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

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.

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.

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/m², 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.

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.