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Original Investigation
July 19, 2016

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

Author Affiliations
  • 1Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
  • 2Department of Primary Education, School of Education, University of Ioannina, University Campus, Dourouti, Ioannina, Greece
  • 3Department of Hygiene and Epidemiology, School of Health Sciences, University of Ioannina, University Campus, Dourouti, Ioannina, Greece
  • 4Center for Outcomes Research and Clinical Epidemiology (CORESEARCH), Pescara, Italy
  • 5Division of Medicine, Department of Renal Medicine, University of Queensland at the Princess Alexandra Hospital, Woolloongabba, Australia
  • 6Translational Research Institute, University of Queensland, Woolloongabba, Australia
  • 7Cumming School of Medicine, Health Sciences Centre, University of Calgary, Foothills Campus, Calgary, Alberta, Canada
  • 8Sydney School of Public Health, University of Sydney, Sydney, Australia
  • 9Division of Nephrology and Transplantation, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
  • 10Diaverum Medical Scientific Office, Lund, Sweden
  • 11The George Institute for Global Health, Sydney, Australia
  • 12Nephrology Division, Department of Medicine, University of Montreal, Montreal, Quebec, Canada
  • 13Department of Medicine, Royal Alexandra Hospital, Edmonton, Alberta, Canada
  • 14Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
  • 15Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
JAMA. 2016;316(3):313-324. doi:10.1001/jama.2016.9400

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 A1c (HbA1C) 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 α-glucosidase inhibitor (SMD, 0.35 [95% CI, 0.12 to 0.58]) monotherapy were associated with higher HbA1C 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 HbA1C 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 HbA1C 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.