Do PPIs contribute to chronic illness?

In contrast to previous research, the use of proton pump inhibitors (PPIs) was not correlated with clinically meaningful differences in serum biomarkers of inflammation, insulin resistance, cardiovascular risk, and renal function, according to a recently published study in the Journal of Clinical Gastroenterology.

However, increased body mass index (BMI) was strongly associated PPIs and clinically significant differences in these biomarkers, the researchers found. Thus, it may be that higher BMI, not necessarily the use of PPIs, is associated with the development of chronic illness.

“Because of their highly prevalent and often chronic use, attention has focused on the potential harmful effects of long-term PPI use,” wrote authors led by Gregory L. Austin, MD, MPH, Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, CO.

In previous research, investigators found a possible link between the chronic use of PPIs and the pathogenesis of cardiovascular disease, chronic kidney disease, and dementia.

Although the mechanism underlying this potential association is not yet fully understood, the authors noted that obesity may be the likely culprit due to the increased likelihood of gastroesophageal reflux disease in obese individuals and, thus, the consequential chronic use of PPI treatment.

Checking blood biomarkers

For this study, the researchers analyzed the independent association of PPI use with serum markers of inflammation, insulin resistance, cardiovascular risk, and renal function, and assessed the differences in these biomarkers between PPI users and nonusers. They collected and analyzed data from 5,189 individuals aged 18-85 years using the National Health and Nutrition Examination Survey (NHANES). Of these, 383 were PPI users and 4,806 were not.

The team assessed the following biomarker outcomes in the sample: serum levels of fasting glucose, fasting insulin, hemoglobin A_1c (HbA_1c), homocysteine, fasting total cholesterol, fasting high-density lipoprotein (HDL), fasting low-density lipoprotein (LDL), fasting apolipoprotein B (apoB), fasting triglycerides, C-reactive protein (CRP), blood urea nitrogen (BUN), creatinine, and uric acid.

They also accounted for confounding variables, including body mass index (BMI), duration of PPI use, use of other non-PPI medications, and health behaviors.

They noted that PPI users were older, more likely to be white, and have higher BMI measures compared with nonusers. The median duration for PPI use was 730 days.

After analysis, the researchers found that PPI use was associated with differences in mean fasting LDL (P=0.006) and apoB (P=0.01), but not associated with total cholesterol (P=0.13), mean fasting HDL (P=0.27), mean fasting triglycerides (P=0.70), CRP (P=0.52), the homeostatic model assessment-insulin resistance (P=0.48), HbA_1c (P=0.39), or homocysteine (P=0.87).

Additionally, PPI use was associated with a reduction in BUN (P=0.008), but not serum creatinine (P=0.38) or uric acid (P=0.34).

The importance of BMI

Except for LDL and apoB biomarkers, chronic PPI use was not associated with biomarkers of inflammation, insulin resistance, cardiovascular risk, and renal function, the researchers determined. However, higher BMI—which was correlated with PPI use—was independently associated with significant differences in biomarkers.

“One explanation for the lack of associations between serum biomarkers in our study that would correlate with the adverse effects reported in the literature is that we accounted for BMI, for obesity-related comorbidities, for treatments directed at obesity-related comorbidities, and for other health behaviors, whereas prior studies did not account (or only partially accounted) for these factors,” the authors wrote.

Dr. Austin and colleagues acknowledged that their study had certain limitations. For instance, even though heightened levels of LDL and apoB are risk factors for chronic kidney disease and dementia, other unmeasured confounders could actually mediate increased LDL and apoB levels in PPI users.

“PPI users represent a distinct group of individuals that are more likely to be obese, have obesity-related complications, and engage in different types of health behaviors compared with non-users of PPIs,” the researchers concluded. “Studies that fail to adequately account for these differences may incorrectly conclude harmful associations of PPI use when there is not a true difference.”

This research was supported by a grant from the American Gastroenterological Association.