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2000
Volume 4, Issue 1
  • ISSN: 2666-2906
  • E-ISSN: 2666-2914

Abstract

Introduction

Proton pump inhibitors (PPIs) and the prevalence of diabetes and hyperglycemia have been the subject of numerous publications in recent years.

Objective

The clinical evidence of diabetes and hyperglycemia in patients taking PPIs for an extended period of time is the main topic of our current review.

Methods

To find publications, including randomized controlled trials, observational cohort studies, systematic reviews, and meta-analyses, keywords such as diabetes mellitus, new-onset diabetes mellitus, drug-induced, proton pump inhibitors, PPI-induced, diabetogenic, and iatrogenic were used to search online databases like Medline/Pubmed/PMC, Scopus, Web of Science, Google Scholar, and reference lists.

Results and Discussion

Prolonged PPI therapy has been linked to New-onset Diabetes Mellitus (NODM), according to a number of prospective and retrospective observational studies, meta-analyses, and randomized controlled clinical trials.

Conclusion

A number of mechanisms, including hypergastrinemia, gut dysbiosis, hypomagnesemia, decreased IGF-1 levels, and progesterone X receptor (PXR) activation, have been proposed to explain the development of NODM in relation to long-term PPI usage. The increased risk of NODM linked to long-term PPI usage should be known to clinicians, particularly gastroenterologists, and other prescribers, pharmacists, and other healthcare professionals.

