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Meta-analysis finds antidiabetic drugs lower glucose similarly when added to metformin in type 2 diabetes mellitus

According to a systematic review in the April 13, 2010 edition of the Journal of the American Medical Association, noninsulin antidiabetic drugs show similar reductions in glycosylated HbA1c when used in combination with metformin in type 2 diabetics, but differ in their rates of hypoglycemia and weight gain.

Recommendations for the treatment of type 2 diabetes mellitus are given jointly by the American Diabetes Association and European Association for the Study of Diabetes in a consensus statement. Guidelines suggest that metformin should be used as a first-line therapy unless contraindicated. If metformin alone is insufficient to treat to glycemic targets, addition of basal insulin or a sulfonylurea are tier 1 recommendations, while the addition of either pioglitazone or exenatide are tier 2 recommendations in select clinical settings. Remaining classes of agents (glinides, alpha-glucosidase inhibitors, and DPP-4 inhibitors) get little mention.

Recently, the evidence basis of the current guidelines has been called into question by 16 clinicians and researchers from the United States and Europe. Their critical analysis of the guidelines suggested that the "algorithm seems to be based more on an outdated expert opinion model than on the evidence-based approach that represents the current standard for guideline development." One particular criticism of current guidelines is that the recommendations for second-line therapy appear to be based on the glucose-lowering ability of each class of drug as monotherapy and not in addition to metformin.

"There is a disconnect between evidence provided in the consensus statement and the actual recommendations," stated by Olivia J. Phung, MD, lead investigator on the meta-analysis. She continued, "If we are going to be adding a drug to metformin, we need to see how the different drugs stack up in combination with metformin, not how they stack up when used as monotherapy."


Investigators from the University of Connecticut School of Pharmacy and Hartford Hospital screened citations to identify randomized controlled trials of at least 3 months in duration and comparing a noninsulin antidiabetic drug to another drug or placebo in addition to metformin in patients with inadequate response to maximized and stable metformin monotherapy (≥4 weeks at ≥1,500 mg or maximally tolerated dose). Data sources included MEDLINE and Cochrane Central Register of Controlled Trials from the earliest available date through January 2010.

Altogether, investigators identified 27 randomized trials (n=11,198) for inclusion in their meta-analysis. Upon meta-analysis, the different classes of drugs were found to exhibit similar A1c reductions (range, 0.64%–0.97%) compared with placebo. Craig I. Coleman, MD, senior investigator on the project noted, "FDA considers drugs that lower A1c within 0.3% to 0.4% of each other to be noninferior. Using this margin, the results of our meta-analysis show that all the classes perform similarly on glucose-lowering."

The meta-analysis also demonstrated that thiazolidinediones, sulfonylureas, and glinides were associated with weight gain (1.77 kg–2.08 kg), but GLP-1 analogs, alpha-glucosidase inhibitors, and DPP-4 inhibitors were associated with weight loss or neutrality. Furthermore, sulfonylureas and glinides were associated with higher rates of hypoglycemia (RR range 4.57–7.50), while the other drugs had no significant effect on this end point.

Dr Phung stressed, "While efficacy is important, other factors must be considered when choosing a regimen." She suggests that contraindications and precautions, safety profiles, and cost should also weigh into the decision.


1. Phung OJ, Scholle JM, Talwar, M, Coleman CI. Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA. 2010;303:1410–1418.

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