Short Term Efficacy Of DPP-4 Inhibitors Combined With Metformin In The Treatment Of T2DM And Its Long Term Pharmacoeconomics Evaluation

OBJECTIVEDiabetes is a serious global health issue, with type 2 diabetes mellitus (T2DM) accounting for approximately 90～95% of all cases. T2DM is a chronic disease and have a longer duration. The blood glucose need to be better control for a long time and if it lose control, serious microvascular and macrovascular complications will be happen. It not only influences the quality of life but also brings about a great economic burden to patient and society. Metformin is the first-line medication for the treatment of T2DM and the essential drug in combination therapy. Metformin treatment is usually effective at the beginning, but with the progression of the disease the second antidiabetic drug need to be added. Which antidiabetic drug added to the basis of the treatment of metformin is a problem that we have been exploring for a long time. However, according to the UK Prospective Diabetes Study (UKPDS), with the development of T2DM, the function of pancreatic cell would progressive decline no matter which mode of intervention. Defective β-cell function may result in deterioration in glycemic control. Therefore, progressive β-cell dysfunction is a key target for new therapies. Incretin therapies which focus on increasing levels of the incretin hormone glucagonlike peptide-1 (GLP-1). glucose-dependent insulinotropic polypeptide (GIP) and also protecting the β-cell have provided a novel therapeutic alternative for patients with T2DM. With the widely use of dipeptidyl peptidase-4 (DPP-4) inhibitors, it is necessary to understand the efficacy and economy of DPP-4 inhibitors and metformin combination therapy for better guide clinical practice. Thus, this study compared the clinical efficacy and safety of between DPP-4 inhibitors and metformin combination therapy and metformin monotherapy. We also guessed that an ethnic difference in response to treatment with DPP-4 inhibitors and metformin exist between Asian and Caucasian T2DM patients and thus assessed the difference of clinical efficacy between Asian and Caucasian.At present, the research method of pharmacoeconomics in our country was single and we only had a short term economic evaluation of the treatment plan. In order to further studied the long-term economic treatment measures, on the basis of meta analysis, we established the Markov model according to the natural process of T2DM. The thirty year cost-utility analysis of DPP-4 inhibitors and metformin using Markov model was performed for the purpose of choosing a secure and effective therapy for T2DM.METHODS1 Meta-analysisMedline (pubmed) databases, Clinical trial sites and reference lists from the articles were searched for trials. All randomized clinical trials (RCTs) met the inclusive criteria were included. RevMan 5.3 was used to analysis the extracted data.2 Comparison between Asian and CaucasianWe compared the differences effects of DPP-4 inhibitors and metformin combination therapy in the treatment of Asian and Caucasian using SPSS 19 software.3 Long term economic evaluation of DPP-4 inhibitors and metformin combination therapy3.1 To establish the Markov modelWe built Markov state transition model to simulate the changes of the three state (diabetes, diabetes with complications and death) in T2DM patients. The cost-utility analysis of DPP-4 inhibitors and metformin were performed according to the meta-analysis, transition probability, cost and utility.3.2 Markov model analysisWe used Markov model practicing Roll back analysis, Markov cohort simulation and incremental cost-utility analysis (ICUR) to project the costs and utility for T2DM patients who had been treated with DPP-4 inhibitors and metformin combination therapy or metformin monotherapy for a long time. Sensitivity analysis was also carried out to determine the robustness of this baseline results.RESULTS1 Meta-analysis results27 studies and a total of 10089 patients met the inclusion criteria. Compared with metformin, DPP-4 inhibitor plus metformin therapy was associated with higher reduction in glycosylated hemoglobin (HbA1c)-0.61%(-0.69 to-0.52, p<0.00001), fasting plasma glucose (FPG)-1.10 mmol/1 (-1.29 to-0.92, p<0.00001), total cholesterol (TC)-0.11 mmol/1 (-0.20 to-0.02, p=0.02), triglyceride (TG)-0.21 mmol/1 (-0.33 to-0.10, p=0.0002), homeostasis model assessment of insulin resistance (HOMA-IR)-0.19 (-0.36 to-0.02, p=0.03), gastrointestinal adverse events RR 0.88 (0.79 to 0.98, p=0.02) and higher increment in homeostasis β cell function index (HOMA-β) 8.86 (7.4 to 10.32, p<0.00001).2 Comparison the efficacy of DPP-4 inhibitor and metformin combination therapy in Asian and Caucasian patientsThere were 4 trials in Asian patients and 23 trials in Caucasian patients. Comparison of HbA1c, FPG, body weight and HOMA-IR changes between Asian and Caucasian patients didn’t show a significant between-group difference of-0.05% (-0.30 to 0.20; p=0.69),0.17 (-0.52 to 0.85; p=0.62),-0.15 (-0.64 to 0.35; p=0.53) and 0.27 (-0.98 to 1.53; p=0.64) compared with metformin. Comparisons HOMA-β between Asian and Caucasian patients showed a between-group difference of-5.79 (-10.26 to-1.32, p=0.01).3 Markov model analysis resultsThe results of Roll back analysis showed that the cost-utility ratio separately were:sitagliptin+metformin 10713.41yuan/QALY, saxagliptin+metformin 11261.50 yuan/QALY, vildgliptin+metformin 11001.28yuan/QALY, linagliptin+metformin 11169.58yuan/QALY and alogliptin+metformin 10815.48yuan/QALY. Thus sitagliptin and metformin combination therapy was of the most cost-effectiveness. The Markov cohort analysis showed that compared with metformin monotherapy,53 persons were free of death for the cohort of 1000 people treatment with sitagliptin and metformin combination therapy. The Markov cost-utility analysis showed that when the discount rate was 3%, the cost in the combination therapy was 157808.48 yuan with 37533.14 yuan of incremental cost and the effectiveness was 14.73 QALY with 0.53 QALY of incremental effectiveness in comparision to metformin monotherapy. The ICUR was 70817.24 yuan/QALY. Sitagliptin and metformin combination was an cost-utility choice when compared with the threshold standard (3GDP) that WHO recommended. Sensitivity analysis showed that the change of key parameters in the set range didn’t affect the model results.CONCLUSIONSAbove all, the study made a systematic and comprehensive assessment in the short-term efficacy and safety of DPP-4 inhibitor plus metformin combination therapy, providing a certain basis for clinical rational use of drug. Moreover, the cost and utility of the combined therapy were simulated by the Markov model, improving patients’ quality of life, reducing the economic burden of patients and society to a certain extent.