit into the bigger picture of how your body responds to your medications.

A version of this article appeared on Medscape.com.

What if there were tests that could tell you whether the following drugs were a good match for your patients: Antidepressants, statins, painkillers, anticlotting medicines, chemotherapy agents, HIV treatments, organ transplant antirejection drugs, proton pump inhibitors for heartburn, and more?

That’s quite a list. And that’s pharmacogenetics, testing patients for genetic differences that affect how well a given drug will work for them and what kind of side effects to expect.

“About 9 out of 10 people will have a genetic difference in their DNA that can impact how they respond to common medications,” said Emily J. Cicali, PharmD, a clinical associate at the University of Florida College of Pharmacy, Gainesville.

Dr. Cicali is the clinical director of UF Health’s MyRx, a virtual program that gives Florida and New Jersey residents access to pharmacogenetic (PGx) tests plus expert interpretation by the health system’s pharmacists. Genetic factors are thought to contribute to about 25% or more of inappropriate drug responses or adverse events, said Kristin Wiisanen, PharmD, dean of the College of Pharmacy at Rosalind Franklin University of Medicine and Science in North Chicago.

“Pharmacogenetics helps consumers avoid drugs that may not work well for them or could cause serious adverse events. It’s personalized medicine,” Dr. Cicali said.

Through a cheek swab or blood sample, the MyRx program — and a growing number of health system programs, doctors’ offices, and home tests available across the United States — gives consumers a window on inherited gene variants that can affect how their body activates, metabolizes, and clears away medications from a long list of widely used drugs.

Why PGx Tests Can Have a Big Impact

These tests work by looking for genes that control drug metabolism.

“You have several different drug-metabolizing enzymes in your liver,” Dr. Cicali explained. “Pharmacogenetic tests look for gene variants that encode for these enzymes. If you’re an ultrarapid metabolizer, you have more of the enzymes that metabolize certain drugs, and there could be a risk the drug won’t work well because it doesn’t stay in the body long enough. On the other end of the spectrum, poor metabolizers have low levels of enzymes that affect certain drugs, so the drugs hang around longer and cause side effects.”

While pharmacogenetics is still considered an emerging science, it’s becoming more mainstream as test prices drop, insurance coverage expands, and an explosion of new research boosts understanding of gene-drug interactions, Dr. Wiisanen said.

Politicians are trying to extend its reach, too. The Right Drug Dose Now Act of 2024, introduced in Congress in late March, aims to accelerate the use of PGx by boosting public awareness and by inserting PGx test results into consumers’ electronic health records. (Though a similar bill died in a US House subcommittee in 2023.)

“The use of pharmacogenetic data to guide prescribing is growing rapidly,” Dr. Wiisanen said. “It’s becoming a routine part of drug therapy for many medications.”

What the Research Shows

When researchers sequenced the DNA of more than 10,000 Mayo Clinic patients, they made a discovery that might surprise many Americans: Gene variants that affect the effectiveness and safety of widely used drugs are not rare glitches. More than 99% of study participants had at least one. And 79% had three or more.

The Mayo-Baylor RIGHT 10K Study — one of the largest PGx studies ever conducted in the United States — looked at 77 gene variants, most involved with drug metabolism in the liver. Researchers focused closely on 13 with extensively studied, gene-based prescribing recommendations for 21 drugs including antidepressants, statins, pain killers, anticlotting medications for heart conditions, HIV treatments, chemotherapy agents, and antirejection drugs for organ transplants.

When researchers added participants’ genetic data to their electronic health records, they also sent semi-urgent alerts, which are alerts with the potential for severe harm, to the clinicians of 61 study volunteers. Over half changed patients’ drugs or doses.

The changes made a difference. One participant taking the pain drug tramadol turned out to be a poor metabolizer and was having dizzy spells because blood levels of the drug stayed high for long periods. Stopping tramadol stopped the dizziness. A participant taking escitalopram plus bupropion for major depression found out that the combo was likely ineffective because they metabolized escitalopram rapidly. A switch to a higher dose of bupropion alone put their depression into full remission.

“So many factors play into how you respond to medications,” said Mayo Clinic pharmacogenomics pharmacist Jessica Wright, PharmD, BCACP, one of the study authors. “Genetics is one of those pieces. Pharmacogenetic testing can reveal things that clinicians may not have been aware of or could help explain a patient’s exaggerated side effect.”

Pharmacogenetics is also called pharmacogenomics. The terms are often used interchangeably, even among PGx pharmacists, though the first refers to how individual genes influence drug response and the second to the effects of multiple genes, said Kelly E. Caudle, PharmD, PhD, an associate member of the Department of Pharmacy and Pharmaceutical Sciences at St. Jude Children’s Research Hospital in Memphis, Tennessee. Dr. Caudle is also co-principal investigator and director of the National Institutes of Health (NIH)-funded Clinical Pharmacogenetics Implementation Consortium (CPIC). The group creates, publishes, and posts evidence-based clinical practice guidelines for drugs with well-researched PGx influences.

By any name, PGx may help explain, predict, and sidestep unpredictable responses to a variety of drugs:

• In a 2023 multicenter study of 6944 people from seven European countries in The Lancet, those given customized drug treatments based on a 12-gene PGx panel had 30% fewer side effects than those who didn’t get this personalized prescribing. People in the study were being treated for cancer, heart disease, and mental health issues, among other conditions.
• In a 2023  from China’s Tongji University, Shanghai, of 650 survivors of strokes and transient ischemic attacks, those whose antiplatelet drugs (such as clopidogrel) were customized based on PGx testing had a lower risk for stroke and other vascular events in the next 90 days. The study was published in Frontiers in Pharmacology.
• In a University of Pennsylvania  of 1944 adults with major depression, published in the Journal of the American Medical Association, those whose antidepressants were guided by PGx test results were 28% more likely to go into remission during the first 24 weeks of treatment than those in a control group. But by 24 weeks, equal numbers were in remission. A 2023 Chinese  of 11 depression studies, published in BMC Psychiatry, came to a similar conclusion: PGx-guided antidepressant prescriptions may help people feel better quicker, perhaps by avoiding some of the usual trial-and-error of different depression drugs.

PGx checks are already strongly recommended or considered routine before some medications are prescribed. These include abacavir (Ziagen), an antiviral treatment for HIV that can have severe side effects in people with one gene variant.

The US Food and Drug Administration (FDA) recommends genetic testing for people with colon cancer before starting the drug irinotecan (Camptosar), which can cause severe diarrhea and raise infection risk in people with a gene variant that slows the drug’s elimination from the body.

Genetic testing is also recommended by the FDA for people with acute lymphoblastic leukemia before receiving the chemotherapy drug mercaptopurine (Purinethol) because a gene variant that affects drug processing can trigger serious side effects and raise the risk for infection at standard dosages.

“One of the key benefits of pharmacogenomic testing is in preventing adverse drug reactions,” Dr. Wiisanen said. “Testing of the thiopurine methyltransferase enzyme to guide dosing with 6-mercaptopurine or azathioprine can help prevent myelosuppression, a serious adverse drug reaction caused by lower production of blood cells in bone marrow.”

When, Why, and How to Test

“A family doctor should consider a PGx test if a patient is planning on taking a medication for which there is a CPIC guideline with a dosing recommendation,” said Teri Klein, PhD, professor of biomedical data science at Stanford University in California, and principal investigator at PharmGKB, an online resource funded by the NIH that provides information for healthcare practitioners, researchers, and consumers about PGx. Affiliated with CPIC, it’s based at Stanford University.

You might also consider it for patients already on a drug who are “not responding or experiencing side effects,” Dr. Caudle said.

Here’s how four PGx experts suggest consumers and physicians approach this option.

Find a Test

More than a dozen PGx tests are on the market — some only a provider can order, others a consumer can order after a review by their provider or by a provider from the testing company. Some of the tests (using saliva) may be administered at home, while blood tests are done in a doctor’s office or laboratory. Companies that offer the tests include ARUP Laboratories, Genomind, Labcorp, Mayo Clinic Laboratories, Myriad Neuroscience, Precision Sciences Inc., Tempus, and OneOme, but there are many others online. (Keep in mind that many laboratories offer “lab-developed tests” — created for use in a single laboratory — but these can be harder to verify. “The FDA regulates pharmacogenomic testing in laboratories,” Dr. Wiisanen said, “but many of the regulatory parameters are still being defined.”)

Because PGx is so new, there is no official list of recommended tests. So you’ll have to do a little homework. You can check that the laboratory is accredited by searching for it in the NIH Genetic Testing Laboratory Registry database. Beyond that, you’ll have to consult other evidence-based resources to confirm that the drug you’re interested in has research-backed data about specific gene variants (alleles) that affect metabolism as well as research-based clinical guidelines for using PGx results to make prescribing decisions.

The CPIC’s guidelines include dosing and alternate drug recommendations for more than 100 antidepressants, chemotherapy drugs, the antiplatelet and anticlotting drugs clopidogrel and warfarin, local anesthetics, antivirals and antibacterials, pain killers and anti-inflammatory drugs, and some cholesterol-lowering statins such as lovastatin and fluvastatin.

For help figuring out if a test looks for the right gene variants, Dr. Caudle and Dr. Wright recommended checking with the Association for Molecular Pathology’s website. The group published a brief list of best practices for pharmacogenomic testing in 2019. And it keeps a list of gene variants (alleles) that should be included in tests. Clinical guidelines from the CPIC and other groups, available on PharmGKB’s website, also list gene variants that affect the metabolism of the drug.

Consider Cost

The price tag for a test is typically several hundred dollars — but it can run as high as $1000-$2500. And health insurance doesn’t always pick up the tab.

In a 2023 University of Florida study of more than 1000 insurance claims for PGx testing, the number reimbursed varied from 72% for a pain diagnosis to 52% for cardiology to 46% for psychiatry.

Medicare covers some PGx testing when a consumer and their providers meet certain criteria, including whether a drug being considered has a significant gene-drug interaction. California’s Medi-Cal health insurance program covers PGx as do Medicaid programs in some states, including Arkansas and Rhode Island. You can find state-by-state coverage information on the Genetics Policy Hub’s website.

Understand the Results

As more insurers cover PGx, Dr. Klein and Dr. Wiisanen say the field will grow and more providers will use it to inform prescribing. But some health systems aren’t waiting.

In addition to UF Health’s MyRx, PGx is part of personalized medicine programs at the University of Pennsylvania in Philadelphia, Endeavor Health in Chicago, the Mayo Clinic, the University of California, San Francisco, Sanford Health in Sioux Falls, South Dakota, and St. Jude Children’s Research Hospital in Memphis, Tennessee.

Beyond testing, they offer a very useful service: A consult with a pharmacogenetics pharmacist to review the results and explain what they mean for a consumer’s current and future medications.

Physicians and curious consumers can also consult CPIC’s guidelines, which give recommendations about how to interpret the results of a PGx test, said Dr. Klein, a co-principal investigator at CPIC. CPIC has a grading system for both the evidence that supports the recommendation (high, moderate, or weak) and the recommendation itself (strong, moderate, or optional).

Currently, labeling for 456 prescription drugs sold in the United States includes some type of PGx information, according to the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling and an annotated guide from PharmGKB.

Just 108 drug labels currently tell doctors and patients what to do with the information — such as requiring or suggesting testing or offering prescribing recommendations, according to PharmGKB. In contrast, PharmGKB’s online resources include evidence-based clinical guidelines for 201 drugs from CPIC and from professional PGx societies in the Netherlands, Canada, France, and elsewhere.

Consumers and physicians can also look for a pharmacist with pharmacogenetics training in their area or through a nearby medical center to learn more, Dr. Wright suggested. And while consumers can test without working with their own physician, the experts advise against it. Don’t stop or change the dose of medications you already take on your own, they say . And do work with your primary care practitioner or specialist to get tested and understand how the results fit into the bigger picture of how your body responds to your medications.

A version of this article appeared on Medscape.com.

What if there were tests that could tell you whether the following drugs were a good match for your patients: Antidepressants, statins, painkillers, anticlotting medicines, chemotherapy agents, HIV treatments, organ transplant antirejection drugs, proton pump inhibitors for heartburn, and more?

That’s quite a list. And that’s pharmacogenetics, testing patients for genetic differences that affect how well a given drug will work for them and what kind of side effects to expect.

“About 9 out of 10 people will have a genetic difference in their DNA that can impact how they respond to common medications,” said Emily J. Cicali, PharmD, a clinical associate at the University of Florida College of Pharmacy, Gainesville.

Dr. Cicali is the clinical director of UF Health’s MyRx, a virtual program that gives Florida and New Jersey residents access to pharmacogenetic (PGx) tests plus expert interpretation by the health system’s pharmacists. Genetic factors are thought to contribute to about 25% or more of inappropriate drug responses or adverse events, said Kristin Wiisanen, PharmD, dean of the College of Pharmacy at Rosalind Franklin University of Medicine and Science in North Chicago.

“Pharmacogenetics helps consumers avoid drugs that may not work well for them or could cause serious adverse events. It’s personalized medicine,” Dr. Cicali said.

Through a cheek swab or blood sample, the MyRx program — and a growing number of health system programs, doctors’ offices, and home tests available across the United States — gives consumers a window on inherited gene variants that can affect how their body activates, metabolizes, and clears away medications from a long list of widely used drugs.

Why PGx Tests Can Have a Big Impact

These tests work by looking for genes that control drug metabolism.

“You have several different drug-metabolizing enzymes in your liver,” Dr. Cicali explained. “Pharmacogenetic tests look for gene variants that encode for these enzymes. If you’re an ultrarapid metabolizer, you have more of the enzymes that metabolize certain drugs, and there could be a risk the drug won’t work well because it doesn’t stay in the body long enough. On the other end of the spectrum, poor metabolizers have low levels of enzymes that affect certain drugs, so the drugs hang around longer and cause side effects.”

While pharmacogenetics is still considered an emerging science, it’s becoming more mainstream as test prices drop, insurance coverage expands, and an explosion of new research boosts understanding of gene-drug interactions, Dr. Wiisanen said.

Politicians are trying to extend its reach, too. The Right Drug Dose Now Act of 2024, introduced in Congress in late March, aims to accelerate the use of PGx by boosting public awareness and by inserting PGx test results into consumers’ electronic health records. (Though a similar bill died in a US House subcommittee in 2023.)

“The use of pharmacogenetic data to guide prescribing is growing rapidly,” Dr. Wiisanen said. “It’s becoming a routine part of drug therapy for many medications.”

What the Research Shows

When researchers sequenced the DNA of more than 10,000 Mayo Clinic patients, they made a discovery that might surprise many Americans: Gene variants that affect the effectiveness and safety of widely used drugs are not rare glitches. More than 99% of study participants had at least one. And 79% had three or more.

The Mayo-Baylor RIGHT 10K Study — one of the largest PGx studies ever conducted in the United States — looked at 77 gene variants, most involved with drug metabolism in the liver. Researchers focused closely on 13 with extensively studied, gene-based prescribing recommendations for 21 drugs including antidepressants, statins, pain killers, anticlotting medications for heart conditions, HIV treatments, chemotherapy agents, and antirejection drugs for organ transplants.

When researchers added participants’ genetic data to their electronic health records, they also sent semi-urgent alerts, which are alerts with the potential for severe harm, to the clinicians of 61 study volunteers. Over half changed patients’ drugs or doses.

The changes made a difference. One participant taking the pain drug tramadol turned out to be a poor metabolizer and was having dizzy spells because blood levels of the drug stayed high for long periods. Stopping tramadol stopped the dizziness. A participant taking escitalopram plus bupropion for major depression found out that the combo was likely ineffective because they metabolized escitalopram rapidly. A switch to a higher dose of bupropion alone put their depression into full remission.

“So many factors play into how you respond to medications,” said Mayo Clinic pharmacogenomics pharmacist Jessica Wright, PharmD, BCACP, one of the study authors. “Genetics is one of those pieces. Pharmacogenetic testing can reveal things that clinicians may not have been aware of or could help explain a patient’s exaggerated side effect.”

Pharmacogenetics is also called pharmacogenomics. The terms are often used interchangeably, even among PGx pharmacists, though the first refers to how individual genes influence drug response and the second to the effects of multiple genes, said Kelly E. Caudle, PharmD, PhD, an associate member of the Department of Pharmacy and Pharmaceutical Sciences at St. Jude Children’s Research Hospital in Memphis, Tennessee. Dr. Caudle is also co-principal investigator and director of the National Institutes of Health (NIH)-funded Clinical Pharmacogenetics Implementation Consortium (CPIC). The group creates, publishes, and posts evidence-based clinical practice guidelines for drugs with well-researched PGx influences.

By any name, PGx may help explain, predict, and sidestep unpredictable responses to a variety of drugs:

• In a 2023 multicenter study of 6944 people from seven European countries in The Lancet, those given customized drug treatments based on a 12-gene PGx panel had 30% fewer side effects than those who didn’t get this personalized prescribing. People in the study were being treated for cancer, heart disease, and mental health issues, among other conditions.
• In a 2023  from China’s Tongji University, Shanghai, of 650 survivors of strokes and transient ischemic attacks, those whose antiplatelet drugs (such as clopidogrel) were customized based on PGx testing had a lower risk for stroke and other vascular events in the next 90 days. The study was published in Frontiers in Pharmacology.
• In a University of Pennsylvania  of 1944 adults with major depression, published in the Journal of the American Medical Association, those whose antidepressants were guided by PGx test results were 28% more likely to go into remission during the first 24 weeks of treatment than those in a control group. But by 24 weeks, equal numbers were in remission. A 2023 Chinese  of 11 depression studies, published in BMC Psychiatry, came to a similar conclusion: PGx-guided antidepressant prescriptions may help people feel better quicker, perhaps by avoiding some of the usual trial-and-error of different depression drugs.

PGx checks are already strongly recommended or considered routine before some medications are prescribed. These include abacavir (Ziagen), an antiviral treatment for HIV that can have severe side effects in people with one gene variant.

The US Food and Drug Administration (FDA) recommends genetic testing for people with colon cancer before starting the drug irinotecan (Camptosar), which can cause severe diarrhea and raise infection risk in people with a gene variant that slows the drug’s elimination from the body.

Genetic testing is also recommended by the FDA for people with acute lymphoblastic leukemia before receiving the chemotherapy drug mercaptopurine (Purinethol) because a gene variant that affects drug processing can trigger serious side effects and raise the risk for infection at standard dosages.

“One of the key benefits of pharmacogenomic testing is in preventing adverse drug reactions,” Dr. Wiisanen said. “Testing of the thiopurine methyltransferase enzyme to guide dosing with 6-mercaptopurine or azathioprine can help prevent myelosuppression, a serious adverse drug reaction caused by lower production of blood cells in bone marrow.”

When, Why, and How to Test

“A family doctor should consider a PGx test if a patient is planning on taking a medication for which there is a CPIC guideline with a dosing recommendation,” said Teri Klein, PhD, professor of biomedical data science at Stanford University in California, and principal investigator at PharmGKB, an online resource funded by the NIH that provides information for healthcare practitioners, researchers, and consumers about PGx. Affiliated with CPIC, it’s based at Stanford University.

You might also consider it for patients already on a drug who are “not responding or experiencing side effects,” Dr. Caudle said.

Here’s how four PGx experts suggest consumers and physicians approach this option.

Find a Test

More than a dozen PGx tests are on the market — some only a provider can order, others a consumer can order after a review by their provider or by a provider from the testing company. Some of the tests (using saliva) may be administered at home, while blood tests are done in a doctor’s office or laboratory. Companies that offer the tests include ARUP Laboratories, Genomind, Labcorp, Mayo Clinic Laboratories, Myriad Neuroscience, Precision Sciences Inc., Tempus, and OneOme, but there are many others online. (Keep in mind that many laboratories offer “lab-developed tests” — created for use in a single laboratory — but these can be harder to verify. “The FDA regulates pharmacogenomic testing in laboratories,” Dr. Wiisanen said, “but many of the regulatory parameters are still being defined.”)

Because PGx is so new, there is no official list of recommended tests. So you’ll have to do a little homework. You can check that the laboratory is accredited by searching for it in the NIH Genetic Testing Laboratory Registry database. Beyond that, you’ll have to consult other evidence-based resources to confirm that the drug you’re interested in has research-backed data about specific gene variants (alleles) that affect metabolism as well as research-based clinical guidelines for using PGx results to make prescribing decisions.

