Comparative Effectiveness of Adding Alogliptin to Metformin Plus Sulfonylurea with Other DPP-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Network Meta-Analysis

Abstract

Introduction: Alogliptin is an oral antihyperglycemic agent that is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), approved for the treatment of type 2 diabetes mellitus (T2DM). There currently exists no comparative data to support the use of alogliptin in combination with metformin (met) and sulfonylurea (SU). A decision-focused network meta-analysis (NMA) was performed to compare the relative efficacy and safety of alogliptin 25 mg once daily to other DPP-4 inhibitors as part of a triple therapy regimen for patients inadequately controlled on metformin and SU dual therapy.

Methods: A systematic literature review was conducted to identify published papers of randomized controlled trials (RCTs) that compared alogliptin with other DPP-4 inhibitors (linagliptin, saxagliptin, sitagliptin, and vildagliptin) at their Summary of Product Characteristics (SmPC) recommended daily doses, added on to metformin and SU. Comprehensive comparative analysis involving frequentist meta-analysis and Bayesian NMA compared alogliptin to each DPP-4 inhibitor separately and collectively as a group. Quasi-random effect models were introduced when random effect models could not be estimated.

Results: The review identified 2186 articles, and 94 full-text articles were assessed for eligibility. Eight RCTs contained appropriate data for inclusion in the NMA. All analyses over all trial population sets produced very similar results, and show that alogliptin 25 mg is as least as effective (as measured by change in HbA1c from baseline, but supported by other outcome measures: change in body weight and FPG from baseline) and safe (as measured by incidence of hypoglycemia and adverse events leading to study discontinuation) as all the other DPP-4 inhibitors in triple therapy.

Conclusion: This decision-focused systematic review and NMA demonstrated alogliptin 25 mg daily to have similar efficacy and safety compared to other DPP-4 inhibitors, for the treatment of T2DM in adults inadequately controlled on metformin and SU. (Funded by Takeda Development Centre Americas; EXAMINE ClinicalTrials.gov number, NCT00968708).

Keywords: Alogliptin once daily; DPP-4 inhibitor; Network meta-analysis; Systematic review; Triple therapy; Type 2 diabetes mellitus.

Fig. 1

HbA1c (%) change from baseline: main analysis set—network plot

Fig. 2

HbA1c (%) change from baseline: main analysis set—forest plot of frequentist meta-analysis showing individual trial results and grouped DPP-4 treatments against placebo fixed and random effect models (all with metformin + SU). MD mean difference

Fig. 3

HbA1c (%) change from baseline: main analysis set fixed and quasi-random (between-trial SD fixed at 0.17) effects models forest plot—pairwise differences between DPP-4 treatments (with metformin + SU)

Fig. 4

HbA1c (%) change from baseline: main analysis set forest plot—mean differences between alogliptin and other grouped DPP-4 treatments (with metformin + SU) under various random and fixed effects models

Fig. 5

HbA1c change from baseline: main analysis set (fixed effects model)—leverage versus deviance residual plot incorporating model fit statistics. Values that lie outside the drawn smooth parabola with a constant of 3 (the red curves) can generally be identified as contributing to the model’s poor fit

Fig. 6

HbA1c (%) change from baseline: main analysis set excluding two outlier studies with higher baseline HbA1c values—pairwise differences between DPP-4 treatments (with metformin + SU) under fixed, partial pooling, and quasi-random effects (SD = 0.2) model assumptions

Fig. 7

Body weight (kg) change from baseline: forest plot of frequentist meta-analysis showing individual trial results and grouped DPP-4 treatments against placebo fixed and random effects models (all with metformin + SU)

Fig. 8

Body weight (kg) change from baseline: main analysis set—fixed and quasi-random (between-trial SD fixed at 0.25 kg) effects models forest plot. Pairwise differences between DPP-4 treatments (with metformin + SU)

Fig. 9

Incidence of hypoglycemic events: forest plot of frequentist meta-analysis showing individual trial results and grouped DPP-4 treatments against placebo, fixed and random effect models (all with metformin + SU)

Fig. 10

Incidence of hypoglycemic events: main analysis set; fixed and quasi-random (between-trial SD fixed at 1) effects models forest plot. Pairwise comparisons between DPP-4 treatments (with metformin + SU) measured by log odds ratios

Fig. 11

Adverse events leading to study discontinuation: forest plot of frequentist meta-analysis showing individual trial results and grouped DPP-4 treatments against placebo, fixed and random effects models (all with metformin + SU)

Fig. 12

Adverse events leading to treatment discontinuation; main analysis set; fixed and quasi-random (between-trial SD fixed at 0.5) effects models. Forest plot of pairwise comparisons between DPP-4 treatments (with metformin + SU) measured by log odds ratios