(149) Effect of Dipeptidyl Peptidase-4 Inhibitors on Fracture Risk in Patients with Type 2 Diabetes Mellitus: A Network Meta-Analysis of Randomized Controlled Trials

Publication Number: 810

Background: Diabetes mellitus is associated with abnormal bone health and an increased risk of fracture. Anti-diabetic drugs have diverse effects on bone and available evidence on dipeptidyl peptidase-4 inhibitors (DPP-4i) use and fracture risk are inconsistent.

Objectives: To perform a network meta-analysis (NMA) of randomized controlled trials (RCTs) assessing effect of DPP-4i on fracture risk in T2DM patients.

Methods: A systematic literature search was performed on PubMed/Medline, Cochrane library and ClinicalTrials.gov from inception to October, 2022 to identify RCTs reporting fracture cases with the use of DPP-4i compared to control group in T2DM patients. Pairwise meta-analysis (MA) was carried out using Review Manager 5.3 and random- effects model was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI). In addition, NMA was performed within Bayesian framework and Monte Carlo Markov Chain simulation method to calculate the OR and 95% credible intervals (CrI) using R software. Node splitting method was used to evaluate the presence of inconsistency for NMA and surface under the cumulative ranking curve (SUCRA) was used to check rank probability of DPP-4i. Quality of the included studies were assessed by using Cochrane risk of bias (RoB) 2 tool.

Results: A total of 91 RCTs including 92,087 T2DM patients with 1,090 fracture cases were identified. Patients age, HbA1c level and duration of diabetes were ranged from 50-72 years; 6.7-9.9%; and 1.1-17.89 years, respectively).
Pairwise MA showed no significant association between risk of fracture and DPP-4 inhibitors use compared with the control group (OR=1.04, 95%CI 0.92-1.17; p=0.57; I2=0%). Results from NMA also did not show any significant association with fracture risk and alogliptin (OR=1.20, 95%CrI 0.66-2.70), linagliptin (OR=0.70, 95%CrI 0.39-1.30), sitagliptin (OR=1.10, 95%CrI 0.83-1.6), vildagliptin (OR=1.5, 95%CrI 0.30-9.5), and saxagliptin (OR=0.78, 95%CrI 0.47-1.10) use when compared to placebo. In addition, no significant fracture risk was observed among DPP-4i in diabetic patients. From the SUCRA analysis, alogliptin ranked best (75%) treatment, followed by the vildagliptin (70%), sitagliptin (63%), saxagliptin (21%) and linagliptin (18%). No significant inconsistency was observed between direct and indirect comparison. Quality of the included studies were moderate.

Conclusions: Pairwise MA suggests that DDP-4i does not affect the fracture risk when compared with control in T2DM patients. Similarly, NMA also failed to show any significant association with the risk of fractures in DPP-4i treated T2DM patients. Further long term RCTs and real-world studies required to justify current findings.