A novel model-based meta-analysis to indirectly estimate the comparative efficacy of two medications: an example using DPP-4 inhibitors, sitagliptin and linagliptin, in treatment of type 2 diabetes mellitus

Abstract

Objectives: To develop a longitudinal statistical model to indirectly estimate the comparative efficacies of two drugs, using model-based meta-analysis (MBMA). Comparison of two oral dipeptidyl peptidase (DPP)-4 inhibitors, sitagliptin and linagliptin, for type 2 diabetes mellitus (T2DM) treatment was used as an example.

Design: Systematic review with MBMA.

Data sources: MEDLINE, EMBASE, http://www.ClinicalTrials.gov, Cochrane review of DPP-4 inhibitors for T2DM, sitagliptin trials on Food and Drug Administration website to December 2011 and linagliptin data from the manufacturer.

Eligibility criteria for selecting studies: Double-blind, randomised controlled clinical trials, ≥12 weeks' duration, that analysed sitagliptin or linagliptin efficacies as changes in glycated haemoglobin (HbA1c) levels, in adults with T2DM and HbA1c >7%, irrespective of background medication. MODEL DEVELOPMENT AND APPLICATION: A Bayesian model was fitted (Markov Chain Monte Carlo method). The final model described HbA1c levels as function of time, dose, baseline HbA1c, washout status/duration and ethnicity. Other covariates showed no major impact on model parameters and were not included. For the indirect comparison, a population of 1000 patients was simulated from the model with a racial composition reflecting the average racial distribution of the linagliptin trials, and baseline HbA1c of 8%.

Results: The model was developed using longitudinal data from 11 234 patients (10 linagliptin, 15 sitagliptin trials), and assessed by internal evaluation techniques, demonstrating that the model adequately described the observations. Simulations showed both linagliptin 5 mg and sitagliptin 100 mg reduced HbA1c by 0.81% (placebo-adjusted) at week 24. Credible intervals for participants without washout were -0.88 to -0.75 (linagliptin) and -0.89 to -0.73 (sitagliptin), and for those with washout, -0.91 to -0.76 (linagliptin) and -0.91 to -0.75 (sitagliptin).

Conclusions: This study demonstrates the use of longitudinal MBMA in the field of diabetes treatment. Based on an example evaluating HbA1c reduction with linagliptin versus sitagliptin, the model used seems a valid approach for indirect drug comparisons.

Figures

Figure 1

(A) Graphic representation of the components of the final model, for study arms that included patients washing out their prior antihyperglycaemic medication in the run-in period. (B) Graphic representation of the components of the final model, for study arms that included patients who were treatment-naïve or had completely washed out their prior antihyperglycaemic medication before enrolment.

Figure 2

Drug effects (as glycated haemoglobin (HbA1c) percentage points) of the studies with relevant treatment arms (ie, studies with linagliptin 5 mg, or sitagliptin 100 mg and placebo arms) over time: (A) comparison of observed and predicted HbA1c change from baseline and (B) difference from placebo. For visual clarity, Hermansen et al represented only for the arms that excluded metformin background; both sets of arms are shown in figure 3. The study by Seck et al is omitted from figure 2A because of long treatment duration. Filled dots represent observed data, the shaded regions show the unconditional 90% prediction intervals, and the central line represents the median prediction.

Figure 3

Drug effects (as glycated haemoglobin (HbA1c) percentage points) of the relevant studies at their respective endpoints. Filled dots represent observed data; horizontal lines show the 90% unconditional prediction intervals and also represent the median predicted value. (A) Linagliptin change from baseline. (B) Sitagliptin change from baseline. (C) Linagliptin difference from placebo. (D) Sitagliptin difference from placebo.

Figure 4

(A) Estimated drug effects on glycated haemoglobin (HbA1c) for reference population, with no pretreatment washout, over 24 weeks (difference from placebo). (B) Estimated drug effects on HbA1c for reference population, with 4-week washout plus 2-week placebo run-in period, over 24 weeks (difference from placebo). Reference population of 1000 participants, baseline HbA1c: 8%, racial composition: 61.5% White, 1.5% Black, 37% Asian.

Figure 5

Posterior distribution for the difference in effect estimates between linaglitpin (5 mg) and sitagliptin (100 mg) at 24 weeks. Reference population of 1000 participants (therefore involving 106 simulated patients), baseline glycated haemoglobin (HbA1c): 8%, racial composition: 61.5% White, 1.5% Black, 37% Asian.