The CPIC’s guidelines include dosing and alternate drug recommendations for more than 100 antidepressants, chemotherapy drugs, the antiplatelet and anticlotting drugs clopidogrel and warfarin, local anesthetics, antivirals and antibacterials, pain killers and anti-inflammatory drugs, and some cholesterol-lowering statins such as lovastatin and fluvastatin.

For help figuring out if a test looks for the right gene variants, Dr. Caudle and Dr. Wright recommended checking with the Association for Molecular Pathology’s website. The group published a brief list of best practices for pharmacogenomic testing in 2019. And it keeps a list of gene variants (alleles) that should be included in tests. Clinical guidelines from the CPIC and other groups, available on PharmGKB’s website, also list gene variants that affect the metabolism of the drug.

Consider Cost

The price tag for a test is typically several hundred dollars — but it can run as high as $1000-$2500. And health insurance doesn’t always pick up the tab.

In a 2023 University of Florida study of more than 1000 insurance claims for PGx testing, the number reimbursed varied from 72% for a pain diagnosis to 52% for cardiology to 46% for psychiatry.

Medicare covers some PGx testing when a consumer and their providers meet certain criteria, including whether a drug being considered has a significant gene-drug interaction. California’s Medi-Cal health insurance program covers PGx as do Medicaid programs in some states, including Arkansas and Rhode Island. You can find state-by-state coverage information on the Genetics Policy Hub’s website.

Understand the Results

As more insurers cover PGx, Dr. Klein and Dr. Wiisanen say the field will grow and more providers will use it to inform prescribing. But some health systems aren’t waiting.

In addition to UF Health’s MyRx, PGx is part of personalized medicine programs at the University of Pennsylvania in Philadelphia, Endeavor Health in Chicago, the Mayo Clinic, the University of California, San Francisco, Sanford Health in Sioux Falls, South Dakota, and St. Jude Children’s Research Hospital in Memphis, Tennessee.

Beyond testing, they offer a very useful service: A consult with a pharmacogenetics pharmacist to review the results and explain what they mean for a consumer’s current and future medications.

Physicians and curious consumers can also consult CPIC’s guidelines, which give recommendations about how to interpret the results of a PGx test, said Dr. Klein, a co-principal investigator at CPIC. CPIC has a grading system for both the evidence that supports the recommendation (high, moderate, or weak) and the recommendation itself (strong, moderate, or optional).

Currently, labeling for 456 prescription drugs sold in the United States includes some type of PGx information, according to the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling and an annotated guide from PharmGKB.

Just 108 drug labels currently tell doctors and patients what to do with the information — such as requiring or suggesting testing or offering prescribing recommendations, according to PharmGKB. In contrast, PharmGKB’s online resources include evidence-based clinical guidelines for 201 drugs from CPIC and from professional PGx societies in the Netherlands, Canada, France, and elsewhere.

Consumers and physicians can also look for a pharmacist with pharmacogenetics training in their area or through a nearby medical center to learn more, Dr. Wright suggested. And while consumers can test without working with their own physician, the experts advise against it. Don’t stop or change the dose of medications you already take on your own, they say . And do work with your primary care practitioner or specialist to get tested and understand how the results fit into the bigger picture of how your body responds to your medications.

A version of this article appeared on Medscape.com.

BOSTON — The US Food and Drug Administration (FDA) approved 55 new medications in 2023 and 11 more in 2024 to date. During a presentation on April 18 at the annual American College of Physicians Internal Medicine Meeting, Gerald Smetana, MD, professor of medicine in the Division of General Medicine at Beth Israel Deaconess Medical Center in Boston, reviewed four of these new therapies that are likely to be particularly important for primary care clinicians. 

A New First-Line for GERD?

Vonoprazan, an oral potassium-competitive acid blocker — which received FDA approval in November 2023 — may be a good alternative for patients whose symptoms continue to linger despite taking medications designated to treat gastroesophageal reflux disease (GERD). 

GERD is the most common gastrointestinal symptom encountered by primary care physicians. Proton-pump inhibitors (PPIs) are the first-line treatment for the condition but can have long-term side effects such as Clostridioides difficile infection and kidney lesions.

“We know that not all patients are going to have symptom relief with H2 blockers and PPIs, so there’s an opportunity for patients who don’t get full symptom relief,” Dr. Smetana told attendees. 

Vonoprazan blocks potassium binding to ATPase proton pumps and inhibits the secretion of gastric acid.

The approval of vonoprazan for erosive GERD was based on results from the phase 3 PHALCON-EE study, a randomized, double-blind, multicenter study that found the drug to be more effective than lansoprazole in treating erosive esophagitis.

Vonoprazan “has more rapid absorption than PPIs [and a] longer half-life and is more potent than PPIs, so theoretically it could be more effective in certain settings,” Dr. Smetana said.

Vonoprazan is FDA approved for only 6 months of use. Despite its efficacy, cost may be a barrier to many patients. H2 blockers generally cost patients less than $10 for 1 month’s supply, whereas vonoprazan can cost up to $650.
 

Nonhormonal Drug for Menopause

Fezolinetant, the first neurokinin receptor antagonist to receive approval from the FDA to treat vasomotor symptoms, may be an option for women concerned about hormone-based therapy for menopausal hot flashes.

“[Fezolinetant] specifically works in the area of the brain that’s involved in body temperature regulation and sweating,” Dr. Smetana said.

Results from the SKYLIGHT 1 randomized controlled trial of fezolinetant found the medication reduced the frequency and severity of hot flashes. Some of the side effects include abdominal pain, diarrhea, and insomnia. 

Other nonestrogen treatments, including selective serotonin reuptake inhibitors (SSRIs), gabapentin, cognitive-behavioral therapy, and hypnosis, are modestly effective, according to the North American Menopause Society.

“[Fezolinetant] offers a different option that physicians may be more comfortable prescribing,” Dr. Smetana said. “And I think this will be an important addition to nonhormonal therapy.”
 

RSV Vaccine for Everyone 

Once considered an illness that is more prevalent in young children, respiratory syncytial virus (RSV) has become more prevalent and severe among older adults. Between 60,000 and 120,000 older adults are hospitalized and 6000-10,000 die of RSV infection each year, according to the US Centers for Disease Control and Prevention. 

The FDA has approved two RSV vaccines approved for older adults, but clinicians may find it challenging to get older patients vaccinated for this and other preventable illnesses.

Patients who received the RSV vaccine had an 83% relative risk reduction for the illness, according to a recent study, and an overall lower risk for hospitalization.

Moderna is developing an mRNA vaccine for RSV that is similar to many COVID-19 vaccines. A study published in 2023 in The New England Journal of Medicine found no cases of neuroinflammatory disorders among patients who received the mRNA RSV vaccine, with a median follow-up of 112 days.

“This is important given ongoing concerns of neurological safety,” among older adults who receive the RSV vaccine, Dr. Smetana said.

As of March 2024, the CDC recommends shared decision-making for adults older than 60 years and for healthcare providers to “consider” rather than “recommend” the vaccine for their patients. The agency’s Adult RSV Work Group plans to meet at June 2024 to reconsider whether shared clinical decision-making remains the preferred policy option.
 

New Antidepressants

A medication thrice rejected by the FDA is now heading a new class of drugs to treat major depressive disorder.

Gepirone, a 5-HT1A receptor agonist, has a different mechanism of action from that of SSRIs, which are currently considered the first-line treatment for depression. 

Gepirone was rejected by the FDA in 2002, 2004, and 2007, with concerns that the efficacy studies were too small. In 2015, an FDA advisory committee agreed that the evidence to date did not support approval of an extended-release form of the drug. But the agency decided to approve the medication in September 2023.

“So why is this medication worth discussing now?” Dr. Smetana said. “It’s because the side effect profile is different from existing antidepressants.” 

Many patients may stop using SSRIs because of side effects such as insomnia and loss of libido, Dr. Smetana said. Gepirone has the potential to avoid activation of other 5-HT receptors that mediate side effects, he said. 

Studies suggest that gepirone reduces both anxiety and depression scores on the Hamilton Depression Rating Scale in patients who have both conditions and decreases rates of depression relapse compared with placebo through at least 48 weeks. The drug also may be less likely than SSRIs to cause sexual dysfunction in men, Dr. Smetana said. 

Gepirone will be available to prescribe to patients in fall 2024.

Dr. Smetana reported no relevant financial conflicts of interest. 
 

A version of this article appeared on Medscape.com.

BOSTON — The US Food and Drug Administration (FDA) approved 55 new medications in 2023 and 11 more in 2024 to date. During a presentation on April 18 at the annual American College of Physicians Internal Medicine Meeting, Gerald Smetana, MD, professor of medicine in the Division of General Medicine at Beth Israel Deaconess Medical Center in Boston, reviewed four of these new therapies that are likely to be particularly important for primary care clinicians. 

A New First-Line for GERD?

Vonoprazan, an oral potassium-competitive acid blocker — which received FDA approval in November 2023 — may be a good alternative for patients whose symptoms continue to linger despite taking medications designated to treat gastroesophageal reflux disease (GERD). 

GERD is the most common gastrointestinal symptom encountered by primary care physicians. Proton-pump inhibitors (PPIs) are the first-line treatment for the condition but can have long-term side effects such as Clostridioides difficile infection and kidney lesions.

“We know that not all patients are going to have symptom relief with H2 blockers and PPIs, so there’s an opportunity for patients who don’t get full symptom relief,” Dr. Smetana told attendees. 

Vonoprazan blocks potassium binding to ATPase proton pumps and inhibits the secretion of gastric acid.

The approval of vonoprazan for erosive GERD was based on results from the phase 3 PHALCON-EE study, a randomized, double-blind, multicenter study that found the drug to be more effective than lansoprazole in treating erosive esophagitis.

Vonoprazan “has more rapid absorption than PPIs [and a] longer half-life and is more potent than PPIs, so theoretically it could be more effective in certain settings,” Dr. Smetana said.

Vonoprazan is FDA approved for only 6 months of use. Despite its efficacy, cost may be a barrier to many patients. H2 blockers generally cost patients less than $10 for 1 month’s supply, whereas vonoprazan can cost up to $650.
 

Nonhormonal Drug for Menopause

Fezolinetant, the first neurokinin receptor antagonist to receive approval from the FDA to treat vasomotor symptoms, may be an option for women concerned about hormone-based therapy for menopausal hot flashes.

“[Fezolinetant] specifically works in the area of the brain that’s involved in body temperature regulation and sweating,” Dr. Smetana said.

Results from the SKYLIGHT 1 randomized controlled trial of fezolinetant found the medication reduced the frequency and severity of hot flashes. Some of the side effects include abdominal pain, diarrhea, and insomnia. 

Other nonestrogen treatments, including selective serotonin reuptake inhibitors (SSRIs), gabapentin, cognitive-behavioral therapy, and hypnosis, are modestly effective, according to the North American Menopause Society.

“[Fezolinetant] offers a different option that physicians may be more comfortable prescribing,” Dr. Smetana said. “And I think this will be an important addition to nonhormonal therapy.”
 

RSV Vaccine for Everyone 

Once considered an illness that is more prevalent in young children, respiratory syncytial virus (RSV) has become more prevalent and severe among older adults. Between 60,000 and 120,000 older adults are hospitalized and 6000-10,000 die of RSV infection each year, according to the US Centers for Disease Control and Prevention. 

The FDA has approved two RSV vaccines approved for older adults, but clinicians may find it challenging to get older patients vaccinated for this and other preventable illnesses.

Patients who received the RSV vaccine had an 83% relative risk reduction for the illness, according to a recent study, and an overall lower risk for hospitalization.

Moderna is developing an mRNA vaccine for RSV that is similar to many COVID-19 vaccines. A study published in 2023 in The New England Journal of Medicine found no cases of neuroinflammatory disorders among patients who received the mRNA RSV vaccine, with a median follow-up of 112 days.

“This is important given ongoing concerns of neurological safety,” among older adults who receive the RSV vaccine, Dr. Smetana said.

As of March 2024, the CDC recommends shared decision-making for adults older than 60 years and for healthcare providers to “consider” rather than “recommend” the vaccine for their patients. The agency’s Adult RSV Work Group plans to meet at June 2024 to reconsider whether shared clinical decision-making remains the preferred policy option.
 

New Antidepressants

A medication thrice rejected by the FDA is now heading a new class of drugs to treat major depressive disorder.

Gepirone, a 5-HT1A receptor agonist, has a different mechanism of action from that of SSRIs, which are currently considered the first-line treatment for depression. 

Gepirone was rejected by the FDA in 2002, 2004, and 2007, with concerns that the efficacy studies were too small. In 2015, an FDA advisory committee agreed that the evidence to date did not support approval of an extended-release form of the drug. But the agency decided to approve the medication in September 2023.

“So why is this medication worth discussing now?” Dr. Smetana said. “It’s because the side effect profile is different from existing antidepressants.” 

Many patients may stop using SSRIs because of side effects such as insomnia and loss of libido, Dr. Smetana said. Gepirone has the potential to avoid activation of other 5-HT receptors that mediate side effects, he said. 

Studies suggest that gepirone reduces both anxiety and depression scores on the Hamilton Depression Rating Scale in patients who have both conditions and decreases rates of depression relapse compared with placebo through at least 48 weeks. The drug also may be less likely than SSRIs to cause sexual dysfunction in men, Dr. Smetana said. 

Gepirone will be available to prescribe to patients in fall 2024.

Dr. Smetana reported no relevant financial conflicts of interest. 
 

A version of this article appeared on Medscape.com.

BOSTON — The US Food and Drug Administration (FDA) approved 55 new medications in 2023 and 11 more in 2024 to date. During a presentation on April 18 at the annual American College of Physicians Internal Medicine Meeting, Gerald Smetana, MD, professor of medicine in the Division of General Medicine at Beth Israel Deaconess Medical Center in Boston, reviewed four of these new therapies that are likely to be particularly important for primary care clinicians. 

A New First-Line for GERD?

Vonoprazan, an oral potassium-competitive acid blocker — which received FDA approval in November 2023 — may be a good alternative for patients whose symptoms continue to linger despite taking medications designated to treat gastroesophageal reflux disease (GERD). 

GERD is the most common gastrointestinal symptom encountered by primary care physicians. Proton-pump inhibitors (PPIs) are the first-line treatment for the condition but can have long-term side effects such as Clostridioides difficile infection and kidney lesions.

“We know that not all patients are going to have symptom relief with H2 blockers and PPIs, so there’s an opportunity for patients who don’t get full symptom relief,” Dr. Smetana told attendees. 

Vonoprazan blocks potassium binding to ATPase proton pumps and inhibits the secretion of gastric acid.

The approval of vonoprazan for erosive GERD was based on results from the phase 3 PHALCON-EE study, a randomized, double-blind, multicenter study that found the drug to be more effective than lansoprazole in treating erosive esophagitis.

Vonoprazan “has more rapid absorption than PPIs [and a] longer half-life and is more potent than PPIs, so theoretically it could be more effective in certain settings,” Dr. Smetana said.

Vonoprazan is FDA approved for only 6 months of use. Despite its efficacy, cost may be a barrier to many patients. H2 blockers generally cost patients less than $10 for 1 month’s supply, whereas vonoprazan can cost up to $650.
 

Nonhormonal Drug for Menopause

Fezolinetant, the first neurokinin receptor antagonist to receive approval from the FDA to treat vasomotor symptoms, may be an option for women concerned about hormone-based therapy for menopausal hot flashes.

“[Fezolinetant] specifically works in the area of the brain that’s involved in body temperature regulation and sweating,” Dr. Smetana said.

Results from the SKYLIGHT 1 randomized controlled trial of fezolinetant found the medication reduced the frequency and severity of hot flashes. Some of the side effects include abdominal pain, diarrhea, and insomnia. 

Other nonestrogen treatments, including selective serotonin reuptake inhibitors (SSRIs), gabapentin, cognitive-behavioral therapy, and hypnosis, are modestly effective, according to the North American Menopause Society.

“[Fezolinetant] offers a different option that physicians may be more comfortable prescribing,” Dr. Smetana said. “And I think this will be an important addition to nonhormonal therapy.”
 

RSV Vaccine for Everyone 

Once considered an illness that is more prevalent in young children, respiratory syncytial virus (RSV) has become more prevalent and severe among older adults. Between 60,000 and 120,000 older adults are hospitalized and 6000-10,000 die of RSV infection each year, according to the US Centers for Disease Control and Prevention. 

The FDA has approved two RSV vaccines approved for older adults, but clinicians may find it challenging to get older patients vaccinated for this and other preventable illnesses.

Patients who received the RSV vaccine had an 83% relative risk reduction for the illness, according to a recent study, and an overall lower risk for hospitalization.

Moderna is developing an mRNA vaccine for RSV that is similar to many COVID-19 vaccines. A study published in 2023 in The New England Journal of Medicine found no cases of neuroinflammatory disorders among patients who received the mRNA RSV vaccine, with a median follow-up of 112 days.

“This is important given ongoing concerns of neurological safety,” among older adults who receive the RSV vaccine, Dr. Smetana said.

As of March 2024, the CDC recommends shared decision-making for adults older than 60 years and for healthcare providers to “consider” rather than “recommend” the vaccine for their patients. The agency’s Adult RSV Work Group plans to meet at June 2024 to reconsider whether shared clinical decision-making remains the preferred policy option.
 

New Antidepressants

A medication thrice rejected by the FDA is now heading a new class of drugs to treat major depressive disorder.

Gepirone, a 5-HT1A receptor agonist, has a different mechanism of action from that of SSRIs, which are currently considered the first-line treatment for depression. 

Gepirone was rejected by the FDA in 2002, 2004, and 2007, with concerns that the efficacy studies were too small. In 2015, an FDA advisory committee agreed that the evidence to date did not support approval of an extended-release form of the drug. But the agency decided to approve the medication in September 2023.

“So why is this medication worth discussing now?” Dr. Smetana said. “It’s because the side effect profile is different from existing antidepressants.” 

Many patients may stop using SSRIs because of side effects such as insomnia and loss of libido, Dr. Smetana said. Gepirone has the potential to avoid activation of other 5-HT receptors that mediate side effects, he said. 

Studies suggest that gepirone reduces both anxiety and depression scores on the Hamilton Depression Rating Scale in patients who have both conditions and decreases rates of depression relapse compared with placebo through at least 48 weeks. The drug also may be less likely than SSRIs to cause sexual dysfunction in men, Dr. Smetana said. 

Gepirone will be available to prescribe to patients in fall 2024.

Dr. Smetana reported no relevant financial conflicts of interest. 
 

A version of this article appeared on Medscape.com.

Erosive esophagitis (EE) is erosion of the esophageal epithelium due to chronic irritation. It can be caused by a number of factors but is primarily a result of gastroesophageal reflux disease (GERD). The main symptoms of EE are heartburn and regurgitation; other symptoms can include epigastric pain, odynophagia, dysphagia, nausea, chronic cough, dental erosion, laryngitis, and asthma. Symptoms can be exacerbated by eating certain trigger foods or when lying down. Diagnosis requires testing to differentiate EE from other manifestations of GERD, including nonerosive esophagitis and Barrett esophagus (BE). EE occurs in approximately 30% of cases of GERD, and EE may evolve to BE in 1%-13% of cases.

Long-term management of EE focuses on relieving symptoms to allow the esophageal lining to heal, thereby reducing both acute symptoms and the risk for other complications. Management plans may incorporate lifestyle changes, such as dietary modifications and weight loss, alongside pharmacologic therapy. In extreme cases, surgery may be considered to repair a damaged esophagus and/or to prevent ongoing acid reflux. If left untreated, EE may progress, potentially leading to more serious conditions.

Here are five things to know about EE.

1. GERD is the main risk factor for EE, but not the only risk factor.

An estimated 1% of the population has EE. Risk factors other than GERD include:

Radiation therapy toxicity can cause acute or chronic EE. For individuals undergoing radiotherapy, radiation esophagitis is a relatively frequent complication. Acute esophagitis generally occurs in all patients taking radiation doses of 6000 cGy given in fractions of 1000 cGy per week. The risk is lower among patients on longer schedules and lower doses of radiotherapy.

Bacterial, viral, and fungal infections can cause EE. These include herpes, CMV, HIV, Helicobacter pylori, and Candida.

Food allergies, asthma, and eczema are associated with eosinophilic esophagitis, which disproportionately affects young men and has an estimated prevalence of 55 cases per 100,000 population.

