Long-term use of dipeptidyl peptidase-4 inhibitors and risk of fracture: a retrospective population-based cohort study

Abstract

INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fracture as compared to patients without T2DM. It has been suggested based on clinical trial data that use of dipeptidyl peptidase-4 inhibitors (DPP4-Is), an anti-hyperglycaemic drug, is associated with a decreased risk of fracture as compared to patients with and without T2DM. However, observational studies have failed to show this association, which might be due to the short duration of use. Therefore, the aim of the present study was to investigate the association between long-term DPP4-I use and risk of fracture. METHODS: A retrospective population based cohort study, using data from the Clinical Practice Research Datalink (CPRD) database (2007-2015), was conducted. All patients (N = 328,254) with at least one prescription for a non-insulin anti-diabetic drug (NIAD), aged 18+ during data collection, were included. Cox proportional hazards models were used to estimate the hazard ratio of any, osteoporotic and hip fracture in DPP4-I users versus other NIAD users. Analyses were stratified by continuous duration of DPP4-I use. Time-dependent adjustments were made for age, sex, life-style, comorbidity and concomitant drug use. RESULTS: Current use of DPP4-Is was not associated with risk of any fracture (adjusted (adj.) hazard ratio (HR): 0.99 (95% confidence interval (CI) 0.93 - 1.06) as compared to current other NIAD use. Current use of DPP4-Is was also not associated with risk of osteoporotic or hip fracture. After stratification by continuous duration of DPP4-I use the highest category was not associated with any (>4.0 - 8.5 years of DPP4-I use; adj. HR: 0.99 (0.70 - 1.41)), osteoporotic (>3.0 - 8.5 years of DPP4-I use; adj. HR: 0.75 (0.52 - 1.09)), or hip (>2.0 - 8.5 years of DPP4-I use; adj. HR: 1.24 (0.85 - 1.79)) fracture. CONCLUSION: Continuous long-term DPP4-I use (defined as >4.0 - 8.5 years of DPP4-I use for any fracture, >3.0 - 8.5 years for osteoporotic fracture and >2.0 - 8.5 years for hip fracture, respectively) was not associated with risk of any, osteoporotic, or hip fracture. These findings may be of value for clinical decisions regarding treatment of T2DM patients, especially those at high fracture risk.