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15-03-2011 | Diabetes | Article

Literature review supports metformin as first-line diabetes drug


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MedWire News: A major review of diabetes medications supports the use of metformin as a first-line agent, but has failed to demonstrate superior efficacy of any particular two-drug combination with respect to glucose control.

The report, by Wendy Bennett (Johns Hopkins University School of Medicine, Baltimore, Maryland, USA), is published in the Annals of Internal Medicine. The study was funded by the federal Agency for Healthcare Research and Quality and was an update of the 2007 review of the comparative benefits and harms associated with pharmacologic regimens used to treat Type 2 diabetes mellitus.

By searching the published literature and clinical trial data, together with unpublished data from the drug regulators and others, Bennett's team identified 140 randomized controlled trials and 26 observational studies that met their inclusion criteria.

They extracted data from these articles with a focus on intermediate outcomes (eg, glycated hemoglobin [HbA1c]), long-term clinical outcomes (eg, mortality), and harms (eg, hypoglycemia) in head-to-head or monotherapy combinations.

The drugs and drug classes examined included metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase (DPP)-4 inhibitors, and glucagon-like peptide-1 receptor (GLP-1) agonists, used either alone or in two-drug combinations.

Most medications lowered HbA1c by around 1%, report Bennett et al, and metformin was more effective than the DPP-4 inhibitors. Metformin also reduced low-density lipoprotein cholesterol relative to pioglitazone, sulfonylureas, and DPP-4 inhibitors.

Two-drug combinations all achieved similar reductions in HbA1c, of about 1% more than monotherapy, they note.

The risk for mild or moderate hypoglycemia was around four times higher with sulfonylureas than with metformin; furthermore, sulfonylureas, in combination with metformin, had more than a five-fold increased risk for hypoglycemia compared with metformin plus a thiazolidinedione.

Finally, thiazolidinediones were associated with an increased risk for congestive heart failure compared with sulfonylureas, and bone fractures compared with metformin. Conversely, diarrhea occurred more often with metformin than with thiazolidinediones.

Taken together, these data indicate that metformin, both on its own and in combination with other medications, has the most favorable benefit-risk profile, say the authors.

"We were unable to draw any firm conclusions about the safety and long-term clinical outcomes of the newest agents, the DPP-4 inhibitors, and GLP-1 agonists," they add.

"Most two-drug combinations had similar effects on glycemic control, but some combinations had lower comparative risk of hypoglycemia, weight gain, congestive heart failure and fractures, which may impact choice of a second agent."

MedWire ( is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2011

By Joanna Lyford