Oral medication in pill form causes esophagitis at an estimated rate of 3.9 cases per 100,000 population per year. The mean age at diagnosis is 41.5 years. Oral bisphosphonates such as alendronate are the most common agents, along with antibiotics such as tetracycline, doxycycline, and clindamycin. There have also been reports of pill-induced esophagitis with NSAIDs, aspirin, ferrous sulfate, potassium chloride, and mexiletine.

Excessive vomiting can, in rare cases, cause esophagitis.

Certain autoimmune diseases can manifest as EE.

2. Proton pump inhibitors (PPIs) remain the preferred treatment for EE.

Several over-the-counter and prescription medications can be used to manage the symptoms of EE. PPIs are the preferred treatment both in the acute setting and for maintenance therapy. PPIs help to alleviate symptoms and promote healing of the esophageal lining by reducing the production of stomach acid. Options include omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole. Many patients with EE require a dose that exceeds the FDA-approved dose for GERD. For instance, a 40-mg/d dosage of omeprazole is recommended in the latest guidelines, although the FDA-approved dosage is 20 mg/d.

H2-receptor antagonists, including famotidine, cimetidine, and nizatidine, may also be prescribed to reduce stomach acid production and promote healing in patients with EE due to GERD, but these agents are considered less efficacious than PPIs for either acute or maintenance therapy.

The potassium-competitive acid blocker (PCAB) vonoprazan is the latest agent to be indicated for EE and may provide more potent acid suppression for patients. A randomized comparative trial showed noninferiority compared with lansoprazole for healing and maintenance of healing of EE. In another randomized comparative study, the investigational PCAP fexuprazan was shown to be noninferior to the PPI esomeprazole in treating EE.

Mild GERD symptoms can be controlled by traditional antacids taken after each meal and at bedtime or with short-term use of prokinetic agents, which can help reduce acid reflux by improving esophageal and stomach motility and by increasing pressure to the lower esophageal sphincter. Gastric emptying is also accelerated by prokinetic agents. Long-term use is discouraged, as it may cause serious or life-threatening complications.

In patients who do not fully respond to PPI therapy, surgical therapy may be considered. Other candidates for surgery include younger patients, those who have difficulty adhering to treatment, postmenopausal women with osteoporosis, patients with cardiac conduction defects, and those for whom the cost of treatment is prohibitive. Surgery may also be warranted if there are extraesophageal manifestations of GERD, such as enamel erosion; respiratory issues (eg, coughing, wheezing, aspiration); or ear, nose, and throat manifestations (eg, hoarseness, sore throat, otitis media). For those who have progressed to BE, surgical intervention is also indicated.

The types of surgery for patients with EE have evolved to include both transthoracic and transabdominal fundoplication. Usually, a 360° transabdominal fundoplication is performed. General anesthesia is required for laparoscopic fundoplication, in which five small incisions are used to create a new valve at the level of the esophagogastric junction by wrapping the fundus of the stomach around the esophagus.

Laparoscopic insertion of a small band known as the LINX Reflux Management System is FDA approved to augment the lower esophageal sphincter. The system creates a natural barrier to reflux by placing a band consisting of titanium beads with magnetic cores around the esophagus just above the stomach. The magnetic bond is temporarily disrupted by swallowing, allowing food and liquid to pass.

Endoscopic therapies are another treatment option for certain patients who are not considered candidates for surgery or long-term therapy. Among the types of endoscopic procedures are radiofrequency therapy, suturing/plication, and mucosal ablation/resection techniques at the gastroesophageal junction. Full-thickness endoscopic suturing is an area of interest because this technique offers significant durability of the recreated lower esophageal sphincter.

3. PPI therapy for GERD should be stopped before endoscopy is performed to confirm a diagnosis of EE.

A clinical diagnosis of GERD can be made if the presenting symptoms are heartburn and regurgitation, without chest pain or alarm symptoms such as dysphagia, weight loss, or gastrointestinal bleeding. In this setting, once-daily PPIs are generally prescribed for 8 weeks to see if symptoms resolve. If symptoms have not resolved, a twice-daily PPI regimen may be prescribed. In patients who do not respond to PPIs, or for whom GERD returns after stopping therapy, an upper endoscopy with biopsy is recommended after 2-4 weeks off therapy to rule out other causes. Endoscopy should be the first step in diagnosis for individuals experiencing chest pain without heartburn; those in whom heart disease has been ruled out; individuals experiencing dysphagia, weight loss, or gastrointestinal bleeding; or those who have multiple risk factors for BE.

4. The most serious complication of EE is BE, which can lead to esophageal cancer.

Several complications can arise from EE. The most serious of these is BE, which can lead to esophageal adenocarcinoma. BE is characterized by the conversion of normal distal squamous esophageal epithelium to columnar epithelium. It has the potential to become malignant if it exhibits intestinal-type metaplasia. In the industrialized world, adenocarcinoma currently represents more than half of all esophageal cancers. The most common symptom of esophageal cancer is dysphagia. Other signs and symptoms include weight loss, hoarseness, chronic or intractable cough, bleeding, epigastric or retrosternal pain, frequent pneumonia, and, if metastatic, bone pain.

5. Lifestyle modifications can help control the symptoms of EE.

Guidelines recommend a number of lifestyle modification strategies to help control the symptoms of EE. Smoking cessation and weight loss are two evidence-based strategies for relieving symptoms of GERD and, ultimately, lowering the risk for esophageal cancer. One large prospective Norwegian cohort study (N = 29,610) found that stopping smoking improved GERD symptoms, but only in those with normal body mass index. In a smaller Japanese study (N = 191) specifically surveying people attempting smoking cessation, individuals who successfully stopped smoking had a 44% improvement in GERD symptoms at 1 year, vs an 18% improvement in those who continued to smoke, with no statistical difference between the success and failure groups based on patient body mass index (P = .60).

Other recommended strategies for nonpharmacologic management of EE symptoms include elevation of the head when lying down in bed and avoidance of lying down after eating, cessation of alcohol consumption, avoidance of food close to bedtime, and avoidance of trigger foods that can incite or worsen symptoms of acid reflux. Such trigger foods vary among individuals, but they often include fatty foods, coffee, chocolate, carbonated beverages, spicy foods, citrus fruits, and tomatoes.

Dr. Puerta has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Erosive esophagitis (EE) is erosion of the esophageal epithelium due to chronic irritation. It can be caused by a number of factors but is primarily a result of gastroesophageal reflux disease (GERD). The main symptoms of EE are heartburn and regurgitation; other symptoms can include epigastric pain, odynophagia, dysphagia, nausea, chronic cough, dental erosion, laryngitis, and asthma. Symptoms can be exacerbated by eating certain trigger foods or when lying down. Diagnosis requires testing to differentiate EE from other manifestations of GERD, including nonerosive esophagitis and Barrett esophagus (BE). EE occurs in approximately 30% of cases of GERD, and EE may evolve to BE in 1%-13% of cases.

Long-term management of EE focuses on relieving symptoms to allow the esophageal lining to heal, thereby reducing both acute symptoms and the risk for other complications. Management plans may incorporate lifestyle changes, such as dietary modifications and weight loss, alongside pharmacologic therapy. In extreme cases, surgery may be considered to repair a damaged esophagus and/or to prevent ongoing acid reflux. If left untreated, EE may progress, potentially leading to more serious conditions.

Here are five things to know about EE.

1. GERD is the main risk factor for EE, but not the only risk factor.

An estimated 1% of the population has EE. Risk factors other than GERD include:

Radiation therapy toxicity can cause acute or chronic EE. For individuals undergoing radiotherapy, radiation esophagitis is a relatively frequent complication. Acute esophagitis generally occurs in all patients taking radiation doses of 6000 cGy given in fractions of 1000 cGy per week. The risk is lower among patients on longer schedules and lower doses of radiotherapy.

Bacterial, viral, and fungal infections can cause EE. These include herpes, CMV, HIV, Helicobacter pylori, and Candida.

Food allergies, asthma, and eczema are associated with eosinophilic esophagitis, which disproportionately affects young men and has an estimated prevalence of 55 cases per 100,000 population.

Oral medication in pill form causes esophagitis at an estimated rate of 3.9 cases per 100,000 population per year. The mean age at diagnosis is 41.5 years. Oral bisphosphonates such as alendronate are the most common agents, along with antibiotics such as tetracycline, doxycycline, and clindamycin. There have also been reports of pill-induced esophagitis with NSAIDs, aspirin, ferrous sulfate, potassium chloride, and mexiletine.

Excessive vomiting can, in rare cases, cause esophagitis.

Certain autoimmune diseases can manifest as EE.

2. Proton pump inhibitors (PPIs) remain the preferred treatment for EE.

Several over-the-counter and prescription medications can be used to manage the symptoms of EE. PPIs are the preferred treatment both in the acute setting and for maintenance therapy. PPIs help to alleviate symptoms and promote healing of the esophageal lining by reducing the production of stomach acid. Options include omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole. Many patients with EE require a dose that exceeds the FDA-approved dose for GERD. For instance, a 40-mg/d dosage of omeprazole is recommended in the latest guidelines, although the FDA-approved dosage is 20 mg/d.

H2-receptor antagonists, including famotidine, cimetidine, and nizatidine, may also be prescribed to reduce stomach acid production and promote healing in patients with EE due to GERD, but these agents are considered less efficacious than PPIs for either acute or maintenance therapy.

The potassium-competitive acid blocker (PCAB) vonoprazan is the latest agent to be indicated for EE and may provide more potent acid suppression for patients. A randomized comparative trial showed noninferiority compared with lansoprazole for healing and maintenance of healing of EE. In another randomized comparative study, the investigational PCAP fexuprazan was shown to be noninferior to the PPI esomeprazole in treating EE.

Mild GERD symptoms can be controlled by traditional antacids taken after each meal and at bedtime or with short-term use of prokinetic agents, which can help reduce acid reflux by improving esophageal and stomach motility and by increasing pressure to the lower esophageal sphincter. Gastric emptying is also accelerated by prokinetic agents. Long-term use is discouraged, as it may cause serious or life-threatening complications.

In patients who do not fully respond to PPI therapy, surgical therapy may be considered. Other candidates for surgery include younger patients, those who have difficulty adhering to treatment, postmenopausal women with osteoporosis, patients with cardiac conduction defects, and those for whom the cost of treatment is prohibitive. Surgery may also be warranted if there are extraesophageal manifestations of GERD, such as enamel erosion; respiratory issues (eg, coughing, wheezing, aspiration); or ear, nose, and throat manifestations (eg, hoarseness, sore throat, otitis media). For those who have progressed to BE, surgical intervention is also indicated.

The types of surgery for patients with EE have evolved to include both transthoracic and transabdominal fundoplication. Usually, a 360° transabdominal fundoplication is performed. General anesthesia is required for laparoscopic fundoplication, in which five small incisions are used to create a new valve at the level of the esophagogastric junction by wrapping the fundus of the stomach around the esophagus.

Laparoscopic insertion of a small band known as the LINX Reflux Management System is FDA approved to augment the lower esophageal sphincter. The system creates a natural barrier to reflux by placing a band consisting of titanium beads with magnetic cores around the esophagus just above the stomach. The magnetic bond is temporarily disrupted by swallowing, allowing food and liquid to pass.

Endoscopic therapies are another treatment option for certain patients who are not considered candidates for surgery or long-term therapy. Among the types of endoscopic procedures are radiofrequency therapy, suturing/plication, and mucosal ablation/resection techniques at the gastroesophageal junction. Full-thickness endoscopic suturing is an area of interest because this technique offers significant durability of the recreated lower esophageal sphincter.

3. PPI therapy for GERD should be stopped before endoscopy is performed to confirm a diagnosis of EE.

A clinical diagnosis of GERD can be made if the presenting symptoms are heartburn and regurgitation, without chest pain or alarm symptoms such as dysphagia, weight loss, or gastrointestinal bleeding. In this setting, once-daily PPIs are generally prescribed for 8 weeks to see if symptoms resolve. If symptoms have not resolved, a twice-daily PPI regimen may be prescribed. In patients who do not respond to PPIs, or for whom GERD returns after stopping therapy, an upper endoscopy with biopsy is recommended after 2-4 weeks off therapy to rule out other causes. Endoscopy should be the first step in diagnosis for individuals experiencing chest pain without heartburn; those in whom heart disease has been ruled out; individuals experiencing dysphagia, weight loss, or gastrointestinal bleeding; or those who have multiple risk factors for BE.

4. The most serious complication of EE is BE, which can lead to esophageal cancer.

Several complications can arise from EE. The most serious of these is BE, which can lead to esophageal adenocarcinoma. BE is characterized by the conversion of normal distal squamous esophageal epithelium to columnar epithelium. It has the potential to become malignant if it exhibits intestinal-type metaplasia. In the industrialized world, adenocarcinoma currently represents more than half of all esophageal cancers. The most common symptom of esophageal cancer is dysphagia. Other signs and symptoms include weight loss, hoarseness, chronic or intractable cough, bleeding, epigastric or retrosternal pain, frequent pneumonia, and, if metastatic, bone pain.

5. Lifestyle modifications can help control the symptoms of EE.

Guidelines recommend a number of lifestyle modification strategies to help control the symptoms of EE. Smoking cessation and weight loss are two evidence-based strategies for relieving symptoms of GERD and, ultimately, lowering the risk for esophageal cancer. One large prospective Norwegian cohort study (N = 29,610) found that stopping smoking improved GERD symptoms, but only in those with normal body mass index. In a smaller Japanese study (N = 191) specifically surveying people attempting smoking cessation, individuals who successfully stopped smoking had a 44% improvement in GERD symptoms at 1 year, vs an 18% improvement in those who continued to smoke, with no statistical difference between the success and failure groups based on patient body mass index (P = .60).

Other recommended strategies for nonpharmacologic management of EE symptoms include elevation of the head when lying down in bed and avoidance of lying down after eating, cessation of alcohol consumption, avoidance of food close to bedtime, and avoidance of trigger foods that can incite or worsen symptoms of acid reflux. Such trigger foods vary among individuals, but they often include fatty foods, coffee, chocolate, carbonated beverages, spicy foods, citrus fruits, and tomatoes.

Dr. Puerta has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Erosive esophagitis (EE) is erosion of the esophageal epithelium due to chronic irritation. It can be caused by a number of factors but is primarily a result of gastroesophageal reflux disease (GERD). The main symptoms of EE are heartburn and regurgitation; other symptoms can include epigastric pain, odynophagia, dysphagia, nausea, chronic cough, dental erosion, laryngitis, and asthma. Symptoms can be exacerbated by eating certain trigger foods or when lying down. Diagnosis requires testing to differentiate EE from other manifestations of GERD, including nonerosive esophagitis and Barrett esophagus (BE). EE occurs in approximately 30% of cases of GERD, and EE may evolve to BE in 1%-13% of cases.

Long-term management of EE focuses on relieving symptoms to allow the esophageal lining to heal, thereby reducing both acute symptoms and the risk for other complications. Management plans may incorporate lifestyle changes, such as dietary modifications and weight loss, alongside pharmacologic therapy. In extreme cases, surgery may be considered to repair a damaged esophagus and/or to prevent ongoing acid reflux. If left untreated, EE may progress, potentially leading to more serious conditions.

Here are five things to know about EE.

1. GERD is the main risk factor for EE, but not the only risk factor.

An estimated 1% of the population has EE. Risk factors other than GERD include:

Radiation therapy toxicity can cause acute or chronic EE. For individuals undergoing radiotherapy, radiation esophagitis is a relatively frequent complication. Acute esophagitis generally occurs in all patients taking radiation doses of 6000 cGy given in fractions of 1000 cGy per week. The risk is lower among patients on longer schedules and lower doses of radiotherapy.

Bacterial, viral, and fungal infections can cause EE. These include herpes, CMV, HIV, Helicobacter pylori, and Candida.

Food allergies, asthma, and eczema are associated with eosinophilic esophagitis, which disproportionately affects young men and has an estimated prevalence of 55 cases per 100,000 population.

Oral medication in pill form causes esophagitis at an estimated rate of 3.9 cases per 100,000 population per year. The mean age at diagnosis is 41.5 years. Oral bisphosphonates such as alendronate are the most common agents, along with antibiotics such as tetracycline, doxycycline, and clindamycin. There have also been reports of pill-induced esophagitis with NSAIDs, aspirin, ferrous sulfate, potassium chloride, and mexiletine.

Excessive vomiting can, in rare cases, cause esophagitis.

Certain autoimmune diseases can manifest as EE.

2. Proton pump inhibitors (PPIs) remain the preferred treatment for EE.

Several over-the-counter and prescription medications can be used to manage the symptoms of EE. PPIs are the preferred treatment both in the acute setting and for maintenance therapy. PPIs help to alleviate symptoms and promote healing of the esophageal lining by reducing the production of stomach acid. Options include omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole. Many patients with EE require a dose that exceeds the FDA-approved dose for GERD. For instance, a 40-mg/d dosage of omeprazole is recommended in the latest guidelines, although the FDA-approved dosage is 20 mg/d.

H2-receptor antagonists, including famotidine, cimetidine, and nizatidine, may also be prescribed to reduce stomach acid production and promote healing in patients with EE due to GERD, but these agents are considered less efficacious than PPIs for either acute or maintenance therapy.

The potassium-competitive acid blocker (PCAB) vonoprazan is the latest agent to be indicated for EE and may provide more potent acid suppression for patients. A randomized comparative trial showed noninferiority compared with lansoprazole for healing and maintenance of healing of EE. In another randomized comparative study, the investigational PCAP fexuprazan was shown to be noninferior to the PPI esomeprazole in treating EE.

Mild GERD symptoms can be controlled by traditional antacids taken after each meal and at bedtime or with short-term use of prokinetic agents, which can help reduce acid reflux by improving esophageal and stomach motility and by increasing pressure to the lower esophageal sphincter. Gastric emptying is also accelerated by prokinetic agents. Long-term use is discouraged, as it may cause serious or life-threatening complications.

In patients who do not fully respond to PPI therapy, surgical therapy may be considered. Other candidates for surgery include younger patients, those who have difficulty adhering to treatment, postmenopausal women with osteoporosis, patients with cardiac conduction defects, and those for whom the cost of treatment is prohibitive. Surgery may also be warranted if there are extraesophageal manifestations of GERD, such as enamel erosion; respiratory issues (eg, coughing, wheezing, aspiration); or ear, nose, and throat manifestations (eg, hoarseness, sore throat, otitis media). For those who have progressed to BE, surgical intervention is also indicated.

The types of surgery for patients with EE have evolved to include both transthoracic and transabdominal fundoplication. Usually, a 360° transabdominal fundoplication is performed. General anesthesia is required for laparoscopic fundoplication, in which five small incisions are used to create a new valve at the level of the esophagogastric junction by wrapping the fundus of the stomach around the esophagus.

Laparoscopic insertion of a small band known as the LINX Reflux Management System is FDA approved to augment the lower esophageal sphincter. The system creates a natural barrier to reflux by placing a band consisting of titanium beads with magnetic cores around the esophagus just above the stomach. The magnetic bond is temporarily disrupted by swallowing, allowing food and liquid to pass.

Endoscopic therapies are another treatment option for certain patients who are not considered candidates for surgery or long-term therapy. Among the types of endoscopic procedures are radiofrequency therapy, suturing/plication, and mucosal ablation/resection techniques at the gastroesophageal junction. Full-thickness endoscopic suturing is an area of interest because this technique offers significant durability of the recreated lower esophageal sphincter.

3. PPI therapy for GERD should be stopped before endoscopy is performed to confirm a diagnosis of EE.

A clinical diagnosis of GERD can be made if the presenting symptoms are heartburn and regurgitation, without chest pain or alarm symptoms such as dysphagia, weight loss, or gastrointestinal bleeding. In this setting, once-daily PPIs are generally prescribed for 8 weeks to see if symptoms resolve. If symptoms have not resolved, a twice-daily PPI regimen may be prescribed. In patients who do not respond to PPIs, or for whom GERD returns after stopping therapy, an upper endoscopy with biopsy is recommended after 2-4 weeks off therapy to rule out other causes. Endoscopy should be the first step in diagnosis for individuals experiencing chest pain without heartburn; those in whom heart disease has been ruled out; individuals experiencing dysphagia, weight loss, or gastrointestinal bleeding; or those who have multiple risk factors for BE.

4. The most serious complication of EE is BE, which can lead to esophageal cancer.

Several complications can arise from EE. The most serious of these is BE, which can lead to esophageal adenocarcinoma. BE is characterized by the conversion of normal distal squamous esophageal epithelium to columnar epithelium. It has the potential to become malignant if it exhibits intestinal-type metaplasia. In the industrialized world, adenocarcinoma currently represents more than half of all esophageal cancers. The most common symptom of esophageal cancer is dysphagia. Other signs and symptoms include weight loss, hoarseness, chronic or intractable cough, bleeding, epigastric or retrosternal pain, frequent pneumonia, and, if metastatic, bone pain.

