Gut: People with stomach problems, use this medicine with caution!

Readers suffering from acid-related diseases such as gastric ulcer and gastroesophageal reflux should be very familiar with proton pump inhibitors (PPI), which can quickly, powerfully and lastingly inhibit the secretion of gastric acid, and provide gentle treatment to the damaged gastric mucosa.
Restoring the environment is the first choice for the treatment of the above-mentioned diseases.

Commonly used PPIs include omeprazole, pantoprazole, rabeprazole and other "prazoles".

But as it is said that water can carry a boat, it can also overturn it, and medicine can cure and cause disease.

Many previous studies have found that excessive use of PPI or excessive use of PPI may increase the risk of pneumonia, fractures, chronic kidney disease and Clostridium difficile infection [1,2].

Recently, researchers from Hanlin University in South Korea found that compared with patients who used other drugs, patients who used PPI for 30 days or more had a 1.
37 times higher risk of gastric cancer, and the longer the PPI was used, the higher the risk of disease.

The relevant results were published in Gut, the top journal in the digestive field [3].

Originally, using PPI to treat gastric ulcer is beneficial to prevent the disease from getting worse and progressing to gastric cancer.
I didn't expect it to turn back.
.
.
Let’s take a look at how researchers discovered that PPI is related to gastric cancer.

This is a retrospective study based on the NHIS-NSC cohort.

NHIS-NSC is composed of about 1 million Korean residents (randomly sampled from across the country), followed up from 2002 to 2013, and contains a wealth of medical information and health information.

In order to explore the relationship between long-term use of PPI and gastric cancer, the researchers retrieved the medication information of all residents ≥19 years of age, who had never had gastric cancer, and had not undergone gastrectomy from the NHIS-NSC standard library, and classified them according to the type of medication.
And the duration of medication is divided into the following 3 groups: (1) Exposure group-PPI group (continuous use of PPI ≥ 30 days, excluding 30 days of H2 receptor antagonist [H2RA] before use of PPI, or use of PPI after use Subjects with H2RA) (2) Control 1 group-non-PPI group (continuous use of PPI-free drugs for ≥30 days) (3) Control 2 group-H2RA group (continuous use of H2RA for ≥30 days, use if not included Subjects who have passed PPI) H2RA is a kind of acid-suppressing drugs that have a slower onset, lower intensity, and shorter action time than PPI.
The names of the drugs usually end with "tidine", such as cimetidine, ranitidine, and famotidine.
Wait.

The researchers used the prescribing date of the above-mentioned drugs as the enrollment date of the study, and excluded subjects who were in this cohort for less than 1 year before enrollment (not sure of their follow-up compliance) and subjects who were diagnosed with gastric cancer within 1 year after enrollment (medications) May have had cancer before, but it was not found).

Grouping situation and observation time In addition, given that Helicobacter pylori (HP) is not only related to gastric ulcer and other acid-related diseases, but also the most important risk factor for gastric cancer, researchers believe that it is necessary to consider HP infection when exploring the relationship between PPI and gastric cancer The status of treatment.

Therefore, they also selected from the NHIS-NSC original library, subjects aged ≥19 years old who had been eradicated with clarithromycin triple therapy or bismuth quadruple therapy to explore the relationship between long-term use of PPI and gastric cancer after HP eradication therapy .

After excluding subjects who were diagnosed with gastric cancer within 1 year of eradication therapy and used PPI within six months, the remaining subjects were divided into PPI group and non-PPI group according to whether they used PPI ≥ 30 days after eradication therapy.

Unlike the previous PPI group, the PPI group here does not exclude those who have used H2RA because the vast majority of people have used both drugs at the same time.

Then, regardless of whether it is the PPI group that does not consider HP radical cure or not, or the PPI group that has received HP eradication treatment, they are further subdivided into 4 groups ≥30 days, ≥90 days, ≥180 days and ≥365 days according to the duration of medication.
To investigate the dose-response relationship.

Triple or quadruple therapy does require a lot of drugs.
There are 1,025,340 study subjects in the NHIS-NSC standard library, of which 514,724 meet the criteria for entry into the study.

To increase the comparability between groups, the researchers used propensity scores to match the comparison objects.

