More potent inhibition of gastric acid secretion than the 20 mg esomeprazole,20 and 40 mg omeprazole as well as the standard doses of the other commercially available proton-pump inhibitors 44. Consequently, 40 mg of esomeprazole was chosen as the standard dose when esomeprazole was launched as Nexium in 2000.
Proton pump inhibitors (or 'PPI's) are a group of whose main action is a pronounced and long-lasting reduction of production. They are the most potent inhibitors of acid secretion available today.
The group followed and has largely superseded another group of with similar effects, but different mode-of-action, called. These drugs are among the most widely-selling drugs in the world as a result of their outstanding efficacy and safety. Structurally, the vast majority of these drugs are derivatives; however, promising new research indicates that derivatives may be a more effective means of treatment. Clinical use These drugs are utilized in the treatment of many conditions such as:. disease (PUD). (GORD/GERD). prevention of stress.
and other conditions that cause hypersecretion of acid. Despite their widespread use for these conditions, proton pump inhibitors effectiveness has not been demonstrated in every case. For example, proton pump inhibitors do not change the length of Barrett's esophagus. Mechanism of action inhibitors act by irreversibly blocking the / system (the, or more commonly just gastric ) of the gastric.
The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H + ions into the gastric lumen, making it an ideal target for inhibiting acid secretion. ('Irreversibility' refers to the effect on a single copy of the enzyme; the effect on the overall human digestive system is reversible, as the enzymes are naturally destroyed and replaced with new copies.) Targeting the terminal-step in acid production, as well as the irreversible nature of the inhibition, result in a class of drugs that are significantly more effective than and reduce gastric acid secretion by up to 99%. The lack of the acid in the stomach will aid in the healing of ulcers, and reduces the pain from indigestion and, which can be exacerbated by stomach acid. However, lack of stomach acid is also called, the lack of sufficient, or HCl. Hydrochloric acid is required for the digestion of proteins and for the absorption of nutrients, particularly of vitamin B12 and of calcium.
The proton pump inhibitors are given in an inactive form. The inactive form is neutrally charged and readily crosses into intracellular compartments (like the parietal cell canaliculus) that have acidic environments.
In an acid environment, the inactive drug is protonated and rearranges into its active form. As described above, the active form will and irreversibly bind to the gastric proton pump, deactivating it. Potassium-competitive acid blockers (P-CABs) Potassium-competitive inhibitors are experimental drugs which reversibly block the potassium binding site of the proton pump. Soraprazan and revaprazan block H + secretion much more quickly than classical PPIs (within half an hour). The development of soraprazan, however, has been discontinued in 2007.
Pharmacokinetics Generally, the absorption of proton pump inhibitors is unaffected by co-administration with food. The rate of omeprazole absorption, however, is decreased by concomitant food intake. Additionally, the absorption of lansoprazole and esomeprazole is decreased and delayed by food. These effects, however, reportedly have no significant impact on efficacy.
The of proton pump inhibitors ranges from 0.5–2 hours, however the effect of a single dose on acid secretion usually persists up to 2–3 days. This is because of accumulation of the drug in and the irreversible nature of proton pump inhibition. Examples of proton pump inhibitors. The proton pump inhibitor Omeprazole.
Clinically used proton pump inhibitors:. (brand names: Losec, Prilosec, Zegerid, ocid, Lomac, Omepral, Omez). (brand names: Prevacid, Zoton, Inhibitol, Levant, Lupizole).
(brand name: Kapidex). (brand names: Nexium, Esotrex). (brand names: Protonix, Somac, Pantoloc, Pantozol, Zurcal, Pan). (brand names: Rabecid, Aciphex, Pariet, Rabeloc.
Dorafem: combination with ) All proton pump inhibitors except rabeprazole and dexlansoprazole have intravenous formulations. Adverse effects Proton pump inhibitors are generally well tolerated, and the incidence of short-term adverse effects is relatively uncommon. The range and occurrence of are similar for all of the proton pump inhibitors, though they have been reported more frequently with omeprazole. This may be due to its longer availability and hence clinical experience. Common adverse effects include:,. Infrequent adverse effects include:,.