5. Lifestyle modifications can help control the symptoms of EE.

Guidelines recommend a number of lifestyle modification strategies to help control the symptoms of EE. Smoking cessation and weight loss are two evidence-based strategies for relieving symptoms of GERD and, ultimately, lowering the risk for esophageal cancer. One large prospective Norwegian cohort study (N = 29,610) found that stopping smoking improved GERD symptoms, but only in those with normal body mass index. In a smaller Japanese study (N = 191) specifically surveying people attempting smoking cessation, individuals who successfully stopped smoking had a 44% improvement in GERD symptoms at 1 year, vs an 18% improvement in those who continued to smoke, with no statistical difference between the success and failure groups based on patient body mass index (P = .60).

Other recommended strategies for nonpharmacologic management of EE symptoms include elevation of the head when lying down in bed and avoidance of lying down after eating, cessation of alcohol consumption, avoidance of food close to bedtime, and avoidance of trigger foods that can incite or worsen symptoms of acid reflux. Such trigger foods vary among individuals, but they often include fatty foods, coffee, chocolate, carbonated beverages, spicy foods, citrus fruits, and tomatoes.

Dr. Puerta has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

What dietary recommendations are appropriate for gastroesophageal reflux disease (GERD)? While 85% of patients identify at least one food associated with reflux symptoms, misconceptions about diet in GERD are widespread. The issue was discussed during a dedicated session at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology.

GERD occurs when the contents, especially acid, of the stomach back up into the esophagus, leading to symptoms or lesions of the esophageal mucosa.

In addition to proton pump inhibitors, several hygienic-dietary rules are integrated into the therapeutic management of GERD. Some, such as elevating the head of the bed and allowing a 2- to 3-hour gap between meals and bedtime, have proven effective.

Diet and obesity also play a role in the onset of GERD symptoms. Thus, hygienic-dietary rules are an integral part of current recommendations.

“Weight loss is effective in reducing reflux symptoms and should be recommended,” stated Frank Zerbib, MD, head of Hepatology, Gastroenterology, and Digestive Oncology at University Hospital of Bordeaux in France, during the presentation.

Furthermore, most patients with GERD identify foods that may trigger their symptoms, even if there is no evidence to support this in the literature. However, it has been shown that reducing the consumption of these foods is effective.
 

Caloric Intake and Lipid Content

Meal intake affects esophagogastric physiology in several ways: It reduces the tone of the lower esophageal sphincter (LES) and increases the number of transient LES relaxations (TLESRs), which are induced by distension and relaxation of the proximal stomach. These effects are mediated by vagal afferent stimulation and the stretching of the mechanoreceptors of the fundic wall. They are influenced by neuropeptide effects such as cholecystokinin (CCK), which is released in the presence of lipids in the duodenal lumen. Hence, the importance of caloric intake and lipid content, even though it is difficult to distinguish their respective effects.

A high-calorie meal slows gastric emptying, thus prolonging gastric distension, reducing LES tone, and promoting the onset of TLESRs. Several studies have emphasized that at equivalent caloric intake, lipid composition has no impact on LES tone and the number of TLESRs in healthy patients or those with GERD. However, with equivalent caloric intake, and thus equivalent acid exposure, the presence of lipids in the meal increases the perception of reflux. This “reflux hypersensitivity” effect induced by lipids is caused by the endogenous release of CCK and its action on vagal afferents. This effect also is observed in the perception of functional dyspepsia symptoms.

Several studies have established a correlation between saturated fat consumption and the presence of GERD symptoms.
 

The Role of Carbohydrates

While the protein component of a meal has little impact on esophagogastric physiology, carbohydrates produce effects on esophagogastric motility that are mediated by their fermentation products, especially short-chain fatty acids (SCFAs), which are synthesized in the colon. Colonic perfusion of these SCFAs leads to fundus relaxation, reduced LES tone, and increased TLESRs. Moreover, in patients with GERD, adding prebiotics (fructo-oligosaccharide) to the meal content increases the number of TLESRs, acid reflux, and symptoms by amplifying colonic fermentation and SCFA production.

Several studies have evaluated low-carbohydrate diets in GERD. A small study of eight patients with morbid obesity on a very low–carbohydrate diet observed benefits on symptoms and esophageal acid exposure in pH probe testing.

A randomized French study of 31 patients with refractory GERD found no significant difference between a low fermentable oligo-, di-, monosaccharides, and polyols diet and usual dietary advice.

A recent American study of 95 veterans found an improvement in pH in the group reducing simple sugars but symptomatic improvement in all groups reducing sugar consumption in general.

Therefore, based on all these data, according to Dr. Zerbib, “high-calorie meals, rich in fats or carbohydrates, promote the onset of reflux episodes and their perception. Diets low in fats and carbohydrates should be recommended.”
 

Questionable Studies

Certain foods can reduce LES pressure, such as coffee (excluding decaf), chocolate, and white wine. Moreover, white wine, beer, and chocolate have been associated with increased esophageal acid exposure. No significant effects on LES pressure or reflux have been observed with the consumption of citrus fruits or spicy foods. These conclusions, however, are based on older studies and subject to methodological criticisms.

Population studies on tea and coffee yield conflicting results. A recent study of 48,000 nurses without documented GERD found that consumption of tea, coffee, or sodas increased the risk for reflux symptoms by about 30% at least once per week, while water, milk, or fruit juice had no effect. Furthermore, the consumption of carbonated beverages also does not seem to increase the risk for GERD.

Regarding alcohol consumption as a risk factor for GERD, epidemiological data do not allow for a definitive conclusion. Most studies have not found a significant link, a finding confirmed by a recent meta-analysis of 24 publications.

Obesity contributes to GERD by promoting increased abdominal pressure and constraints on the esophagogastric junction. A high-resolution manometry study provided robust evidence for this mechanism. Generally, the relative risk for symptomatic GERD with obesity is 2-3 compared with normal body mass index (BMI), with a linear increase according to BMI.

Dr. Zerbib reported no relevant financial conflicts related to his presentation.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

What dietary recommendations are appropriate for gastroesophageal reflux disease (GERD)? While 85% of patients identify at least one food associated with reflux symptoms, misconceptions about diet in GERD are widespread. The issue was discussed during a dedicated session at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology.

GERD occurs when the contents, especially acid, of the stomach back up into the esophagus, leading to symptoms or lesions of the esophageal mucosa.

In addition to proton pump inhibitors, several hygienic-dietary rules are integrated into the therapeutic management of GERD. Some, such as elevating the head of the bed and allowing a 2- to 3-hour gap between meals and bedtime, have proven effective.

Diet and obesity also play a role in the onset of GERD symptoms. Thus, hygienic-dietary rules are an integral part of current recommendations.

“Weight loss is effective in reducing reflux symptoms and should be recommended,” stated Frank Zerbib, MD, head of Hepatology, Gastroenterology, and Digestive Oncology at University Hospital of Bordeaux in France, during the presentation.

Furthermore, most patients with GERD identify foods that may trigger their symptoms, even if there is no evidence to support this in the literature. However, it has been shown that reducing the consumption of these foods is effective.
 

Caloric Intake and Lipid Content

Meal intake affects esophagogastric physiology in several ways: It reduces the tone of the lower esophageal sphincter (LES) and increases the number of transient LES relaxations (TLESRs), which are induced by distension and relaxation of the proximal stomach. These effects are mediated by vagal afferent stimulation and the stretching of the mechanoreceptors of the fundic wall. They are influenced by neuropeptide effects such as cholecystokinin (CCK), which is released in the presence of lipids in the duodenal lumen. Hence, the importance of caloric intake and lipid content, even though it is difficult to distinguish their respective effects.

A high-calorie meal slows gastric emptying, thus prolonging gastric distension, reducing LES tone, and promoting the onset of TLESRs. Several studies have emphasized that at equivalent caloric intake, lipid composition has no impact on LES tone and the number of TLESRs in healthy patients or those with GERD. However, with equivalent caloric intake, and thus equivalent acid exposure, the presence of lipids in the meal increases the perception of reflux. This “reflux hypersensitivity” effect induced by lipids is caused by the endogenous release of CCK and its action on vagal afferents. This effect also is observed in the perception of functional dyspepsia symptoms.

Several studies have established a correlation between saturated fat consumption and the presence of GERD symptoms.
 

The Role of Carbohydrates

While the protein component of a meal has little impact on esophagogastric physiology, carbohydrates produce effects on esophagogastric motility that are mediated by their fermentation products, especially short-chain fatty acids (SCFAs), which are synthesized in the colon. Colonic perfusion of these SCFAs leads to fundus relaxation, reduced LES tone, and increased TLESRs. Moreover, in patients with GERD, adding prebiotics (fructo-oligosaccharide) to the meal content increases the number of TLESRs, acid reflux, and symptoms by amplifying colonic fermentation and SCFA production.

Several studies have evaluated low-carbohydrate diets in GERD. A small study of eight patients with morbid obesity on a very low–carbohydrate diet observed benefits on symptoms and esophageal acid exposure in pH probe testing.

A randomized French study of 31 patients with refractory GERD found no significant difference between a low fermentable oligo-, di-, monosaccharides, and polyols diet and usual dietary advice.

A recent American study of 95 veterans found an improvement in pH in the group reducing simple sugars but symptomatic improvement in all groups reducing sugar consumption in general.

Therefore, based on all these data, according to Dr. Zerbib, “high-calorie meals, rich in fats or carbohydrates, promote the onset of reflux episodes and their perception. Diets low in fats and carbohydrates should be recommended.”
 

Questionable Studies

Certain foods can reduce LES pressure, such as coffee (excluding decaf), chocolate, and white wine. Moreover, white wine, beer, and chocolate have been associated with increased esophageal acid exposure. No significant effects on LES pressure or reflux have been observed with the consumption of citrus fruits or spicy foods. These conclusions, however, are based on older studies and subject to methodological criticisms.

Population studies on tea and coffee yield conflicting results. A recent study of 48,000 nurses without documented GERD found that consumption of tea, coffee, or sodas increased the risk for reflux symptoms by about 30% at least once per week, while water, milk, or fruit juice had no effect. Furthermore, the consumption of carbonated beverages also does not seem to increase the risk for GERD.

Regarding alcohol consumption as a risk factor for GERD, epidemiological data do not allow for a definitive conclusion. Most studies have not found a significant link, a finding confirmed by a recent meta-analysis of 24 publications.

Obesity contributes to GERD by promoting increased abdominal pressure and constraints on the esophagogastric junction. A high-resolution manometry study provided robust evidence for this mechanism. Generally, the relative risk for symptomatic GERD with obesity is 2-3 compared with normal body mass index (BMI), with a linear increase according to BMI.

Dr. Zerbib reported no relevant financial conflicts related to his presentation.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

What dietary recommendations are appropriate for gastroesophageal reflux disease (GERD)? While 85% of patients identify at least one food associated with reflux symptoms, misconceptions about diet in GERD are widespread. The issue was discussed during a dedicated session at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology.

GERD occurs when the contents, especially acid, of the stomach back up into the esophagus, leading to symptoms or lesions of the esophageal mucosa.

In addition to proton pump inhibitors, several hygienic-dietary rules are integrated into the therapeutic management of GERD. Some, such as elevating the head of the bed and allowing a 2- to 3-hour gap between meals and bedtime, have proven effective.

Diet and obesity also play a role in the onset of GERD symptoms. Thus, hygienic-dietary rules are an integral part of current recommendations.

“Weight loss is effective in reducing reflux symptoms and should be recommended,” stated Frank Zerbib, MD, head of Hepatology, Gastroenterology, and Digestive Oncology at University Hospital of Bordeaux in France, during the presentation.

Furthermore, most patients with GERD identify foods that may trigger their symptoms, even if there is no evidence to support this in the literature. However, it has been shown that reducing the consumption of these foods is effective.
 

Caloric Intake and Lipid Content

Meal intake affects esophagogastric physiology in several ways: It reduces the tone of the lower esophageal sphincter (LES) and increases the number of transient LES relaxations (TLESRs), which are induced by distension and relaxation of the proximal stomach. These effects are mediated by vagal afferent stimulation and the stretching of the mechanoreceptors of the fundic wall. They are influenced by neuropeptide effects such as cholecystokinin (CCK), which is released in the presence of lipids in the duodenal lumen. Hence, the importance of caloric intake and lipid content, even though it is difficult to distinguish their respective effects.

A high-calorie meal slows gastric emptying, thus prolonging gastric distension, reducing LES tone, and promoting the onset of TLESRs. Several studies have emphasized that at equivalent caloric intake, lipid composition has no impact on LES tone and the number of TLESRs in healthy patients or those with GERD. However, with equivalent caloric intake, and thus equivalent acid exposure, the presence of lipids in the meal increases the perception of reflux. This “reflux hypersensitivity” effect induced by lipids is caused by the endogenous release of CCK and its action on vagal afferents. This effect also is observed in the perception of functional dyspepsia symptoms.

Several studies have established a correlation between saturated fat consumption and the presence of GERD symptoms.
 

The Role of Carbohydrates

While the protein component of a meal has little impact on esophagogastric physiology, carbohydrates produce effects on esophagogastric motility that are mediated by their fermentation products, especially short-chain fatty acids (SCFAs), which are synthesized in the colon. Colonic perfusion of these SCFAs leads to fundus relaxation, reduced LES tone, and increased TLESRs. Moreover, in patients with GERD, adding prebiotics (fructo-oligosaccharide) to the meal content increases the number of TLESRs, acid reflux, and symptoms by amplifying colonic fermentation and SCFA production.

Several studies have evaluated low-carbohydrate diets in GERD. A small study of eight patients with morbid obesity on a very low–carbohydrate diet observed benefits on symptoms and esophageal acid exposure in pH probe testing.

A randomized French study of 31 patients with refractory GERD found no significant difference between a low fermentable oligo-, di-, monosaccharides, and polyols diet and usual dietary advice.

A recent American study of 95 veterans found an improvement in pH in the group reducing simple sugars but symptomatic improvement in all groups reducing sugar consumption in general.

Therefore, based on all these data, according to Dr. Zerbib, “high-calorie meals, rich in fats or carbohydrates, promote the onset of reflux episodes and their perception. Diets low in fats and carbohydrates should be recommended.”
 

Questionable Studies

Certain foods can reduce LES pressure, such as coffee (excluding decaf), chocolate, and white wine. Moreover, white wine, beer, and chocolate have been associated with increased esophageal acid exposure. No significant effects on LES pressure or reflux have been observed with the consumption of citrus fruits or spicy foods. These conclusions, however, are based on older studies and subject to methodological criticisms.

Population studies on tea and coffee yield conflicting results. A recent study of 48,000 nurses without documented GERD found that consumption of tea, coffee, or sodas increased the risk for reflux symptoms by about 30% at least once per week, while water, milk, or fruit juice had no effect. Furthermore, the consumption of carbonated beverages also does not seem to increase the risk for GERD.

Regarding alcohol consumption as a risk factor for GERD, epidemiological data do not allow for a definitive conclusion. Most studies have not found a significant link, a finding confirmed by a recent meta-analysis of 24 publications.

Obesity contributes to GERD by promoting increased abdominal pressure and constraints on the esophagogastric junction. A high-resolution manometry study provided robust evidence for this mechanism. Generally, the relative risk for symptomatic GERD with obesity is 2-3 compared with normal body mass index (BMI), with a linear increase according to BMI.

Dr. Zerbib reported no relevant financial conflicts related to his presentation.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

From heartburn to hemorrhoids and everything in between, gastrointestinal troubles affect 60 million to 70 million Americans. Part of what makes them so frustrating – besides the frequent flights to the bathroom – are the invasive and uncomfortable tests one must endure for diagnosis, such as endoscopy (feeding a flexible tube into a person’s digestive tract) or x-rays that can involve higher radiation exposure.

But a revolutionary new option promising greater comfort and convenience could become available within the next few years.

A group of researchers has developed a small pill-like device that, once swallowed, can provide precise real-time data as it moves through your system. The technology is described in Nature Electronics, along with the results of in vitro and animal testing of how well it works.

“You can think of this like a GPS that you can see on your phone as your Lyft or Uber driver is moving around,” says study author Azita Emami, PhD, a professor of electrical engineering and medical engineering at the California Institute of Technology, Pasadena. “You can see the driver coming through the streets, and you can track it in real time, but imagine you can do that with much higher precision for a much smaller device inside the body.”

It’s not the first option for GI testing that can be swallowed. A “capsule endoscopy” camera can take pictures of the digestive tract. And a “wireless motility capsule” uses sensors to measure pH, temperature, and pressure. But these technologies may not work for the entire time it takes to pass through the gut, usually about 1-3 days. And while they gather information, you can’t track their location in the GI tract in real time. Your doctor can learn a lot from this level of detail.

“If a patient has motility problems in their GI tract, it can actually tell the [doctor] where the motility problem is happening, where the slowdown is happening, which is much more informative,” says Dr. Emami. Such slowdowns are common in notoriously frustrating GI issues like irritable bowel syndrome, or IBS, and inflammatory bowel disease, or IBD.

To develop this technology, the research team drew inspiration from magnetic resonance imaging, or MRI. Magnetic fields transmit data from the Bluetooth-enabled device to a smartphone. An external component, a magnetic field generator that looks like a flat mat, powers the device and is small enough to be carried in a backpack – or placed under a bed, attached to a jacket, or mounted to a toilet seat. The part that can be swallowed has tiny chips embedded in a capsulelike package.

Before this technology can go to market, more testing is needed, including clinical trials in humans, says Dr. Emami. That will likely take a few years.

The team also aims to make the device even smaller (it now measures about 1 cm wide and 2 cm long) and less expensive, and they want it to do more things, such as sending medicines to the GI tract. Those innovations could take a few more years.

A version of this article first appeared on WebMD.com.

From heartburn to hemorrhoids and everything in between, gastrointestinal troubles affect 60 million to 70 million Americans. Part of what makes them so frustrating – besides the frequent flights to the bathroom – are the invasive and uncomfortable tests one must endure for diagnosis, such as endoscopy (feeding a flexible tube into a person’s digestive tract) or x-rays that can involve higher radiation exposure.

But a revolutionary new option promising greater comfort and convenience could become available within the next few years.

A group of researchers has developed a small pill-like device that, once swallowed, can provide precise real-time data as it moves through your system. The technology is described in Nature Electronics, along with the results of in vitro and animal testing of how well it works.

“You can think of this like a GPS that you can see on your phone as your Lyft or Uber driver is moving around,” says study author Azita Emami, PhD, a professor of electrical engineering and medical engineering at the California Institute of Technology, Pasadena. “You can see the driver coming through the streets, and you can track it in real time, but imagine you can do that with much higher precision for a much smaller device inside the body.”

It’s not the first option for GI testing that can be swallowed. A “capsule endoscopy” camera can take pictures of the digestive tract. And a “wireless motility capsule” uses sensors to measure pH, temperature, and pressure. But these technologies may not work for the entire time it takes to pass through the gut, usually about 1-3 days. And while they gather information, you can’t track their location in the GI tract in real time. Your doctor can learn a lot from this level of detail.

“If a patient has motility problems in their GI tract, it can actually tell the [doctor] where the motility problem is happening, where the slowdown is happening, which is much more informative,” says Dr. Emami. Such slowdowns are common in notoriously frustrating GI issues like irritable bowel syndrome, or IBS, and inflammatory bowel disease, or IBD.

To develop this technology, the research team drew inspiration from magnetic resonance imaging, or MRI. Magnetic fields transmit data from the Bluetooth-enabled device to a smartphone. An external component, a magnetic field generator that looks like a flat mat, powers the device and is small enough to be carried in a backpack – or placed under a bed, attached to a jacket, or mounted to a toilet seat. The part that can be swallowed has tiny chips embedded in a capsulelike package.

Before this technology can go to market, more testing is needed, including clinical trials in humans, says Dr. Emami. That will likely take a few years.

The team also aims to make the device even smaller (it now measures about 1 cm wide and 2 cm long) and less expensive, and they want it to do more things, such as sending medicines to the GI tract. Those innovations could take a few more years.

A version of this article first appeared on WebMD.com.

