Comparison of Glucose-Lowering Drugs as Second-Line Treatment for Type 2 Diabetes: A Systematic Review and Meta-Analysis

Background: Multiple glucose-lowering drugs are available as add-ons to metformin for a second-line treatment for type 2 diabetes. However, no systematic and comparative data are available for them in China. We aimed to compare the effects of glucose-lowering drugs added to metformin in China. Methods: PubMed, Embase, Web of Science, CNKI, WanFang Data, and Chongqing VIP from 1 January 2000 until 31 December 2020 were systematically searched for randomized controlled trials comparing a glucose-lowering drug added to metformin with metformin in Chinese type 2 diabetes patients. Drug classes included sulfonylureas (SUs), glinides (NIDEs), thiazolidinediones (TZDs), α-glucosidase inhibitors (AGIs), dipeptidyl peptidase-4 inhibitors (DPP-4is), sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and insulins (INSs). Two reviewers independently screened studies, extracted data, and appraised the risk of bias. Results: 315 trials were included. In patients receiving metformin alone, the addition of NIDEs produced the greatest additional HbA1c reductions (1.29%; 95% CI 0.97, 1.60); while INSs yielded both the largest additional FPG reductions (1.58 mmol/L; 95% CI 1.22, 1.94) and 2 hPG reductions (2.52 mmol/L; 95% CI 1.83, 3.20). INS add-ons also conferred the largest additional HDL-C increases (0.40 mmol/L; 95% CI 0.16, 0.64), whereas AGI add-ons generated the greatest TC reductions (1.08 mmol/L; 95% CI 0.78, 1.37). The greatest incremental SBP reductions (6.65 mmHg; 95% CI 4.13, 9.18) were evident with SGLT2i add-ons. GLP-1RA add-ons had the greatest BMI reductions (1.96 kg/m(2), 95% CI 1.57, 2.36), meanwhile with the lowest (0.54 time) hypoglycemia risk. Overall, only the GLP-1RA add-ons demonstrated a comprehensive beneficial effect on all outcomes. Furthermore, our results corroborated intraclass differences among therapies. Given the limited evidence, we could not reach a conclusion about the optimal therapies regarding mortality and vascular outcomes. Conclusion: The results suggested a potential treatment hierarchy for clinicians and patients, with the GLP-1RA add-ons being most preferred based on their favorable efficacy and safety profiles; and provided a unified hierarchy of evidence for conducting country-specific cost-effectiveness analyses.