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References

  1. Galicia-GarciaU. Benito-VicenteA. JebariS. Larrea-SebalA. SiddiqiH. UribeK.B. OstolazaH. MartínC. Pathophysiology of type 2 diabetes mellitus.Int. J. Mol. Sci.20202117627510.3390/ijms21176275 32872570
     [Google Scholar]
  2. MaideenN.M.P. Antidiabetic activity of Nigella sativa (black seeds) and its active constituent (thymoquinone): A review of human and experimental animal studies.Chonnam Med. J.202157316917510.4068/cmj.2021.57.3.169 34621636
     [Google Scholar]
  3. CloeteL. Diabetes mellitus: An overview of the types, symptoms, complications and management.Nurs. Stand.1987371616610.7748/ns.2021.e11709
     [Google Scholar]
  4. ImamK. AhmadS.I. Clinical features, diagnostic criteria and pathogenesis of diabetes mellitus. In: Diabetes Advances in Experimental Medicine and Biology.New York, NYSpringer201334035510.1007/978‑1‑4614‑5441‑0_25
     [Google Scholar]
  5. AlamS. HasanM.K. NeazS. HussainN. HossainM.F. RahmanT. Diabetes Mellitus: Insights from epidemiology, biochemistry, risk factors, diagnosis, complications and comprehensive management.Diabetology202122365010.3390/diabetology2020004
     [Google Scholar]
  6. SiddiquiA.A. SiddiquiS.A. AhmadS. SiddiquiS. AhsanI. SahuK. Diabetes: Mechanism, pathophysiology and management-A review.Int. J. Drug Dev. Res.201352123
     [Google Scholar]
  7. BalajiR. DuraisamyR. KumarM.P. Complications of diabetes mellitus: A review.Drug Invention Today201912198
     [Google Scholar]
  8. OrbanJ.C. ObberghenV.E. IchaiC. IchaiC. QuintardH. Acute complications of diabetes. In:Metabolic Disorders and Critically Ill Patients.ChamSpringer201834136310.1007/978‑3‑319‑64010‑5_15
     [Google Scholar]
  9. AvogaroA. FadiniG.P. Microvascular complications in diabetes: A growing concern for cardiologists.Int. J. Cardiol.2019291293510.1016/j.ijcard.2019.02.030 30833106
     [Google Scholar]
  10. KhalilH. Diabetes microvascular complications—A clinical update.Diabetes Metab. Syndr.201711Suppl. 1S133S13910.1016/j.dsx.2016.12.022 27993541
     [Google Scholar]
  11. HuangD. RefaatM. MohammediK. JayyousiA. SuwaidiA.J. KhalilA.C. Macrovascular complications in patients with diabetes and prediabetes.BioMed Res. Int.2017201711910.1155/2017/7839101 29238721
     [Google Scholar]
  12. ShanP.F. LiQ. KhamaisiM. QiangG. Type 2 diabetes mellitus and macrovascular complications.Int. J. Endocrinol.201720171210.1155/2017/4301461 29230243
     [Google Scholar]
  13. Diagnosis and classification of diabetes mellitus: Standards of care in Diabetes-2024.Diabetes Care2024371S81S90
     [Google Scholar]
  14. PleusS. TytkoA. LandgrafR. HeinemannL. WernerC. Müller-WielandD. ZieglerA.G. MüllerU.A. FreckmannG. KleinwechterH. SchleicherE. NauckM. PetersmannA. Definition, classification, diagnosis and differential diagnosis of diabetes mellitus: Update 2023.Exp. Clin. Endocrinol. Diabetes2024132311212410.1055/a‑2166‑6643 38378016
     [Google Scholar]
  15. JainV. PatelR.K. KapadiaZ. GaliveetiS. BanerjiM. HopeL. Drugs and hyperglycemia: A practical guide.Maturitas2017104808310.1016/j.maturitas.2017.08.006 28923179
     [Google Scholar]
  16. FathallahN. SlimR. LarifS. HmoudaH. SalemB.C. Drug-induced hyperglycaemia and diabetes.Drug Saf.201538121153116810.1007/s40264‑015‑0339‑z 26370106
     [Google Scholar]
  17. FèveB. ScheenA.J. When therapeutic drugs lead to diabetes.Diabetologia202265575176210.1007/s00125‑022‑05666‑w 35244742
     [Google Scholar]
  18. JenkinsD. ModolellI. Proton pump inhibitors.BMJ2023383e07075210.1136/bmj‑2022‑070752
     [Google Scholar]
  19. KhanA.M. HowdenC.W. The role of proton pump inhibitors in the management of upper gastrointestinal disorders.Gastroenterol. Hepatol.2018143169175 29928161
     [Google Scholar]
  20. StrandD.S. KimD. PeuraD.A. 25 years of proton pump inhibitors: A comprehensive review.Gut Liver2017111273710.5009/gnl15502 27840364
     [Google Scholar]
  21. YibirinM. OliveiraD.D. ValeraR. PlittA.E. LutgenS. Adverse effects associated with proton pump inhibitor use.Cureus2021131e1275910.7759/cureus.12759 33614352
     [Google Scholar]
  22. MaideenN.M.P. Adverse effects associated with long-term use of proton pump inhibitors.Chonnam Med. J.202359211512710.4068/cmj.2023.59.2.115 37303818
     [Google Scholar]
  23. LoosenS.H. KostevK. LueddeM. QvartskhavaN. LueddeT. RoderburgC. Long-term use of proton pump inhibitors (PPIs) is associated with an increased risk of type 2 diabetes.Gut202271816871688 34725199
