PPIs and diabetes – is there a link?

PPIs

13th May 2022, Dr Chee L Khoo

Another month, another commonly used class of drugs are implicated in either aggravating glucose control in patients with type 2 diabetes (T2D) or actually, increase the risk of developing T2D. This month, we a report suggesting the use of proton pump inhibitors (PPIs), as a class of agent, is associated with increased risk of developing T2D. Further more, the same study demonstrated that the longer the exposure to PPIs the higher the risk of developing T2D. How real are the results and what may be the pathogenesis of that association?

PPIs have become the first-choice therapy in patients with acid-related disorders such as gastroesophageal reflux disease, Barrett oesophagus, and peptic ulcers and to prevent gastrointestinal bleeding while on nonsteroidal anti-inflammatory drugs. Many of our patients who are at risk of T2D are overweight or obese. Excessive adiposity is associated with increased risk of GORD. Many of the same patients may be on anti-inflammatory medications which predisposed them to gastrointestinal irritation. Many may also be on anti-platelet therapy for cardiovascular protection of one sort or another. Yet, this same cohort of patients are at higher risk of development of T2D.

Over the years, we have explored the various potential adverse reactions to the prolonged use of PPIs including fractures, malabsorption, gastric carcinoids, dementia, and the increased risk of infection including Clostridium difficile diarrhea (1-4).

More recently, it became evident that PPIs can alter the normal bacterial milieu at the distal esophagus, stomach, small bowel, and colon (5). Importantly, changes in the gut microbiome have been postulated to play a role in the pathophysiology of metabolic diseases including obesity, insulin resistance (6), non-alcoholic fatty liver disease (7), and diabetes (8).

Perhaps, that’s the reason why clinical data on the association between PPI use and diabetes are conflicted. Evidence on the topic has been recently summarized in a systematic review and meta-analysis including 3 cohort studies for a total of 244 439 participants. Although no significant association between PPI use and incident diabetes (pooled risk ratio, 1.10; 95% CI, 0.89-1.34; P = 0.385) was found, it should be stressed that a high degree of heterogeneity was identified (I2 = 93.5%), leading the authors to state that evidence was insufficient and inconsistent to make any definite conclusions (9).

A study was therefore conceived to investigate the relationship between PPI use in terms of duration of and adherence to treatment and the risk of diabetes in the general population. To achieve these goals, Ciardullo S et al performed a large, nested case-control study in the real-world setting of the Italian Lombardy region (10).  777 420 patients newly treated with PPIs between 2010 and 2015 in Lombardy, Italy. A total of 50 535 people diagnosed with diabetes until 2020 were matched with an equal number of controls that were randomly selected from the cohort members according to age, sex and clinical status.

What did they find?

Cases and controls showed similar baseline characteristics, except for the use of antihypertensive and lipid-lowering drugs, which was greater among patients who developed diabetes. Compared with patients who used PPIs for < 8 weeks, patients who used PPIs for 8 weeks – 6 months, for 6 months – 2 years and > 2 years had higher odds of diabetes of 19%, 43%, and 56% respectively. In other words, the longer patients used PPIs for, the higher the risks of them developing diabetes.

The odds ratios were even higher for younger patients. Patients aged 45-60 years who used PPIs for < 8 weeks, patients who used PPIs for 8 weeks – 6 months, for 6 months – 2 years and > 2 years had higher odds of diabetes of 19%, 50%, and 74% respectively.

The trends of increased risks remained regardless of age, sex and clinical profile. They considered obesity as a confounder but did not find that influenced the increased risks of developing diabetes.

What might be the cause of the link between PPI use and diabetes risk?

This study, obviously did not demonstrate the potential mechanisms linking PPIs and diabetes but did suggest perhaps, PPIs alter the gut microbiota. Previous studies have shown PPI users have a significant increase in the Enterococcus, Streptococcus, and Staphylococcus genera and the bacterium Escherichia coli (11). These changes may cause less efficient caloric extraction from the diet, intestinal epithelial damage, and greater entry of bacterial components into the portal circulation (12,13).

Other hypotheses linking PPIs and diabetes were also suggested. This include PPI-induced hypomagnesaemia (leading to low-grade inflammation and insulin resistance), reduction in IGF-1, and pregnane X receptor activation, which is involved in the regulation of hepatic glucose metabolism (14).

In summary, while there has been conflicting evidence linking PPI use to diabetes, this study provides more evidence suggesting that that prolonged treatment with PPIs is associated with a higher risk of developing diabetes, particularly in younger individuals. We should all therefore, avoid unnecessary prescription of this class of drugs, particularly for long-term use.

References

  1. Kwok CS, Yeong JK-Y, Loke YK. Meta-analysis: risk of fractures with acid-suppressing medication. Bone 2011;48(4):768-776.
  2. Gomm W, von Holt K, Thomé F, et al.  Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol 2016;73(4):410-416
  3. Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol 2012;107(7):1001-1010.
  4. Lazarus B, Chen Y, Wilson FP, et al.  Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med 2016;176(2):238-246.
  5. Jackson MA, Goodrich JK, Maxan M-E, et al.  Proton pump inhibitors alter the composition of the gut microbiota. Gut 2016;65(5):749-756.
  6. Vrieze A, Van Nood E, Holleman F, et al.  Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012;143(4):913-6.e7
  7. Sharpton SR, Ajmera V, Loomba R. Emerging role of the gut microbiome in nonalcoholic fatty liver disease: from composition to function. Clin Gastroenterol Hepatol. 2019;17(2): 296-306..
  8. Forslund K, Hildebrand F, Nielsen T, et al.  Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 2015;528(7581):262-266.
  9. Peng CC-H, Tu Y-K, Lee GY, et al.  Effects of proton pump inhibitors on glycemic control and incident diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2021;106(11):3354-3366.
  10. Stefano Ciardullo, Federico Rea, Laura Savaré, Gabriella Morabito, Gianluca Perseghin, Giovanni Corrao, Prolonged use of proton pump inhibitors and risk of type 2 diabetes: Results from a large population-based nested case-control study, The Journal of Clinical Endocrinology & Metabolism, 2022;, dgac231, https://doi.org/10.1210/clinem/dgac231
  11. Imhann F, Bonder MJ, Vila AV, et al.  Proton pump inhibitors affect the gut microbiome. Gut 2016;65(5):740-748.
  12. Mehal WZ. The Gordian Knot of dysbiosis, obesity and NAFLD. Nat Rev Gastroenterol Hepatol 2013;10(11):637-644.
  13. Kolodziejczyk AA, Zheng D, Shibolet O, Elinav E. The role of the microbiome in NAFLD and NASH. EMBO Mol Med. 2019;11(2):e9302.
  14. Czarniak P, Ahmadizar F, Hughes J, et al.  Proton pump inhibitors are associated with incident type 2 diabetes mellitus in a prospective population-based cohort study. Br J Clin Pharmacol. 2021.