From heartburn to hemorrhoids and everything in between, gastrointestinal troubles affect 60 million to 70 million Americans. Part of what makes them so frustrating – besides the frequent flights to the bathroom – are the invasive and uncomfortable tests one must endure for diagnosis, such as endoscopy (feeding a flexible tube into a person’s digestive tract) or x-rays that can involve higher radiation exposure.

But a revolutionary new option promising greater comfort and convenience could become available within the next few years.

A group of researchers has developed a small pill-like device that, once swallowed, can provide precise real-time data as it moves through your system. The technology is described in Nature Electronics, along with the results of in vitro and animal testing of how well it works.

“You can think of this like a GPS that you can see on your phone as your Lyft or Uber driver is moving around,” says study author Azita Emami, PhD, a professor of electrical engineering and medical engineering at the California Institute of Technology, Pasadena. “You can see the driver coming through the streets, and you can track it in real time, but imagine you can do that with much higher precision for a much smaller device inside the body.”

It’s not the first option for GI testing that can be swallowed. A “capsule endoscopy” camera can take pictures of the digestive tract. And a “wireless motility capsule” uses sensors to measure pH, temperature, and pressure. But these technologies may not work for the entire time it takes to pass through the gut, usually about 1-3 days. And while they gather information, you can’t track their location in the GI tract in real time. Your doctor can learn a lot from this level of detail.

“If a patient has motility problems in their GI tract, it can actually tell the [doctor] where the motility problem is happening, where the slowdown is happening, which is much more informative,” says Dr. Emami. Such slowdowns are common in notoriously frustrating GI issues like irritable bowel syndrome, or IBS, and inflammatory bowel disease, or IBD.

To develop this technology, the research team drew inspiration from magnetic resonance imaging, or MRI. Magnetic fields transmit data from the Bluetooth-enabled device to a smartphone. An external component, a magnetic field generator that looks like a flat mat, powers the device and is small enough to be carried in a backpack – or placed under a bed, attached to a jacket, or mounted to a toilet seat. The part that can be swallowed has tiny chips embedded in a capsulelike package.

Before this technology can go to market, more testing is needed, including clinical trials in humans, says Dr. Emami. That will likely take a few years.

The team also aims to make the device even smaller (it now measures about 1 cm wide and 2 cm long) and less expensive, and they want it to do more things, such as sending medicines to the GI tract. Those innovations could take a few more years.

A version of this article first appeared on WebMD.com.

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports

For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)

And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.

However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.

U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
 

Long-term PPI use threatens harm

“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”

The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.

The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine₂ receptor antagonists, a drug class with indications similar to those for PPIs.

The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.

The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports

For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)

And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.

However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.

U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
 

Long-term PPI use threatens harm

“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”

The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.

The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine₂ receptor antagonists, a drug class with indications similar to those for PPIs.

The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.

The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports

For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)

And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.

However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.

U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
 

Long-term PPI use threatens harm

“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”

The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.

The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine₂ receptor antagonists, a drug class with indications similar to those for PPIs.

The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.

The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The debate about a possible link between food allergy (FA) and pediatric gastroesophageal reflux disease (GERD) continues, and more, better-designed research is needed, a position paper by the European Academy of Allergy and Clinical Immunology reports.

The report offers consensus-based recommendations and a graphical decision pathway to guide providers through assessing and treating food allergy–related GERD. And the authors call for further, better-designed related research.

Food allergy and GERD are common in babies under 1 year of age and can lead to bothersome GERD, the authors write.

“An extensive literature search has found that whilst food proteins, in particular cow milk protein, can be a contributing factor to FA-associated” GERD, distinguishing between FA and non–FA-associated GERD is difficult, lead author Rosan Meyer, RD, PhD, senior lecturer at Imperial College London, and colleagues from the Academy task force on non-IgE mediated allergy, write in Pediatric Allergy and Immunology.
 

Consensus despite limited data

Dr. Meyer and colleagues developed clinical questions that addressed various aspects of the relationship between food allergy and GERD – pathophysiology, symptoms, diagnosis, dietary and medical management, prevalence, and impact on quality of life.

To address these issues, they systematically searched the literature for randomized controlled, observational, case-control, and retrospective studies of infants and children diagnosed with non-IgE gastrointestinal food allergies and GERD, published in English until February 2021.

Because of limited data in many of these areas, they used a modified Delphi method to reach consensus and provide practical advice on food allergy–associated GERD management.

The task force concludes:

• Food proteins, especially cow’s milk protein, can contribute to food allergy–associated GERD. The confirmation of food allergy is based on the elimination diet, always followed by reintroducing the offending allergen, and the diagnosis and treatment pathway should consider effects on quality of life.
• Breastfeeding should be supported in food allergy–associated GERD, and dietary advice should consider the potential nutritional impact on the breastfeeding mother. When breast milk is not available or is insufficient, formula and dietary advice to counteract the child’s nutrient deficiencies should be considered.
• Although some clarity exists about when GERD medications may be considered, they are often used inappropriately and may harm patients, especially infants.

Rigorous research needed

“Clinicians can use this algorithm to help them identify patients who may be affected by food allergy–related GERD,” Jonathan Tam, MD, medical director of the Gores Family Allergy Center at Children’s Hospital Los Angeles, told this news organization by email.

“Clinicians who suspect their patients may have food allergy–related GERD now have clearer guidance on how to systemically evaluate their patients,” added Dr. Tam, who was not involved in developing the report.

“Many allergists fear that patients may be labeled with a food allergy unnecessarily. Because no biomarkers or tests for food allergy–related GERD are available, elimination diets are a crucial part of the evaluation,” he said.

Dr. Tam added that the authors point out two key parts of a trial elimination: First, the trial should last at least 2 weeks, but full resolution may not occur until 6 weeks. Second, targeted elimination must be followed by reintroduction to confirm that the food was causing the symptoms, not that time itself may have been responsible for the clinical change.

“The authors’ note on allergy testing is important,” he said. “Allergy testing is not necessary when a clinician is concerned about food allergy–related GERD unless there are other associated atopic comorbidities, like eczema or IgE-mediated immediate food allergies.”

Jonathan M. Spergel, MD, PhD, chief of the allergy section at Children’s Hospital of Philadelphia, said in an email that families often ask whether food allergy is causing their child’s reflux.

“Both conditions are common and, in most cases, may not be related. As the report highlights, the risk of food allergy is increased if the patient has other atopic disease (atopic dermatitis), and standard allergy testing (skin testing, specific IgE) and IgG4 testing are not recommended,” he explained. “Food allergy in a patient with reflux can be considered if standard therapy is failing.”
 

Expert opinion on diagnosis and management

Dr. Spergel, also not involved in the report, joined the authors in advocating further, stronger studies. “While the expert opinion is a major strength,” he said, “with most available studies being neither randomized nor placebo-controlled, the true prevalence of food allergy reflux is unknown.”

Jay M. Portnoy, MD, specialist in pediatric allergy and immunology and medical director of telemedicine at Children’s Mercy Kansas City, said: “While most physicians believe that food allergy contributes to GERD, the evidence for the relationship is minimal. Reflux often occurs regardless of what food is eaten,” said Dr. Portnoy, who was not associated with the research.

Before removing a food from the diet, it’s important to determine whether that food is causing the problem, he urged.

“Blaming a food is easy. Food allergy is often suspected to cause symptoms it does not cause,” he said. “This unfounded blame can lead to unnecessary avoidance, reduce a family’s quality of life, and cause malnutrition.

“How a child is evaluated and treated depends as much on which physician they see as on whether the food is the culprit,” Dr. Portnoy said. “This report is an attempt to clarify the issues and to standardize an approach to the condition, so each provider evaluates and manages the condition in a consistent and evidence-based manner.

“It is important to see how well this report is incorporated into practice and whether following its guidance actually improves patient care,” Dr. Portnoy noted.

Funding information was not provided. Dr. Meyer and two coauthors report financial relationships with the nutritional health care industry. The full list can be found with the original article. The remaining authors and Dr. Tam, Dr. Spergel, and Dr. Portnoy report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The debate about a possible link between food allergy (FA) and pediatric gastroesophageal reflux disease (GERD) continues, and more, better-designed research is needed, a position paper by the European Academy of Allergy and Clinical Immunology reports.

The report offers consensus-based recommendations and a graphical decision pathway to guide providers through assessing and treating food allergy–related GERD. And the authors call for further, better-designed related research.

Food allergy and GERD are common in babies under 1 year of age and can lead to bothersome GERD, the authors write.

“An extensive literature search has found that whilst food proteins, in particular cow milk protein, can be a contributing factor to FA-associated” GERD, distinguishing between FA and non–FA-associated GERD is difficult, lead author Rosan Meyer, RD, PhD, senior lecturer at Imperial College London, and colleagues from the Academy task force on non-IgE mediated allergy, write in Pediatric Allergy and Immunology.
 

Consensus despite limited data

Dr. Meyer and colleagues developed clinical questions that addressed various aspects of the relationship between food allergy and GERD – pathophysiology, symptoms, diagnosis, dietary and medical management, prevalence, and impact on quality of life.

To address these issues, they systematically searched the literature for randomized controlled, observational, case-control, and retrospective studies of infants and children diagnosed with non-IgE gastrointestinal food allergies and GERD, published in English until February 2021.

Because of limited data in many of these areas, they used a modified Delphi method to reach consensus and provide practical advice on food allergy–associated GERD management.

The task force concludes:

• Food proteins, especially cow’s milk protein, can contribute to food allergy–associated GERD. The confirmation of food allergy is based on the elimination diet, always followed by reintroducing the offending allergen, and the diagnosis and treatment pathway should consider effects on quality of life.
• Breastfeeding should be supported in food allergy–associated GERD, and dietary advice should consider the potential nutritional impact on the breastfeeding mother. When breast milk is not available or is insufficient, formula and dietary advice to counteract the child’s nutrient deficiencies should be considered.
• Although some clarity exists about when GERD medications may be considered, they are often used inappropriately and may harm patients, especially infants.

Rigorous research needed

“Clinicians can use this algorithm to help them identify patients who may be affected by food allergy–related GERD,” Jonathan Tam, MD, medical director of the Gores Family Allergy Center at Children’s Hospital Los Angeles, told this news organization by email.

“Clinicians who suspect their patients may have food allergy–related GERD now have clearer guidance on how to systemically evaluate their patients,” added Dr. Tam, who was not involved in developing the report.

“Many allergists fear that patients may be labeled with a food allergy unnecessarily. Because no biomarkers or tests for food allergy–related GERD are available, elimination diets are a crucial part of the evaluation,” he said.

Dr. Tam added that the authors point out two key parts of a trial elimination: First, the trial should last at least 2 weeks, but full resolution may not occur until 6 weeks. Second, targeted elimination must be followed by reintroduction to confirm that the food was causing the symptoms, not that time itself may have been responsible for the clinical change.

“The authors’ note on allergy testing is important,” he said. “Allergy testing is not necessary when a clinician is concerned about food allergy–related GERD unless there are other associated atopic comorbidities, like eczema or IgE-mediated immediate food allergies.”

Jonathan M. Spergel, MD, PhD, chief of the allergy section at Children’s Hospital of Philadelphia, said in an email that families often ask whether food allergy is causing their child’s reflux.

“Both conditions are common and, in most cases, may not be related. As the report highlights, the risk of food allergy is increased if the patient has other atopic disease (atopic dermatitis), and standard allergy testing (skin testing, specific IgE) and IgG4 testing are not recommended,” he explained. “Food allergy in a patient with reflux can be considered if standard therapy is failing.”
 

Expert opinion on diagnosis and management

Dr. Spergel, also not involved in the report, joined the authors in advocating further, stronger studies. “While the expert opinion is a major strength,” he said, “with most available studies being neither randomized nor placebo-controlled, the true prevalence of food allergy reflux is unknown.”

Jay M. Portnoy, MD, specialist in pediatric allergy and immunology and medical director of telemedicine at Children’s Mercy Kansas City, said: “While most physicians believe that food allergy contributes to GERD, the evidence for the relationship is minimal. Reflux often occurs regardless of what food is eaten,” said Dr. Portnoy, who was not associated with the research.

Before removing a food from the diet, it’s important to determine whether that food is causing the problem, he urged.

“Blaming a food is easy. Food allergy is often suspected to cause symptoms it does not cause,” he said. “This unfounded blame can lead to unnecessary avoidance, reduce a family’s quality of life, and cause malnutrition.

“How a child is evaluated and treated depends as much on which physician they see as on whether the food is the culprit,” Dr. Portnoy said. “This report is an attempt to clarify the issues and to standardize an approach to the condition, so each provider evaluates and manages the condition in a consistent and evidence-based manner.

“It is important to see how well this report is incorporated into practice and whether following its guidance actually improves patient care,” Dr. Portnoy noted.

Funding information was not provided. Dr. Meyer and two coauthors report financial relationships with the nutritional health care industry. The full list can be found with the original article. The remaining authors and Dr. Tam, Dr. Spergel, and Dr. Portnoy report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The debate about a possible link between food allergy (FA) and pediatric gastroesophageal reflux disease (GERD) continues, and more, better-designed research is needed, a position paper by the European Academy of Allergy and Clinical Immunology reports.

The report offers consensus-based recommendations and a graphical decision pathway to guide providers through assessing and treating food allergy–related GERD. And the authors call for further, better-designed related research.

Food allergy and GERD are common in babies under 1 year of age and can lead to bothersome GERD, the authors write.

“An extensive literature search has found that whilst food proteins, in particular cow milk protein, can be a contributing factor to FA-associated” GERD, distinguishing between FA and non–FA-associated GERD is difficult, lead author Rosan Meyer, RD, PhD, senior lecturer at Imperial College London, and colleagues from the Academy task force on non-IgE mediated allergy, write in Pediatric Allergy and Immunology.
 

Consensus despite limited data

Dr. Meyer and colleagues developed clinical questions that addressed various aspects of the relationship between food allergy and GERD – pathophysiology, symptoms, diagnosis, dietary and medical management, prevalence, and impact on quality of life.

To address these issues, they systematically searched the literature for randomized controlled, observational, case-control, and retrospective studies of infants and children diagnosed with non-IgE gastrointestinal food allergies and GERD, published in English until February 2021.

Because of limited data in many of these areas, they used a modified Delphi method to reach consensus and provide practical advice on food allergy–associated GERD management.

The task force concludes:

• Food proteins, especially cow’s milk protein, can contribute to food allergy–associated GERD. The confirmation of food allergy is based on the elimination diet, always followed by reintroducing the offending allergen, and the diagnosis and treatment pathway should consider effects on quality of life.
• Breastfeeding should be supported in food allergy–associated GERD, and dietary advice should consider the potential nutritional impact on the breastfeeding mother. When breast milk is not available or is insufficient, formula and dietary advice to counteract the child’s nutrient deficiencies should be considered.
• Although some clarity exists about when GERD medications may be considered, they are often used inappropriately and may harm patients, especially infants.

Rigorous research needed

“Clinicians can use this algorithm to help them identify patients who may be affected by food allergy–related GERD,” Jonathan Tam, MD, medical director of the Gores Family Allergy Center at Children’s Hospital Los Angeles, told this news organization by email.

“Clinicians who suspect their patients may have food allergy–related GERD now have clearer guidance on how to systemically evaluate their patients,” added Dr. Tam, who was not involved in developing the report.

“Many allergists fear that patients may be labeled with a food allergy unnecessarily. Because no biomarkers or tests for food allergy–related GERD are available, elimination diets are a crucial part of the evaluation,” he said.

Dr. Tam added that the authors point out two key parts of a trial elimination: First, the trial should last at least 2 weeks, but full resolution may not occur until 6 weeks. Second, targeted elimination must be followed by reintroduction to confirm that the food was causing the symptoms, not that time itself may have been responsible for the clinical change.

“The authors’ note on allergy testing is important,” he said. “Allergy testing is not necessary when a clinician is concerned about food allergy–related GERD unless there are other associated atopic comorbidities, like eczema or IgE-mediated immediate food allergies.”

Jonathan M. Spergel, MD, PhD, chief of the allergy section at Children’s Hospital of Philadelphia, said in an email that families often ask whether food allergy is causing their child’s reflux.

“Both conditions are common and, in most cases, may not be related. As the report highlights, the risk of food allergy is increased if the patient has other atopic disease (atopic dermatitis), and standard allergy testing (skin testing, specific IgE) and IgG4 testing are not recommended,” he explained. “Food allergy in a patient with reflux can be considered if standard therapy is failing.”
 

Expert opinion on diagnosis and management

Dr. Spergel, also not involved in the report, joined the authors in advocating further, stronger studies. “While the expert opinion is a major strength,” he said, “with most available studies being neither randomized nor placebo-controlled, the true prevalence of food allergy reflux is unknown.”

Jay M. Portnoy, MD, specialist in pediatric allergy and immunology and medical director of telemedicine at Children’s Mercy Kansas City, said: “While most physicians believe that food allergy contributes to GERD, the evidence for the relationship is minimal. Reflux often occurs regardless of what food is eaten,” said Dr. Portnoy, who was not associated with the research.

Before removing a food from the diet, it’s important to determine whether that food is causing the problem, he urged.

“Blaming a food is easy. Food allergy is often suspected to cause symptoms it does not cause,” he said. “This unfounded blame can lead to unnecessary avoidance, reduce a family’s quality of life, and cause malnutrition.

“How a child is evaluated and treated depends as much on which physician they see as on whether the food is the culprit,” Dr. Portnoy said. “This report is an attempt to clarify the issues and to standardize an approach to the condition, so each provider evaluates and manages the condition in a consistent and evidence-based manner.

“It is important to see how well this report is incorporated into practice and whether following its guidance actually improves patient care,” Dr. Portnoy noted.

Funding information was not provided. Dr. Meyer and two coauthors report financial relationships with the nutritional health care industry. The full list can be found with the original article. The remaining authors and Dr. Tam, Dr. Spergel, and Dr. Portnoy report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Managing children’s cow’s milk allergy is costly to families and to health care systems, largely owing to costs of prescriptions, according to an industry-sponsored study based on data from the United Kingdom.

“This large cohort study provides novel evidence of a significant health economic burden of cow’s milk allergy in children,” Abbie L. Cawood, PhD, RNutr, MICR, head of scientific affairs at Nutricia Ltd in Trowbridge, England, and colleagues wrote in Clinical and Translational Allergy.

“Management of cow’s milk allergy necessitates the exclusion of cow’s milk protein from the diet. Whilst breastmilk remains the ideal nutrient source in infants with cow’s milk allergy, infants who are not exclusively breastfed require a hypoallergenic formula,” added Dr. Cawood, a visiting research fellow at University of Southampton, and her coauthors.

Cow’s milk allergy, an immune‐mediated response to one or more proteins in cow’s milk, is one of the most common childhood food allergies and affects 2%-5% of infants in Europe. Management involves avoiding cow’s milk protein and treating possible related gastrointestinal, skin, respiratory, and other allergic conditions, the authors explained.

In their retrospective matched cohort study, Dr. Cawood and colleagues turned to The Health Improvement Network (THIN), a Cegedim Rx proprietary database of 2.9 million anonymized active patient records. They extracted data from nearly 7,000 case records covering 5 years (2015-2020).

They examined medication prescriptions and health care professional contacts based on diagnosis read-codes and hypoallergenic formula prescriptions and compared health care costs for children with cow’s milk allergy with the costs for those without.

They matched 3,499 children aged 1 year or younger who had confirmed or suspected cow’s milk allergy with the same number of children without cow’s milk allergy. Around half of the participants were boys, and the mean observation period was 4.2 years.
 

Children with cow’s milk allergy need more, costly health care

The researchers found:

• Medications were prescribed to significantly more children with cow’s milk allergy (CMA), at a higher rate, than to those without CMA. In particular, prescriptions for antireflux medication increased by almost 500%.
• Children with CMA needed significantly more health care contacts and at a higher rate than those without CMA.
• CMA was linked with additional potential health care costs of £1381.53 per person per year. Assuming a 2.5% prevalence from the estimated 2%-5% CMA prevalence range and extrapolating to the UK infant population, CMA may have added more than £25.7 million in annual health care costs nationwide.

“Several conditions in infancy necessitate the elimination of cow milk–based formulas and require extensively hydrolyzed or amino acid formulas or, if preferred or able, exclusive breast milk,” Kara E. Coffey, MD, assistant professor of pediatrics at the University of Pittsburgh, said by email.