     [Google Scholar]
  24. KuoH.Y. LiangC.S. TsaiS.J. ChenT.J. ChuC.S. ChenM.H. Dose-dependent proton pump inhibitor exposure and risk of type 2 diabetes: A nationwide nested case-control study.Int. J. Environ. Res. Public Health20221914873910.3390/ijerph19148739 35886592
     [Google Scholar]
  25. CiardulloS. ReaF. SavaréL. MorabitoG. PerseghinG. CorraoG. Prolonged use of proton pump inhibitors and risk of type 2 diabetes: Results from a large population-based nested case-control study.J. Clin. Endocrinol. Metab.20221077e2671e267910.1210/clinem/dgac231 35428888
     [Google Scholar]
  26. CzarniakP. AhmadizarF. HughesJ. ParsonsR. KavousiM. IkramM. StrickerB.H. Proton pump inhibitors are associated with incident type 2 diabetes mellitus in a prospective population-based cohort study.Br. J. Clin. Pharmacol.20228862718272610.1111/bcp.15182 34907592
     [Google Scholar]
  27. HeQ. YangM. QinX. FanD. YuanJ. PanY. Risk stratification for proton pump inhibitor-associated type 2 diabetes: A population-based cohort study. Gut202170112215.2221610.1136/gutjnl‑2020‑323816 33443025
     [Google Scholar]
  28. YuanJ. HeQ. NguyenL.H. WongM.C.S. HuangJ. YuY. XiaB. TangY. HeY. ZhangC. Regular use of proton pump inhibitors and risk of type 2 diabetes: Results from three prospective cohort studies.Gut20217061070107710.1136/gutjnl‑2020‑322557 32989021
     [Google Scholar]
  29. ChenchulaS. SharmaP. GhantaM.K. AmerneniK.C. RajakarunakaranP. SaggurthiP. ChandraM.B. GuptaR. ChavanM. Association and mechanisms of proton pump inhibitors use with type-2 diabetes mellitus incidence in adults: A systemic review and meta-analysis.Curr. Diabetes Rev.20242010e12012422558110.2174/0115733998254869231101095222 38243950
     [Google Scholar]
  30. GuoY.R. LiuX.M. WangG.X. Exposure to proton pump inhibitors and risk of diabetes: A systematic review and meta-analysis.World J. Diabetes202314212012910.4239/wjd.v14.i2.120 36926660
     [Google Scholar]
  31. ChenY. HuL. SunC. BaoJ. LiuJ. BhanC. KimK.Y. ManemR. ThapaP. MaS. LiuM. ChengX. ChengC. ZhouQ. Will proton pump inhibitors increase the risk of diabetes mellitus? A systemic review and meta-analysis.Turk. J. Gastroenterol.202233649750410.5152/tjg.2022.21480 35786618
     [Google Scholar]
  32. PengC.C.H. TuY.K. LeeG.Y. ChangR.H.E. HuangY. BukhariK. TsaiY.C. FuY. HuangH.K. MunirK.M. Effects of proton pump inhibitors on glycemic control and incident diabetes: A systematic review and meta-analysis.J. Clin. Endocrinol. Metab.2021106113354336610.1210/clinem/dgab353 34170301
     [Google Scholar]
  33. Sánchez-GarcíaA. Simental-MendíaM. Simental-MendíaL.E. Effect of proton-pump inhibitors on glucose and insulin metabolism on patients with type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials.Curr. Pharm. Des.202026324007401310.2174/1381612826666200523170718 32445448
     [Google Scholar]
  34. Gómez-IzquierdoJ.C. YuO.H.Y. The influence of proton-pump inhibitors on glycemic control: A systematic review of the literature and a meta-analysis.Can. J. Diabetes201741435136110.1016/j.jcjd.2016.11.004 28373033
     [Google Scholar]
  35. DrygałaZ. WyrwałJ. KrasuskaM. NowakK. OlejarzZ. ZielińskaZ. SłowikM. NowakK. NiećM. GierlachK. The consequences of long-term therapy with proton pump inhibitors.J. Educ. Health Sport202453445910.12775/JEHS.2024.53.004
     [Google Scholar]
  36. LiuY. LuuS. MaysB. Severe hypergastrinemia secondary to prolonged proton pump inhibitor therapy: 2987. Off J.Amer Coll Gastroent ACG2017112S1587S1589
     [Google Scholar]
  37. ShiotaniA. KatsumataR. GoudaK. FukushimaS. NakatoR. MuraoT. IshiiM. FujitaM. MatsumotoH. SakakibaraT. Hypergastrinemia in long-term use of proton pump inhibitors.Digestion201897215416210.1159/000484688 29310112
     [Google Scholar]
  38. RoomanI. LardonJ. BouwensL. Gastrin stimulates β-cell neogenesis and increases islet mass from transdifferentiated but not from normal exocrine pancreas tissue.Diabetes200251368669010.2337/diabetes.51.3.686 11872667
     [Google Scholar]
  39. DianeA. AllouchA. Mu-U-MinR.B.A. Al-SiddiqiH.H. Endoplasmic reticulum stress in pancreatic β-cell dysfunctionality and diabetes mellitus: A promising target for generation of functional hPSC-derived β-cells in vitro.Front. Endocrinol.202415138647110.3389/fendo.2024.1386471 38966213
     [Google Scholar]
