insights

It is well accepted that the commonly prescribed class of drugs known as proton pump inhibitors (PPIs) carry with them an increased risk of several adverse effects, including bone fractures,¹ chronic kidney disease,² pneumonia,¹ enteric infections,³ and gastric cancer.⁴ Now a new study has provided evidence that PPI use increases risk for type 2 diabetes, especially if taken long term. Perhaps even more interesting is that the proposed mechanism for this increased risk is changes in the gut microbiome.

This new study comes on the heels of a recent randomized controlled trial that found a modest, but not statistically significant, increased risk of diabetes in PPI users.³ In the more recent study, researchers performed a prospective analysis of over 200,000 participants free of diabetes in the Nurses’ Health Study (NHS), NHS II, and Health Professionals Follow-up Study (HPFS). They found that after adjustment for lagging PPI use for two years and stratification by age and study period, PPI use was associated with a 74% increased relative risk of diabetes (HR = 1.74).⁵ However, there were fundamental differences among the population who took PPIs and those who did not: regular PPI users tended to be less physically active, had higher rates of hypertension and hypercholesterolemia, and were also more likely to use non-steroidal anti-inflammatory drugs and steroids versus non-PPI users. After adjusting for these differences and some other factors, the association was attenuated, but not eliminated (HR = 1.24).⁵

There was also a difference in the impact of PPIs depending on duration: at zero to two years of use, PPI use was associated with a 5% increase in diabetes risk, while more than two years of use was associated with a 26% increase in risk. At one year, the number needed to harm (NNH) with PPIs was 318.9, at two years, it was 170.8, and at three years, it was 77.3.⁵

The good news is that, similar to statins, stopping PPI use was associated with a decreased risk of diabetes: compared with current PPI users, those who had stopped within the past two years had a 17% reduction in risk, and those who had stopped for more than two years had a 19% reduction.⁵

The study also examined the impact of the other major class of acid blocking drugs, H2 receptor antagonists, and found that their use was also associated with increased diabetes risk, although to a lesser degree (HR = 1.14).⁵ The authors posit that this impact may vary linearly with the acid-blocking potential of the medications, as H2 blockers are less potent than PPIs, and that this suggests that the acid suppression itself is at least partly behind the mechanism of the increase in diabetes risk. This is where the potential for a role of the gut microbiome comes in.

The authors suggest that changes to the gut microbiota may underlie increased risk. PPI use has been shown to reduce gut microbiome diversity and alter its phenotype,⁶ perhaps due to its profound impact on gastric acidity. Such changes could lead to weight gain, metabolic syndrome, and chronic liver disease, which could in turn heighten risk. Both PPI use and diabetes have been associated with an increase in the gut abundance of Blautia and Lactobacillus and a decrease in the genus Bifidobacterium.^7,8 Additionally, the authors note that observational studies have suggested that other medicines with a major impact on gut microbiota, such as antibiotics, are associated with an increased risk of diabetes.^9-11

Interestingly, the authors also found that participants with lower BMI or normal blood pressure seemed to be at a greater risk for diabetes in association with PPI use, which is a pattern similar to the association between diabetes risk and statin use,^12,13 which could be a consideration in selecting appropriate treatments for patients. While the reason behind this association is not known, one potential explanation is that the participants with hypertension or obesity were already at very high risk of diabetes, so the added effects of medications are comparatively weak. Another possibility is that participants with hypertension or obesity may have gotten more lifestyle counseling for those conditions compared to normotensive, normal weight individuals, which could reduce their risk of diabetes.

Due to the widespread use of PPIs (at least 15 million Americans¹⁴), previous work has suggested that at a population level, they may have an even more pronounced effect on the gut microbiome than other commonly used drugs such as antibiotics. This is all the more reason to use PPIs sparingly and for short duration, and to help transition patients off of them when possible.

Read more about the functional medicine approach to GERD and how to help patients get off of PPIs

References

1. Takagi T, Naito Y, Inoue R, et al. The influence of long-term use of proton pump inhibitors on the gut microbiota: an age-sex-matched case-control study. J Clin Biochem Nutr. 2018;62(1):100-105. doi:10.3164/jcbn.17-78
2. Li T, Xie Y, Al-Aly Z. The association of proton pump inhibitors and chronic kidney disease: cause or confounding? Curr Opin Nephrol Hypertens. 2018;27(3):182-187. doi:10.1097/MNH.0000000000000406
3. Moayyedi P, Eikelboom JW, Bosch J, et al. Safety of proton pump inhibitors based on large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology. 2019;157(3):682-691.e2. doi:10.1053/j.gastro.2019.05.056
4. Cheung KS, Chan EW, Wong AYS, Chen L, Wong ICK, Leung WK. Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: a population-based study. Gut. 2018;67(1):28-35. doi:10.1136/gutjnl-2017-314605
5. Yuan J, He Q, Nguyen LH, et al. Regular use of proton pump inhibitors and risk of type 2 diabetes: results from three prospective cohort studies. Gut. Published online September 28, 2020. doi:10.1136/gutjnl-2020-322557
6. Jackson MA, Goodrich JK, Maxan ME, et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut. 2016;65(5):749-756. doi:10.1136/gutjnl-2015-310861
7. 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
8. Gurung M, Li Z, You H, et al. Role of gut microbiota in type 2 diabetes pathophysiology. EBioMedicine. 2020;51:102590. doi:10.1016/j.ebiom.2019.11.051
9. Boursi B, Mamtani R, Haynes K, Yang YX. The effect of past antibiotic exposure on diabetes risk. Eur J Endocrinol. 2015;172(6):639-648. doi:10.1530/EJE-14-1163
10. Mikkelsen KH, Knop FK, Frost M, Hallas J, Pottegård A. Use of antibiotics and risk of type 2 diabetes: a population-based case-control study. J Clin Endocrinol Metab. 2015;100(10):3633-3640. doi:10.1210/jc.2015-2696
11. Davis PJ, Liu M, Alemi F, et al. Prior antibiotic exposure and risk of type 2 diabetes among Veterans. Prim Care Diabetes. 2019;13(1):49-56. doi:10.1016/j.pcd.2018.07.001
12. Culver AL, Ockene IS, Balasubramanian R, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Intern Med. 2012;172(2):144-152. doi:10.1001/archinternmed.2011.625
13. Macedo AF, Douglas I, Smeeth L, Forbes H, Ebrahim S. Statins and the risk of type 2 diabetes mellitus: cohort study using the UK clinical practice pesearch datalink. BMC Cardiovasc Disord. 2014;14:85. doi:10.1186/1471-2261-14-85
14. Aitken M, Kleinrock M, Lyle J, Caskey L. Medicine Use and Shifting Costs of Healthcare: A Review of the Use of Medicines in the United States in 2013. IMS Institute for Healthcare Informatics; 2014. Accessed October 8, 2020. https://democrats-oversight.house.gov/sites/democrats.oversight.house.gov/files/documents/IMS-Medicine%20use%20and%20shifting%20cost%20of%20healthcare.pdf