“This study shows that, regardless of the reason for cow milk–based avoidance, these infants require more healthcare service utilizations (clinic visits, nutritional assessments, prescriptions) than [do] their peers, which is certainly a commitment of a lot of time and money for their families to ensure their ability to grow and thrive,” added Dr. Coffey, who was not involved in the study.

Jodi A. Shroba, MSN, APRN, CPNP, the coordinator for the Food Allergy Program at Children’s Mercy Kansas City, Mo., did not find these numbers surprising.

“Children with food allergies typically have other atopic comorbidities that require more visits to primary care physicians and specialists and more prescriptions,” Ms. Shroba, who was not involved in the study, said by email.

“An intriguing statement is that the U.K. guidelines recommend the involvement of a dietitian for children with cow’s milk allergy,” she noted. “In the United States, having a dietitian involved would be a wonderful addition to care, as avoidance of cow’s milk can cause nutritional and growth deficiencies. But not all healthcare practices have those resources available.

“The higher rate of antibiotic use and the almost 500% increase of antireflux prescriptions by the children with cow’s milk allergy warrant additional research,” she added.

Nutricia Ltd. funded the study. Dr. Cawood and one coauthor are employed by Nutricia, and all other coauthors have been employees of or have other financial relationships with Nutricia. One coauthor is employed by Cegedim Rx, which was funded for this research by Nutricia. Ms. Shroba and Dr. Coffey report no conflicts of interest with the study.

A version of this article first appeared on Medscape.com.

Managing children’s cow’s milk allergy is costly to families and to health care systems, largely owing to costs of prescriptions, according to an industry-sponsored study based on data from the United Kingdom.

“This large cohort study provides novel evidence of a significant health economic burden of cow’s milk allergy in children,” Abbie L. Cawood, PhD, RNutr, MICR, head of scientific affairs at Nutricia Ltd in Trowbridge, England, and colleagues wrote in Clinical and Translational Allergy.

“Management of cow’s milk allergy necessitates the exclusion of cow’s milk protein from the diet. Whilst breastmilk remains the ideal nutrient source in infants with cow’s milk allergy, infants who are not exclusively breastfed require a hypoallergenic formula,” added Dr. Cawood, a visiting research fellow at University of Southampton, and her coauthors.

Cow’s milk allergy, an immune‐mediated response to one or more proteins in cow’s milk, is one of the most common childhood food allergies and affects 2%-5% of infants in Europe. Management involves avoiding cow’s milk protein and treating possible related gastrointestinal, skin, respiratory, and other allergic conditions, the authors explained.

In their retrospective matched cohort study, Dr. Cawood and colleagues turned to The Health Improvement Network (THIN), a Cegedim Rx proprietary database of 2.9 million anonymized active patient records. They extracted data from nearly 7,000 case records covering 5 years (2015-2020).

They examined medication prescriptions and health care professional contacts based on diagnosis read-codes and hypoallergenic formula prescriptions and compared health care costs for children with cow’s milk allergy with the costs for those without.

They matched 3,499 children aged 1 year or younger who had confirmed or suspected cow’s milk allergy with the same number of children without cow’s milk allergy. Around half of the participants were boys, and the mean observation period was 4.2 years.
 

Children with cow’s milk allergy need more, costly health care

The researchers found:

• Medications were prescribed to significantly more children with cow’s milk allergy (CMA), at a higher rate, than to those without CMA. In particular, prescriptions for antireflux medication increased by almost 500%.
• Children with CMA needed significantly more health care contacts and at a higher rate than those without CMA.
• CMA was linked with additional potential health care costs of £1381.53 per person per year. Assuming a 2.5% prevalence from the estimated 2%-5% CMA prevalence range and extrapolating to the UK infant population, CMA may have added more than £25.7 million in annual health care costs nationwide.

“Several conditions in infancy necessitate the elimination of cow milk–based formulas and require extensively hydrolyzed or amino acid formulas or, if preferred or able, exclusive breast milk,” Kara E. Coffey, MD, assistant professor of pediatrics at the University of Pittsburgh, said by email.

“This study shows that, regardless of the reason for cow milk–based avoidance, these infants require more healthcare service utilizations (clinic visits, nutritional assessments, prescriptions) than [do] their peers, which is certainly a commitment of a lot of time and money for their families to ensure their ability to grow and thrive,” added Dr. Coffey, who was not involved in the study.

Jodi A. Shroba, MSN, APRN, CPNP, the coordinator for the Food Allergy Program at Children’s Mercy Kansas City, Mo., did not find these numbers surprising.

“Children with food allergies typically have other atopic comorbidities that require more visits to primary care physicians and specialists and more prescriptions,” Ms. Shroba, who was not involved in the study, said by email.

“An intriguing statement is that the U.K. guidelines recommend the involvement of a dietitian for children with cow’s milk allergy,” she noted. “In the United States, having a dietitian involved would be a wonderful addition to care, as avoidance of cow’s milk can cause nutritional and growth deficiencies. But not all healthcare practices have those resources available.

“The higher rate of antibiotic use and the almost 500% increase of antireflux prescriptions by the children with cow’s milk allergy warrant additional research,” she added.

Nutricia Ltd. funded the study. Dr. Cawood and one coauthor are employed by Nutricia, and all other coauthors have been employees of or have other financial relationships with Nutricia. One coauthor is employed by Cegedim Rx, which was funded for this research by Nutricia. Ms. Shroba and Dr. Coffey report no conflicts of interest with the study.

A version of this article first appeared on Medscape.com.

Managing children’s cow’s milk allergy is costly to families and to health care systems, largely owing to costs of prescriptions, according to an industry-sponsored study based on data from the United Kingdom.

“This large cohort study provides novel evidence of a significant health economic burden of cow’s milk allergy in children,” Abbie L. Cawood, PhD, RNutr, MICR, head of scientific affairs at Nutricia Ltd in Trowbridge, England, and colleagues wrote in Clinical and Translational Allergy.

“Management of cow’s milk allergy necessitates the exclusion of cow’s milk protein from the diet. Whilst breastmilk remains the ideal nutrient source in infants with cow’s milk allergy, infants who are not exclusively breastfed require a hypoallergenic formula,” added Dr. Cawood, a visiting research fellow at University of Southampton, and her coauthors.

Cow’s milk allergy, an immune‐mediated response to one or more proteins in cow’s milk, is one of the most common childhood food allergies and affects 2%-5% of infants in Europe. Management involves avoiding cow’s milk protein and treating possible related gastrointestinal, skin, respiratory, and other allergic conditions, the authors explained.

In their retrospective matched cohort study, Dr. Cawood and colleagues turned to The Health Improvement Network (THIN), a Cegedim Rx proprietary database of 2.9 million anonymized active patient records. They extracted data from nearly 7,000 case records covering 5 years (2015-2020).

They examined medication prescriptions and health care professional contacts based on diagnosis read-codes and hypoallergenic formula prescriptions and compared health care costs for children with cow’s milk allergy with the costs for those without.

They matched 3,499 children aged 1 year or younger who had confirmed or suspected cow’s milk allergy with the same number of children without cow’s milk allergy. Around half of the participants were boys, and the mean observation period was 4.2 years.
 

Children with cow’s milk allergy need more, costly health care

The researchers found:

• Medications were prescribed to significantly more children with cow’s milk allergy (CMA), at a higher rate, than to those without CMA. In particular, prescriptions for antireflux medication increased by almost 500%.
• Children with CMA needed significantly more health care contacts and at a higher rate than those without CMA.
• CMA was linked with additional potential health care costs of £1381.53 per person per year. Assuming a 2.5% prevalence from the estimated 2%-5% CMA prevalence range and extrapolating to the UK infant population, CMA may have added more than £25.7 million in annual health care costs nationwide.

“Several conditions in infancy necessitate the elimination of cow milk–based formulas and require extensively hydrolyzed or amino acid formulas or, if preferred or able, exclusive breast milk,” Kara E. Coffey, MD, assistant professor of pediatrics at the University of Pittsburgh, said by email.

“This study shows that, regardless of the reason for cow milk–based avoidance, these infants require more healthcare service utilizations (clinic visits, nutritional assessments, prescriptions) than [do] their peers, which is certainly a commitment of a lot of time and money for their families to ensure their ability to grow and thrive,” added Dr. Coffey, who was not involved in the study.

Jodi A. Shroba, MSN, APRN, CPNP, the coordinator for the Food Allergy Program at Children’s Mercy Kansas City, Mo., did not find these numbers surprising.

“Children with food allergies typically have other atopic comorbidities that require more visits to primary care physicians and specialists and more prescriptions,” Ms. Shroba, who was not involved in the study, said by email.

“An intriguing statement is that the U.K. guidelines recommend the involvement of a dietitian for children with cow’s milk allergy,” she noted. “In the United States, having a dietitian involved would be a wonderful addition to care, as avoidance of cow’s milk can cause nutritional and growth deficiencies. But not all healthcare practices have those resources available.

“The higher rate of antibiotic use and the almost 500% increase of antireflux prescriptions by the children with cow’s milk allergy warrant additional research,” she added.

Nutricia Ltd. funded the study. Dr. Cawood and one coauthor are employed by Nutricia, and all other coauthors have been employees of or have other financial relationships with Nutricia. One coauthor is employed by Cegedim Rx, which was funded for this research by Nutricia. Ms. Shroba and Dr. Coffey report no conflicts of interest with the study.

A version of this article first appeared on Medscape.com.

Four days is an optimal time for wireless reflux monitoring to determine which patients can stop taking proton pump inhibitors (PPIs) and which ones need long-term antireflux therapy, researchers report.

“This first-of-its kind double-blinded clinical trial demonstrates the comparable, and in some cases better, performance of a simple assessment of daily acid exposure from multiple days of recording compared to other composite or complex assessments,” write Rena Yadlapati, MD, with the Division of Gastroenterology at the University of California, San Diego, and her coauthors.

Their findings were published online in the American Journal of Gastroenterology.

A substantial percentage of patients who have esophageal reflux symptoms do not have gastroesophageal reflux disease (GERD) and can stop taking PPIs.

Wireless reflux monitoring performed while patients are not taking PPIs is the gold standard for determining whether a patient has abnormal acid from GERD, but the optimal daily acid exposure time (AET) and the optimal duration of monitoring have not been well studied.

Aiming to fill this knowledge gap, Dr. Yadlapati and her colleagues conducted a single-arm, double-blinded clinical trial over 4 years at two tertiary care centers. They enrolled adult patients who had demonstrated an inadequate response to more than 8 weeks’ treatment with PPIs.

Study participants were asked to stop taking their PPI for 3 weeks in order for the investigators to determine the rate of relapse after PPI use and establish the study reference standard to discontinue therapy. During the 3-week period, after having stopped taking PPIs for at least a week, patients underwent 96-hour wireless reflux monitoring. They were then told to continue not taking PPIs for an additional 2 weeks. They could use over-the-counter antacids for symptom relief.

The primary outcome was whether PPIs could be successfully discontinued or restarted within 3 weeks. Of the 132 patients, 30% were able to stop taking PPIs.
 

AET less than 4.0% best discontinuation predictor

The team came to two key conclusions.

They found that acid exposure time of less than 4.0% was the best predictor of when stopping PPIs will be effective without worsening symptoms (odds ratio, 2.9; 95% confidence interval, 1.4-6.4). Comparatively, 45% (22 of 49 patients) with total AET of 4.0% or less discontinued taking PPIs, versus 22% (18 of 83 patients) with total AET of more than 4.0%.

Additionally, the investigators concluded that 96 hours of monitoring was better than 48 hours or fewer in predicting whether patients could stop taking PPIs (area under curve [AUC] for 96 hours, 0.63, versus AUC for 48 hours, 0.57).

Dr. Yadlapati told this news organization that the findings should be practice-changing.

“You really need to test for 4 days,” she said. She noted that the battery life of the monitor is 96 hours, and clinicians commonly only test for 2 days.

With only 1-2 days of monitoring, there is too much variability in how much acid is in the esophagus from one day to another. Monitoring over a 4-day period gives a clearer picture of acid exposure burden, she said.

Her advice: “If you have a patient with heartburn or chest pain and you think it might be from reflux, and they’re not responding to a trial of PPI, get the reflux monitoring. Don’t wait.”

After 4 days of monitoring, if exposure to acid is low, “they should really be taken off their PPI therapy,” she said.

They likely have a condition that requires a different therapy, she added.

“It is very consistent with what we have thought to be the case and what some lower-quality studies have shown,” she said. “It just hadn’t been done in a clinical trial with a large patient population and with a full outcome.”
 

PPI often used inappropriately

Interest is high both in discontinuing PPI in light of widespread and often inappropriate use and in not starting treatment with PPIs for patients who need a different therapy.

As this news organization has reported, some studies have linked long-term PPI use with intestinal infections, pneumonia, stomach cancer, osteoporosis-related bone fractures, chronic kidney disease, vitamin deficiencies, heart attacks, strokes, dementia, and early death.

Avin Aggarwal, MD, a gastroenterologist and medical director of Banner Health’s South Campus endoscopy services and clinical assistant professor at the University of Arizona, Tucson, said in an interview that this study provides the evidence needed to push for practice change.

He said his center has been using 48-hour reflux monitoring. He said that anecdotally, they had gotten better data with 4-day monitoring, but evidence was not directly tied to a measurable outcome such as this study provides.

With 4-day monitoring, “we get way more symptoms on the recorder to actually correlate them with reflux or not,” he said.

He said he will now push for the 96-hour monitoring in his clinic.

He added that part of the problem is in assuming patients have GERD and initiating PPIs in the first place without a specific diagnosis of acid reflux.

Patients, he said, are often aware of the long-term side effects of PPIs and are approaching their physicians to see whether they can discontinue them.

The data from this study, he said, will help guide physicians on when it is appropriate to discontinue treatment.

Dr. Yadlapati is a consultant for Medtronic, Phathom Pharmaceuticals, and StatLinkMD and receives research support from Ironwood Pharmaceuticals. She is on the advisory board with stock options for RJS Mediagnostix. Other study coauthors report ties to Medtronic, Diversatek, Ironwood, Iso-Thrive, Quintiles, Johnson & Johnson, Reckitt, Phathom Pharmaceuticals, Daewood, Takeda, and Crospon. Study coauthor Michael F. Vaezi, MD, PHD, holds a patent on mucosal integrity by Vanderbilt. Dr. Aggarwal reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Four days is an optimal time for wireless reflux monitoring to determine which patients can stop taking proton pump inhibitors (PPIs) and which ones need long-term antireflux therapy, researchers report.

“This first-of-its kind double-blinded clinical trial demonstrates the comparable, and in some cases better, performance of a simple assessment of daily acid exposure from multiple days of recording compared to other composite or complex assessments,” write Rena Yadlapati, MD, with the Division of Gastroenterology at the University of California, San Diego, and her coauthors.

Their findings were published online in the American Journal of Gastroenterology.

A substantial percentage of patients who have esophageal reflux symptoms do not have gastroesophageal reflux disease (GERD) and can stop taking PPIs.

Wireless reflux monitoring performed while patients are not taking PPIs is the gold standard for determining whether a patient has abnormal acid from GERD, but the optimal daily acid exposure time (AET) and the optimal duration of monitoring have not been well studied.

Aiming to fill this knowledge gap, Dr. Yadlapati and her colleagues conducted a single-arm, double-blinded clinical trial over 4 years at two tertiary care centers. They enrolled adult patients who had demonstrated an inadequate response to more than 8 weeks’ treatment with PPIs.

Study participants were asked to stop taking their PPI for 3 weeks in order for the investigators to determine the rate of relapse after PPI use and establish the study reference standard to discontinue therapy. During the 3-week period, after having stopped taking PPIs for at least a week, patients underwent 96-hour wireless reflux monitoring. They were then told to continue not taking PPIs for an additional 2 weeks. They could use over-the-counter antacids for symptom relief.

The primary outcome was whether PPIs could be successfully discontinued or restarted within 3 weeks. Of the 132 patients, 30% were able to stop taking PPIs.
 

AET less than 4.0% best discontinuation predictor

The team came to two key conclusions.

They found that acid exposure time of less than 4.0% was the best predictor of when stopping PPIs will be effective without worsening symptoms (odds ratio, 2.9; 95% confidence interval, 1.4-6.4). Comparatively, 45% (22 of 49 patients) with total AET of 4.0% or less discontinued taking PPIs, versus 22% (18 of 83 patients) with total AET of more than 4.0%.

Additionally, the investigators concluded that 96 hours of monitoring was better than 48 hours or fewer in predicting whether patients could stop taking PPIs (area under curve [AUC] for 96 hours, 0.63, versus AUC for 48 hours, 0.57).

Dr. Yadlapati told this news organization that the findings should be practice-changing.

“You really need to test for 4 days,” she said. She noted that the battery life of the monitor is 96 hours, and clinicians commonly only test for 2 days.

With only 1-2 days of monitoring, there is too much variability in how much acid is in the esophagus from one day to another. Monitoring over a 4-day period gives a clearer picture of acid exposure burden, she said.

Her advice: “If you have a patient with heartburn or chest pain and you think it might be from reflux, and they’re not responding to a trial of PPI, get the reflux monitoring. Don’t wait.”

After 4 days of monitoring, if exposure to acid is low, “they should really be taken off their PPI therapy,” she said.

They likely have a condition that requires a different therapy, she added.

“It is very consistent with what we have thought to be the case and what some lower-quality studies have shown,” she said. “It just hadn’t been done in a clinical trial with a large patient population and with a full outcome.”
 

PPI often used inappropriately

Interest is high both in discontinuing PPI in light of widespread and often inappropriate use and in not starting treatment with PPIs for patients who need a different therapy.

As this news organization has reported, some studies have linked long-term PPI use with intestinal infections, pneumonia, stomach cancer, osteoporosis-related bone fractures, chronic kidney disease, vitamin deficiencies, heart attacks, strokes, dementia, and early death.

Avin Aggarwal, MD, a gastroenterologist and medical director of Banner Health’s South Campus endoscopy services and clinical assistant professor at the University of Arizona, Tucson, said in an interview that this study provides the evidence needed to push for practice change.

He said his center has been using 48-hour reflux monitoring. He said that anecdotally, they had gotten better data with 4-day monitoring, but evidence was not directly tied to a measurable outcome such as this study provides.

With 4-day monitoring, “we get way more symptoms on the recorder to actually correlate them with reflux or not,” he said.

He said he will now push for the 96-hour monitoring in his clinic.

He added that part of the problem is in assuming patients have GERD and initiating PPIs in the first place without a specific diagnosis of acid reflux.

Patients, he said, are often aware of the long-term side effects of PPIs and are approaching their physicians to see whether they can discontinue them.

The data from this study, he said, will help guide physicians on when it is appropriate to discontinue treatment.

Dr. Yadlapati is a consultant for Medtronic, Phathom Pharmaceuticals, and StatLinkMD and receives research support from Ironwood Pharmaceuticals. She is on the advisory board with stock options for RJS Mediagnostix. Other study coauthors report ties to Medtronic, Diversatek, Ironwood, Iso-Thrive, Quintiles, Johnson & Johnson, Reckitt, Phathom Pharmaceuticals, Daewood, Takeda, and Crospon. Study coauthor Michael F. Vaezi, MD, PHD, holds a patent on mucosal integrity by Vanderbilt. Dr. Aggarwal reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Four days is an optimal time for wireless reflux monitoring to determine which patients can stop taking proton pump inhibitors (PPIs) and which ones need long-term antireflux therapy, researchers report.

“This first-of-its kind double-blinded clinical trial demonstrates the comparable, and in some cases better, performance of a simple assessment of daily acid exposure from multiple days of recording compared to other composite or complex assessments,” write Rena Yadlapati, MD, with the Division of Gastroenterology at the University of California, San Diego, and her coauthors.

Their findings were published online in the American Journal of Gastroenterology.

A substantial percentage of patients who have esophageal reflux symptoms do not have gastroesophageal reflux disease (GERD) and can stop taking PPIs.

Wireless reflux monitoring performed while patients are not taking PPIs is the gold standard for determining whether a patient has abnormal acid from GERD, but the optimal daily acid exposure time (AET) and the optimal duration of monitoring have not been well studied.

Aiming to fill this knowledge gap, Dr. Yadlapati and her colleagues conducted a single-arm, double-blinded clinical trial over 4 years at two tertiary care centers. They enrolled adult patients who had demonstrated an inadequate response to more than 8 weeks’ treatment with PPIs.

