Proton Pump Inhibitors, Nephropathy, and Cardiovascular Disease in Type 2 Diabetes

The Fremantle Diabetes Study

Timothy M. E. Davis; Jocelyn Drinkwater; Wendy A. Davis


J Clin Endocrinol Metab. 2017;102(8):2985-2993. 

In This Article

Abstract and Introduction


Context: There is emerging evidence of various adverse effects of chronic proton pump inhibitor (PPI) therapy.

Objective: To assess the impact of PPI use on nephropathy and cardiovascular disease (CVD) risk in type 2 diabetes.

Design: Longitudinal observational study.

Setting: Urban-dwelling community.

Patients: Patients with type 2 diabetes from the Fremantle Diabetes Study Phase II and on stable renin-angiotensin system blocking therapy were divided into those remaining untreated with a PPI (group 1, n = 686), on PPI therapy throughout (group 2, n = 174), and commencing (group 3, n = 109) or discontinuing regular PPI therapy (group 4, n = 67) during the 2 years between assessments.

Main Outcome Measures: Changes (Δ) in urinary albumin/creatinine ratio (uACR), estimated glomerular filtration rate (eGFR), and predicted 5-year CVD risk.

Results: There were no statistically significant differences in ΔuACR between groups [analysis of variance (ANOVA), P = 0.36], but ΔeGFR was different (ANOVA, P = 0.002), with group 3 exhibiting a greater reduction than group 1 [adjusted mean difference (95% confidence interval), −2.7 (−4.5 to −0.8) mL/min/1.73 m2; P = 0.005]. The Δ5-year CVD risk showed a similar pattern (ANOVA, P < 0.001), with group 3 having a greater increase than group 1 [adjusted mean difference (95% confidence interval), 1.7% (0.6% to 2.8%); P = 0.002].

Conclusions: Although PPI use was not associated with a sustained adverse effect on uACR, the association between PPI initiation and both worsening nephropathy and increasing 5-year CVD risk has potential clinical implications in type 2 diabetes.


A recent in vitro study found that prolonged exposure to the proton pump inhibitor (PPI) esomeprazole impaired endothelial function and accelerated human endothelial senescence by reducing telomere length.[1] The authors postulated that irreversible endothelial damage associated with long-term PPI use could be a unifying mechanism underlying the observation that the PPI class of drugs is associated with cardiovascular disease (CVD), cognitive decline, and renal impairment in administrative database and pharmacovigilance studies.[2–5]

Diabetes is a disease characterized by endothelial dysfunction and premature vascular aging,[6] and the adverse endothelial effects of PPIs[1] could accelerate diabetes-associated angiopathy and contribute to complications and death. Albuminuria is considered to reflect widespread endothelial damage[7,8] and could be used as an in vivo marker of PPI effects on the vasculature.[9] It can be hypothesized, therefore, that patients with type 2 diabetes initiating PPI therapy will manifest a subsequent increase in urinary albumin excretion that will persist after withdrawal of treatment. We have examined this hypothesis and also assessed PPI effects on renal function and cardiovascular risk by using longitudinal observational data from the representative community-based Fremantle Diabetes Study Phase II (FDS2).