title: Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations.
abstract: BACKGROUND
  Given the increase in medications for type 2 diabetes mellitus, clinicians and patients need information about their effectiveness and safety to make informed choices.
  
  
  OBJECTIVE
  To summarize the benefits and harms of metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 receptor agonists, as monotherapy and in combination, to treat adults with type 2 diabetes.
  
  
  METHODS
  MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through April 2010 for English-language observational studies and trials. The MEDLINE search was updated to December 2010 for long-term clinical outcomes.
  
  
  METHODS
  Two reviewers independently screened reports and identified 140 trials and 26 observational studies of head-to-head comparisons of monotherapy or combination therapy that reported intermediate or long-term clinical outcomes or harms.
  
  
  METHODS
  Two reviewers following standardized protocols serially extracted data, assessed applicability, and independently evaluated study quality.
  
  
  RESULTS
  Evidence on long-term clinical outcomes (all-cause mortality, cardiovascular disease, nephropathy, and neuropathy) was of low strength or insufficient. Most medications decreased the hemoglobin A(1c) level by about 1 percentage point and most 2-drug combinations produced similar reductions. Metformin was more efficacious than the DPP-4 inhibitors, and compared with thiazolidinediones or sulfonylureas, the mean differences in body weight were about -2.5 kg. Metformin decreased low-density lipoprotein cholesterol levels compared with pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a 4-fold higher risk for mild or moderate hypoglycemia than metformin alone and, in combination with metformin, had more than a 5-fold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones increased risk for congestive heart failure compared with sulfonylureas and increased risk for bone fractures compared with metformin. Diarrhea occurred more often with metformin than with thiazolidinediones.
  
  
  CONCLUSIONS
  Only English-language publications were reviewed. Some studies may have selectively reported outcomes. Many studies were small, were of short duration, and had limited ability to assess clinically important harms and benefits.
  
  
  CONCLUSIONS
  Evidence supports metformin as a first-line agent to treat type 2 diabetes. Most 2-drug combinations similarly reduce hemoglobin A(1c) levels, but some increased risk for hypoglycemia and other adverse events.
  
  
  BACKGROUND
  Agency for Healthcare Research and Quality.
authors.affiliation: The Johns Hopkins University School of Medicine and The Johns Hopkins Bloomberg School of Public Health, 2024 East Monument Street, Baltimore, MD 21205, USA. wbennet5@jhmi.edu
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Bennett
authors.forename: Nisa M
authors.initials: NM
authors.lastname: Maruthur
authors.forename: Sonal
authors.initials: S
authors.lastname: Singh
authors.forename: Jodi B
authors.initials: JB
authors.lastname: Segal
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Wilson
authors.forename: Ranee
authors.initials: R
authors.lastname: Chatterjee
authors.forename: Spyridon S
authors.initials: SS
authors.lastname: Marinopoulos
authors.forename: Milo A
authors.initials: MA
authors.lastname: Puhan
authors.forename: Padmini
authors.initials: P
authors.lastname: Ranasinghe
authors.forename: Lauren
authors.initials: L
authors.lastname: Block
authors.forename: Wanda K
authors.initials: WK
authors.lastname: Nicholson
authors.forename: Susan
authors.initials: S
authors.lastname: Hutfless
authors.forename: Eric B
authors.initials: EB
authors.lastname: Bass
authors.forename: Shari
authors.initials: S
authors.lastname: Bolen
mesh_terms: D001835:Body Weight / Q000187:drug effects; D057186:Comparative Effectiveness Research; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D017594:Publication Bias
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008055:Lipids; C517652:hemoglobin A1c protein, human