Decreased absorption may occur with long-term use. Rarely PPI cause ‘idiosyncratic’ reactions such as,.
It has been observed that gastric acid suppression, using and proton pump inhibitors, is associated with an increased risk of community-acquired. It is suspected that acid suppression results in insufficient elimination of pathogenic organisms.
It has therefore been suggested that patients at higher risk of pneumonia should only be prescribed proton pump inhibitors at lower doses and only when necessary. PPIs have also been shown to raise risk of infection. Long-term use of proton pump inhibitors has been less studied. But in a study of 135,000 people 50 or older, those taking high doses of PPIs for longer than one year have been found to be 2.6 times more likely to break a hip. Those taking smaller doses for 1 to 4 years were 1.2 to 1.6 times more likely to break a hip. The risk of a fracture increased with the length of time taking PPIs.
Theories as to the cause of the increase are the possibility that the reduction of stomach acid reduces the amount of calcium dissolved in the stomach or that PPIs may interfere with the breakdown and rebuilding of bone by interfering with the acid production of. Also, the reduction of vitamin B 12 (by raising ) may increase bone fragility, an effect that may be offset by the consumption, or by the co-packaging, of about 100 mcg of B12 with the PPI. A recent study has also suggested that proton pump inhibitors significantly decreased the effect of clopidogrel on platelets as tested by VASP phosphorylation. The clinical impact of these results must be assessed by further investigations, but a PPI treatment should not be added to the antiplatelet dual therapy without formal indication. Proton Pump Inhibitors: An Update Since their introduction in the late 1980s, proton pump inhibitors have demonstrated gastric acid suppression superior to that of histamine H 2-receptor blockers. Proton pump inhibitors have enabled improved treatment of various acid-peptic disorders, including gastroesophageal reflux disease, peptic ulcer disease, and nonsteroidal anti-inflammatory druginduced gastropathy.
Proton pump inhibitors have minimal side effects and few significant drug interactions, and they are generally considered safe for long-term treatment. The proton pump inhibitors omeprazole, lansoprazole, rabeprazole, and the recently approved esomeprazole appear to have similar efficacy. (Am Fam Physician 2002;66:273-80. Copyright© 2002 American Academy of Family Physicians.). A PDF version of this document is available. (8 pages / 81 KB). Proton pump inhibitors (PPIs) are one of the most commonly prescribed classes of medications in the primary care setting and are considered a major advance in the treatment of acid-peptic diseases.
Since the introduction of omeprazole (Prilosec) in 1989, several other PPIs have become available in the United States. The intravenous form of pantoprazole (Protonix I.V.) is now available, and the U.S. Food and Drug Administration (FDA) approved the newest PPI, esomeprazole (Nexium), in 2001. The frequency of adverse effects associated with proton pump inhibitors is similar to that of placebo, with an overall incidence of less than 5 percent.
Basic Pharmacology PPIs are substituted benzimidazoles and are generally administered as enteric-coated tablets or capsules that pass through the stomach intact and are absorbed in the proximal small bowel. Once absorbed, all PPIs have a relatively short plasma half-life (about one to two hours). Their duration of action is much longer because of their unique mechanism of action. PPIs are lipophilic weak bases that cross the parietal cell membrane and enter the acidic parietal cell canaliculus.
In this acidic environment, the PPI becomes protonated, producing the activated sulphenamide form of the drug that binds covalently with the H +/K + ATPase enzyme that results in irreversible inhibition of acid secretion by the proton pump. 1-3 The parietal cell must then produce new proton pumps or activate resting pumps to resume its acid secretion.
1,2 In contrast to the other PPIs, rabeprazole (Aciphex) forms a partially reversible bond with the proton pump and is activated at a broader range of gastric pH. Therefore, it may have a more sustained acid-suppressing effect than the other PPIs.