Study participants were asked to stop taking their PPI for 3 weeks in order for the investigators to determine the rate of relapse after PPI use and establish the study reference standard to discontinue therapy. During the 3-week period, after having stopped taking PPIs for at least a week, patients underwent 96-hour wireless reflux monitoring. They were then told to continue not taking PPIs for an additional 2 weeks. They could use over-the-counter antacids for symptom relief.

The primary outcome was whether PPIs could be successfully discontinued or restarted within 3 weeks. Of the 132 patients, 30% were able to stop taking PPIs.
 

AET less than 4.0% best discontinuation predictor

The team came to two key conclusions.

They found that acid exposure time of less than 4.0% was the best predictor of when stopping PPIs will be effective without worsening symptoms (odds ratio, 2.9; 95% confidence interval, 1.4-6.4). Comparatively, 45% (22 of 49 patients) with total AET of 4.0% or less discontinued taking PPIs, versus 22% (18 of 83 patients) with total AET of more than 4.0%.

Additionally, the investigators concluded that 96 hours of monitoring was better than 48 hours or fewer in predicting whether patients could stop taking PPIs (area under curve [AUC] for 96 hours, 0.63, versus AUC for 48 hours, 0.57).

Dr. Yadlapati told this news organization that the findings should be practice-changing.

“You really need to test for 4 days,” she said. She noted that the battery life of the monitor is 96 hours, and clinicians commonly only test for 2 days.

With only 1-2 days of monitoring, there is too much variability in how much acid is in the esophagus from one day to another. Monitoring over a 4-day period gives a clearer picture of acid exposure burden, she said.

Her advice: “If you have a patient with heartburn or chest pain and you think it might be from reflux, and they’re not responding to a trial of PPI, get the reflux monitoring. Don’t wait.”

After 4 days of monitoring, if exposure to acid is low, “they should really be taken off their PPI therapy,” she said.

They likely have a condition that requires a different therapy, she added.

“It is very consistent with what we have thought to be the case and what some lower-quality studies have shown,” she said. “It just hadn’t been done in a clinical trial with a large patient population and with a full outcome.”
 

PPI often used inappropriately

Interest is high both in discontinuing PPI in light of widespread and often inappropriate use and in not starting treatment with PPIs for patients who need a different therapy.

As this news organization has reported, some studies have linked long-term PPI use with intestinal infections, pneumonia, stomach cancer, osteoporosis-related bone fractures, chronic kidney disease, vitamin deficiencies, heart attacks, strokes, dementia, and early death.

Avin Aggarwal, MD, a gastroenterologist and medical director of Banner Health’s South Campus endoscopy services and clinical assistant professor at the University of Arizona, Tucson, said in an interview that this study provides the evidence needed to push for practice change.

He said his center has been using 48-hour reflux monitoring. He said that anecdotally, they had gotten better data with 4-day monitoring, but evidence was not directly tied to a measurable outcome such as this study provides.

With 4-day monitoring, “we get way more symptoms on the recorder to actually correlate them with reflux or not,” he said.

He said he will now push for the 96-hour monitoring in his clinic.

He added that part of the problem is in assuming patients have GERD and initiating PPIs in the first place without a specific diagnosis of acid reflux.

Patients, he said, are often aware of the long-term side effects of PPIs and are approaching their physicians to see whether they can discontinue them.

The data from this study, he said, will help guide physicians on when it is appropriate to discontinue treatment.

Dr. Yadlapati is a consultant for Medtronic, Phathom Pharmaceuticals, and StatLinkMD and receives research support from Ironwood Pharmaceuticals. She is on the advisory board with stock options for RJS Mediagnostix. Other study coauthors report ties to Medtronic, Diversatek, Ironwood, Iso-Thrive, Quintiles, Johnson & Johnson, Reckitt, Phathom Pharmaceuticals, Daewood, Takeda, and Crospon. Study coauthor Michael F. Vaezi, MD, PHD, holds a patent on mucosal integrity by Vanderbilt. Dr. Aggarwal reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The global prevalence of dyspepsia is approximately 20%,¹ and it is often associated with other comorbidities and overlapping gastrointestinal complaints. The effects on the patient’s quality of life, including societal impacts, are considerable. Symptoms and their response to treatment are highly variable, necessitating individualized management. While some patients’ symptoms may be refractory to standard medical treatment initially, evidence suggests that the strategies summarized in our guidance here—including the use of tricyclic antidepressants (TCAs), prokinetics, and adjunctive therapies—may alleviate symptoms and improve patients’ quality of life.

What dyspepsia is—and what it isn’t

Dyspepsia is a poorly characterized disorder often associated with nausea, heartburn, early satiety, and bloating. The American College of Gastroenterology (ACG) now advocates using a clinically relevant definition of dyspepsia as “predominant epigastric pain lasting at least a month” as long as epigastric pain is the patient's primary complaint.² Causes of dyspepsia are listed in TABLE 1.

jfp07009320_t1.jpg

Heartburn, a burning sensation in the chest, is not a dyspeptic symptom but the 2 may often coexist. In general, dyspepsia does not have a colicky or postural component. Symptoms that are relieved by evacuation of feces or gas generally should not be considered a part of dyspepsia.

Functional dyspepsia (FD) is a subset for which no structural pathology has been identified, accounting for up to 70% of all patients with dyspepsia.³ The Rome Foundation, in its recent update (Rome IV), has highlighted 4 key symptoms and 2 proposed subtypes (TABLE 2).⁴ The comorbidities of anxiety, depression, and somatization appear to be more prevalent in these dyspepsia patients than in those with organic issues. The incidence of gastric malignancy is low in this cohort.^3,5 Dyspepsia occurring after an acute infection is referred to as postinfectious functional dyspepsia.

JFP07009320_t2.JPG

Pathophysiology of functional dyspepsia. Dysmotility, visceral hypersensitivity, mucosal immune dysfunction, altered gut microbiota, and disturbed central nervous system processing contribute in varying degrees to the pathophysiology of FD. There is evidence that luminal factors have the potential to trigger local neuronal excitability.^6,7 Early life psychosocial factors may further influence illness behaviors, coping strategies, stress responses, and the intensity of symptoms perceived by the patient.⁸

Clues in the history and physical examination

Patients describe their discomfort using a variety of terms, including pain, gnawing, burning, gassiness, or queasiness. Although allergic reactions to food (swelling of lips and tongue with a rash) are rare in adults, food intolerances are common in patients with dyspepsia.⁹ Consumption of nonsteroidal ­anti-inflammatory drugs is a common cause of dyspepsia, even at over-the-counter strength, and may cause ulceration, gastrointestinal bleeding, and anemia. Narcotic and marijuana use and the anticholinergic effects of antidepressant medications are associated with gastrointestinal dysmotility, including gastroparesis.

Weight loss, night waking, and vomiting make functional dyspepsia less likely and deserve immediate consideration of abdominal imaging or endoscopic examination.

Patients with FD often exhibit symptoms of other functional abdominal disorders including irritable bowel syndrome, functional heartburn, bloating, or chronic nausea, and may have been previously diagnosed with overlapping conditions suggestive of visceral hypersensitivity, including depression, anxiety, fibromyalgia, migraine, and pelvic pain. During the patient’s office visit, be alert to any indication of an underlying psychological issue.

Continue to: The initial diagnostic challenge

The initial diagnostic challenge is to identify those patients who may have a structural disorder requiring expedited and targeted investigation. Weight loss, night waking, and vomiting are unusual in the setting of either FD or Helicobacter pylori gastritis. These and other features of concern (TABLE 3) make a diagnosis of a functional disorder less likely and should prompt immediate consideration of abdominal imaging or endoscopic examination. Epigastric tenderness on palpation is common in patients with FD and is not necessarily predictive of structural pathology—unless accompanied by other findings of concern. Abdominal scars or a history of trauma may be suggestive of abdominal wall pain. Abdominal pain that remains unchanged or increases when the muscles of the abdominal wall are tensed (Carnett sign) suggests abdominal wall pain.

JFP07009320_t3.JPG

Initial testing and Tx assessments focus on H pylori

All 3 of the major US gastroenterology organizations recommend a stepwise approach in patients without alarm symptoms, generally beginning (in those < 60 years) by testing for H pylori with either the stool antigen or urea breath test (UBT)—and initiating appropriate treatment if results are positive.^5,10 (The first step for those ≥ 60 years is discussed later.) Since the serum antibody test cannot differentiate between active and past infection, it is not recommended if other options are available.¹¹ The stool antigen test is preferred; it is a cost-effective option used for both diagnosis and confirmation of H pylori eradication.

The UBT identifies active infection with a sensitivity and specificity of > 95%¹² but is more labor intensive, employs an isotope, and is relatively expensive. Because proton pump inhibitors (PPIs), bismuth, and antibiotics may increase the false-negative rate for both the UBT and stool antigen test, we recommend that these medications be held for 2 to 4 weeks prior to testing.¹¹ H₂-receptor antagonists do not need to be restricted.

Treatment regimens containing clarithromycin have fallen into disfavor given the high rates of resistance that are now encountered. Fourteen-day regimens that can be used empirically (without susceptibility testing) are bismuth quadruple therapy (bismuth, metronidazole, tetracycline, and PPI) or rifabutin triple therapy (rifabutin, amoxicillin, and PPI).¹³ To confirm eradication, perform repeat testing with either stool antigen or UBT no sooner than 4 weeks after completion of therapy. If the first treatment fails, try a second regimen using different antibiotics.¹⁴ Although the impact of H pylori eradication on dyspeptic symptoms is only modest, this strategy is recommended also to reduce the risk of peptic ulceration and gastric neoplasia.

Next-step testing and Tx considerations

Given the heterogeneity of presenting symptoms of dyspepsia, some clinicians may be hesitant to diagnose a functional disorder at the first visit, preferring instead to conduct a limited range of investigations in concert with initial medical management. In these circumstances it would be reasonable, in addition to testing for H pylori, to order a complete blood count (CBC) and to measure serum lipase and liver enzymes. Keep in mind that liver enzymes may not be elevated in uncomplicated biliary colic.

Continue to: Consider ultrasound imaging...

Consider ultrasound imaging if gallstones are a consideration. A computerized tomography scan may not exclude uncomplicated and noncalcified gallstones, but it is an excellent modality for detecting suspected retroperitoneal pathology. Consider working with a gastroenterologist if the patient exhibits alarm features.

Empiric PPI therapy. A trial of daily PPI use over 4 weeks is recommended for patients without H pylori and for those whose symptoms continue despite eradication of the bacterium. A Cochrane meta-analysis found that PPI therapy was more effective than placebo (31% vs 26%; risk ratio, 0.88; number needed to treat [NNT] = 11; 95% CI 0.82 to 0.94; P < .001).¹⁵ PPI therapy appears to be slightly more effective than treatment with H₂-receptor antagonists. Both are proposed in the United Kingdom guideline.¹⁶ Both are generally safe and well tolerated but are not without potential adverse effects when used long term.

Dietary modification. Patients with dyspepsia commonly report that meals exacerbate symptoms. This is likely due to a combination of gastric distension and underlying visceral hypersensitivity rather than food composition.

The stool antigen test is preferred for diagnosing and confirming eradication of H pylori. The serum antibody test cannot differentiate between active and past infection.

There is no reliable “dyspepsia diet,” although a systematic review implicated wheat and high-fat foods as the 2 most common contributors to symptom onset.¹⁷ Recommended dietary modifications would be to consume smaller, more frequent meals and to eliminate recognized trigger foods. Patients with postprandial distress syndrome, a subset of FD, may want to consider reducing fat intake to help alleviate discomfort. If symptoms continue, evaluate for lactose intolerance. Also, consider a trial of a gluten-free diet. The low-FODMAP diet (restricting fermentable oligo-, di- and monosaccharides, as well as polyols) has shown benefit in patients with irritable bowel syndrome and may be considered in those with intractable FD, given the overlap in physiology of the disorders.

Upper gastrointestinal endoscopy. The ACG has suggested that esophagogastroduodenoscopy (EGD) be performed as the first investigative step for patients ≥ 60 years, while testing for H pylori be considered as the first step in younger patients, even if alarm symptoms are present² (FIGURE). This decision must be individualized, particularly in patients of Asian, Central or South American, or Caribbean descent, in whom the incidence of gastric cancer is higher with earlier onset.¹⁸

JFP07009320_f1.JPG

Continue to: Also consider EGD...

Also consider EGD for patients whose symptoms have not improved despite eradication of H pylori or an adequate trial of PPI therapy. While some guidelines do not require EGD in low-risk patients at this stage, other authorities would consider this step prudent, particularly when quality of life has been significantly impaired. An underlying organic cause, mainly erosive esophagitis or peptic ulcer disease, is found in 20% to 30% of patients with dyspepsia.⁵

Most patients without alarm features, with normal findings on upper endoscopy, who do not have H pylori gastritis, and whose symptoms continue despite a trial of PPI therapy, will have FD (FIGURE).²

Offer patients with functional dyspepsia supportive therapy

Neuromodulators

TCAs are superior to placebo in reducing dyspeptic symptoms with an NNT of 6 and are recommended for patients with ongoing symptoms despite PPI therapy or H pylori eradication.² Begin with a low dose and increase as tolerated. It may take a few weeks for improvement to be seen. Exercise caution in the presence of cardiac arrhythmias.

Mirtazapine, 7.5 to 15 mg every night at bedtime, reduces fullness and bloating in postprandial distress syndrome and is useful for patients who have lost weight. It’s important to note that TCAs and mirtazapine both have the potential for QT prolongation, as well as depression and suicidality in younger patients.¹⁹ The anxiolytic buspirone, 10 mg before meals, augments fundic relaxation, improves overall symptom severity, and helps alleviate early satiety, postprandial fullness, and upper abdominal bloating.²⁰

Prokinetics

A recent meta-analysis demonstrated significant benefit in symptom control in dyspeptic patients treated with prokinetics (NNT = 7).²¹ However, the benefit was predominantly due to cisapride, a drug that was withdrawn from the US market due to adverse effects. There are no clinical trials of metoclopramide or domperidone (not available in the United States) in FD. Nonetheless, the ACG has given a conditional recommendation, based on low-quality evidence, for the use of prokinetics in patients with FD not responding to PPI therapy, H pylori eradication, or TCA therapy.²

Continue to: A shortcoming of the established guidelines

A shortcoming of the established guidelines is that they do not provide guidance as to long-term management of those patients who respond to prescription medications. Our practice has been to continue medications for a minimum of 3 months, then begin a slow taper in order to establish the lowest efficacious dose. Some patients may relapse and require full dosage for a longer period of time.

Adjunctive therapies are worth considering

Complementary and alternative medicines. Products containing ginger, carraway oil, artichoke leaf extract, turmeric, and red pepper are readily available without prescription and have long been used with variable results for dyspepsia.²² The 9-herb combination STW-5 has demonstrated superiority over placebo in a number of studies and has a favorable safety profile.²³ The recommended dose is 10 to 20 drops tid. The European manufacturer has recently modified the package insert noting rare cases of hepatotoxicity.²⁴

Because PPIs, bismuth, and antibiotics may increase the false-negative rate for both the UBT and stool antigen test, we recommend that these medications be held for 2 to 4 weeks prior to testing.

A commercially available formulation (FDgard) containing L-menthol (a key component of peppermint oil) and caraway has been found to reduce the intensity of symptoms in patients with FD. Potential adverse effects include nausea, contact dermatitis, bronchospasm, and atrial fibrillation. Cayenne, a red pepper extract, is available over the counter for the benefit for epigastric pain and bloating. Begin with a 500-mg dose before breakfast and a 1000-mg dose before dinner, increasing to 2500 mg/d as tolerated. Cayenne preparations may trigger drug toxicities and are best avoided in patients taking antihypertensives, theophylline, or anticoagulants.

Cognitive behavioral therapy, acupuncture, and hypnosis. These modalities are time consuming, are often expensive, are not always covered by insurance, and require significant motivation. A systematic review found no benefit.²⁵ Subsequent studies summarized in the ACG guidelines² reported benefit; however, a lack of blinding and significant heterogeneity among the groups detract from the quality of the data. It remains unclear whether these are effective strategies for FD, and therefore they cannot be recommended on a routine basis.

CORRESPONDENCE
Norman H. Gilinsky, MD, Division of Digestive Diseases, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0595; norman.gilinsky@ uc.edu

The global prevalence of dyspepsia is approximately 20%,¹ and it is often associated with other comorbidities and overlapping gastrointestinal complaints. The effects on the patient’s quality of life, including societal impacts, are considerable. Symptoms and their response to treatment are highly variable, necessitating individualized management. While some patients’ symptoms may be refractory to standard medical treatment initially, evidence suggests that the strategies summarized in our guidance here—including the use of tricyclic antidepressants (TCAs), prokinetics, and adjunctive therapies—may alleviate symptoms and improve patients’ quality of life.

What dyspepsia is—and what it isn’t

Dyspepsia is a poorly characterized disorder often associated with nausea, heartburn, early satiety, and bloating. The American College of Gastroenterology (ACG) now advocates using a clinically relevant definition of dyspepsia as “predominant epigastric pain lasting at least a month” as long as epigastric pain is the patient's primary complaint.² Causes of dyspepsia are listed in TABLE 1.

jfp07009320_t1.jpg

Heartburn, a burning sensation in the chest, is not a dyspeptic symptom but the 2 may often coexist. In general, dyspepsia does not have a colicky or postural component. Symptoms that are relieved by evacuation of feces or gas generally should not be considered a part of dyspepsia.

Functional dyspepsia (FD) is a subset for which no structural pathology has been identified, accounting for up to 70% of all patients with dyspepsia.³ The Rome Foundation, in its recent update (Rome IV), has highlighted 4 key symptoms and 2 proposed subtypes (TABLE 2).⁴ The comorbidities of anxiety, depression, and somatization appear to be more prevalent in these dyspepsia patients than in those with organic issues. The incidence of gastric malignancy is low in this cohort.^3,5 Dyspepsia occurring after an acute infection is referred to as postinfectious functional dyspepsia.

JFP07009320_t2.JPG

Pathophysiology of functional dyspepsia. Dysmotility, visceral hypersensitivity, mucosal immune dysfunction, altered gut microbiota, and disturbed central nervous system processing contribute in varying degrees to the pathophysiology of FD. There is evidence that luminal factors have the potential to trigger local neuronal excitability.^6,7 Early life psychosocial factors may further influence illness behaviors, coping strategies, stress responses, and the intensity of symptoms perceived by the patient.⁸

Clues in the history and physical examination

Patients describe their discomfort using a variety of terms, including pain, gnawing, burning, gassiness, or queasiness. Although allergic reactions to food (swelling of lips and tongue with a rash) are rare in adults, food intolerances are common in patients with dyspepsia.⁹ Consumption of nonsteroidal ­anti-inflammatory drugs is a common cause of dyspepsia, even at over-the-counter strength, and may cause ulceration, gastrointestinal bleeding, and anemia. Narcotic and marijuana use and the anticholinergic effects of antidepressant medications are associated with gastrointestinal dysmotility, including gastroparesis.

Weight loss, night waking, and vomiting make functional dyspepsia less likely and deserve immediate consideration of abdominal imaging or endoscopic examination.

Patients with FD often exhibit symptoms of other functional abdominal disorders including irritable bowel syndrome, functional heartburn, bloating, or chronic nausea, and may have been previously diagnosed with overlapping conditions suggestive of visceral hypersensitivity, including depression, anxiety, fibromyalgia, migraine, and pelvic pain. During the patient’s office visit, be alert to any indication of an underlying psychological issue.

Continue to: The initial diagnostic challenge

The initial diagnostic challenge is to identify those patients who may have a structural disorder requiring expedited and targeted investigation. Weight loss, night waking, and vomiting are unusual in the setting of either FD or Helicobacter pylori gastritis. These and other features of concern (TABLE 3) make a diagnosis of a functional disorder less likely and should prompt immediate consideration of abdominal imaging or endoscopic examination. Epigastric tenderness on palpation is common in patients with FD and is not necessarily predictive of structural pathology—unless accompanied by other findings of concern. Abdominal scars or a history of trauma may be suggestive of abdominal wall pain. Abdominal pain that remains unchanged or increases when the muscles of the abdominal wall are tensed (Carnett sign) suggests abdominal wall pain.

JFP07009320_t3.JPG

Initial testing and Tx assessments focus on H pylori

All 3 of the major US gastroenterology organizations recommend a stepwise approach in patients without alarm symptoms, generally beginning (in those < 60 years) by testing for H pylori with either the stool antigen or urea breath test (UBT)—and initiating appropriate treatment if results are positive.^5,10 (The first step for those ≥ 60 years is discussed later.) Since the serum antibody test cannot differentiate between active and past infection, it is not recommended if other options are available.¹¹ The stool antigen test is preferred; it is a cost-effective option used for both diagnosis and confirmation of H pylori eradication.