  40. KabalieiA. PalchykV. IzmailovaO. ShynkevychV. ShlykovaO. KaidashevI. Long-term administration of omeprazole-induced hypergastrinemia and changed glucose homeostasis and expression of metabolism-related genes.BioMed Res. Int.20242024111610.1155/2024/7747599 38884019
     [Google Scholar]
  41. KieckaA. SzczepanikM. Proton pump inhibitor-induced gut dysbiosis and immunomodulation: Current knowledge and potential restoration by probiotics.Pharmacol. Rep.202375479180410.1007/s43440‑023‑00489‑x 37142877
     [Google Scholar]
  42. ZhangJ. ZhangC. ZhangQ. YuL. ChenW. XueY. ZhaiQ. Meta-analysis of the effects of proton pump inhibitors on the human gut microbiota.BMC Microbiol.202323117110.1186/s12866‑023‑02895‑w 37337143
     [Google Scholar]
  43. BrunoG. ZaccariP. RoccoG. ScaleseG. PanettaC. PorowskaB. PontoneS. SeveriC. Proton pump inhibitors and dysbiosis: Current knowledge and aspects to be clarified.World J. Gastroenterol.201925222706271910.3748/wjg.v25.i22.2706 31235994
     [Google Scholar]
  44. SuT. LaiS. LeeA. HeX. ChenS. Meta-analysis: Proton pump inhibitors moderately increase the risk of small intestinal bacterial overgrowth.J. Gastroenterol.2018531273610.1007/s00535‑017‑1371‑9 28770351
     [Google Scholar]
  45. SinghA. CresciG.A. KirbyD.F. Proton pump inhibitors: Risks and rewards and emerging consequences to the gut microbiome.Nutr. Clin. Pract.201833561462410.1002/ncp.10181 30071147
     [Google Scholar]
  46. HeQ. XiaB. YangM. LuK. FanD. LiW. LiuY. PanY. YuanJ. Alterations in gut microbiota and bile acids by proton-pump inhibitor use and possible mediating effects on elevated glucose levels and insulin resistance.FASEB J.2024386e2354110.1096/fj.202302558R 38498341
     [Google Scholar]
  47. BobrowiczM. PachuckiJ. PopowM. Hypomagnesaemia leading to parathyroid dysfunction, hypocalcaemia, and hypokalaemia as a complication of long-term treatment with a proton pump inhibitor. A literature review.Endokrynol. Pol.202475435936510.5603/ep.98576 39279305
     [Google Scholar]
  48. JunaidL.M.A. FarazA. VaseemM. SalihI.M.A. KutbiH.A.H. JulifiA.M.Z. AlfhaidF.M. SamiW. Effect of proton pump inhibitors on magnesium levels in type II diabetic patients: A single centre study from Saudi Arabia.Eur. Rev. Med. Pharmacol. Sci.202327310771082 36808355
     [Google Scholar]
  49. MaggioM. LauretaniF. VitaD.F. ButtòV. CattabianiC. MasoniS. SuttiE. BondiG. Dall’AglioE. BandinelliS. CorsonelloA. AbbatecolaA.M. LattanzioF. FerrucciL. CedaG.P. Relationship between use of proton pump inhibitors and IGF system in older subjects.J. Nutr. Health Aging201418442042310.1007/s12603‑013‑0430‑z 24676324
     [Google Scholar]
  50. ItaD.J.R. Castilla-CortázarI. AguirreG.A. Sánchez-YagoC. Santos-RuizM.O. Guerra-MenéndezL. Martín-EstalI. García-MagariñoM. Lara-DíazV.J. PucheJ.E. MuñozU. Altered liver expression of genes involved in lipid and glucose metabolism in mice with partial IGF-1 deficiency: An experimental approach to metabolic syndrome.J. Transl. Med.201513132610.1186/s12967‑015‑0684‑9 26467524
     [Google Scholar]
  51. MuhičM. VardjanN. ChowdhuryH.H. ZorecR. KreftM. Insulin and insulin-like growth factor 1 (IGF-1) modulate cytoplasmic glucose and glycogen levels but not glucose transport across the membrane in astrocytes.J. Biol. Chem.201529017111671117610.1074/jbc.M114.629063 25792745
     [Google Scholar]
  52. HukkanenJ. HakkolaJ. RysäJ. Pregnane X receptor (PXR) - a contributor to the diabetes epidemic?Drug Metabol. Drug Interact.201429131510.1515/dmdi‑2013‑0036 24166671
     [Google Scholar]
  53. RysäJ. BulerM. SavolainenM.J. RuskoahoH. HakkolaJ. HukkanenJ. Pregnane X receptor agonists impair postprandial glucose tolerance.Clin. Pharmacol. Ther.201393655656310.1038/clpt.2013.48 23588309
     [Google Scholar]
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An Overview of Clinical Data and Likely Mechanisms of New-Onset Diabetes Mellitus (NODM) Induced by Proton Pump Inhibitors (PPIs)
Int J Gastroenterol Hepatol Dis 4, E26662906365032 (2025); https://doi.org/10.2174/0126662906365032250415101526
/content/journals/ijghd/10.2174/0126662906365032250415101526
/content/journals/ijghd/10.2174/0126662906365032250415101526
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  • Article Type:     Review Article
Keyword(s): chronic hyperglycemia; diabetic neuropathy; diabetogenic; iatrogenic; new onset diabetes mellitus; PPI-induced diabetes mellitus; Proton pump inhibitors

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