1,2,4 Table 1 2 outlines the pharmacokinetic profiles of four orally administered PPIs. TABLE 1 Pharmacokinetic Profiles of Four Orally Administered PPIs Characteristic Omeprazole (Prilosec) Lansoprazole (Prevacid) Rabeprazole (Aciphex) Pantoprazole (Protonix) Bioavailability (%) 30 to 40 80 to 85 52 77 Time to peak plasma concentration (hours) 0.5 to 3.5 1.7 1.0 to 2.0 1.1 to 3.1 Plasma elimination half-life (hours) 0.5 to 1.0 1.3 to 1.7 1.0 to 2.0 1.0 to 1.9 Protein binding (%) 95 97 96 98 Urinary excretion of oral dose (%) 77 14 to 23 30 to 35 71 to 80 PPIs = proton pump inhibitors. Adapted with permission from Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases. J Am Pharm Assoc 2000;40:53.
Side Effects and Precautions PPIs are generally well tolerated. The frequency of adverse effects associated with PPIs is similar to that of placebo, with an overall incidence of less than 5 percent. 5 The type and frequency of adverse effects are similar to those observed with histamine H 2-receptor blockers. The most common adverse effects are headache, diarrhea, abdominal pain, and nausea. Except for diarrhea, the adverse effects of PPIs do not appear to be related to age, dosage, or duration of treatment. 5,6 The diarrhea seems to be related to the profound acid suppression, which has been shown to alter the bacterial content of the gut. Nevertheless, the overall incidence of diarrhea is less than 5 percent, and this effect appears to be dosage- and age-related.
5 It is appropriate to empirically treat patients with symptoms of classic gastroesophageal reflux disease with lifestyle modification and acid suppression therapy. Short-term safety (less than 12 weeks of treatment) of the oldest agents, omeprazole and lansoprazole (Prevacid), has been well established. 2 The safety profiles of the newer agents, rabeprazole and pantoprazole, appear to be similar to those of the older agents.
2,5,7 PPIs are only contraindicated if the patient has a known history of hypersensitivity to them, and they should be used with caution in patients with severe hepatic disease. Omeprazole is a pregnancy category C agent; the others are pregnancy category B medications. PPIs are not recommended for use in breastfeeding mothers. 8-12 Drug Interactions PPIs cause significant increases in gastric pH, which may alter the absorption of weak acids or bases. They may inhibit the absorption of drugs such as griseofulvin (Grisactin), ketoconazole (Nizoral), itraconazole (Sporanox), iron salts, vitamin B 12, cefpodoxime (Vantin), and enoxacin (Penetrex), many of which are weak bases and require acid for absorption. 2,5,6,13 Coadministration with these agents should be approached cautiously because it may result in clinical treatment failure. 2 PPIs are metabolized to varying degrees by the hepatic cytochrome P450 enzymatic system and may alter drug metabolism by induction or inhibition of the cytochrome P enzymes.
2,5 This is an important consideration in patients taking medications with a narrow therapeutic window, such as diazepam (Valium), phenytoin (Dilantin), and warfarin (Coumadin). Omeprazole has the greatest potential for altering cytochrome P activity; the other PPIs are less likely to cause clinically significant drug interactions with these agents. 5,13 Table 2 2,5 illustrates the effects of PPIs on several medications.
Methods: This was a retrospective cohort study with a follow-up period of 5 years. We identified 388,098 patients who were diagnosed with UGID between 2000 and 2006 from the Longitudinal Health Insurance Database of the Taiwan National Health Insurance program. We used Cox proportional hazard ratio (HR) to compare the risk of DM between UGID patients received PPIs and those did not receive PPIs. HRs were adjusted for possible confounders, including age, sex, hypertension, gout and/or hyperuricemia, coronary artery disease, stroke, pancreatitis, hyperlipidemia, obesity, H2-blocker use, and clozapine or olanzapine use. The dose-related effects of PPIs on the risk of DM were evaluated according to the defined daily dose (DDD).
