• Wendy L Bennett, Nisa M Maruthur, Sonal Singh, Jodi B Segal, Lisa M Wilson, Ranee Chatterjee, Spyridon S Marinopoulos, Milo A Puhan, Padmini Ranasinghe, Lauren Block, Wanda K Nicholson, Susan Hutfless, Eric B Bass, and Shari Bolen.
• 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
• Ann. Intern. Med. 2011 May 3; 154 (9): 602613602-13.

BackgroundGiven the increase in medications for type 2 diabetes mellitus, clinicians and patients need information about their effectiveness and safety to make informed choices.PurposeTo 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.Data SourcesMEDLINE, 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.Study SelectionTwo 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.Data ExtractionTwo reviewers following standardized protocols serially extracted data, assessed applicability, and independently evaluated study quality.Data SynthesisEvidence 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.LimitationsOnly 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.ConclusionEvidence 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.Primary Funding SourceAgency for Healthcare Research and Quality.

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