Effects of Proton Pump Inhibitors on Glycemic Control and Incident Diabetes

A Systematic Review and Meta-analysis

Carol Chiung-Hui Peng; Yu-Kang Tu; Gin Yi Lee; Rachel Huai-En Chang; Yuting Huang; Khulood Bukhari; Yao-Chou Tsai; Yunting Fu; Huei-Kai Huang; Kashif M. Munir


J Clin Endocrinol Metab. 2021;106(11):3354-3366. 

In This Article

Abstract and Introduction


Context: Whether proton pump inhibitors (PPI) can improve glycemic control among individuals with diabetes or decrease the risk of incident diabetes in the general population is unclear.

Objective: To evaluate the impact of PPI therapy on glycemic control among individuals with diabetes and the risk of diabetes among those without diabetes.

Results: PubMed, Embase, Scopus, and ClinicalTrials.gov were searched from inception to November 21, 2020. We included studies comparing glycosylated hemoglobin (HbA1c) or fasting blood glucose (FBG) among individuals with diabetes treated with and without PPI therapy as an add-on to standard therapy. Studies evaluating the risk of incident diabetes among individuals taking PPI were assessed. We performed dual independent review, data extraction, and quality assessment. Weighted mean differences between groups or relative risks were imputed using random-effects models.

Results: Seven studies (n = 342) for glycemic control and 5 studies (n = 244 439) for risk of incident diabetes were included. Compared with standard therapy, add-on PPI was associated with a significant decrease in HbA1c (WMD, −0.36 %; 95% CI, −0.68 to −0.05; P = 0.025) and FBG (WMD, −10.0 mg/dL; 95% CI, −19.4 to −0.6; P = 0.037). PPI use did not reduce the risk of incident diabetes (pooled RR, 1.10; 95% CI, 0.89 to 1.34; P = 0.385).

Conclusion: Add-on PPI improved glycemic indices among individuals with diabetes but did not alter the risk of incident diabetes. The effects of PPI on glycemic control should be considered when prescribing antacids to patients with diabetes.


Type 2 diabetes mellitus (T2DM) is a global public health concern, with a worldwide prevalence of 9.3% in 2019.[1] It is a complex, heterogenous metabolic disorder characterized by hyperglycemia, insulin resistance, and impaired insulin secretion.[2] A higher prevalence of upper gastrointestinal symptoms is observed in patients with diabetes, especially among those with poor glycemic control.[3,4] Currently, there are multiple pharmacologic treatment options to improve glycemic control and prevent vascular complications, each having different glycemic efficacies.[5]

Proton pump inhibitors (PPI), recommended for gastroesophageal-related disorders, are commonly prescribed worldwide.[6] By blocking H+/K + ATPase, PPI are potent gastric acid inhibitors; however, PPI do elevate gastrin levels through negative feedback.[7] Gastrin is considered to be an early incretin candidate as it stimulates β cells to secrete insulin in diabetes animal models.[8,9] Incretin-based therapeutic options for diabetes, such as glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors, have proven efficacy in lowering blood glucose.[5,10] Several observational studies[11,12] and randomized controlled trials[13,14] have demonstrated that PPI decrease glycosylated hemoglobin (HbA1c) levels, although such effects were not observed in other studies.[15,16] Also, evidence about the risk of diabetes associated with the use of PPI among individuals without diabetes is inconclusive.[17,18]

Despite emerging evidence of the potential glucose-lowering effect of PPI in diabetes and of the risk of incident diabetes among individuals without diabetes who use PPI, the effect of PPI on these 2 populations remains unclear. Herein, we conducted a systematic review and meta-analysis to evaluate whether PPI are associated with improved glycemic control in diabetes and a decreased risk of incident diabetes.