Results: The adjusted HR was 0.80 (95% CI, 0.73–0.88) for the study group (UGID patients with PPIs) compared with comparison group I (UGID patients without PPIs). Among patients who used PPIs, those older than 60 years of age had a lower risk of DM (HR, 0.73; 95% CI, 0.63–0.83) than those younger than 40 years. Additionally, the effect of PPIs was significantly dose-dependent ( P for trend 540 DDDs of PPIs exhibited the greatest reduction in the risk of DM. 1. Introduction Diabetes mellitus (DM) is a worldwide epidemic and the number of people with DM has more than doubled globally in the past 3 decades.
Type 2 DM (T2DM) is caused by peripheral insulin resistance and is usually characterized by β-cell hyperplasia and hyperinsulinemia. Proton pump inhibitors (PPIs) are widely used for the treatment of gastric acid-related diseases such as peptic ulcer disease and gastroesophageal reflux disease. , PPIs block the last enzyme in the gastric acid secretion system and, consequently, decrease gastric acid secretion and increase the blood concentration of the hormone gastrin. , Some in vitro studies have demonstrated that gastrin induces β-cell neogenesis from pancreatic exocrine duct cells and increases β-cell mass.
, Several studies have shown that treatment with gastrin can induce the formation of new β-cells under various conditions in animal models. , Retrospective studies in adults with DM have shown that patients who receive PPIs achieve better glycemic control than patients without receiving PPIs. , Singh et al designed a randomized, double-blind, placebo-controlled study to evaluate the effect of pantoprazole therapy on glucose-insulin homeostasis in patients with T2DM; the results showed significantly reduced HbA1c levels and increased gastrin levels. Therefore, we hypothesized that PPIs can induce the formation of new β-cells and, consequently, reduce the risk of DM in patients with upper gastrointestinal disease (UGID). Currently, insufficient clinical data exist regarding the effect of PPIs on DM risk, especially among Asian populations, and available studies have not provided a clear analysis of the effect of PPI dose on DM risk reduction. Therefore, we conducted a hypothesis-generating, retrospective study in a Taiwanese population to assess the risk of DM development among UGID patients treated with PPIs. Data sources This study was a retrospective cohort study.
The study samples were retrieved from the Longitudinal Health Insurance Database (LHID), which consisted of 5% samples (about 1,000,000 subjects) of the population included in the Taiwan National Health Insurance (NHI) program. The NHI program was an insurance system and covered for more than 99% of the national population in Taiwan and provided for research purposes. No significant differences in the distribution of age and gender were found between the patients in the sample group and the original population.
The LHID contained all medical claimed data for approximately 1,000,000 subjects from 2000 to 2011. It included diagnosis codes, drug prescriptions, hospital visits, including detailed clinical and demographic information of all hospital admissions and ambulatory visits. This study was exempt from full review by the Institutional Review Board of Taipei Medical University because the identification numbers of all of the individuals in the NHRI database were encrypted to protect the privacy of the individuals. Study sample For the study cohort, we identified 388,098 patients who were newly diagnosed with UGID (ICD-9-CM codes 530–536, which included diseases of the esophagus, stomach, and duodenum) during an ambulatory care visit between January 1, 2000 and December 31, 2006. Three separate, consecutive diagnoses were required to increase the validity of the diagnosis.
For each patient, we assigned the first ambulatory care visit for the treatment of UGID as the index date. We also identified 415,362 patients without UGID (non-UGID patients) who received care between January 1, 2000 and December 31, 2011. The LHID also provides information on medical orders during ambulatory care visits and hospital admissions. We reviewed this data and determined which subjects had ever filled prescriptions for PPIs during the 5 years after their respective index dates. We classified UGID patients into 2 groups: those who received PPIs (n = 87,679) and those who did not receive PPIs (n = 250,419). In the group of UGID patients who received PPIs, we excluded patients who had been diagnosed with DM and prescribed PPIs before the index date. We also excluded UGID patients who received PPIs after December 31, 2006 and those with fewer than 90 daily doses of PPIs within the first 180 days after the first administration of PPIs.
Finally, we selected 7384 UGID patients who received PPIs as the study group. We also selected 14,768 UGID patients without PPI use as comparison group I. Each patient in the study group was matched to 2 UGID patients without PPI use by age, sex, and index year. Next, we selected 29,536 non-UGID patients as comparison group II.