The UBT identifies active infection with a sensitivity and specificity of > 95%¹² but is more labor intensive, employs an isotope, and is relatively expensive. Because proton pump inhibitors (PPIs), bismuth, and antibiotics may increase the false-negative rate for both the UBT and stool antigen test, we recommend that these medications be held for 2 to 4 weeks prior to testing.¹¹ H₂-receptor antagonists do not need to be restricted.

Treatment regimens containing clarithromycin have fallen into disfavor given the high rates of resistance that are now encountered. Fourteen-day regimens that can be used empirically (without susceptibility testing) are bismuth quadruple therapy (bismuth, metronidazole, tetracycline, and PPI) or rifabutin triple therapy (rifabutin, amoxicillin, and PPI).¹³ To confirm eradication, perform repeat testing with either stool antigen or UBT no sooner than 4 weeks after completion of therapy. If the first treatment fails, try a second regimen using different antibiotics.¹⁴ Although the impact of H pylori eradication on dyspeptic symptoms is only modest, this strategy is recommended also to reduce the risk of peptic ulceration and gastric neoplasia.

Next-step testing and Tx considerations

Given the heterogeneity of presenting symptoms of dyspepsia, some clinicians may be hesitant to diagnose a functional disorder at the first visit, preferring instead to conduct a limited range of investigations in concert with initial medical management. In these circumstances it would be reasonable, in addition to testing for H pylori, to order a complete blood count (CBC) and to measure serum lipase and liver enzymes. Keep in mind that liver enzymes may not be elevated in uncomplicated biliary colic.

Continue to: Consider ultrasound imaging...

Consider ultrasound imaging if gallstones are a consideration. A computerized tomography scan may not exclude uncomplicated and noncalcified gallstones, but it is an excellent modality for detecting suspected retroperitoneal pathology. Consider working with a gastroenterologist if the patient exhibits alarm features.

Empiric PPI therapy. A trial of daily PPI use over 4 weeks is recommended for patients without H pylori and for those whose symptoms continue despite eradication of the bacterium. A Cochrane meta-analysis found that PPI therapy was more effective than placebo (31% vs 26%; risk ratio, 0.88; number needed to treat [NNT] = 11; 95% CI 0.82 to 0.94; P < .001).¹⁵ PPI therapy appears to be slightly more effective than treatment with H₂-receptor antagonists. Both are proposed in the United Kingdom guideline.¹⁶ Both are generally safe and well tolerated but are not without potential adverse effects when used long term.

Dietary modification. Patients with dyspepsia commonly report that meals exacerbate symptoms. This is likely due to a combination of gastric distension and underlying visceral hypersensitivity rather than food composition.

The stool antigen test is preferred for diagnosing and confirming eradication of H pylori. The serum antibody test cannot differentiate between active and past infection.

There is no reliable “dyspepsia diet,” although a systematic review implicated wheat and high-fat foods as the 2 most common contributors to symptom onset.¹⁷ Recommended dietary modifications would be to consume smaller, more frequent meals and to eliminate recognized trigger foods. Patients with postprandial distress syndrome, a subset of FD, may want to consider reducing fat intake to help alleviate discomfort. If symptoms continue, evaluate for lactose intolerance. Also, consider a trial of a gluten-free diet. The low-FODMAP diet (restricting fermentable oligo-, di- and monosaccharides, as well as polyols) has shown benefit in patients with irritable bowel syndrome and may be considered in those with intractable FD, given the overlap in physiology of the disorders.

Upper gastrointestinal endoscopy. The ACG has suggested that esophagogastroduodenoscopy (EGD) be performed as the first investigative step for patients ≥ 60 years, while testing for H pylori be considered as the first step in younger patients, even if alarm symptoms are present² (FIGURE). This decision must be individualized, particularly in patients of Asian, Central or South American, or Caribbean descent, in whom the incidence of gastric cancer is higher with earlier onset.¹⁸

JFP07009320_f1.JPG

Continue to: Also consider EGD...

Also consider EGD for patients whose symptoms have not improved despite eradication of H pylori or an adequate trial of PPI therapy. While some guidelines do not require EGD in low-risk patients at this stage, other authorities would consider this step prudent, particularly when quality of life has been significantly impaired. An underlying organic cause, mainly erosive esophagitis or peptic ulcer disease, is found in 20% to 30% of patients with dyspepsia.⁵

Most patients without alarm features, with normal findings on upper endoscopy, who do not have H pylori gastritis, and whose symptoms continue despite a trial of PPI therapy, will have FD (FIGURE).²

Offer patients with functional dyspepsia supportive therapy

Neuromodulators

TCAs are superior to placebo in reducing dyspeptic symptoms with an NNT of 6 and are recommended for patients with ongoing symptoms despite PPI therapy or H pylori eradication.² Begin with a low dose and increase as tolerated. It may take a few weeks for improvement to be seen. Exercise caution in the presence of cardiac arrhythmias.

Mirtazapine, 7.5 to 15 mg every night at bedtime, reduces fullness and bloating in postprandial distress syndrome and is useful for patients who have lost weight. It’s important to note that TCAs and mirtazapine both have the potential for QT prolongation, as well as depression and suicidality in younger patients.¹⁹ The anxiolytic buspirone, 10 mg before meals, augments fundic relaxation, improves overall symptom severity, and helps alleviate early satiety, postprandial fullness, and upper abdominal bloating.²⁰

Prokinetics

A recent meta-analysis demonstrated significant benefit in symptom control in dyspeptic patients treated with prokinetics (NNT = 7).²¹ However, the benefit was predominantly due to cisapride, a drug that was withdrawn from the US market due to adverse effects. There are no clinical trials of metoclopramide or domperidone (not available in the United States) in FD. Nonetheless, the ACG has given a conditional recommendation, based on low-quality evidence, for the use of prokinetics in patients with FD not responding to PPI therapy, H pylori eradication, or TCA therapy.²

Continue to: A shortcoming of the established guidelines

A shortcoming of the established guidelines is that they do not provide guidance as to long-term management of those patients who respond to prescription medications. Our practice has been to continue medications for a minimum of 3 months, then begin a slow taper in order to establish the lowest efficacious dose. Some patients may relapse and require full dosage for a longer period of time.

Adjunctive therapies are worth considering

Complementary and alternative medicines. Products containing ginger, carraway oil, artichoke leaf extract, turmeric, and red pepper are readily available without prescription and have long been used with variable results for dyspepsia.²² The 9-herb combination STW-5 has demonstrated superiority over placebo in a number of studies and has a favorable safety profile.²³ The recommended dose is 10 to 20 drops tid. The European manufacturer has recently modified the package insert noting rare cases of hepatotoxicity.²⁴

Because PPIs, bismuth, and antibiotics may increase the false-negative rate for both the UBT and stool antigen test, we recommend that these medications be held for 2 to 4 weeks prior to testing.

A commercially available formulation (FDgard) containing L-menthol (a key component of peppermint oil) and caraway has been found to reduce the intensity of symptoms in patients with FD. Potential adverse effects include nausea, contact dermatitis, bronchospasm, and atrial fibrillation. Cayenne, a red pepper extract, is available over the counter for the benefit for epigastric pain and bloating. Begin with a 500-mg dose before breakfast and a 1000-mg dose before dinner, increasing to 2500 mg/d as tolerated. Cayenne preparations may trigger drug toxicities and are best avoided in patients taking antihypertensives, theophylline, or anticoagulants.

Cognitive behavioral therapy, acupuncture, and hypnosis. These modalities are time consuming, are often expensive, are not always covered by insurance, and require significant motivation. A systematic review found no benefit.²⁵ Subsequent studies summarized in the ACG guidelines² reported benefit; however, a lack of blinding and significant heterogeneity among the groups detract from the quality of the data. It remains unclear whether these are effective strategies for FD, and therefore they cannot be recommended on a routine basis.

CORRESPONDENCE
Norman H. Gilinsky, MD, Division of Digestive Diseases, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0595; norman.gilinsky@ uc.edu

The global prevalence of dyspepsia is approximately 20%,¹ and it is often associated with other comorbidities and overlapping gastrointestinal complaints. The effects on the patient’s quality of life, including societal impacts, are considerable. Symptoms and their response to treatment are highly variable, necessitating individualized management. While some patients’ symptoms may be refractory to standard medical treatment initially, evidence suggests that the strategies summarized in our guidance here—including the use of tricyclic antidepressants (TCAs), prokinetics, and adjunctive therapies—may alleviate symptoms and improve patients’ quality of life.

What dyspepsia is—and what it isn’t

Dyspepsia is a poorly characterized disorder often associated with nausea, heartburn, early satiety, and bloating. The American College of Gastroenterology (ACG) now advocates using a clinically relevant definition of dyspepsia as “predominant epigastric pain lasting at least a month” as long as epigastric pain is the patient's primary complaint.² Causes of dyspepsia are listed in TABLE 1.

jfp07009320_t1.jpg

Heartburn, a burning sensation in the chest, is not a dyspeptic symptom but the 2 may often coexist. In general, dyspepsia does not have a colicky or postural component. Symptoms that are relieved by evacuation of feces or gas generally should not be considered a part of dyspepsia.

Functional dyspepsia (FD) is a subset for which no structural pathology has been identified, accounting for up to 70% of all patients with dyspepsia.³ The Rome Foundation, in its recent update (Rome IV), has highlighted 4 key symptoms and 2 proposed subtypes (TABLE 2).⁴ The comorbidities of anxiety, depression, and somatization appear to be more prevalent in these dyspepsia patients than in those with organic issues. The incidence of gastric malignancy is low in this cohort.^3,5 Dyspepsia occurring after an acute infection is referred to as postinfectious functional dyspepsia.

JFP07009320_t2.JPG

Pathophysiology of functional dyspepsia. Dysmotility, visceral hypersensitivity, mucosal immune dysfunction, altered gut microbiota, and disturbed central nervous system processing contribute in varying degrees to the pathophysiology of FD. There is evidence that luminal factors have the potential to trigger local neuronal excitability.^6,7 Early life psychosocial factors may further influence illness behaviors, coping strategies, stress responses, and the intensity of symptoms perceived by the patient.⁸

Clues in the history and physical examination

Patients describe their discomfort using a variety of terms, including pain, gnawing, burning, gassiness, or queasiness. Although allergic reactions to food (swelling of lips and tongue with a rash) are rare in adults, food intolerances are common in patients with dyspepsia.⁹ Consumption of nonsteroidal ­anti-inflammatory drugs is a common cause of dyspepsia, even at over-the-counter strength, and may cause ulceration, gastrointestinal bleeding, and anemia. Narcotic and marijuana use and the anticholinergic effects of antidepressant medications are associated with gastrointestinal dysmotility, including gastroparesis.

Weight loss, night waking, and vomiting make functional dyspepsia less likely and deserve immediate consideration of abdominal imaging or endoscopic examination.

Patients with FD often exhibit symptoms of other functional abdominal disorders including irritable bowel syndrome, functional heartburn, bloating, or chronic nausea, and may have been previously diagnosed with overlapping conditions suggestive of visceral hypersensitivity, including depression, anxiety, fibromyalgia, migraine, and pelvic pain. During the patient’s office visit, be alert to any indication of an underlying psychological issue.

Continue to: The initial diagnostic challenge

The initial diagnostic challenge is to identify those patients who may have a structural disorder requiring expedited and targeted investigation. Weight loss, night waking, and vomiting are unusual in the setting of either FD or Helicobacter pylori gastritis. These and other features of concern (TABLE 3) make a diagnosis of a functional disorder less likely and should prompt immediate consideration of abdominal imaging or endoscopic examination. Epigastric tenderness on palpation is common in patients with FD and is not necessarily predictive of structural pathology—unless accompanied by other findings of concern. Abdominal scars or a history of trauma may be suggestive of abdominal wall pain. Abdominal pain that remains unchanged or increases when the muscles of the abdominal wall are tensed (Carnett sign) suggests abdominal wall pain.

JFP07009320_t3.JPG

Initial testing and Tx assessments focus on H pylori

All 3 of the major US gastroenterology organizations recommend a stepwise approach in patients without alarm symptoms, generally beginning (in those < 60 years) by testing for H pylori with either the stool antigen or urea breath test (UBT)—and initiating appropriate treatment if results are positive.^5,10 (The first step for those ≥ 60 years is discussed later.) Since the serum antibody test cannot differentiate between active and past infection, it is not recommended if other options are available.¹¹ The stool antigen test is preferred; it is a cost-effective option used for both diagnosis and confirmation of H pylori eradication.

The UBT identifies active infection with a sensitivity and specificity of > 95%¹² but is more labor intensive, employs an isotope, and is relatively expensive. Because proton pump inhibitors (PPIs), bismuth, and antibiotics may increase the false-negative rate for both the UBT and stool antigen test, we recommend that these medications be held for 2 to 4 weeks prior to testing.¹¹ H₂-receptor antagonists do not need to be restricted.

Treatment regimens containing clarithromycin have fallen into disfavor given the high rates of resistance that are now encountered. Fourteen-day regimens that can be used empirically (without susceptibility testing) are bismuth quadruple therapy (bismuth, metronidazole, tetracycline, and PPI) or rifabutin triple therapy (rifabutin, amoxicillin, and PPI).¹³ To confirm eradication, perform repeat testing with either stool antigen or UBT no sooner than 4 weeks after completion of therapy. If the first treatment fails, try a second regimen using different antibiotics.¹⁴ Although the impact of H pylori eradication on dyspeptic symptoms is only modest, this strategy is recommended also to reduce the risk of peptic ulceration and gastric neoplasia.

Next-step testing and Tx considerations

Given the heterogeneity of presenting symptoms of dyspepsia, some clinicians may be hesitant to diagnose a functional disorder at the first visit, preferring instead to conduct a limited range of investigations in concert with initial medical management. In these circumstances it would be reasonable, in addition to testing for H pylori, to order a complete blood count (CBC) and to measure serum lipase and liver enzymes. Keep in mind that liver enzymes may not be elevated in uncomplicated biliary colic.

Continue to: Consider ultrasound imaging...

Consider ultrasound imaging if gallstones are a consideration. A computerized tomography scan may not exclude uncomplicated and noncalcified gallstones, but it is an excellent modality for detecting suspected retroperitoneal pathology. Consider working with a gastroenterologist if the patient exhibits alarm features.

Empiric PPI therapy. A trial of daily PPI use over 4 weeks is recommended for patients without H pylori and for those whose symptoms continue despite eradication of the bacterium. A Cochrane meta-analysis found that PPI therapy was more effective than placebo (31% vs 26%; risk ratio, 0.88; number needed to treat [NNT] = 11; 95% CI 0.82 to 0.94; P < .001).¹⁵ PPI therapy appears to be slightly more effective than treatment with H₂-receptor antagonists. Both are proposed in the United Kingdom guideline.¹⁶ Both are generally safe and well tolerated but are not without potential adverse effects when used long term.

Dietary modification. Patients with dyspepsia commonly report that meals exacerbate symptoms. This is likely due to a combination of gastric distension and underlying visceral hypersensitivity rather than food composition.

The stool antigen test is preferred for diagnosing and confirming eradication of H pylori. The serum antibody test cannot differentiate between active and past infection.

There is no reliable “dyspepsia diet,” although a systematic review implicated wheat and high-fat foods as the 2 most common contributors to symptom onset.¹⁷ Recommended dietary modifications would be to consume smaller, more frequent meals and to eliminate recognized trigger foods. Patients with postprandial distress syndrome, a subset of FD, may want to consider reducing fat intake to help alleviate discomfort. If symptoms continue, evaluate for lactose intolerance. Also, consider a trial of a gluten-free diet. The low-FODMAP diet (restricting fermentable oligo-, di- and monosaccharides, as well as polyols) has shown benefit in patients with irritable bowel syndrome and may be considered in those with intractable FD, given the overlap in physiology of the disorders.

Upper gastrointestinal endoscopy. The ACG has suggested that esophagogastroduodenoscopy (EGD) be performed as the first investigative step for patients ≥ 60 years, while testing for H pylori be considered as the first step in younger patients, even if alarm symptoms are present² (FIGURE). This decision must be individualized, particularly in patients of Asian, Central or South American, or Caribbean descent, in whom the incidence of gastric cancer is higher with earlier onset.¹⁸

JFP07009320_f1.JPG

Continue to: Also consider EGD...

Also consider EGD for patients whose symptoms have not improved despite eradication of H pylori or an adequate trial of PPI therapy. While some guidelines do not require EGD in low-risk patients at this stage, other authorities would consider this step prudent, particularly when quality of life has been significantly impaired. An underlying organic cause, mainly erosive esophagitis or peptic ulcer disease, is found in 20% to 30% of patients with dyspepsia.⁵

Most patients without alarm features, with normal findings on upper endoscopy, who do not have H pylori gastritis, and whose symptoms continue despite a trial of PPI therapy, will have FD (FIGURE).²

Offer patients with functional dyspepsia supportive therapy

Neuromodulators

TCAs are superior to placebo in reducing dyspeptic symptoms with an NNT of 6 and are recommended for patients with ongoing symptoms despite PPI therapy or H pylori eradication.² Begin with a low dose and increase as tolerated. It may take a few weeks for improvement to be seen. Exercise caution in the presence of cardiac arrhythmias.

Mirtazapine, 7.5 to 15 mg every night at bedtime, reduces fullness and bloating in postprandial distress syndrome and is useful for patients who have lost weight. It’s important to note that TCAs and mirtazapine both have the potential for QT prolongation, as well as depression and suicidality in younger patients.¹⁹ The anxiolytic buspirone, 10 mg before meals, augments fundic relaxation, improves overall symptom severity, and helps alleviate early satiety, postprandial fullness, and upper abdominal bloating.²⁰

Prokinetics

A recent meta-analysis demonstrated significant benefit in symptom control in dyspeptic patients treated with prokinetics (NNT = 7).²¹ However, the benefit was predominantly due to cisapride, a drug that was withdrawn from the US market due to adverse effects. There are no clinical trials of metoclopramide or domperidone (not available in the United States) in FD. Nonetheless, the ACG has given a conditional recommendation, based on low-quality evidence, for the use of prokinetics in patients with FD not responding to PPI therapy, H pylori eradication, or TCA therapy.²

Continue to: A shortcoming of the established guidelines

A shortcoming of the established guidelines is that they do not provide guidance as to long-term management of those patients who respond to prescription medications. Our practice has been to continue medications for a minimum of 3 months, then begin a slow taper in order to establish the lowest efficacious dose. Some patients may relapse and require full dosage for a longer period of time.

Adjunctive therapies are worth considering

Complementary and alternative medicines. Products containing ginger, carraway oil, artichoke leaf extract, turmeric, and red pepper are readily available without prescription and have long been used with variable results for dyspepsia.²² The 9-herb combination STW-5 has demonstrated superiority over placebo in a number of studies and has a favorable safety profile.²³ The recommended dose is 10 to 20 drops tid. The European manufacturer has recently modified the package insert noting rare cases of hepatotoxicity.²⁴

Because PPIs, bismuth, and antibiotics may increase the false-negative rate for both the UBT and stool antigen test, we recommend that these medications be held for 2 to 4 weeks prior to testing.

A commercially available formulation (FDgard) containing L-menthol (a key component of peppermint oil) and caraway has been found to reduce the intensity of symptoms in patients with FD. Potential adverse effects include nausea, contact dermatitis, bronchospasm, and atrial fibrillation. Cayenne, a red pepper extract, is available over the counter for the benefit for epigastric pain and bloating. Begin with a 500-mg dose before breakfast and a 1000-mg dose before dinner, increasing to 2500 mg/d as tolerated. Cayenne preparations may trigger drug toxicities and are best avoided in patients taking antihypertensives, theophylline, or anticoagulants.

Cognitive behavioral therapy, acupuncture, and hypnosis. These modalities are time consuming, are often expensive, are not always covered by insurance, and require significant motivation. A systematic review found no benefit.²⁵ Subsequent studies summarized in the ACG guidelines² reported benefit; however, a lack of blinding and significant heterogeneity among the groups detract from the quality of the data. It remains unclear whether these are effective strategies for FD, and therefore they cannot be recommended on a routine basis.

CORRESPONDENCE
Norman H. Gilinsky, MD, Division of Digestive Diseases, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0595; norman.gilinsky@ uc.edu