Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes A Meta-analysis

IMPORTANCE Numerous glucose-lowering drugs are used to treat type 2 diabetes. OBJECTIVE To estimate the relative efficacy and safety associated with glucose-lowering drugs including insulin. DATA SOURCES Cochrane Library Central Register of Controlled Trials, MEDLINE, and EMBASE databases through March 21, 2016. STUDY SELECTION Randomized clinical trials of 24 weeks' or longer duration. DATA EXTRACTION AND SYNTHESIS Random-effects network meta-analysis. MAIN OUTCOMES AND MEASURES The primary outcome was cardiovascular mortality. Secondary outcomes included all-cause mortality, serious adverse events, myocardial infarction, stroke, hemoglobin A(1c) (HbA(1C)) level, treatment failure (rescue treatment or lack of efficacy), hypoglycemia, and body weight. RESULTS A total of 301 clinical trials (1 417 367 patient-months) were included; 177 trials (56 598 patients) of drugs given as monotherapy; 109 trials (53 030 patients) of drugs added to metformin (dual therapy); and 29 trials (10 598 patients) of drugs added to metformin and sulfonylurea (triple therapy). There were no significant differences in associations between any drug class as monotherapy, dual therapy, or triple therapy with odds of cardiovascular or all-cause mortality. Compared with metformin, sulfonylurea (standardized mean difference [SMD], 0.18 [95% CI, 0.01 to 0.34]), thiazolidinedione (SMD, 0.16 [95% CI, 0.00 to 0.31]), DPP-4 inhibitor (SMD, 0.33 [95% CI, 0.13 to 0.52]), and alpha-glucosidase inhibitor (SMD, 0.35 [95% CI, 0.12 to 0.58]) monotherapy were associated with higher HbA(1C) levels. Sulfonylurea (odds ratio [OR], 3.13 [95% CI, 2.39 to 4.12]; risk difference [RD], 10% [95% CI, 7% to 13%]) and basal insulin (OR, 17.9 [95% CI, 1.97 to 162]; RD, 10% [95% CI, 0.08% to 20%]) were associated with greatest odds of hypoglycemia. When added to metformin, drugs were associated with similar HbA(1C) levels, while SGLT-2 inhibitors offered the lowest odds of hypoglycemia (OR, 0.12 [95% CI, 0.08 to 0.18]; RD, -22% [-27% to -18%]). When added to metformin and sulfonylurea, GLP-1 receptor agonists were associated with the lowest odds of hypoglycemia (OR, 0.60 [95% CI, 0.39 to 0.94]; RD, -10% [95% CI, -18% to -2%]). CONCLUSIONS AND RELEVANCE Among adults with type 2 diabetes, there were no significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality. Metformin was associated with lower or no significant difference in HbA(1C) levels compared with any other drug classes. All drugs were estimated to be effective when added to metformin. These findings are consistent with American Diabetes Association recommendations for using metformin monotherapy as initial treatment for patients with type 2 diabetes and selection of additional therapies based on patient-specific considerations.