Each patient in comparison group I was matched to 2 non-UGID patients by age, sex, and index year. All of the subjects were followed for 5 years or censored at the date of DM diagnosis.
Dosage of PPI Complete information about all prescriptions of PPIs was extracted from the NRI prescription database. Data collected included the date of prescription, the daily dose, and the number of days supplied. For the PPIs-treatment group, we calculated the total dosage prescribed during the follow-up period. The defined daily dose (DDD) recommended by the World Health Organization of 20 mg per day was used to quantify omeprazole and rabeprazole usage; 30 mg per day for lansoprazole and esomeprazole usage and 40 mg per day for pantoprazole usage. Outcome measurement and confounding factors Each patient was followed for 5 years or until DM was diagnosed, whichever occurred first. The primary outcome was development of DM and the secondary outcome was dose effect of PPIs on the risk of DM.
DM was diagnosed according to ICD-9 code 250.0. The measured outcome of DM diagnosis of patients was those with DM diagnosis at least 2 times and with following HbA1C test. We adjusted the risk of DM development for possible confounding factors, including hypertension, gout and/or hyperuricemia, coronary artery disease (CAD), stroke, pancreatitis, hyperlipidemia, obesity, H2-blocker use, and clozapine or olanzapine. Statistical analysis Statistical analyses were performed using SAS version 9.1 (SAS System for Windows, Version 8.2, Cary, NC). Student t test and Pearson χ 2 test were applied to evaluate differences in sociodemographic characteristics, such as age and sex, and comorbidities among the study cohort and the comparison cohorts. Cox proportional hazard ratios (HRs) were used to estimate HRs and 95% confidence intervals (CIs). Onset time of DM among different DDD groups was evaluated by Student t test.
The Kaplan–Meier method and log-rank test were used to examine the differences in 5-year DM-occurrence rates between the study and comparison cohorts. All tests were 2-tailed, and P values less than 0.05 were considered significant. We assessed the crude HRs and adjusted HRs for the risk of DM during the 5-year follow-up period between comparison group I and II and between the study group and comparison group I.
The adjusted HR for the risk of DM for UGID patients without PPI use (comparison group I) was 1.42 (95% CI, 1.33–1.52) compared with non-UGID patients (comparison group II). The adjusted HR for UGID patients with PPI use (study group) was 0.80 (95% CI, 0.73–0.88) compared with UGID patients without PPI use (comparison group I). Additionally, the adjusted HR for UGID patients with PPI use (study group) was 0.87 (95% CI, 0.78–0.97) compared with non-UGID patients without PPI use (comparison group II). These results demonstrated that UGID patients had an increased risk of DM after adjustment for various potential confounders. We also observed that UGID patients who received PPIs had a decreased risk of DM (Table ). Among patients receiving PPIs, those who were older than 60 years of age had a lower risk of DM (HR, 0.73; 95% CI, 0.63–0.83) than those who were younger than 40 years. Male and female patients receiving PPIs had similarly decreased risks of DM.
Adjusted HRs were 0.81 (95% CI, 0.71–0.91) and 0.80 (95% CI, 0.69–0.93) for males and females, respectively (Fig. We evaluated the effects of cumulative DDD on the risk of DM and observed a significant dose-related effect ( P for trend, P 540 DDD of PPIs had the greatest reduction in the risk of DM (adjusted HR, 0.22; 95% CI, 0.14–0.35).
4. Discussion This study is the first retrospective cohort study evaluating the effect of PPIs on DM risk in patients with UGID. We found that patients with UGID had an increased risk of DM compared to non-UGID patients, but we also found that UGID patients who received PPI therapy had a significantly lower risk of developing DM within 5 years than patients who did not receive PPIs.
Furthermore, we observed a dose-related effect of PPIs on DM risk. One possible explanation for the findings of this study is the mechanism of PPIs, which elevate intragastric pH and increase gastrin concentration. Suarez-Pinzon et al demonstrated that gastrin induced the formation of new β-cells and increased insulin secretion. Several animal studies also showed that treatment with gastrin induced the formation of new β-cells under various conditions.