After matching, the number of people included in the analysis in each group is as follows: (1) 11741 cases each in the PPI group and the non-PPI group (2) 5067 cases each in the PPI group and the H2RA group (3) 6877 cases each in the PPI group and the non-PPI group who have received HP eradication treatment The median follow-up time of the PPI group and the non-PPI group were 4.
4 years and 4.
2 years, respectively; the median duration of medication in the PPI group was 55 days; the median time interval from the start of PPI use to the diagnosis of gastric cancer was 3.
3 years.

During the follow-up period, the risk of gastric cancer in the PPI group was 2.
37 times that of the non-PPI group.

Moreover, the longer the medication, the higher the risk of gastric cancer in the PPI group—when ≥90 days, the risk is 2.
83 times that of the non-PPI group; when ≥365 days, the risk is 3.
50 times that of the non-PPI group, while the PPI group and H2RA group have no gastric cancer risk Significant differences.

The relationship between the duration of PPI medication and the risk of gastric cancer After HP eradication treatment, subjects who used PPI for ≥30 days or ≥90 days had a slightly higher risk of gastric cancer after receiving HP eradication therapy, but they did not constitute a significant difference.

When the PPI administration time was ≥180 days or ≥365 days, the risk of gastric cancer was significantly increased, which was 2.
22 times and 2.
54 times that of the non-PPI group, respectively.

The relationship between the length of PPI medication after HP eradication treatment and the risk of gastric cancer.
Why is the long-term use of PPI related to the increased risk of gastric cancer? This has to start with how the body regulates gastric acid secretion.

As shown in the figure below, G cells in the stomach secrete gastrin.
Gastrin directly stimulates oxyntic cells or indirectly stimulates oxyntic cells to secrete gastric acid by stimulating enterochromaffin-like cells.

Long-term use of PPI reduces gastric acid secretion.
In order to maintain the level of oxyntic acid, the body will compensatively stimulate G cells to secrete gastrin, resulting in hypergastrinemia, which in turn stimulates the proliferation of intestinal chromaffin-like cells, leading to the risk of gastric cancer Increase [4].

Another explanation is that long-term use of PPI may cause atrophic gastritis, intestinal metaplasia or accelerate its progression, thereby increasing the risk of gastric cancer [5].

If combined with HP infection, the situation will get worse.

The occurrence process of gastric malignant tumors [6] The biggest advantage of this study is that the confounding factors are more comprehensive, especially the use of drugs related to gastric cancer (aspirin, metformin, non-steroidal anti-inflammatory drugs, etc.
) that are ignored by other studies.
And comorbid conditions (acute respiratory disease, diabetes, hyperlipidemia, etc.
).

However, the study also has some limitations.
For example, it only knows which subjects have undergone HP eradication treatment, and do not know how effective the treatment is; lack of data on histopathology and endoscopy; using subjects with other drugs as a control may not be possible Represents the general population; retrospective studies cannot draw causal associations.

In short, the study found that long-term use of PPI is associated with an increased risk of gastric cancer, regardless of whether or not you have received HP eradication therapy, prompting everyone to be cautious in medication.

References: [1] Imhann F, Bonder MJ, Vich Vila A, et al.
Proton pump inhibitors affect the gut microbiome.
Gut.
2016;65(5):740-748.
doi:10.
1136/gutjnl-2015-310376[ 2] Vaezi MF, Yang YX, Howden CW.
Complications of Proton Pump Inhibitor Therapy.
Gastroenterology.
2017;153(1):35-48.
doi:10.
1053/j.
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2017.
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047[3] Seo SI, Park CH , You SC, Kim JY, Lee KJ, Kim J, Kim Y, Yoo JJ, Seo WW, Lee HS, Shin WG.
Association between proton pump inhibitor use and gastric cancer: a population-based cohort study using two different types of nationwide databases in Korea.
Gut.
2021 May 11:gutjnl-2020-323845.
doi: 10.
1136/gutjnl-2020-323845.
Epub ahead of print.
PMID: 33975868.
[4] Joo MK, Park JJ, Chun HJ.
Proton pump inhibitor : The dual role in gastric cancer.
World J Gastroenterol.
2019;25(17):2058-2070.
doi:10.
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v25.
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Relationship between long-term use of proton pump inhibitors and risk of gastric cancer: A systematic analysis.
J Gastroenterol Hepatol.
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doi:10.
1111/jgh.
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The role of microRNAs in Helicobacter pylori pathogenesis and gastric carcinogenesis.
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00021 Responsible EditorTan Shuo