–, Suarez-Pinzon et al further showed that the combination of epidermal growth factor and gastrin increased the number of β-cells in adult human pancreatic tissue cultured in vitro and significantly increased β-cell and insulin content in human islet cells implanted in nonobese diabetic/severe combined immunodeficiency mice. Singh et al evaluated the effect of pantoprazole therapy on glucose-insulin homeostasis in patients with T2DM and showed that 12 weeks of pantoprazole therapy significantly increased gastrin and insulin levels and reduced HbA1c levels. Additionally, many clinical studies have commented on the beneficial effects of PPIs on glycemic control in patients with DM. Results of several studies have shown a significant reduction in HbA1c in patients with DM who were taking PPIs.
– Therefore, we hypothesized that UGID patients receiving PPIs may experience a decreased risk of DM. The proposed mechanism for this reduction is that PPIs increase gastrin secretion and gastrin induces islet β-cell neogenesis. Furthermore, gastrin and the related incretin hormones are both gastrointestinal peptides, so PPIs could lower glycemia through a mechanism similar to incretin-based therapies.
Like incretins, gastrin increases the amount of insulin released from the β-cells of the islets of Langerhans after eating. , Additionally, PPIs slow gastric emptying time, which could decrease postprandrial hyperglycemic excursions. This study has several noteworthy strengths. First, the Taiwan National Health Insurance is a large, population-based database which includes data from a longitudinal cohort.
The nationwide Longitudinal Health Insurance Database provided an excellent resource offered a good opportunity to explore the relation between the use of PPIs and risk of DM. Second, we only included newly diagnosed UGID patients without prior DM and these patients with at least 3 consecutive episodes of diagnosed UGID. We could avoid the influence of unknown treatment histories before the study initiated and increase the accuracy of the diagnosis, respectively. Third, we took potential confounding factors for DM into consideration in the regression models. These included including age, gender, hypertension, gout or/and hyperuricemia, coronary artery disease, stroke, pancreatitis and hyperlipidemia, obesity, H2 blockers use, and clozapine/olanzapine use. Last, the further classification of PPIs users according to the dose (defined daily dose) used by the patients, demonstrating an association between larger doses of PPIs and a greater reduction of DM risk.
Nevertheless, there are some several limitations in this study, include the use of an administrative database that lacked records of patient lifestyles (such as smoking and alcohol use) and nonprescription medications use. We could not evaluate the impact of these factors. Besides, the Longitudinal Health Insurance Database is belonged to secondary database hence we could not get patients’ the body weight or body mass index. This factor is our study limitation; however, we added “obesity” as a confounding factor. Our findings indicated that PPIs may decrease the risk of DM and with a dose-dependent effect. Further studies are warranted to determine whether PPIs have the potential to be used clinically as new antidiabetic drugs and prevention agents of DM. We conclude that the risk of DM is increased in patients with UGID, but the risk of DM can be decreased in patients with UGID receiving PPIs.
Further, the decreased DM risk in UGID patients with PPIs use is significantly dose dependent. Abbreviations: CAD = coronary artery disease, CIs = confidence intervals, DDD = defined daily dose, DM = diabetes mellitus, EGF = epidermal growth factor, HRs = hazard ratios, LHID = Longitudinal Health Insurance Database, NHI = National Health Insurance, PPIs = proton pump inhibitors, T2DM = Type 2 diabetes mellitus, UGID = upper gastrointestinal disease. Conception/design: H-CL, Y-TH, L-HW; provision of study materials: H-CL, H-LL, Y-SU, L-HW; data analysis and interpretation: H-CL, Y-TH, H-LL, H-WC, YW, L-HW; collection and/or assembly of data, manuscript writing, final approval of manuscript: All authors. All authors have contributed to this manuscript, and all authors agree with the content of the manuscript. Funding: This work was supported by Taipei Medical University (TMU99-AE1-B04).
The funders had no role in the study design, data collection and analysis, and preparation of the manuscript. No additional external funding was received for this study The authors have no funding and conflicts of interest to disclose.